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FUNCTIONAL AND RADIOLOGICAL EVALUATION OF AUTOLOGOUS CHONDROCYTE IMPLANTATION USING A TYPE I/III COLLAGEN

MEMBRANE: FROM SINGLE DEFECT TREATMENT TO EARLY OSTEOARTHRITIS.

William Brett Robertson (MSc., MAAESS AEP)

Volume I

A thesis submitted to the School of Surgery and Pathology (Orthopaedics) and the School of Human Movement and Exercise Science at the University of Western

Australia as requirement for the degree of Doctor of Philosophy.

October, 2006

ACKNOWLEDGEMENTS

The author wishes to express his sincere appreciation to the following people for their

significant contributions over the course of his PhD canditure. This research thesis

would not have been possible without their involvement:

To my Supervisors. Firstly, Professor David Wood, for providing the initial impetus for

this study and for all of his support and assistance. Secondly, Professor Timothy

Ackland, for all of his time, patience and valuable counsel. I could not have asked for

better supervisors. It has been an honour and a privilege.

To Dr Daniel Fick and Dr James Linklater for their invaluable help with the

development of the MRI scoring system and for all of the countless hours they sent

scoring MRI scans. You are both true gentlemen.

To all of my subjects for their time, patience and shear hard work over the course of this

study.

Finally to my parents, Eric and LeAnne for their love, counsel and support for which I

consider myself truly blessed.

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To Anitra, my Wife, with all my Love

Every obstacle yields to stern resolve.

Leonardo da Vinci

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CONTENTS

Page

VOLUME ONE

Chapter One – The Problem 1

Introduction 1

Significance of the study 2

Requisite Research 3

Issues with Rehabilitation 5

Justification of the study 5

Thesis structure 7

Definition of terms 11

Chapter Two – Review of literature 13

Chapter Three – Standard Practice Exercise Rehabilitation Protocol 33

Rehabilitation Program Aims and Rationale 42

Pre surgery program (8 weeks) 47

Post surgery program (1 year) 51

- phase 1 (0 to 3 weeks) 56



- phase 4 (3 to 6 months) 59



Exercise Progression Summary 62

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Frequently Asked Questions 63

Return to Elite Level Competition 66

References 67

Appendices to Chapter 3 70

VOLUME TWO Chapter Four – MRI and Clinical Evaluation of Collagen-Covered Autologous

Chondrocyte Implantation (CACI) at Two Years 114

Abstract 116

Introduction 117

Materials and Methods 118

Results 127

Discussion 131

Acknowledgements 136

References 137

Chapter Five – MRI and Clinical Evaluation of Matrix-Induced Autologous

Chondrocyte Implantation (MACI) at Two Years 148

Abstract 150

Introduction 151

Materials and Methods 153

Results 159

Discussion 163

Conclusion 167


References 169

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Chapter Six – Combined High Tibial Osteotomy and Matrix-Induced

Autologous Chondrocyte Implantation (MACI) for early

Osteoarthritis of the Knee 179

Abstract 181

Introduction 182

Methods 185

Results 190

Discussion 193

Conclusion 196


References 197

Chapter Seven – Summary, Recommendations and Conclusion 205

Summary 205

Recommendations for Future Research 208

Conclusions 211

Appendix One – Combined Anteromedialisation Tibial Tubercle Osteotomy

and Autologous Chondrocyte Implantation (C-ACI & MACI)

for the Treatment of Isolated Chondral Defects of the

Patellofemoral Joint.

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Appendix Two – An Australian Experience of ACI and MACI

In G. Bentley (ed) Current Developments in Autologous

Chondrocyte Transplantation. The Royal Society of

Medicine Press Ltd, London, 2000 pages 7 – 16.

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CHAPTER ONE

THE PROBLEM

INTRODUCTION

Hyaline articular cartilage is a highly specialised tissue consisting of chondrocytes

embedded in a matrix of proteoglycan and collagens. Hyaline articular cartilage

withstands high levels of mechanical stress and continuously renews its extracellular

matrix. Despite this durability, mature articular cartilage is vulnerable to injury and

disease processes that cause irreparable tissue damage. Native hyaline articular

cartilage has poor regenerative capacity following injury, largely due to the tissue’s lack

of blood and lymphatic supply, as well as the inability of native chondrocytes to migrate

through the dense extracellular matrix into the defect site. Articular cartilage injuries

that fail to penetrate the subchondral bone plate evoke only a short-lived metabolic and

enzymatic response, which fails to provide sufficient new cells or matrix to repair even

minimal damage. Clinically, it has previously been accepted that treatment of such

defects does not result in the restoration of normal hyaline articular cartilage, which is

able to withstand the mechanical demands that are placed on the joint during every day

activities of daily living.

The concept of autologous chondrocyte implantation (ACI) began almost four decades

ago [75], but only recently has the technique become a viable therapeutic option

[11,31,63]. The first evidence supporting ACI came from animal studies by Peterson et

al. [63]. This work led to human trials and subsequently, ACI using periosteal

membrane (PACI) has become a well-established technique for the treatment of

articular cartilage defects, with evidence of improved joint function and formation of

hyaline or hyaline-like cartilage [6,12,34,41,42,64].

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The four cornerstones for successful outcome following ACI are:

1. GMP standard cell culture and stability of cell phenotype;

2. Effective surgical procedure;

3. Complimentary postoperative rehabilitation; and

4. Patient cooperation.

Historically, rehabilitation following ACI has not kept pace with the advances in cell

culture and surgical technique. Subsequently, there exists a significant gap in

knowledge regarding ‘best practice’ in post operative rehabilitation following ACI. The

importance of structured rehabilitation in ACI should not be underestimated when

evaluating the clinical success of this chondral treatment. Patients should not be left to

their own devices following ACI surgery, as the risk of damage to their implant (via

delamination) is high if immediate postoperative movement is not controlled.

Furthermore, the biological longevity and clinical success of the graft is dependent on a

controlled and graduated return to ambulation and physical activity, and the

biomechanical stimulation of the implanted chondrocytes.

SIGNIFICANCE OF THE STUDY

Articular cartilage defects of the knee occur commonly in sports injury and trauma,

often affecting the young. From 1993 to 1997, over 210,000 knee arthroscopies were

performed on patients below the age of 55 in Australia alone. At least five percent of

this patient population were diagnosed with full thickness cartilage defects [20]. In an

unfavourable location (i.e. medial femoral condyle), such defects may progress and lead

to premature degeneration of the articulating surface of the joint. The repair tissue

formed in response to these procedures consists of fibrocartilage, which does not

possess the biomechanical or biochemical properties of hyaline articular cartilage. End

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stage osteoarthritis of the knee is commonly treated by total arthroplasty, but this

presents further problems for the younger age group including limited life span of the

prosthesis, prosthesis loosening, bone fracture and the possible risk of infection [18,

22,25,33].

Requisite Research

In Australia, there was a sequential evolution of the ACI technique from the

conventional periosteum covered ACI (PACI), to the use of a porcine collagen type I/III

membrane sutured as a periosteal substitute (CACI). The CACI technique was then

further modified to the current practice of a): first seeding the cultured autologous

chondrocytes onto the cambium layer of the type I/III membrane and then, b):

implanting the cell-seeded membrane as a single construct via the matrix-induced

autologous chondrocyte implantation technique (MACI).

This thesis has concentrated on the CACI and MACI techniques, since the PACI

method has a number of short-comings, namely, extensive surgical incision, peripheral

graft hypertrophy [40,62], graft delamination [21,40,55], and potential ectopic

calcification of the periosteal patch [55,81]. Postoperatively, it has been documented

that a clinically significant percentage of patients (20-36 percent) present with

symptomatic ‘catching’ of the knee joint due to hypertrophic graft edges, leading to the

need for revision arthroscopy [30,54].

Complications associated with the use of periosteum in the ACI procedure stimulated

the search for an alternative scaffold for the containment of implanted chondrocytes.

To address these problems, a biodegradable type I/III collagen membrane was

developed for use in conjunction with ACI. This membrane comprised highly purified

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porcine collagen and exhibited excellent biocompatibility and low immunogenicity.

The membrane was designed to reproduce the physiological barrier functions of the

periosteum.

Definitive evidence regarding the role of the membrane in enhancing chondrocyte-

mediated cartilage regeneration is sparse. There also existed discrepancies with regard

to the quantification of the ACI surgical outcome. The effectiveness of this new

treatment was limited to clinical evaluation and opportunistic arthroscopic examination.

Arthroscopic examination and biopsy as routine follow up is controversial. Many

consider it unethical to subject ACI patients to routine ‘second-look’ arthroscopies and

biopsy when the ACI graft is considered to be functioning well from a clinical

perspective. Also, the high incidence of inadequate biopsies (55 percent as reported by

ICRS [46]) precludes meaningful interpretation in the majority of specimens. Clinical

evaluation is important to track the patient symptoms, however, it is yet to be correlated

with arthroscopic or MRI data. There remains increasing demand for an accurate,

reproducible and non-invasive method for subsequent monitoring following ACI.

Articular cartilage is approximately 70 percent water by weight. The remainder of the

tissue consists predominantly of type II collagen fibres and glycosaminoglycans. The

latter contain negative charges that attract sodium ions (Na+) in intact cartilage. MRI is

an accurate and non-invasive imaging modality that can delineate signal and

morphological changes in articular cartilage [68], making it an attractive research tool in

the evaluation of chondrocyte grafting [29,35,38,65,66,78]. The correlation between

MRI outcome and graft histological outcome has yet to be determined, though recent

studies have attempted to correlate these two outcome measures with mixed results

[35,78]. This thesis provides novel insight into the morphological progression of the

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regenerative tissue produced following CACI and MACI through the use of established

MRI evaluation parameters [50,51]. The results complement the currently available

clinical and histological information on CACI and MACI, and with MRI assessment of

the cartilage repair, a better understanding of the outcome of ACI with a collagen

membrane is afforded.

Issues with Rehabilitation

At the point in time that CACI was introduced into Australia (February 1999)

information pertaining to the most appropriate post-operative rehabilitation pathway

following CACI was scarce and those for the MACI technique were non-existent. As

no guidelines other than those pertaining to PACI existed, it was necessary to develop a

specific rehabilitation protocol for collagen covered and matrix induced ACI that was

based on biological principles underlying postoperative biomechanical stimulation of

chondrocyte biosynthesis. The neocartilage formed following CACI and MACI surgery

is characterised by tissue high in cell density, water and type II collagen content, but of

weak biomechanical property. Subsequent to cell cultivation and surgical technique,

the key to the therapeutic success of CACI and MACI is the maturation of neocartilage

to functional cartilage through healthy extracellular matrix production by chondrocytes,

a process heavily reliant on effective rehabilitation.

JUSTIFICATION OF THE STUDY

Full thickness chondral defects of the knee remain a difficult clinical problem. With a

strong emphasis on sporting and outdoor activities engrained in the Australian culture,

there is a high incidence of knee injuries and associated cartilage defects requiring

surgical intervention. A wide variety of methods have been developed to encourage the

repair of cartilage defects. Procedures such as debridement, lavage, microfracture,

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subchondral drilling and abrasion arthroplasty have been shown to temporarily alleviate

symptoms, however, it has been shown that they cannot restore the damaged hyaline

articular cartilage. The repair tissue formed in response to these procedures consists of

fibrocartilage, which does not possess the biomechanical or biochemical properties of

hyaline articular cartilage. Attempts to cover the defects with autologous periosteal or

perichondral grafts produce a mixed tissue consisting of hyaline cartilage and

fibrocartilage. This repair tissue tends to calcify and during the course of endochondral

ossification, is replaced by bone. None of the conventional treatment options have been

shown to consistently result in hyaline or hyaline-like cartilage repair tissue with similar

mechanical properties and long term durability. Additionally, defects may be

asymptomatic until progression results in symptomatic lesions followed by

osteoarthritis (OA).

ACI has the potential to effect regeneration of chondral defects of the knee with

hyaline-like articular cartilage, allowing return to normal function and demonstrating

normal durability. An effective cure for these injuries would greatly reduce the burden

on the health care system by preventing the knee joint dysfunction and degeneration

typically associated with chondral defects. Treatment for end-stage OA is by total knee

replacement, but this approach has inherent problems when applied to younger patients

due to the finite life-span of the prosthesis and documented complications of prothesis

loosening, bone fracture and infection.

By investigating advances in the ACI surgical technique and subsequent treatment

outcomes, the long-term benefits in terms of functional and morphological

improvements will become evident. Additionally, this may lead to development of

accurate tests to monitor and predict the progress of treated lesions. It will also lead to

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better patient care by establishing more efficient rehabilitation regimes for patients

recovering from ACI.

Early symptomatic OA of the knee poses a difficult challenge to orthopaedic surgeons,

particularly in the presence of lower limb malalignment in middle-aged patients. Most

surgical options are palliative. The majority of patients exhibit degeneration of the

medial joint compartment and subsequently treatment by total joint arthroplasty is

deemed somewhat excessive. Our aim was to extend the treatment parameters of the

MACI technique by assessing the results of combined high tibial osteotomy (HTO) and

MACI as a treatment option in this patient population.

THESIS STRUCTURE

This thesis comprises seven chapters. The first two introduce the topic and provide an

extended literature review. The specific methodology relating to research papers is

contained within the relevant chapters, however, a complete discussion of the

rehabilitation program has been published and is reproduced as Chapter 3.

Chapter 3: Standard practice exercise rehabilitation protocols for matrix-

induced autologous chondrocyte implantation: femoral condyles.

Robertson W.B., Gilbey H.J. and Ackland T.R.

Hollywood Functional Rehabilitation Clinic, Perth Western Australia,

2004.

Three research papers, which are referred to in the text as Chapters 4-6, represent the

results and discussion section of this thesis. The work presented in these papers

documents the sequential introduction of new orthopaedic technologies through a series

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of prospective clinical investigations. These studies were conducted upon the

completion of laboratory and animal studies executed by colleagues within the

department [84], in accordance with the stepwise algorithm for the introduction of new

technology advocated by Malchau [47], in order to clarify the suitability of CACI and

MACI in the treatment of cartilage defects in a Western Australian patient population.

The final paper (Chapter 6) pertains to the expansion of the treatment parameters of

MACI to a previously untested, early osteoarthritic patient population.

Chapter 4: MRI and clinical evaluation of collagen-covered autologous

chondrocyte implantation (CACI) at two years.

Robertson W.B., Fick D., Wood D.J., Linklater J., Zheng M.H. and

Ackland T.R.

Status: Submitted to The Knee (15/02/2006), 2nd Revision.

Chapter 5: MRI and clinical evaluation of matrix-induced autologous

chondrocyte implantation (MACI) at two years.

Robertson W.B., Willers C., Wood D.J., Linklater J., Zheng M.H. and

Ackland T.R.

Submitted to American Journal of Sports Medicine (31/10/2006),

under review.

Chapter 6: Combined high tibial osteotomy (HTO) and matrix-induced

autologous chondrocyte implantation for early osteoarthritis of the

knee.

Robertson W.B., Khan R.J.K, Yates P.J, Linklater J., Wood D.J., Zheng

M.H. and Ackland T.R.

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Status: Submitted to British Journal of Bone and Joint Surgery,

(31/10/2006), under review.

Finally, a summary and conclusions chapter provides a synthesis of these studies in

order to demonstrate the advancements made in the body of knowledge relating to ACI

procedures. Special emphasis on rehabilitation, and post-surgery evaluation of the

morphology of repair and patient function, are the cornerstones of this thesis.

Changes in style and language

References for chapters 1-2 and chapter 7 are listed at the end of this thesis, and all

figures and tables within these chapters are listed in numerical order. Chapters 4-6 are

presented in the required manuscript format of the journal to which they were submitted

for publication, so some variation in language and style may arise in these chapters. All

references in these chapters are specific to that paper only and are listed at the back of

each individual chapter.

Ancillary Work

The following ancillary work, invited conference presentations and presentations to

learned societies were conducted during my PhD candidature.

Appendix 1: Combined anteromedialisation tibial tubercle osteotomy and

autologous chondrocyte implantation (C-ACI & MACI) for the

treatment of isolated chondral defects of the patellofemoral joint.

Ledger M., Robertson W.B., Fick D., Wood D.J., Zheng M.H. and

Ackland T.R.

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Status: Submitted to Australian and New Zealand Journal of

Orthopaedics, (31/10/2006), under review.

Appendix 2: An Australian experience of ACI and MACI.

Wood D., Zheng M.H., and Robertson B.

In G.Bently (ed) Current Developments in Autologous Chondrocyte

Transplantation. The Royal Society of Medicine Press Ltd, London,

2000 pages 7-16..

Invited Conference Presentation

6th International Cartilage Repair Society (ICRS) Symposium, San Diego, CA, United States of America. January 8-11th 2006. Comprehensive Approaches to Articular Cartilage Disorders, Etiology, Pathogenesis and Management “All roads meet in Rome”. Invited to present at the Rehabilitation Session entitled: Cartilage repair rehabilitation: A multidisciplinary approach to challenges, controversies and future directions. Presentation Topic: (7a-C) “Biomechanics of Cartilage Repair Rehabilitation: The Perth Experience.”

Presentations to Learned Societies

Invited Speaker: Garvan Institute of Medical Research, Matrix-Induced Autologous Chondrocyte Implantation Workshop, 384 Victoria St Darlinghurst, Sydney, 27th November 2003.

Invited Speaker: Orthopaedic Learning Centre, The Chinese University of Hong Kong, Matrix-Induced Autologous Chondrocyte Implantation Workshop, 1/F Li Ka Shing Specialist Centre, North Wing, Prince of Wales Hospital, Shatin N.T., Hong Kong, November 2002.

Invited Speaker: Royal National Orthopaedic Hospital NHS Trust, Cartilage transplantation user group meeting, “Perioperative Rehabilitation for the ACI patient: An Australian Perspective”, Royal National Orthopaedic Institute, Stanmore, United Kingdom, 24th June 2002.

Invited Speaker: Sir Hector Stewart Surgical Club Symposium, Autologous Chondrocyte Implantation Workshop, “Functional Rehabilitation of ACI”, CTEC University of Western Australia, 2nd Entrance Hackett Drive Crawley WA 6009. 31st May 2002.

Invited Speaker: Orthopaedic Learning Centre, The Chinese University of Hong Kong, Frontiers of cell based tissue engineering in orthopaedics: Autologous chondrocyte implantation workshop. Orthopaedic

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Learning Centre, 1/F Li Ka Shing Specialist Centre, North Wing, Prince of Wales Hospital, Shatin N.T., Hong Kong. 13th November 2001.

Invited Speaker: Royal National Orthopaedic Hospital NHS Trust, Cartilage transplantation user group meeting, “Perioperative Rehabilitation for the CACI patient: An Australian Perspective”, Royal National Orthopaedic Institute, Stanmore, United Kingdom. December 2000.

DEFINITION OF TERMS

The following terms used throughout this thesis require definition, as follows:

ACI Autologous chondrocyte implantation

ACL Anterior cruciate ligament

CACI Collagen covered autologous chondrocyte implantation

CPM Continuous passive motion

ECM Extra cellular matrix

GMP Good manufacturing process

HFRC Hollywood functional rehabilitation clinic

HTO High tibial osteotomy

ICRS International Cartilage Repair Society

MACI Matrix-induced autologous chondrocyte implantation

MUA Manipulation under anaesthesia

OA Osteoarthritis

OCD Osteochondritis dissecans

PACI Periosteal covered autologous chondrocyte implantation

PCL Posterior cruciate ligament

ROM Range of motion

TKA Total knee arthroplasty

TTT Tibial tubercle transfer

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UKA Unicompartmental knee arthroplasty

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CHAPTER TWO

REVIEW OF LITERATURE

INTRODUCTION

This chapter provides an expanded review of literature to complement chapters three to

six and also provides some background on the response of cartilage to injury and the

shortcomings of traditional treatment methods. I have focused on the current literature

pertaining to the evolution of the PACI, CACI and MACI techniques. I have also

reviewed the role of ‘second look’ arthroscopy, core biopsy, MRI and postoperative

rehabilitation in order to ‘set the scene’ for the ensuing chapters. Chondrocyte cell

biology, cartilage histology and gross anatomy of the knee have not been addressed and

I direct the reader to the list of references should further information be required.

PATHOGENESIS OF CARTILAGE DEFECTS

Hyaline articular cartilage lining the knee is a highly differentiated tissue consisting of

chondrocytes embedded in a matrix of amorphous ground substance with glycoproteins

and predominantly type II collagen [83]. Devoid of blood and lymphatic supply, there

is a limited capacity to regenerate and the exchange of metabolites depends on diffusion

through the ground substance. Cartilage injury leads to a disruption of the

macromolecular framework of the matrix at the molecular level and water content

increases [24,48,49]. Alteration in the collagenous framework, including changes in the

relationship between the minor collagens and collagen fibrils, leads to further swelling

of aggrecan molecules. The resulting increase in permeability and decreased stiffness

of the matrix leads to increased mechanical damage. In response to tissue damage and

alterations in osmolarity, release of mediators by chondrocytes stimulates a cellular

response. Anabolic and mitogenic growth factors play an important role in stimulating

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synthesis of matrix molecules and proliferation of chondrocytes – clusters of

proliferating cells surrounded by newly synthesised matrix are an histological feature of

cartilage degeneration [45,52]. Chondrocyte apoptosis results when the stability and

protection of a functional matrix is lost.

Additionally, nitric oxide released by chondrocytes in response to stress diffuses and

induces production of interleukin-1, which stimulates expression of metaloproteases

that degrade matrix molecules [7]. Molecules present in damaged tissue, such as

fibronectin, promote continued production of interleukin-1 and enhance release of

proteases. Degradation of type IX and XI collagen and other molecules destabilises the

type II collagen – fibril meshwork again allowing expansion of aggrecans and increased

water content [17,36].

Chondrocyte apoptosis results when stability and protection of a functional matrix is

lost. This may lead to progressive loss of articular cartilage especially with increasing

age, resulting in pain, dysfunction and a progression to osteoarthritis (OA) [13,14].

Clinical studies confirm the long-term prognosis for severe damage to weight bearing

cartilage in the knee. Function deteriorates with time and radiographic findings imply

permanent deterioration due to the chondral defect, with joint space reduction limited to

the involved compartment.

CONVENTIONAL TREATMENT OPTIONS

Joint Debridement

Debridement via arthrotomy and more recently arthroscopy, has long been used to treat

chondral injuries. Removal of cartilage fragments causing specific mechanical

disturbances directly improves joint function and decreases symptoms [3,8,9,77].

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However, documentation of benefits of superficial cartilage debridement is lacking and

formation of new tissue by chondrocytes has not been evidenced. Despite this, many

reports indicate decreased symptoms in most patients post-debridement, possibly due to

either a placebo effect, or reduction of tissue debris and catabolic enzyme levels

reducing the stimulus for pain [8,9, 37,39,58].

Penetration of Subchondral Bone

Penetration of subchondral bone via resection, drilling or abrasion disrupts subchondral

blood vessels resulting in the formation of fibril clots. Undifferentiated mesenchymal

cells migrate into the fibril clot forming chondroblasts and chondrocytes [13,14]. The

resulting fibrocartilaginous repair tissue contains predominantly type I collagen with

little type II. This fibrous tissue repair fails to replicate the properties of hyaline

cartilage, lacking its composition, mechanical properties and durability.

This procedure was originally described by Pridie in 1959 [67], whereby drilling though

subchondral bone to stimulate fibrocartilaginous repair, 46 out of 60 patients reported

improvement in knee function. However, all had established OA [67]. Despite

confirmatory reports of a decrease in symptoms for isolated articular cartilage defects,

the clinical value of this approach remains uncertain. Short follow up periods, lack of

randomised control trials and the possibility of improvement due to irrigation of the

joint alone make it difficult to define its indications [58].

Osteotomy

Osteotomy is performed to decrease loads on damaged chondral surfaces and to correct

malalignment that may contribute to symptoms. Joint alignment is generally corrected

in the coronal plane, shifting weight to the undamaged compartment. Most studies have

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concentrated on patients with established unicompartmental OA rather than isolated

chondral defects. Results are adversely affected by increasing age, instability and

stiffness, but even in optimal candidates good initial outcomes tend to deteriorate

progressively over time [7,19]. Thus, osteotomy is probably best viewed as a procedure

that postpones replacement arthroplasty rather than regenerates cartilage defects.

Periosteal and Perichondral Grafts

Potential benefits of periosteal and perichondral grafts include: introduction of a

germinal cell population with an organic matrix, decrease in fibrous adhesions, and

mechanical protection of regenerating cells from excessive loading. Clinical

observation suggests repair with hyaline cartilage-like tissue with corresponding

improvement of symptoms, especially in the young. However, long term results are

uncertain and the lack of prospective randomised clinical trials do not support routine

use for treatment of chondral defects [45,60,82].

Osteochondral Grafts

Osteochondral grafts have the advantage of providing a fully formed articular matrix

and are implanted following penetration of the subchondral bone plate. Allografts

harvested from non-weight bearing articular surfaces of the knee have healed on

implantation and improved knee function has been reported in a small number of

patients [14,86]. However, resorption of subchondral bone may occur leading to

fracture, collapse and lack of healing of the chondral portion of the autograft to adjacent

cartilage. Additionally, limited availability of donor sites restricts use to small defects.

Fresh and frozen allografts have also been shown to decrease pain and dysfunction,

however, while the osseous segment may unite to host bone, consistent incorporation of

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the chondral elements has not been demonstrated. Potential transmission of disease and

shortages of donors remains a concern.

It is evident that a wide variety of methods have been developed to encourage the repair

of cartilage defects. Procedures such as debridement, lavage, microfracturing,

subchondral drilling and abrasion arthroplasty have been shown to temporarily alleviate

symptoms, but cannot restore the damaged hyaline articular cartilage. The repair tissue

formed in response to these procedures consists of fibrocartilage, which does not

possess the biomechanical or biochemical properties of hyaline articular cartilage.

Attempts to cover defects with autologous periosteal or perichondral grafts produce a

mixed tissue consisting of hyaline cartilage and fibrocartilage. The repair tissue tends

to undergo calcification and, during the course of endochondral ossification, is replaced

by bone. None of the conventional treatment options have been shown to consistently

result in cartilage-like repair tissue with similar mechanical properties and long-term

durability [55].

AUTOLOGOUS CHONDROCYTE IMPLANTATION

The breakthrough in research on cartilage transplantation occurred in 1965 when Smith

was able to successfully isolate and culture condrocytes [75]. In 1984, an experimental

model in the rabbit was presented using cultured chondrocytes for autologous

transplantation [63]. This experiment was repeated by Grande et al. [31] who showed

that full thickness regeneration of cartilage defects could be created in rabbit patellae.

Cartilage was harvested from the medial femoral condyle and cultured for two to three

weeks before reimplantation in the same rabbit under a periosteal flap. The opposite

patella was treated in an identical fashion, but without chondrocyte transplantation.

Subsequent histological evaluation confirmed healing with tissue showing similar

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characteristics to normal cartilage on the transplanted side but no healing on the control

[31].

Autologous Chondrocyte Implantation using Periosteum (PACI)

The first clinical trial of chondrocyte transplantation using a periosteum patch involved

23 patients with symptomatic, full thickness, articular cartilage defects (down to, but

not through subchondral bone) diagnosed arthroscopically [11]. Sixteen defects

involved the femoral condyle (13 due to trauma, three due to osteochondritis dissecans)

and seven were located in the patella (six due to chondromalacia patella, one due to

trauma). Cartilage biopsy for tissue culture was obtained arthroscopically and was

harvested from the non-weight bearing, upper medial femoral condyle (300-500mg).

The cells obtained were cultured and after 14-21 days, approximately 2-5 x 106 cells

were ready for implantation.

At a second open operation, the cartilage defect was currettaged and covered with a

periosteal flap (harvested from the medial tibia), which was sutured into place. The

cultured chondrocytes were then injected beneath the periosteal membrane into the

‘bioactive chamber’. Active movements commenced after two to three days and full

weight bearing was permitted between eight to 12 weeks post surgery. Patients were

graded clinically every eight to 12 weeks. In addition, arthroscopic evaluation of

hardness and appearance was performed firstly at three months and then at 12 to 46

months.

Outcomes for femoral condyle defects were encouraging with 88% good/excellent

clinical results [11]. At arthroscopic evaluation, all the good/excellent transplants had a

good appearance with level borders and were firm on probing as opposed to the two

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poor results, which showed severe, central wear. Of the 15 transplants biopsied, 73%

showed normal articular cartilage regeneration with irregular fibrous and hyaline tissue

in the remaining 27%. Of the patella subgroup, only 28% showed good/excellent

results, while 72% were fair/poor. And of the five biopsied samples, only one showed

an intact articular surface of hyaline cartilage; the remainder exhibited a combination of

irregular fibrous and hyaline tissue. This somewhat disappointing result may be

attributed to other factors such as extensor mechanism malaligment, patella subluxation,

or maltracking – the correction of which, may have improved results. The authors

concluded that “cultured autologous chondrocytes can be used to repair deep cartilage

defects in the femorotibial joint and that this treatment restores the function of the joint

by forming predominantly hyaline-like cartilage containing type II collagen” [11, p.

894].

Since 1987, further clinical experience has been gained with autologous chondrocyte

implantation. For example, in 1998 Peterson et al. [64] presented a two to 10 year

follow-up of 213 patients that assessed efficacy and durability of the procedure. All

patients underwent comprehensive clinical grading and 46 patients underwent

arthroscopic assessment of graft appearance, filling, integration to adjacent native

cartilage and biomechanical evaluation (via probing for stiffness). Of the 46 patients

that underwent arthroscopic assessment, 19 grafts were biopsied. Treated femoral

condyle defects gave the best results with 90% good/excellent scores for traumatic

lesions, 84% good/excellent for osteochondritis dissecans and 74% with a simultaneous

anterior cruciate ligament repair.

Patella defects again exhibited a less favourable outcome with 69% good/excellent

results (although this improved with correction of malalignment). The reported

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outcomes were worse for trochlear defects with 58% good/excellent results, although it

should be noted that these were generally size dependent. Thirty one patients graded

good/excellent at the two year post-implantation point were graded again at an average

of 7.4 years. Long-term durability was 96%, indicated by patients remaining in the

good/excellent category.

Mechanical testing showed that stiffness corresponded to the nature of repair tissue and

the clinical outcome – the closer the resemblance to hyaline cartilage, the more stiff the

tissue and the higher the function grade. Of the 19 biopsies, 74% showed hyaline

cartilage, all of which had good/excellent function grades. Of the remaining 26%, in

which histological evaluation revealed fibrous tissue repair, 40% were good/excellent

and 60% fair/poor. Thus, an association was again noted between the presence of

hyaline cartilage and a good/excellent clinical outcome. This series also demonstrated

good results for traumatic femoral condylar defects (with or without anterior cruciate

ligament repair) and those due to osteochondritis dessicans.

Subsequently, ACI using periosteal membrane (PACI) has become a well-established

technique for the treatment of articular cartilage defects, with evidence of improved

joint function and formation of hyaline or hyaline-like cartilage. Whilst acknowledging

the contribution PACI has made to the treatment of chondral defects, especially in

young patients, the technique does have a number of short-comings, namely the

requirement for a large surgical incision [11,56], peripheral graft hypertrophy [40,62],

graft delamination [21,40,55], and potential ectopic calcification of the periosteal patch

[55,81]. Postoperatively, it has been documented that a clinically significant percentage

of patients (20-36%) present with symptomatic ‘catching’ of the knee joint due to

hypertrophic graft edges, leading to the need for revision arthroscopy [30,54].

20

Autologous Chondrocyte Implantation using Collagen I/III Membrane (CACI)



According to Geistlich Biomaterials [27], the use of a type I/III collagen membrane

instead of periosteum to seal the cartilage defect is a better choice and collagen

membrane bioscaffolds have been ultilised by numerous studies for chondral repair and

have exhibited bioresorbility and porosity for chondrocyte seeding and delivery [59,72].

Willers et al. [84] conducted an independent assessment of the characteristics of a

similar type I/III collagen membrane (ACI-Maix®) manufactured by Matricel in

Germany. In this study the membrane was initially assessed by scanning electron

microscopy, Hoechst staining and confocal microscopy in order to characterise its

microstructure [84]. Hoechst nuclear staining data irrevocably confirmed (through

absence of signal) that the membrane possessed no cellular component [84].

Furthermore, confocal imaging of the membrane showed absolutely no fluorescence,

thereby confirming the acellular nature of the membrane [84].

Following their morphological assessment of the membrane, Willers et al. [84] assessed

the inflammatory response after long-term subcutaneous implantation using a rat model.

Results indicated that the type I/III collagen membrane employed elicited no significant

inflammatory response. Their results were supported by numerous studies that have

assessed the clinical efficacy and safety of the bilayer type I/III collagen membrane

[1,10,16,61,74]. None of these studies have reported complication or immune reaction

stemming from the implantation of the biomaterial [1,10,16,61,74]. According to

Willers et al. [84] notably, one similar study on the cellular inflammatory response to

21

porcine collagen membrane implantation (Bio-Gide®, Chondrocell®, and Collagen-S®)

found that monolayer cell counts were similar to those obtained after saline

administration, and were significantly less (p<0.001) than turpentine injection [61].

The patented CACI technique (by Verigen Transplantation Service, Copenhagen,

Denmark) is a modification of Peterson’s technique and addresses the aforementioned

problems of using a periosteum patch by replacing it with an inert collagen membrane.

The type I/III collagen employed is biocompatible and has been used in plastic and

other forms of surgery for many thousands of patients. Several studies investigating the

CACI procedure are reported in the literature [2,10,32,43,44]. All used clinical and

histological evaluation postoperatively to measure durability and outcome of the CACI

procedure. The results generally indicated improved functional outcome from pre-

operative scores following CACI and a lower rate of postoperative graft hypertrophy,

with reported incidences ranging from 6-9% compared with the 20-36% reported for

PACI [33,40].

Arthroscopic evaluation has been performed using the ICRS grading system and biopsy

samples were obtained at one year ‘whenever possible’ [30,2,43,44]. It is important to

note that only two of these studies collected biopsy data on the entire sample [10,32].

On average, the remaining studies reported biopsy data on 44% of the sample (range:

32-62%) [20,2,43,44]. Furthermore, the use of ‘gold standard’ biopsies, has been stated

by one author to render MRI evaluation of “limited benefit” [43, p205]. However,

durability of the implanted tissue remains undetermined due to limited biopsy data

taken in the majority of studies at the one year post-surgery time point [30, 2,43,44].

22

Clinical follow-up is reported in the literature ranging from two to seven years, but it is

questionable if clinical follow-up alone has sufficient sensitivity to accurately reflect

graft durability. Arthroscopic examination and biopsy as routine follow-up is

controversial, and provides an inconsistent measure of durability, especially considering

biopsy is not always possible [6,30]. Many consider it unethical to subject ACI patients

to routine ‘second-look’ arthroscopy and biopsy when the ACI graft is considered to be

functioning well from a clinical perspective. Also, the high incidence of inadequate

biopsies (55% as reported by ICRS Histological Endpoint Committee [46]) precludes

meaningful interpretation in the majority of specimens that are obtained

arthroscopically. The majority of biopsy specimens obtained in these studies were

collected at the one year postoperative time point, despite a general consensus in the

literature that the neocartilage regenerated by ACI continues to remodel and mature up

until 24 months postoperatively [6,64].

Although CACI had been shown to exhibit commendable postoperative outcomes, its

surgical technique remains cumbersome. A large surgical incision is required in order

to microsuture the membrane to the circumference of the chondral defect - a tedious

task that increases the length and technical difficulty of the surgical procedure.

Furthermore, concern remains regarding the uneven distribution of chondrocytes within

the fluid suspension, possible leakage of suspension fluid through the graft-cartilage

interface, and creation of microdefects in the native cartilage by the suturing process

[16,69,76].

Matrix-induced Autologous Chondrocyte Implantation (MACI®)

The associated complications with the PACI and CACI procedures have resulted in the

search for alternative bioscaffolds that are thought to be less problematic. Naturally-

23

derived bioscaffolds such as collagen, hyaluronan, fibrin glue, chitosan and various

polysaccharides have been investigated to act as three-dimensional templates for

cellular propagation and growth factor seeding [85]. Matrix-induced autologous

chondrocyte implantation (MACI®, Verigen Transplantation Service, Copenhagen,

Denmark) has applied the concept of direct cell inoculation onto a collagen scaffold for

implantation. In this procedure, the chondrocytes are no longer injected under a

collagen membrane into a sealed defect compartment. Instead, they are directly seeded

onto the type I/III collagen membrane and delivered into the chondral defect as a cell-

scaffold construct. This modified delivery method, effaces the need for periosteal

harvest and is generally suture free. Once prepared, the cell-seeded membrane can be

secured to the base of the recipient defect using a thin layer of fibrin glue. The MACI

procedure can be performed through mini-arthrotomy or arthroscopically depending

upon the defect location [71].

Bartlett et al. [2] conducted a prospective, randomised comparison of CACI and MACI

in 91 patients, 44 of whom received CACI and the remaining 47 received MACI. In

this study both treatment approaches resulted in significant clinical improvements at the

one year postoperative time point [2]. The frequency of good/excellent outcomes was

higher for the MACI group than it was for the CACI group, however, there was no

significant difference between clinical outcomes of each group [2]. Results indicated

that the arthroscopic and histological outcomes were comparable between both CACI

and MACI [2]. According to Bartlett et al. [2], there was no significant difference

between the arthroscopic and the histological findings between the two treatment

groups. However, as the authors themselves advocate, “caution is required in

interpreting our results” since they only conducted tissue biopsy on a small percentage

of their sample population (27% of entire sample underwent core biopsy) [2, p644].

24

This study reports a low incidence of graft hypertrophy following both CACI (9%) and

MACI (6%) and a further 7% of patients required manipulation under anaesthesia

(MUA) [2]. Bartlett et al. [2] concluded that MACI was technically simpler to perform

than the CACI technique and that the suture-free application allowed a minimally

invasive surgical approach. However, they cautioned that prior to the wide-spread

adoption of MACI, further longer term outcome assessment was warranted [2].

Behrans et al. [5] report two to five year follow-up using the MACI technique in a

series of 25 patients (minimum of two years follow-up) and claim that the study

represented the first clinical presentation of mid-term results of MACI up to 60 months

[5]. A significant improvement was reported at the five year time point compared to

baseline preoperative data for the Meyer score, the Lysholm-Gilquist and the ICRS

score (representing the IKDC evaluation) [5]. No significant improvement was seen in

the Tegner-Lsyholm score at the five year assessment time point, when compared to the

preoperative baseline values [5]. Behrans et al. [5] also reported that arthroscopic

evaluation of the grafted defect area showed increasing hardness (to probing) over time.

However, the authors commented that the consistency of the surrounding native hyaline

cartilage could not be achieved [5]. No incidence of graft hypertrophy was reported,

nor was any evidence of ossification seen [5]. According to the author’s histological

evaluation, the technique produced “predominantly living cells in all specimen

preparations” [5, p.201], with separate cells in an unorganised manner observed in 50%

of specimens, cells surrounded in fibrocartilaginous matrix observed in 75% of

specimens and cells surrounded by a fibrous matrix was observed in 25% of cases.

Brehans et al. [5] reported no correlation between histological and clinical outcomes.

25

It therefore appears that MACI resulted in objective and subjective improvement up to

the five year postoperative time point [5]. The results presented by Behrens et al. [5]

are based on 25 patients with a minimum of two year follow-up, 15 of whom were at, or

beyond the five year postoperative time point. However, of these 15 patients, only 11

had suitable clinical follow up [5]. The five year subjective clinical outcomes that were

reported in Brehans et al. [5] study, were representative of less than half of the sample.

Subsequently, any conclusion drawn in regard to the five year outcomes of MACI, are

beleaguered by lack of statistical power.

Arthoscopic Evaluation of ACI

Arthroscopic examination and biopsy as routine follow up is controversial; considered

by many to be unethical to subject ACI patients to routine ‘second look’ arthroscopies

and core biopsy when the graft was functioning well from a clinical perspective. Also,

the high incidence of inadequate biopsies precluded meaningful interpretation in the

majority of specimens, with such problems as biopsy sample being incomplete,

fragmented, not orientated, no inclusion of graft/native cartilage border, not

perpendicular to surface due to accessibility issues, no inclusion of subchondral bone

and inability to measure graft centre and border without taking multiple samples [46].

The true ‘gold standard’ evaluation of cartilage repair would be the complete removal of

the reparative tissue for cross-sectional histological evaluation, however, this defeats the

purpose of the procedure and is unethical. Arthroscopic biopsy does not provide a

complete histological picture of the regenerating graft. Rather, it only provides a

sample from one portion of the graft, and the decision as to where to obtain the biopsy

can be quite arbitrary. Furthermore, as the graft continues to remodel over time, the

clinical relevance of biopsies taken at one year post surgery is questionable.

26

Arthroscopic biopsy is invasive and it is often difficult to gain the patient’s consent to

further surgical trauma when they are clinically asymptomatic [6,54].

Whilst numerous studies have used arthroscopic assessment and biopsy as an outcome

measure for the evaluation of cartilage repair, the majority of data presented are derived

from only a small sub-group of the patient population [2,30,64,42,44]. Whilst not

meaning to diminish the importance of the information gained through arthroscopic

biopsy, its use as a standard measure of outcome following ACI is fraught with

problems, both ethical and logistical. Subsequently, there remains an increasing

demand for an accurate, reproducible and non-invasive method for repair tissue

monitoring after ACI [80].

Role of MRI in Evaluation of ACI

Articular cartilage is approximately 70% water by weight [29]. The remainder of the

tissue consists predominantly of type II collagen fibres and glycosaminoglycans [29].

The latter contain negative charges that attract sodium ions (Na+) in intact cartilage

[29]. Collagen fibres have an ordered structure, making the water associated with them

exhibit both magnetisation transfer and magic angle effects [29]. MRI provides a non-

invasive, high resolution investigation, which can visualise articular cartilage [68].

MRI allows evaluation of articular cartilage thickness, graft incorporation and congruity

of the articular surface. Post-operative complications such as delamination,

arthrofibrosis, fissure formation, and hyperthrophy of implant material results can be

assessed reliably, along with the signal characteristics of the subchondral bone. All of

this information is obtained non-invasively. These factors make MRI an attractive

outcome measure of the morphological status of cartilage defects, and its role in the

27

evaluation of cartilage repair is well supported in the literature

[29,35,38,50,51,65,66,68,80].

Reccht et al. [68] defined the MRI acquisition protocols for cartilage imaging as

recommended by the Articular Cartilage Imaging Group of the International Cartilage

Repair Society (ICRS). The most commonly used cartilage sensitive MRI techniques

are intermediate-weighted fast spin-echo (FSE) and three-dimensional (3D) fat-

suppressed gradient-echo (GRE) acquisition [18,20,50,51]. A recent study by

Marlovitis et al. [50] revealed that high-resolution MRI could be achieved on standard

1.0 or 1.5 Tesla MRI scanners by using a surface phased array coil in conjunction with

specific cartilage sensitive imaging sequences. Importantly, this increased image

quality could be achieved without substantial increases in total imaging time [50].

Marlovitis et al. [51] also defined the pertinent variables for the description of articular

cartilage repair tissue following surgical intervention in the form of the MOCART scale

(Magnetic Resonance Observation of Cartilage Repair Tissue). This scale presented

nine grading variables, as follows:

1. Degree of defect repair and filling of the defect;

2. Integration to border zone;

3. Surface of the repair tissue;

4. Structure of the repair tissue;

5. Signal characteristics of the repair tissue;

6. Subchondral lamina;

7. Subchondral bone;

8. Adhesions; and

9. Synovitis.

28

The method was also supported by schematic diagrams and high-resolution MRI images

[51].

According to the authors [51], the variables defined in the MOCART scale afforded an

accurate description of the pertinent morphological features of cartilage repair. The

wide-spread use of a such a classification system may facilitate meaningful comparison

between study populations and improve the quality of the information provided by

longitudinal follow-up across the field. This scoring system has now undergone inter-

observer variability testing using the intraclass correlation coefficant (ICC) to determine

reliability [51]. Results showed a ‘very good’ strength of agreement in all variables,

with an ‘almost perfect’ agreement in eight of the nine MOCART variables (ICC values

>0.81) [51]. Whilst the sample size of this study was small (n=13), the authors were

able to show a good correlation between some of the MRI variables and clinical

outcome scores [51].

The association between MRI and graft histological outcome is not conclusive.

However, recent studies have attempted correlation of the two outcome measures, but

with mixed results. Tins et al. [78] concluded that MRI findings were not predictive of

graft histological features following ACI. However, according to Trattnig et al. [80] the

findings of this study were limited by the use of the PACI technique, which is known to

have numerous postoperative complications. Trattnig et al. [80] also criticised the MRI

sequences used by Tins et al. [78], stating that they were not aligned with current

recommendations. The quality of the inter-observer correlation was also questionable

for certain pertinent graft assessment parameters [80]. Conversely, several other studies

have reported good correlation of the results generated by MRI evaluation and cartilage

histology [20,35,51,54]. Further investigation of the relationship between MRI and

29

clinical outcome following chondrocyte implantation is imperative, as it remains to be

determined whether the native ultrastructure of cartilage needs to be restored in order to

achieve good, durable, clinical results.

THE ROLE OF POSTOPERATIVE REHABILITATION IN ACI

The rehabilitation guidelines pertained to the PACI technique primarily advocated

extensive use of continuous passive motion (CPM) machines during the first six weeks

of the recovery process in order to decrease the likelihood of intra-articular adhesions

[56,57]. Isometric muscle exercises were also advocated to regain muscle tone and

prevent atrophy [11,56,57]. However, weight bearing was to be protected for six to 12

weeks following PACI in order to prevent periosteal overload and subsequent graft

delamination [11,56,57,64]. ‘Touch weight bearing’ for the initial six post-operative

weeks was advocated for defects of the femoral condyle. Thereafter, weight-bearing

was to be gradually increased to full body loading at the 12 week post-operative time

point [11,56,57].

However, research has demonstrated that the elastic functional behaviour of articular

cartilage is maintained by the continuous remodelling of chondrocyte extracellular

matrix in response to mechanical stimuli and other physiological pressures

[15,26,73,79]. Primarily, type II collagen and aggregates of proteoglycan (aggrecan)

constitute the main biosynthetic cellular response to biomechanical transduction

through the joint. These extracellular proteins provide the tensile and compressive

thickness of the cartilage, and it has been shown that mechanical exercise of the knee

joint increases the aggrecan content of cartilage in vivo, whereas inactivity can facilitate

decreased aggrecan content [4].

30

Collagen and proteoglycans are the most important extra cellular matrix (ECM) proteins

within articular cartilage. They are responsible for the tissue’s mechanical resilience via

regulation of fluid flow and tension, and resistance to compression. Various studies

have demonstrated strong evidence for the relationship between articular cartilage

matrix biosynthesis and biomechanical stimuli [21,40,54,55,62,81]. Of course, the

mechanical and biochemical cues received and transformed by articular chondrocytes

are constantly changing during everyday locomotion. Regardless, there are three basic

principles of biomechanical force effecting cartilage metabolism:

1. Static compression;

2. Cyclic or intermittent (‘dynamic’) compression; and

3. Shear force.

During normal joint loading within the body, the cartilage experiences a complex mix

of shear and compressive deformation, having both static and dynamic components.

Studies have illustrated that the dynamic compression of articular cartilage stimulates

proteoglycan biosynthesis dependent on loading frequency and amplitude [21,40,55],

whereas increased static compression by mechanical or osmotic stress has been shown

to decrease proteoglycan synthesis and cartilage hydration [21,30,40,46,62,68].

Similarly, dynamic shear forces have been shown to elevate matrix accumulation and

mechanical properties after long-term culture [29,65,66]. More specifically, long-term

intermittent shear force has been shown to produce 40% more collagen, and 35% more

proteoglycan after four weeks of stimulation [54].

Following surgery, patients should undergo an intensive, specialised rehabilitation

program that underpins the chondrocyte maturation process [70]. This has been

demonstrated at the cellular level with various studies showing the relationship between

31

cartilage matrix synthesis and biomechanical stimulation [15,26,73,79]. Continuous

passive motion (CPM) has been shown to improve matrix biosynthesis postoperatively

by introducing controlled dynamic compression [68]. Therefore, reduced cartilage

thickness and/or matrix synthesis observed in some patients may be related to a lack of

biomechanical stimulation of the graft through the absence of structured rehabilitation.

In summary, to improve cartilage regeneration of the joint, the introduction of

biomechanical stimuli through controlled postoperative rehabilitation may act to

enhance cartilage matrix synthesis and aid both qualitative and quantitative aspects of

cartilage repair. However, at the time this research was begun, there existed very little

published information on rehabilitation following ACI that had a strong evidence-basis.

32

CHAPTER THREE

STANDARD PRACTICE EXERCISE REHABILITATION PROTOCOLS

Note 1. References cited in this chapter appear in a reference list at the end of the

chapter. Note 2. Appendices noted within this chapter appear at the end of the chapter.

33

STANDARD PRACTICE EXERCISE REHABILITATION

PROTOCOLS

for

MATRIX-INDUCED AUTOLOGOUS CHONDROCYTE

IMPLANTATION

- FEMORAL CONDYLES -

Authors: Brett Robertson MSc

Helen Gilbey PhD

Timothy Ackland PhD

34

HO L L Y W O O D FU N C T I O N A L RE HA BI LI TA T I ON CL I NI C

V E R I G E N AUSTRALIA PTY LTD

THE UNI V E R S I T Y O F WE ST E R N AU S T R A L I A

©2003

HFRC, UWA & Verigen Australia’s Rehabilitation Protocols © 2003

FOREWORD

This publication has been produced under license by Verigen Australia in order to

disseminate the standard rehabilitation protocol that is applied to patients at the

Hollywood Functional Rehabilitation Clinic (HFRC) in preparation for, and

rehabilitation following their patented matrix-induced autologous chondrocyte

implantation (MACI®) surgery. It is intended as a resource tool for your practice.

Hollywood Functional Rehabilitation Clinic (HFRC) is a purpose built facility that is

located within the Perth Orthopaedic Institute, Hollywood Private Hospital, Perth,

Western Australia. It was officially opened in October 1998 by the Honorable Max

Evans. This MACI® rehabilitation program has been specifically developed over the

last four years through close liaison with the University of Western Australia (Schools

of Surgery & Pathology, and Human Movement & Exercise Science) and Verigen

Australia Pty Ltd.

All HFRC rehabilitation protocols have been subjected to scientific scrutiny through

peer reviewed research. This research focus is an integral part of our commitment to

development as a centre of excellence within Australia and South East Asia. Outcome

measures from these research projects are summarised in this document. This

intellectual property is protected by copyright and cannot be reproduced without the

permission of the authors.

35


CONTENTS Page Introduction 38 Rehabilitation Program Aims and Rationale 42 Pre surgery program (8 weeks) 47 Post surgery program (1 year) 51







Exercise Progression Summary 62 Frequently Asked Questions 63 Return to Elite Level Competition 66 References 67

This material does not constitute medical advice. It is intended for informational purposes only. All rights reserved. The material included in this publication, is solely for the purpose of education, treatment or rehabilitation of patients within your facility. Reproduction of materials in advertising or in other publications is not permitted. No other comerical or non-comercial use of the ‘Standard Practice Exercise Rehabilitation Protocols for Matrix-Induced Autologous Chondrocyte Implantation: Femoral Condyles is permitted, without the prior permission of the copyright owner.

36


Appendices

A) MACI Knee Assessment Form 70

B) Knee Pain Scale 72

C) Knee Injury and Osteoarthritis Outcome Score (KOOS) 73

D) Clinical Review Form 76

E) Pre Surgery Program Structure 77

F) Pre Surgery Clinic & Home Based Flexibility Program 78

G) Pre Surgery Clinic Exercise Program 81

H) Pre Surgery Hydrotherapy Program 83

I) Pre Surgery Home Exercise Instructions 84

J) Pre Surgery Home Exercise Program 85

K) OAsys Brace Information 86

L) Inpatient Physiotherapy Protocol 87

M) MACI Operative Procedure Form 88

N) Post Surgery Hydrotherapy Program 89

O) Post Surgery Clinic & Home Based Exercise Program 97

P) Post Surgery Proprioception Program 110

Q) Schedule of Testing 111

37


INTRODUCTION This exercise protocol is intended as a guide only, and professional discretion must be

applied at all times when prescribing and monitoring exercises for individual

orthopaedic patients. Enclosed is the general framework by which staff at the HFRC

service patients who are preparing for, or recovering from matrix-induced autologous

chondrocyte implantation (MACI®) surgery for defects of the femoral condyle.

This is by no means the definitive rehabilitation plan for all MACI patients and should

not be applied in a ‘recipe’ fashion. There is great individual variation between patients

(including age, body weight, and defect size) that must be taken into consideration

before commencing the rehabilitation process.

The program should be conducted under the supervision of a qualified physiotherapist

or exercise physiologist with accreditation in musculoskeletal rehabilitation. We

strongly advise that health professionals involved in the rehabilitation of MACI patients

liaise closely with the patient’s orthopaedic specialist throughout the course of the

program.

38


EPIDEMIOLOGY AND HEALTH ECONOMICS

Articular cartilage defects of the knee occur commonly in sports injury and trauma,

often affecting the young. Curl et al. [1] reported a 63% incidence of chondral lesions

when they reviewed more than 31,000 arthroscopic surgical procedures. These patients

are at high risk of developing OA and it is estimated that approximately 60% of patients

will have significant symptomatic OA within 20 years of generating an articular

cartilage defect. The costs of musculoskeletal illness have risen in recent years

accounting for up to 1-2.5% of the gross national product for those countries including

the USA, Canada, UK, France and Australia [2].

CONVENTIONAL TREATMENT OPTIONS

A wide variety of methods have been developed to encourage the repair of cartilage

defects. Procedures such as debridement, lavage, microfracturing, subchondral drilling

and abrasion arthroplasty have been shown to temporarily alleviate symptoms, but

cannot restore the damaged hyaline articular cartilage. The repair tissue formed in

response to these procedures consists of fibrocartilage, which does not possess the

biomechanical or biochemical properties of hyaline articular cartilage [3,4]. Attempts

to cover defects with autologous periosteal or perichondral grafts produce a mixed

tissue consisting of hyaline cartilage and fibrocartilage. The repair tissue tends to

undergo calcification and during the course of endochondral ossification it is replaced

by bone [4]. None of the conventional treatment options have been shown to

consistently result in cartilage-like repair tissue with similar mechanical properties and

long term durability.

39


THE ACI PROCEDURE

Autologous chondrocyte implantation (ACI), in combination with periosteal grafts,

have been employed to treat cartilage defects since 1987 with successful results [5-7].

However, use of the periosteal flap has several drawbacks including hypertrophy, flap

delamination and donor site morbidity [8-11]. Periosteum also contains pluripotential

mesenchymal cells with a tendency to undergo fibroblastic differentiation resulting in

‘fibrohyaline’ rather than hyaline cartilage in-fill [4].

The patented collagen-covered ACI technique (by Verigen) was the first modification of

the periosteal ACI technique and addressed the problems of using a periosteum patch by

replacing it with an inert collagen membrane [12,13]. The type I/III collagen employed

is biocompatible and has been used in plastic surgery for many thousands of patients.

Whilst collagen-covered ACI successfully addressed the problems associated with the

periosteum patch, there remained room for improvement. Firstly, a full arthrotomy had

to be performed in order to gain the necessary access for suturing the membrane into

position. Secondly, the process of securing the membrane onto adjacent healthy

cartilage with a series of 6/0 vicryl sutures creates multiple new microdefects that will

not heal (6/0 vicryl sutures are not commonly used by orthopaedic surgeons and can be

difficult to work with). A watertight seal must be created by the surgeon in order to

ensure that the cells do not escape once injected into position, and finally, if the

cartilage defect is not surrounded by healthy tissue or extends to the joint margin, the

bioactive chamber may be compromised.

The MACI technique is the second generation of the ACI techniques patented by

Verigen. In this technique, the cells are actually seeded directly onto the collagen type

I/III biomembrane to form a biocomposite. Cells adhering to the inert membrane are

40


mechanically stable at the time of implantation so there is no longer the risk of leakage.

The MACI technique is more convenient as the pre-cut patch is now glued in position

with fibrin glue that only takes one minute to set, compared to the hour required to

suture a patch of collagen or periosteum. The MACI technique can also be performed

via mini arthrotomy due to the fact that sutures are no longer required. This has the

added benefit of reducing soft tissue damage to the affected knee.

Figure 1. Electron micrograph scan of MACI biocomposite in culture.

(Courtesy of Verigen Australia, Perth, Western Australia)

41


REHABILITATION PROGRAM AIMS AND RATIONALE

THE IMPORTANT ROLE OF STRUCTURED REHABILITATION

Patients cannot be left to their own devices following surgery, as the risk of damage to

the implant is high. Therefore, the four cornerstones for successful outcomes following

MACI surgery include:

Successful cell culture; •

•

•

•

Efficient surgical procedure;

Complimentary postoperative rehabilitation; and

Patient cooperation.

BIOMECHANICAL MODULATION OF CHONDROCYTE BIOSYNTHESIS

The biological principle underlying our rehabilitation protocol for MACI is based on the

postoperative biomechanical stimulation of chondrocyte biosynthesis. In other terms,

the rehabilitation protocol is designed to activate the cell-mediated progression of

MACI-induced regenerative cartilage into physiologically functional articular cartilage.

The ice-like, elastic functional behavior of articular cartilage is maintained by the

continuous remodeling of chondrocyte extracellular matrix in response to mechanical

stimuli and other physiological pressures. Primarily, type II collagen and aggregates of

proteoglycan (aggrecan) constitute the main biosynthetic cellular response to

biomechanical transduction through the joint. These extracellular proteins provide the

tensile and compressive thickness of the cartilage. It has been shown that mechanical

exercise of the knee joint increases the aggrecan content in cartilage in vivo, whereas

inactivity can facilitate decreased aggrecan content [14,15].

42


The neocartilage formed following MACI surgery is characterized by tissue high in cell

density, water, and type II collagen content, but of weak biomechanical property.

Subsequently, after cell cultivation and surgical technique, the biggest key to the

therapeutic success of MACI is the maturation of neocartilage to functional cartilage

through healthy extracellular matrix production by chondrocytes post-implantation, a

process heavily reliant on effective rehabilitation. Together with correct joint

biomechanics, the synthesis of healthy chondrocyte matrix proteins such as

proteoglycan and type II collagen is crucial to the longevity of MACI-induced

regenerative cartilage. Collagen and proteoglycans are the most important ECM

proteins within articular cartilage. They are responsible for the tissue’s mechanical

resilience via regulation of fluid flow and tension, and resistance to compression.

Various studies have evidenced the relationship between articular cartilage matrix

biosynthesis and biomechanical stimuli [16-21]. Of course, the mechanical and

biochemical cues received and transformed by articular chondrocytes are constantly

changing during everyday locomotion.

Regardless, there are three basic principles of biomechanical force effecting cartilage

metabolism: (1) Static compression, (2) Cyclic or Intermittent ("dynamic")

compression, and (3) Shear force. During normal joint loading within the body, the

cartilage experiences a complex mixture of shear and compressive deformation, having

both static and dynamic components. Studies have illustrated that the dynamic

compression of articular cartilage stimulates proteoglycan biosynthesis dependent on

loading frequency and amplitude [16,18,19], whereas increased static compression by

mechanical or osmotic stress has been evidenced to decrease proteoglycan synthesis and

cartilage hydration [16-19,22-24]. Similarly, dynamic shear forces have been shown to

43


elevate matrix accumulation and mechanical properties after long-term culture [25-27].

More specifically, long-term intermittent shear force has been shown to produce 40%

more collagen, and 35% more proteoglycan after 4 weeks stimulation [21].

Upon comparison of such data, it becomes obvious that chondrocytes are sensitive to

specific biomechanical stimuli, and that conditions closer to native loading

(predominantly dynamic compression and shear force) stimulate chondrocytes towards

a biosynthetic profile more capable of healthy physiologic functioning. Armed with the

knowledge of numerous basic science and preclinical studies, the introduction of

techniques like continuous passive motion (CPM) have improved postoperative matrix

biosynthesis and joint function by controlled biomechanical stimulation following

surgery [28,29]. Using CPM and other cartilage-specific rehabilitation protocols, we

have consolidated our knowledge of chondrocyte mechanostimulation to improve the

clinical outcome of MACI treatment. The development of our graduated load-bearing

rehabilitation protocol has been specifically targeted at providing the appropriate

biomechanical stimulus over the first postoperative year to maximize autologous

chondrocyte-mediated defect regeneration.

In summary, the biomechanical modulation of chondrocyte biosynthesis is dominated

by two opposing mechanotransduction pathways. Constant static compression leads to

a biological pathway cascade characterized by matrix catabolism and inevitable tissue

degeneration. Whereas, dynamic compression and shear force (normal joint

locomotion) trigger anabolic pathway cascades depicted by increased hyaline-specific

matrix protein biosynthesis. This increased biosynthesis facilitates the postoperative

progression of biomechanically inferior regenerative tissue to functional articular

cartilage, a process directly dependent on the introduction of functional rehabilitation.

44


PRE SURGERY PROGRAM (8 weeks)

We strongly recommend that the rehabilitation process should begin prior to surgery, as

patients need to be physically and mentally prepared for their operative procedure and

the lengthy rehabilitation process.

Objectives of the presurgery program are to:

Increase the strength of the muscles and connective tissue of the knee and lower

limb in which the surgery is to be undertaken;

•

•

•

•

•

•

•

Increase knee active range of motion (AROM) and reduce pre-operative contracture;

Improve muscular strength of the upper limbs and trunk to assist early post surgery

tasks of bed/chair transfers and crutch ambulation;

Improve the level of cardiovascular fitness which may aid faster recovery from

surgery;

Ensure patient is proficient in ambulating and negotiating stairs using two crutches

and non-weight bearing on the affected side;

Provide pre surgery education regarding the surgical procedure and chondrocyte

maturation process, thus preparing the patient psychologically for surgery and the

lengthy rehabilitation process; and

Where appropriate, facilitate weight loss for normal height to weight ratio.

On return to the clinic post surgery, the patient is familiar with the clinic protocols, the

staff, and the exercise routines. In addition, there is support and social interaction from

the other patients and staff.

45


POST SURGERY PROGRAM (1 year)

Following surgery it is necessary to undergo an intensive specialised rehabilitation

program for two important reasons:

1. A protection phase is required to prevent disruption of the implanted collagen

patch. In particular, the repair surface must be protected against high

compression and shear forces. For example, patients are required to protect their

repair from weight bearing stresses and are restricted to toe-touch ambulation

with two crutches for the first three postoperative weeks (Table 1).

Furthermore, the amount of knee flexion immediately after surgery needs to be

controlled, and so a brace should be worn to ensure the protection of the

cartilage repair in this early phase of the recovery process.

2. A graduated loading phase (Figure 2) is then required to give the implanted

chondrocytes the necessary stimulus to cause hypertrophy and adaptation in

order to restore their natural function. Over the weeks following

the protection phase, a stepwise increase in weight bearing occurs so that by

12 weeks post surgery, the patient is ready to fully bear weight. At the 12-week

time-point compressive and de-compressive forces, provided by full weight

bearing, further stimulate the chondrocytes to synthesise the correct matrix

molecules

46


PRE SURGERY PROGRAM (8 weeks)

INITIAL ASSESSMENT AND EDUCATION SESSION

Patients scheduled for MACI knee surgery are referred to the HFRC four weeks prior to

their arthroscopic cartilage harvest. An initial assessment is completed during the first

session to record baseline data. Patients are asked a series of standardised introductory

questions regarding their medical history and previous injuries (Appendix A). Patients

also receive a complete synopsis of the MACI technique and the postoperative

rehabilitation pathway in lay terms (Appendix R). Normal height to weight ratio is

necessary in order to reduce joint stresses crossing the knee. During the stance phase of

walking gait and when ascending and descending stairs, joint stress approximating 1.5

to 8.0 times body weight can be generated through the knee. Patients who are required

to reduce body mass before being considered for surgery can opt to follow a dietary

plan of their choice. We have the facility to combine a weight loss regimen with the

presurgery exercise program.

Quantification of perceived pain, symptoms, function and psychological state are

assessed using the Knee Pain Scale [30] (Appendix B) and the Knee Injury and

Osteoarthritis Outcome Score (KOOS) [31] (Appendix C). Patients also participate in

a series of musculoskeletal capacity tests (Appendix D) including: stretch stature, body

mass, resting blood pressure, bilateral active range of motion (AROM) of the knee,

bilateral thigh girth (mid-thigh) and a six minute walk test [32]. Bilateral leg

flexion/extension strength is measured using the Keylink isokinetic dynamometer and

patients also perform a 3RM straight leg raise test in order to determine the dynamic

strength of the quadriceps and hip flexor musculature.

47


During each assessment patients are asked to perform the tests to the best of their

ability. Therefore, the highest strength and AROM scores attained are recorded as the

patient’s baseline data. If a patient reports that they are experiencing high levels of pain

and discomfort, or they are unable to perform a test due to lack of mobility in

conjunction with pain, then the test is modified or excluded. It is deemed inappropriate

to exacerbate patient pain levels or to cause unnecessary distress. The perceived level of

pain experienced during each test is also recorded.

Figure 2. Gradual loading of the joint is required to stimulate hypertrophy and adaptation of the hyaline-like cartilage in-fill material.

FullyMaturedHyaline-

likeCartilage

RepairMatrix production & Adaptation of regenerating cartilage to natural function

Time & Appropriate Stimulus

Load Bearing Capacity

Post+1yrPost+6moPost+3moImplantation

48


PRE SURGERY PROGRAM - CLINIC COMPONENT

The structured presurgery clinic program involves a twice-weekly exercise intervention

that is individually tailored to the patient with each exercise session lasting

approximately 1.5 hours. Patients are fully supervised using variable resistance

machines for upper and lower body strength training as well as an aerobic fitness

program using cycle, arm and/or rowing ergometers (Appendices E – G). If patients

are unable to participate in the standard exercise program due to pain or functional

limitation, hydrotherapy (water-based) resistance and aerobic programs are

implemented (Appendix H). Patients are also shown how to walk correctly and

negotiate stairs and obstacles using crutches.

PRE SURGERY PROGRAM - HOME BASED COMPONENT

Patients are required to complete three ‘home based’ exercise sessions per week using a

training kit consisting of TherabandsTM and other simple equipment found in most

homes. The patient is taught their home-based program by an exercise physiologist and

receives an instruction sheet on how to perform each exercise correctly (Appendices I

& J).

FINAL ASSESSMENT AND PRESURGERY PROGRAM CONCLUSION

Approximately one week prior to chondrocyte implantation a final assessment is

conducted in order to assess the impact of the presurgery program and to document the

changes in functional capacity of the patient.

Quantification of perceived pain, symptoms and function are again assessed using the

Knee Pain Scale (Appendix B) and the Knee Injury and Osteoarthritis Outcome Score

49


(KOOS) (Appendix C). The musculoskeletal capacity tests (Appendix D) are also

repeated.

If at any stage an operation is cancelled or postponed or the patient has not reached the

required body weight for surgery, then they continue on a maintenance program at

HFRC until surgery is rescheduled. Following arthroscopic cartilage harvest, patients

are fitted with a supportive knee brace (Appendix K). Patients take the knee brace to

hospital when they are admitted, which ensures that upon discharge, they leave with

two crutches and knee brace for stability and implant protection.

50


POST SURGERY PROGRAM (1 year)

INTRODUCTION

Following ACI knee surgery patients benefit from a coordinated rehabilitation program

of progressive exercise and graduated weight bearing to protect and stimulate the

healing process. Between months 6 to 12 a gradual increase in knee compression force

is required to stimulate maturation of the chondrocyte cells. However, return to heavy

manual work, sport and recreational activities should be carefully controlled and

gradually progressed. Although the defect may well have been filled with hyaline-like

cartilage within the first few months, it is not advisable to undertake resisted leg

extension or weight bearing activities, such as squats or running before 12 months post-

surgery. Maturation and hardening of the new-formed cartilage will not be complete

until this time. From 12 months onwards patients can expect to return to their pre-

injury recreational and sporting activities.

NOTE OF CAUTION

The progressions outlined in this section of the document represent a generic form of

post operative rehabilitation and it is standard practice at HFRC to off-set program

progression by one to two weeks when treating patients who exhibit the following:

Overweight patients (>1.5 times recommended weight for height); •

•

•

•

Patients with a large defect (> 6 cm2);

Multiple implantations (eg trochlea groove and medial femoral condyle), and

When auxiliary procedures have been performed to correct joint malalignment or

instability.

51


INPATIENT TREATMENT (Postoperative day 1 to day 3 or 4)

During the early stages of the postoperative recovery process, the primary goals are to

maintain joint mobility and muscle tone and to prevent joint stiffness and excessive

muscle atrophy while adhering to all postoperative precautions. Treatment is to be

initiated on postoperative day 1 (unless otherwise instructed by operating surgeon).

Early treatment should comprise the following.

1. Appropriate analgesic prescription will be necessary for pain control;

2. It is important to be aware that the MACI procedure may well be the patient’s

first hospital stay and first recovery following orthopeadic surgery;

3. CPM (0 to 30°) to be commenced 12 to 24hrs following surgery, for a

minimum of 1hr daily;

4. Post-operative ROM control brace to be fitted (initially set to 0 to 30°). Brace to

be worn 24hrs a day for the first three weeks;

5. Cryotherapy to be applied as standard oedema control (20 min ice at least three

times per day);

6. Active dorsiflexion and plantar flexion of the ankle are performed to encourage

lower extremity circulation;

7. Isometric contraction of the quadriceps, hamstrings and gluteal musculature help to

maintain muscle tone;

8. Breathing exercises are practiced to ensure proper technique during

therapeutic exercise;

9. Emphasize proficient toe-touch ambulation (using two crutches, with 10-15% of

body weight through operated limb), and safety with transfers and stairs; and

52


10. Ensure that patients are given detailed verbal and written instructions on how to

perform activities of daily living and functional tasks while adhering to the

postoperative precautions and proper weight-bearing status.

CONTRAINDICATIONS

1. Excessive load bearing (>20% of body weight) especially in combination with

knee flexion;

2. Ambulation without crutches and protective knee brace;

3. Generation of shear forces within the knee;

4. Knee flexion >30°; and

5. Active knee extension (especially against resistance).

PRIOR TO DISCHARGE

1. Ensure that patient has an appointment for outpatient physiotherapy or functional

rehabilitation;

2. Ensure that patient has a two week review appointment scheduled with the

orthopaedic surgeon;

3. If required, ensure that patient has an appointment for removal of staples;

4. Instruct patient to follow ‘RICE’ protocol for oedema control;

5. Reinforce weight bearing constraints and brace protocol; and

6. Review home exercise regime.

POST SURGERY REHABILITATION PROGRAM

The majority of patients begin their post surgery rehabilitation program at HFRC within

two weeks of MACI surgery, provided the incision wound has sufficiently healed.

Those with postoperative complications begin rehabilitation after gaining appropriate

53


medical clearance. Patients are encouraged to attend HFRC twice weekly until week-12

postsurgery, with the option of continuing a program until the 12 month time point.

Each session lasts approximately 1.5 hours and is fully supervised. Use and positioning

of the knee brace during rehabilitation is determined by the orthopaedic specialist.

54


Table 1: Generic MACI Postoperative Weight Bearing Progression

Postoperative

Time Point

% of BW Comments

• Weeks 1 to 3 ≤20% Two crutches and protective knee brace to be used at all

times

• Week 4 30%

• Week 5 40%

• Week 6 50% Begin ambulating with one crutch and knee brace indoors,

two crutches outdoors*

• Week 7 60% One crutch indoors, knee brace and two crutches outdoors*

• Week 8 70-80%

• Week 9 80 - 90% One crutch only, brace outdoors*

• Week 10 90%

• Week 11 90 - 100% Begin ambulating in clinic and indoors without crutches,

one crutch and brace outdoors*

• Week 12 100% Knee brace or one crutch only when ambulating on uneven

ground*

• Week 13-24 100% Crutch/brace as required

• Week 24-52 100%

* Depending upon the patient’s progress and upon clearance from the Orthopaedic Specialist

55


HFRC’s postsurgery rehabilitation program is broken into six phases as follows:

• Phase 1: 1 to 3 weeks post surgery;



• Phase 4: 3 to 6 months post surgery;

• Phase 5: 6 to 9 months post surgery; and

• Phase 6: 9 to 12 months post surgery.

Phase 1: 1 to 3 weeks post surgery

The objective of the first postoperative session is to review the patient’s level of pain,

swelling and function as well as to reiterate instructions and movement

contraindications outlined by the orthopaedic specialist and the hospital

physiotherapists (Appendix L). Until week-3 post surgery supervised exercise sessions

are conducted in the hydrotherapy pool (Appendix N) and a home-based program is

developed as tolerated (Appendix O). Clearance massage and cryotherapy is

performed each session to assist in the reduction of soft tissue oedema. Ultrasound and

interferential therapy is applied as required. Active knee ROM is measured and

recorded.

Outcomes: By week-3 post surgery patients are expected to achieve the following:

1. Pain free knee AROM of 0° to 60o - 90°;

2. Heel toe gait with toe touch pressure (≤20% of body weight), using two

crutches and knee brace;

3. Reduced oedema and postoperative pain;

4. Full extension; and generate a quadriceps contraction.

56



During Phase 2, land-based exercises are introduced as tolerated. Patients perform arm

ergometry for cardiovascular conditioning, resistance exercise for the trunk, shoulders

and arms to aid in mobility using crutches, and resistance work for the lower limbs to

reduce atrophy in the operated leg. Specific open kinetic chain exercises and isometric

exercises to improve quadriceps strength are introduced. A graduated program of

weight bearing using two crutches and the protective knee brace is introduced,

beginning at week-4 with 30% body weight pressure being transferred though the

operated knee. Pressure placed through the affected knee rises by approximately 10%

of body weight each week.

Gait retraining and knee AROM continue in the hydrotherapy pool. Remedial massage,

cryotherapy, ultrasound and interferential therapy are implemented as necessary.


1. Pain-free active knee ROM of 0° to 90° - 120°;

2. Proficient straight leg raise; and

3. Pain-free gait using two crutches, knee brace and 50% body weight

pressure.


During Phase 3 of the postsurgery rehabilitation program patients continue with the

exercises prescribed during phase 2. The knee brace continues to be used when

ambulating out of doors. Land-based exercises to strengthen the stabilising muscles of

the knee are introduced.

57


Weight bearing pressure through the knee is increased as follows:

Postoperative Time Point % of BW Comments • Week 7 60% One crutch indoors, knee brace and two crutches

outdoors* • Week 8 70-80% • Week 9 80 - 90% One crutch only, brace outdoors* • Week 10 90% • Week 11 90 - 100% Begin ambulating in clinic and indoors without

crutches, one crutch and brace outdoors* • Week 12 100% Knee brace or one crutch only when ambulating

on uneven ground*

Beginning week-9, proprioception work is introduced in the hydrotherapy pool

(Appendix N) graduating from single leg balance with eyes open to single leg balance

with eyes closed. Within the clinic, proprioception activities are initially performed in a

partial weight bearing position and graduate in difficulty to full weight bearing

FitballTM, DuradiscTM and wobble board activities (Appendix P). During week-9 cycle

ergometry (0.5-1.0 Kp or 30-60 Watts) is introduced for 5 minutes duration. Retraining

of gait continues in the hydrotherapy pool and remedial massage, cryotherapy,

ultrasound and interferential therapy are administered as appropriate. At the end of

phase 3 patients undergo a three month post surgery assessment, and a written report is

sent to the orthopaedic specialist to coincide with the patient’s review.


1. Pain-free AROM within normal anatomical limits (0° to 130º -160º);

2. Pain free 6-min walk test with or without walking aids;

3. Use cycle ergometers pain-free without knee brace.

58


Phase 4: 3 to 6 months post surgery

During Phase 4, clinic resistance and cardiovascular exercises are consolidated. Full

weight bearing propriocetion retraining is commenced and the degree of difficulty of

these exercises is slowly increased through exercises using a rocker board, Dura discTM,

wobble board, TheraballTM and trampette as tolerated (Appendix P).

By the start of phase 4 the majority of patients have returned to work either on a part-

time or full-time basis. Patients now attend the clinic one or two times per week as the

constraints of their job allow, and are instructed to continue with their home exercise

program as prescribed.

Functional activities are gradually introduced and progressed, for example:

• Home exercise program - minimum of three sessions per week; and/or

• Walk (on grass) twice a week, begin with 500m and add 50m per session - target = 2/3km by six months;

and/or • Cycle twice a week, begin with 10min (0.5-1.0kp or 50-60 watts)

and add 5min per week

- target = 20/30min (1.5-2.0kp or 70-100 Watts) by six months; and/or

• Swim twice a week, begin with 200m add 100m per week

- target = 1km by six months.

Outcomes: By month-6 post surgery patients are expected to achieve the following:

1. Normal gait pattern without pain and without walking aids;

2. Return to work (part-time / full-time) depending on demands of job;

and

3. Perform proprioception activities: 30s single leg balance on trampette.

59



During phase 5, complex closed chain load bearing exercises are commenced

(Appendix O) in conjunction with the resumption of more diverse low impact

recreational activities.

Outcomes: By month-9 post surgery patients are expected to achieve the following:

1. Able to tolerate walk distances of up to 5kms;

2. Able to negotiate stairs and mild gradients;

3. Able to effectively traverse uneven ground, including soft sand; and

4. Able to return to preoperative low impact recreational activities.


During phase 6 patients are gradually reintroduced to functional activities that form the

basis of his or her particular sport. These activities prepare the patient physically and

mentally to cope with the demands of returning to sport. Sport-specific functional

activities (e.g. power walking, striding) are commenced and gradually progressed.

Walking on soft sand and agility drills on grass relevant to the patient’s recreational and

sporting interests are introduced. These are initially performed in isolation, and then

with appropriate sport specific equipment, for example a basketball or hockey stick.

At the end of phase 6 patients undergo the final functional assessment with a written

report sent to the orthopaedic specialist prior to appointment date. Collision and high

impact sports, such as football, rugby and basketball should not be commenced until the

18 month post surgery time point.

60


Outcomes: By one year post surgery patients are expected to achieve the following:

1. Able to perform all activities of daily living;

2. Able to commence return to running program, for example: walk/jog,

jog/run, run on soft surface (grass or soft sand only); and

3. Resume dynamic recreational activities. However, sports with high

knee loading and twisting or shear forces are to be avoided.

Please note that all sport and recreational activities involve an element of risk regardless of knee condition and patients should make a value judgement regarding their personal safety prior to participation.

61


EXERCISE PROGRESSION SUMMARY WEEK ACTIVITY % BW Crutches Brace

1-3 • Clinic: Assess - wound healing; - level of oedema; - quadriceps control; - AROM (knee flexion/extension). Strength - Staggered introduction of Phase 1 exercises. • Hydro: Working at depth of xiphoid process, begin Phase 1 exercises. • Review inpatient exercise’s and teach home exercise program. • Ice, elevation, compression, ultrasound, interferential and clearance massage as appropriate.

Toe

touch pressure ≤20%

2

4 As above and begin: • Clinic: Strength - Introduce Phase 2 exercises. • Hydro: Introduce Phase 2 exercises.

30%

2

5 As above

40% 2

6 As above Commence supervised one crutch walking in clinic

50% 2

7 As above and begin: • Clinic: Strength – Introduce Phase 3 progressions and

commence Phase 3 exercises. • Hydro: Begin working at the level of the umbilicus,

introduce Phase 3 progressions. •

60%

1

indoors 2

outdoors

8 As above 70 - 80% As above

9 As above and begin: • Hydro: Introduce Phase 3 exercises • Clinic: Commence seated cycle ergo, “spider kills”

and static SLR hold with Theraball Proprioception work (seated)

80 - 90%

1 crutch

Outdoors

only

10 As above

90% 1 Outdoors

11 As above and begin: • Clinic: Walking in clinic no crutches

90-100%

0 in

1 out

Outdoors

12 As above 100%

0 in

1 out

Uneven ground

only 13-26 As above and begin:

• Clinic: Commence Phase 4 exercises • Hydro: Commence Phase 4 exercises • Full weight bearing proprioception: Rocker

board / dura disc / wobble board / trampette • Begin walking, cycling and swimming

100%

0

or as required

As

required

27-52 As above and begin: • Power walking on grass, soft sand strides

100%

0

As

required

62


FREQUENTLY ASKED QUESTIONS

1. FOR WHOM IS MACI TREATMENT SUITABLE?

- MACI is indicated for symptomatic full thickness weight-bearing chondral injuries of the articular surfaces of the femoral condyles, trochlea groove, patella and talar dome in physiologically young patients. The procedure is designed for the treatment of symptomatic unipolar lesions. Defects that are grades 3 or 4 on the Outerbridge classification of chondral injuries and have no greater that grade 1 to 2 changes on the opposing surface are amenable to treatment using MACI.

2. WHAT ARE THE PATIENT SELECTION GUIDELINES?

- Patients are selected along the following guidelines based on the Swedish clinical experiences of Lars Peterson, the pioneer of ACI technology:

• Defect location: medial or lateral femoral condyle, trochlea, patella (single lesions only);

• Size and depth: <10cm2 down to intact subchondral bone plate;

• Aetiology: trauma or osteochondritis dissecans;

• Age: 15 – 55 years;

• Joint condition: absence of progressive inflammatory or osteoarthritis;

• Joint stability: absence of menisectomy or instability;

• Abnormal weight bearing: absence of significant varus/valgus

abnormality, patella maltracking or obesity > 50% body weight (Metropolitan Life Index); and

• Compliance with rehabilitation: must be able, willing.

3. IF A PATIENT HAS ENDSTAGE OSTEOARTHRITIS AND IS SCHEDULED FOR TOTAL KNEE ARTHROPLASTY, ARE THEY CANDIDATES FOR MACI?

- No. If a patient is scheduled for knee replacement, the joint degeneration has progressed beyond the treatment parameters of MACI.

4. IS MACI SUITABLE TO REPLACE TORN CARTILAGE?

- There are two types of cartilage in the knee, firstly the joint lining and secondly the menisci, which act as shock absorbers between the two joint surfaces. It is the joint lining that is suitable for MACI. The so called “torn cartilage” or meniscus is not suitable for this kind of technique although research is currently being conducted on the development of transplant menisci and this technology will be available in time.

5. IS MACI SUITABLE FOR TREATING RHEUMATOID

ARTHRITIS?

- No. Progressive inflammatory or rheumatoid arthritis would simply continue to erode the area of repair.

63


6. WHY ISN’T MACI RECOMMENDED FOR PEOPLE OVER THE AGE OF 55?

- The chondrocyte cells of older patients do not grow as successfully as those from young patients. In addition, the articular cartilage within the knees of patients over 55 years are usually too damaged for the procedure to be beneficial.

7. IS MACI SUITABLE TO TREAT CARTILAGE DEFECTS IN OTHER JOINTS OF THE BODY?

- Whilst MACI is restricted currently to treatments of defects within the knee, ankle and shoulder joints, the use of MACI for articular cartilage defects in other joints is under investigation.

8. WHEN SHOULD PATIENTS COMMENCE DRIVING FOLLOWING SURGERY?

- Approval needs to be obtained from the operating surgeon; however, it has been our experience that patients are usually are given clearance to recommence driving approximately 4/6 weeks following implantation.

9. WHEN SHOULD PATIENTS RETURN TO WORK FOLLOWING SURGERY?

- Upon clearance from the operating surgeon, but timing also depends on the demands of the job. For example, it has been our experience that patients can return to desk jobs after three weeks.

10. WHAT IS THE LENGTH OF HOSPITAL STAY FOLLOWING IMPLANTATION?

- This depends on the extent of the surgery and whether there are any post surgery complications. Most patients are generally are eligible for discharge after three to four days.

11. SHOULD PATIENTS CONTINUE TO TAKE ANTI-INFLAMMATORY MEDICATION FOLLOWING MACI?

- This is not recommended, but check with the operating surgeon.

12. ARE CARTILAGE SUPPLEMENTS SUCH AS GLUCOSAMINE AND CHONDROTIN SULPHATE BENEFICAL PRIOR TO AND FOLLOWING MACI?

- The benefits have yet to be proven, however, patients may take these supplements if the operating surgeon agrees.

13. WHAT HAPPENS TO THE TYPE I/III COLLAGEN MEMBRANE FOLLOWING IMPLANTATION?

- Animal studies conducted by the School of Surgery and Pathology, UWA, indicate that the type I/III collagen membrane used in the MACI procedure degrades over time. It was discovered that in the mouse model 50% of the implanted membranes had completely disappeared 21 days following implantation. According to Associate Professor Ming-Hao Zheng from the School of Surgery and Pathology, UWA, the extent of degeneration of the collagen membrane depends on the degree of cross linking of the collagens and the elastin content. In humans the degradation of the membrane is thought to be complete by the six months postsurgery.

64


14. WHEN SHOULD PATIENTS RECOMMENCE HIGH IMPACT SPORT AND RECREATION ACTIVITIES?

- Approval needs to be obtained from the operating surgeon, however, it has been our experience that return to heavy manual work, sport and recreational activities should be carefully controlled and gradually progressed. Although the cartilage defect may be filled with hyaline-like cartilage within the first few months, it is not advisable to undertake resisted knee extension or activities, such as squats or running before 12 months post-surgery. Maturation and hardening of the new-formed cartilage will not be complete until this time.

65


RETURN TO ELITE LEVEL COMPETITION

There exists great individual variation between patients (including age, defect size, defect location and type of auxiliary procedure performed in conjunction with MACI) that must be taken into consideration whilst considering a player’s long term outcome and ability to return to competition at an elite level. It is our experience that patients accrue the full functional benefits from MACI between the first and second year following surgery. Cartilage implantation is not a quick-fix procedure, but a highly specialised and involved biological regeneration process. Cellular regeneration, matrix production and adaptation of the regenerating tissue to natural function, takes time and it is unrealistic and impractical to expect players to return to elite competition within the first postoperative year. We advise that patients suffering from an isolated, well contained defect on the medial femoral condyle should be given the benefit of the doubt and recommence playing after an appropriately managed rehabilitation program of sufficient intensity and duration. The long term prognosis of this patient sub-group is excellent and it is reasonable to expect that they will be able to return to elite competition. The elite level playing potential of patients that suffer from defects on the lateral femoral condyle, patella, trochlea groove or from multiple defects and those that have undergone MACI in conjunction with a ligamentous reconstruction or have meniscal damage, is uncertain and should be evaluated using the following criteria:

• Overall value of the patient as a player; • Have undergone clinical assessment with an orthopaedic surgeon appropriately

experienced with the results of MACI; and • The commitment and psychological profile of the player.

66


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following 20km daily running exercise for 15 weeks. Connect Tissue Res. 1994; 30(3):191-201.

16. Burton-Wurster N, Vernier-Singer M, Farquhar T, Lust G. Effect of compressive loading and unloading on the total protein, proteoglycan, and fibronectin by canine cartilage explants. J Orthop Res 1993; 717-729.

17. Fitzgerald JB, Jin M, Dean D, Wood DJ, Zheng MH and Grodzinsky AJ. Mechanical compression of cartilage explants induces multiple time- dependent gene expression patterns and involves intracellular calcium and cyclic AMP. J Biol Chem 2004; 7: 279(19):19502-19511.

18. Sah RL, Kim YL, Doong J-YH, Grodzinsky AJ, Plaas AHK and Sandy JD. Biosynthetic response of cartilage explants to dynamic compression. J Orthop Res 1989; 7:619-636.

19. Sah RL, Kim YL, Grodzinsky AJ, Plaas AHK and Sandy JD. Effects of static and dynamic compression on cartilage metabolism in cartilage explants. In: Kuettner KE, Peyron JG, Schleyerbach R, Hascall VC., Eds Articular Cartilage and Osteoarthritis 1992, New York, Raven Press:373-392.

20. Torzilli PA, Grigiene R, Huang C, Friedman SE, Doty SB, Boskey AL and Lust G. Characterization of cartilage metabolic response to static and dynamic stress using a mechanical explant system. J Biomech 1997; 30:1-9.

21. Waldman SD, Spiteri CG, Grynpas MD, Pilliar RM, Hong J, Kandel RA. Effect of biomechanical conditioning on cartilaginous tissue formation in vitro. J Bone Joint Surg [Am] 2003; 85-A(2):101-105.

22. Gray ML, Pizzanelli AM, Grodzinzky AJ and Lee RC. Mechanical and physiochemical determinants of the chondrocyte biosynthetic response. J Orthop Res 1998; 6:777-792.

23. Urban JPG and Hall AC. The effects of hydrostatic and osmotic pressures on chondrocyte metabolism. In: Mow VC, Guilak F, Tran-Son-Tray R, Hochmuth RM., Eds., Cell Mechanics and Cellular Engineering 1994, New York, Springer-Verlag: 398-419.

24. Urban JPG, Hall AC and Gehl KA. Regulation of matrix synthesis rates by the ionic and osmotic environment of articular chondrocytes. J Cell Phys 1993; 154:262-270.

25. Gooch KJ, Blunk T, Courter DL, Sieminski AL, Bursac PM, Vunjuk-Novakovic G and Freed LE. IGF-1 and mechanical environment interact to modulate engineered cartilage development. Biochem Biophys Res Commun. 2001; 286(5):909-915.

26. Martin I, Obradovic B, Treppo S, Grodzinsky AJ, Langer R, Freed LE and Vunjak-Novakovic G. Modulation of the mechanical properties of tissue engineered cartilage. Biorheology 2000; 37(1-2):141-147.

27. Vunjak-Novakovic G, Obradovic B, Martin I, Bursac PM, Langer R and Freed LE. Dynamic cell seeding of polymer scaffolds for cartilage tissue engineering. Biotechnol Prog 1998; 14:193-202.

28. Rodrigo JJ, Steadman RJ, Silliman JF, Fullstone HA. Improvement of full-thickness chondral defect healing in the human knee after debridement and microfracture using continuous passive motion. Am J Knee Surg 1994; 7:109-116.

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29. Salter RB, Simmonds DF, Malcolm BW, Rumble EJ, MacMichael D and Clements ND. The biological effect of continuous passive motion on the healing of full-thickness defects in articular cartilage: an experimental investigation in the rabbit. J Bone Joint Surg [Am] 1980; 62:1232-1251.

30. Rejeski J, Ettinger W, Shumaker S, Heuser M, James P, Monu J and Burns R. The evaluation of pain in patients with knee osteoarthritis: The Knee Pain Scale. The Journal of Rheumatology 1995; 22(6):1124-1129.

31. Roos E, Roos H, Lohmander L, Ekdahl C and Beynnon B. Knee Injury and Osteoarthritis Outcome Score (KOOS) – Development of a Self-Administered Outcome Measure. JOPST 1998; 78(2):88-96.

32. ATS statement: guidelines for the six-minute walk test. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. Am J Respir Crit Care Med.

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MACI KNEE: Appendix APATIENT ASSESSMENT FORM

Date of Referral: ______________ Date of Initial Assessment: _______________

Name Date of Birth

Address Phone No:

(Wk) (Mb)

GP Other Referring Specialist Insurance Company or Health Fund Address & Contact

Claim/Ref No Phone No Fax No

Approval Fax : Date Sent / / Date Approved: / /

1. DESCRIPTION OF CLIENTS CONDITION AT PRESENTATION: Date of Injury/Surgery: ____/____/____ 2. MEDICAL HISTORY 3. GENERAL HEALTH / OTHER HEALTH PROBLEMS: (CHD, Diabetes, Asthma, other

joints) 4. MEDICATION

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5. LOCATION AND LEVEL OF PAIN (0-10 SCALE)

Notes:

RR L L

71


1. PAIN FREQUENCY Using the following scale,

5 4 3 2 1

always almost always sometimes almost never never

Please indicate HOW OFTEN in the past week you have experienced pain in your knee (by placing the

corresponding number in the space provided) when you:

L R a. got in or out of bed

b. walked on level ground

c. got into or out of a chair

d. walked up stairs or an incline

e. got in or out of a car

f. walked down stairs or a decline

2. PAIN SEVERITY Using the following scale,

1 2 3 4 5 6

no pain mild

pain

uncomfortable pain distressing

pain

horrible pain excruciating

pain

Please indicate HOW SEVERE the average pain in your knee has been in the past week (by placing the

corresponding number in the space provided) when you:

L R a. got in or out of bed

b. walked on level ground

c. got into or out of a chair

d. walked up stairs or an incline

e. got in or out of a car

f. walked down stairs or a decline

KNEE PAIN SCALE Appendix B(Rejeski, J.et al, 1995).

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KNEE INJURY AND OSTEOARTHRITIS OUTCOME SCORE (Roos, E., et al., 1998).

Appendix C

SUBJECT No: ___________________ TEST : PRE / POST______ DATE:________ Instructions: Please tick ( ) the most appropriate response.

PAIN Never Monthly Weekly Daily Always

1. How often is your knee painful? What degree of pain have you experienced in the last week when…..? None Mild Moderate Severe Extreme 2. Twisting/pivoting on your knee 3. Straightening your knee fully 4. Bending knee fully 5. Walking on a flat surface 6. Going up or down stairs 7. At night while in bed 8. Sitting or lying 9. Standing upright

SYMPTOMS None Mild Moderate Severe Extreme 1. How severe is your stiffness after first

waking in the morning? 2. How severe is your stiffness after

sitting, lying or resting later in the day?

3. Do you have swelling in your knee? 4. Do you feel grinding, hear clicking, or

any other type of noise when your knee moves?

5. Does your knee catch or hang up when moving?

6. Do you have any difficulty

straightening your knee fully? 7. Do you have any difficulty bending your knee fully?

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74

ACTIVITIES OF DAILY LIVING

What degree of difficulty (not pain) have you experienced in the last week….? None Mild Moderate Severe Extreme 1. Descending stairs 2 Ascending stairs 3 Rising from sitting 4 Standing 5 Bending to floor/pick up object 6 Walking on flat surface 7 Getting in/ out of car 8 Going shopping 9 Putting on socks/ stockings 10 Rising from bed 11 Taking off socks/ stockings 12 Lying in bed (turning over maintaining

knee position)

13 Getting in/out of bath or shower 14 Sitting 15 Getting on/ off toilet 16 Heavy domestic duties (shoveling,

scrubbing floors etc.)

17 Light domestic duties (cooking, dusting)

SPORT AND RECREATION FUNCTION

What difficulty have you experienced in the last week ….? None Mild Moderate Severe Extreme 1. Running 2. Jumping 3. Turning/Twisting on you injured knee 4. Kneeling 5. Squatting


KNEE-RELATED QUALITY OF LIFE Never Monthly Weekly Daily Always

1. How often are you aware of your knee problems?

Not at all Mildly Moderately Severely Totally

2. Have you modified your lifestyle to avoid potentially damaging activities to your knee?

3. How troubled are you with lack of

confidence in your knee?

None Mild Moderate Severe Extreme 4. In general, how much difficulty do

you have with your knee?

------------------------------------------------------------------------------------------------------------------------ Official Use Only ---------------------------------------------------------------------------------------------------------- Score all items from 0 = Best 4= Worst Scale Possible Raw Actual Transformed

Score Range Raw Score Score 0-100 Pain 36 Symptoms 28 ADL 68 Sport/Rec 20 QOL 16 Transformed scale = 100 – Actual raw score x 100 Possible raw score range ----------------------------------------------------------------------------------------------------------

75


CCLLIINNIICCAALL RREEVVIIEEWW FFOORRMM

Patient category: A. Unilateral B. Unilateral with other knee symptomatic C. Bilateral D. Multiple joint involvement or medical infirmity Patient Details: Pt No: DOB: Name: Height: Tester’s Name: Weight: Assessment (circle & date) Pre-op: Date: Blood Pressure: Post-op: Date: Knee: L / R

Left Leg Right Leg AROM Knee

(Degrees) AROM Knee

(Degrees) 1. 1. 2. 2. 3. 3.

Keylink Isokinetic Knee Machine (Newton Meters)

Keylink Isokinetic Knee Machine (Newton Meters)

Extn 1. Flex 1. Extn 1. Flex 1. Extn 2. Flex 2. Extn 2. Flex 2. Extn 3. Flex 3. Extn 3. Flex 3.

3RM SLR Test (kg) 3RM SLR Test (kg) 1. 1.

THIGH GIRTH (cm) (Mid Thigh)

THIGH GIRTH (cm) (Mid Thigh)

1. 1.

Six-minute Walk Test (m) Crutches Brace

Total: Tally:

MACI KNEE: Appendix DCLINICAL REVIEW FORM

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MACI KNEE: Appendix E PRE SURGERY PROGRAM STRUCTURE

1. Warm-Up /Cardiovascular training (5 –10 minutes)

a. Use most appropriate ergometer :

- Cycle ergometer;

- Row ergometer; or

- Arm ergometer.

b. Time: begin with 5 minutes

- 2 minutes easy;

- 1 minute up tempo; and

- 2 minutes easy.

c. Build up to 10-15 minutes :

- Always start with 2 minutes of easy rhythmical work;

- Alternate 30sec to 1 minute hard / 30 sec to 1 minute easy; and

- Always finish with 2 minutes of easy rhythmical work.

2. Stretching/flexibility Routine

a. Hold each stretch for 20 seconds repeat x 3.

3. Strength Circuit

a. Ensure patient performs abdominal bracing.

b. Build up to 3 sets of 10 reps before increasing resistance.

4. Crutch Walking Practice (5 minutes)

a. Patient to practice toe-touch ambulation with crutches, protecting affected

limb.

b. Patient to be shown how to negotiate stairs and obstacles (good leg to

“heaven, bad to “hell”).

5. Cardiovascular training and/or Cool Down (5-10 minutes)

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MACI KNEE: Appendix F

PRE SURGERY CLINIC & HOME FLEXIBILITY PROGRAM

FLEXIBILITY

1. Lumbar/Gluteal

a. Knee to chest

- Lie on your back with both legs extended;

- Bend one leg and hug the knee as close to your chest as possible;

- Hold for 20 s, then return to the starting position; and

- Repeat with other leg.

2. Hamstring

a. Sitting hamstring stretch

- Sit on the floor with both legs straight in front of you;

- Bend the right knee, and place the sole of the right foot on the inside of the left

thigh;

- Keeping the left knee extended, reach forward and attempt to grasp the toes of

the left foot;

- Look forward, keeping the back straight;

- The stretch should be felt at the back of the thigh, and lower back; and

- Hold the position for 20 s, and repeat on the opposite side.

b. Half sitting hamstring stretch

- Sit on the edge of a bed, in a long seated position (right leg and buttock in

contact with the bed, and left leg supporting your weight on the floor);

- Keeping the right knee extended, reach forward and attempt to grasp the toes

of the right foot;


- The stretch should be felt at the back of the thigh, and lower back; and

- Hold the position for 20 s, and repeat on the opposite side.

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3. Quadriceps

a. Quadriceps stretch in side lying

- Lie on your right side on the floor or bed;

- Keeping your thighs parallel, bend your left knee back until you can grasp it

- with your left hand, gently pull the left foot toward the left buttock to increase the intensity of the stretch;

- The stretch should be felt at the front of the thigh;

- Hold the final position for 20 s, slowly straighten the knee and repeat on the opposite side.

b. Assisted quadriceps stretch

- Begin in a standing position within arms length of a wall;

- With a low chair behind you slowly bend the right knee, until it rests on the

chair;

- Keep the body straight, the stretch should be felt at the front of the thigh;

- Use the wall to assist with balance if necessary;

- Hold the final position for 20 seconds, slowly straighten the knee and repeat

on the opposite side.

c. Standing quadriceps stretch

- Begin in a standing position, with feet shoulder width apart;

- Slowly bend the right knee, and grasp it with the right hand;

- Pull the heel towards the buttocks, the stretch should be felt at the front of

the thigh;

- Use a chair to assist with balance if necessary, hold the final position for 20

seconds;

- Slowly straighten the knee and repeat on the opposite side.

4. Hip Flexors

a. Hip Flexor stretch

- Begin by kneeling on the right knee, which is placed as far back as

comfortable;

- The foot of the left leg should be well in front of the right knee;

79


- Support the remainder of the body’s weight on the left leg;

- Place the right hand on your right buttock, directly behind the right hip;

- Use the right hand to push the right hip forwards as far as comfortable;

- Holding this position, bend the left knee and arch the back slightly to allow

your body weight to push down and stretch the front of the right hip;

- Hold for 20 seconds and return to the starting position;

- Repeat on the opposite side.

5. Groin

a. Adductor stretch

- Sit on the floor;

- Place the heels together and pull the feet towards the groin;

- Use the elbows to help push the thighs towards the floor;


- Hold the final position for 20 s.

6. Calf

a. Gastrocnemius stretch

- Stand close to the wall;

- Extend one leg behind you keeping the knee straight, and slightly flex the

front knee;

- Keeping the heels on the floor, lean into the wall, focusing on stretching the

upper calf of the rear leg;

- Hold the final position for 20 s and repeat on the opposite side.

b. Soleus stretch

- Stand close to the wall;

- Extend one leg behind you keeping the knee straight, and slightly flex the

front knee;

- With both feet facing forward transfer your weight onto the rear leg and bend that knee;

- Focus on stretching the lower calf of the rear leg;

- Hold the final position for 20 seconds, repeat on the opposite side.

* Adequate emphasis to be placed on additional stretching that may be deemed necessary to individual patients, to be decided at the therapists’ discretion.

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MACI KNEE: PRE SURGERY CLINIC EXERCISE PROGRAM

Appendix G

STRENGTH

(See Appendix O for description of italicized exercises)

Teach Abdominal Bracing to protect lower back whilst performing strength activities

1. Thigh abductors

a. Seated hip abduction (resistance machine); or

b. Standing abduction (theraband); or

c. Side lying abduction (ankle weights).

2. Thigh adductors

a. Seated hip adduction (resistance machine); or

b. Standing adduction (theraband); or

c. Side lying adduction (ankle weights).

3. Thigh Extensors

a. Standing hip extension (resistance machine);

b. Prone thigh extension (ankle weights);and

- straight leg

- bent knee

c. Isometric gluteal set.

4. Thigh Flexors

a. Standing hip flexion (resistance machine); or

b. Knee raises (ankle weights)

- standing

- seated.

5. Leg Flexors

a. Seated leg flexion (resistance machine);

b. Prone leg flexion (ankle weight);

c. Standing leg flexion (ankle weight).

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6. Leg Extensors (open chain)

a. Supine straight leg raise (ankle weight);

b. Supine 45° straight leg raise (ankle weight);

c. Isometric quadriceps (with muscle stimulation).

7. Foot Plantar Flexors

a. Standing heel raises.

8. Trunk Flexors*

a. Trunk flexion: resistance machine; or

b. Partial sit-up.

9. Shoulder/Arm Flexors and Extensors*

a. Reverse lateral pulldown;

b. Tricep extension (resistance machine); and

c. Bicep curls: free weights.

* Adequate emphasis to be placed on trunk and upper body strengthening and endurance in order to assist with postoperative bed to chair transfers and crutch walking.

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MACI KNEE: Appendix H PRE SURGERY HYDROTHERAPY PROGRAM

(See Appendix N for description of italicized exercises)

Water depth for presurgery patients is dependent on severity of knee pain (eg. intense pain = deeper water).

1. Introductory Activity - WALKING (10 minutes)

Patients cued for improved gait pattern without use of the guard-rail. a. Forwards b. Backwards c. On toes - forwards and backwards d. Side stepping, Left and Right 2. Stretching (5 minutes)

In the standing position, patients use the wall or ladder for active stretching exercises.

a. Hamstring group b. Quadriceps group c. Thigh adductor group d. Thigh flexor group e. Calf (gastrocnemius & soleus)

3. Knee ROM

a. Floatation assisted flexion b. Gentle ROM Lunge

4. Strengthening for Knee, Hip and Ankle

A selection of these exercises are included if the subject has completed a clinic program. Exercises begin in the buoyancy assisted position and progressed to buoyancy resisted exercises (with floats added to the extremity for resistance).

a. Heel raise b. Thigh flexion/extension c. Thigh abduction/adduction d. Diagonals e. Thigh circles

5. Exercise Program in Deep Water

A selection of these exercises are carried out using appropriate floatation equipment.

Vertical position

a. Abduction adduction of legs b. Straight leg flexion/extension

83


MACI KNEE: Appendix IPRE SURGERY HOME EXERCISE PROGRAM GUIDELINES

GENERAL INSTRUCTIONS 1. Remember to exercise within a pain-free/pain tolerant range of motion if possible.

2. Brace abdominal muscles to protect your low back when performing strength

exercises.

3. Flexibility and strength exercises should be performed slowly.

4. If an exercise causes undue pain or discomfort, discontinue that exercise until you

have spoken to your therapist.

5. Monitor your pain/discomfort level both before and after exercise using a 0 to 10

scale.

If your pre-exercise pain level is elevated for 2 hours or more after exercise then you have either done too much, or you have performed the exercise incorrectly. Contact the clinic.

6. Breathe normally when performing the flexibility exercises.

7. Do not hold your breath when performing the strength exercises. Try to breathe

out during the hardest part of the exercise.

9. Complete the exercise log to keep a track of your progress. This is very important.

If you cannot complete the number of sets or repetitions, write down the number you have done. Do not complete more repetitions than advised.

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MACI KNEE: PRE SURGERY HOME EXERCISE PROGRAM

Appendix J

STRENGTH (See Appendix O for description of italicized exercises)

Teach Abdominal Bracing to protect lower back whilst performing strength

activities 1. Thigh abductors a. Side lying abduction (ankle weights) 2. Thigh adductors a. Side lying adduction (ankle weights) 3. Thigh Extensors

a. Prone thigh extension (ankle weights) - straight leg - bent knee

b. Isometric gluteals 4. Thigh Flexors

c. Seated hip flexion (ankle weights) - standing - seated

5. Leg Flexors (open chain)

d. Prone leg flexion (ankle weight) e. Standing leg flexion (ankle weight)

6. Leg Extensors (open chain) a. Straight leg raises (ankle weights) b. 45° straight leg raises (ankle weights) 7. Plantar Flexors a. Standing heel raises

8. Shoulder/Arm Flexors and Extensors

d. Bicep curls: free weights e. Tricep extension: free weights

85


86

Rehabilitative knee braces have been designed to provide a compromise

between protection and motion. That is, they allow the knee to move, but

within specific limits, which has been shown to be beneficial to the injured

knee. Rehabilitative knee braces generally are more effective in protecting

against excessive flexion and extension than in protecting against anterior

and posterior motion. Rehabilitative knee braces aid in the control of

unstable knees. Studies have shown that some of the currently available

braces are very effective in controlling abnormal motions under low load

conditions.

At HFRC we primarily prescribe the OAsys unloading brace

(www.isports.com) for patients that have MACI on the medial or lateral

condyle. However, standard post operative braces that allow the controlled

restoration of knee range of motion are also acceptable. Richards splints are

also a feasible option for the first postoperative week, especially for large

lesions (>8cm2) or for uncontained defects. The issue of brace selection

needs to be addressed in accordance to the preference of the patient’s

orthopaedic surgeon. It has been our experience over the last four years that

when properly fitted, used in conjunction with a graduated knee

rehabilitation program, and with a compliant patient, a rehabilitative knee

brace provides an important adjunct in the post operative treatment of

patients who have undergone MACI surgery.

MACI KNEE: KNEE BRACE RECOMMENDATIONS

Appendix K


Courtesy of HPH Physiotherapy Services (For further information please contact Hollywood Private Hospital, Monash Avenue, NEDLANDS, WA 6009. Ph: (08) 9346 6000)

Orders specified on the operation report override routine protocol. These MUST be documented & read by the therapist prior to treatment

ACI CARTILAGE IMPLANTATION

KNEE ARTHROSCOPY/ MENISECTOMY

Precautions

Must wear brace at all times

Encourage ↓ activity levels 1/52

to allow wound healing

Inpatient Exercise

Day 1-2

1 hour CPM 0-30 ° or as tolerates (Consultant must specify safe range in post-op orders before any

physiotherapy intervention)

Wear Brace while exercising SQ, IRQ, SLR, ROM exercises (outlined in ex handout)

Day 0 or 1

SQ, IRQ, SLR, ROM exercises

(outlined in ex handout)

Ambulation

Day 1 Touch WB (< 20%) with brace on

Practice stairs prior to D/C

Day 0 or 1 mobilise with crutches (if required)

Practice stairs prior to D/C

Rehabilitation Following D/C

Provided with Physiotherapy D/C letter

↑rom flexion aim 60° by 3/52, 90° 6/52, full 12/52 Progressive ↑WB aim one crutch by 8/52

Advised when to safely cease use of crutches Follow-up physiotherapy usually not required

MACI KNEE: INPATIENT PHYSIOTHERAPY PROTOCOL

Appendix L

APPROVED BY: __________________________________ (Orthopaedic Consultant) 07/2002

87


Date of Operation: Name: Unit No: MACI: (use sticker if available) Surgical Approach (tick): Incision Size: cm Medial parapatellar Lateral Defect Details: Mid vastus Defect Size: mm X mm Other Details: Defect Location (please indicate):

Auxiliary Procedures (tick): ACL reconstruction Details: PCL reconstruction Medial ligament reconstruction Lateral ligament reconstruction Oesteotomy Tibial tubicle transfer Menisectomy Other (please specify): Lateral Release: Yes / No Extent of soft tissue release: lateral patellofemoral ligament (please tick) other (please specify) Patella Tracking: Satisfactory / Unsatisfactory Technical Problems? (please specify) Surgery Time mins Tourniquet Time mins Hospital: Surgeon/Doctor: Signature: Date:

S MACI KNEE: Appendix MOPERATIVE PROCEDURE FORM

U

R

G

E

O

N

T

O

C

O

M

P

L

E

T

E 88


MACI KNEE: POST SURGERY HYDROTHERAPY PROGRAM

Appendix N

Post surgery between weeks 2-6: patients must exercise in deep water (xiphoid process to C7 levels).

1. Introductory Activity - WALKING (15 minutes)

Patients cued for improved gait pattern without use of the guard-rail. a. Forwards b. Backwards c. Side stepping, Left and Right 2. Stretching (5 minutes)

In the standing position, patients use the wall or ladder for active stretching exercises. a. Hamstring group* b. Quadriceps group* c. Adductors group* d. Thigh flexor group* e. Calf (gastrocnemius & soleus)*

3. Knee ROM

a. Floatation assisted flexion* b. Gentle ROM lunge* c. Floatation assisted quadriceps stretch*

4. Strengthening for Knee, Hip and Ankle

A selection of these exercises are included if the subject has completed a clinic program.

Exercises begin in the buoyancy assisted position and progressed to buoyancy resisted exercises (with floats added to the extremity for resistance).

a. Thigh abduction/adduction b. Thigh flexion/extension c. Thigh circles d. Heel raise e. Diagonals f. Thigh half “clock”

5. Exercise Program in Deep Water

A selection of these exercises are carried out using appropriate floatation equipment.

Vertical position a. Abduction/adduction of legs

b. Straight leg flexion/extension c. Bicycle/running movements with legs*

Advanced Postsurgery Exercises in the prone position a. Flutter kick * b. Step ups* c. Squats* d. Squat lunge variations*

6. Proprioception Activities Complexity of activities increases from week 9 to week 24 postsurgery

a. Single leg balance – eyes open/closed b. Side step - crossover Left & Right * c. Bouncing, jogging, hopping interspersed with single leg balance *

* Therapist will indicate at which stage the exercise is to be included in program.

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MACI - KNEE


During Phase 1, when full weight bearing on land is contraindicated, partial weight bearing exercises can be commenced in water depth at the level of the

xiphoid process.

Walking - Forwards Time: 5 minutes

Patient walks forward with emphasis on bilateral heel-to-toe motion;

Patients who have difficulty with gait or lack confidence in the water can begin forwards walking at the side of the pool using the guide rail.

Walking - Backwards Time: 5 minutes

Patient walks backwards with emphasis on bilateral toe-to-heel motion;

Patients who have difficulty with gait or lack confidence in the water can begin backwards walking at the side of the pool using the guide rail.

Walking - Sideways Time: 5 minutes

Patient walks sideways with feet in neutral position, placing emphasis on maintaining straight legs;

Patients who have difficulty with gait or lack confidence in the water can begin sideways walking at the side of the pool using the guide rail.

Thigh Abduction/Adduction Sets: Reps:

Patient is stationary, abducts the thigh while weight bearing on non-operated leg and supported by rail. Motion paused for 2 seconds at end and beginning of range.

Emphasis is placed on correct upright posture, with abdominal bracing.

90


MACI - KNEE


Continued…

Thigh Flexion/Extension Sets: Reps:

Patient stands supported by the rail with weight on non-operated leg. Extend thigh of operated leg, return to neutral and follow through to flexion.

Motion is paused for 2 seconds at neutral and the end/beginning of range.


Thigh Circles Sets: Reps:

Patient stands supported by the rail with weight on non-operated leg.

Performs circumduction movement of the thigh of operated leg.

Motion is paused for 2 seconds at end of each full movement. Then circumduct thigh in the opposite direction


Calf Raises Sets: Reps:

Patient stands supported by the rail with weight evenly distributed.

Perform calf raises on flat surface of pool. Motion is paused for 2 seconds at end of range.

Progress to performing calf raises on step.


Diagonals Sets: Reps:

Patient stands supported by the rail with weight on non-operated limb.

Performs a ‘diagonal’ abduction/extension movement through to adduction /flexion of the thigh of the operated limb.

Motion paused for 2 seconds at end and beginning of range.


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MACI - KNEE


COMMENCE: Thigh Half “Clock” Time: 2-5 minutes

Patient is stationary. Perform movements of the thigh whereby the final poses approximate the position of half of the numbers on an analog clock face.

The patient begins by flexing the thigh of the operated limb to “12 o’clock”, and then extends to neutral. This movement is repeated through to “6 o’clock”, with the numbers in between gauging the angle at which motion is to occur.

Movement paused for 2 seconds at end and beginning of range.


Flotation Assisted Flexion Time: 2-5 minutes

Patient is stationary with floatation device attached to the leg. Performs leg flexion, focusing on using the ‘floaty’ to assist the movement. Patient bears weight on non-operated leg and is supported by rail. Motion paused for 2 seconds at beginning and end of range.


Gentle AROM Lunge Time: 2-5 minutes

Patient initially stands stationary supported by rail. The knee of the operated limb is flexed to 90 degrees by placing the foot on a low box or step. The knee must be inline with the ankle. Focus is placed on increasing range of knee movement by slowly moving knee over and beyond the toes. Motion paused for 2 seconds at end of range.


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MACI - KNEE


During Phase 3, when full weight bearing on land is being gradually introduced, weight bearing exercises can be performed in water depth at the level of the

umbilicus. COMMENCE….

Walking - Forwards Time: 5-10 minutes

Patient walks forward with emphasis on bilateral heel-to-toe motion;

Patients who have difficulty with gait or lack confidence in the water can begin forwards walking at the side of the pool using the guide rail.

Walking - Backwards Time: 5-10 minutes

Patient walks backwards with emphasis on bilateral toe-to-heel motion;

Patients who have difficulty with gait or lack confidence in the water can begin backwards walking at the side of the pool using the guide rail.

Walking - Sideways Time: 5-10 minutes

Patient walks sideways with feet in neutral position, placing emphasis on maintaining straight legs;

Patients who have difficulty with gait or lack confidence in the water can begin sideways walking at the side of the pool using the guide rail.

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MACI - KNEE


COMMENCE (Week 8/9): Single Leg Balance Time: 2-5 minutes

Patient is stationary, flexes non-operated thigh so as to be bearing weight on operated leg, then attempts to maintain balance for 10 seconds, assisted by rail (when needed). Emphasis is placed on correct upright posture, with abdominal bracing.

Cycling

Time: 2-5 minutes

The patient moves to the corner of the pool. Facing the inside of the pool, with the arms supported by the rails, the patient lifts the legs off the floor, so that the trunk and lower limb are suspended in the water.

A cycling motion is then initiated with the legs. Emphasis is placed on improving knee and hip ROM and muscular coordination.

Thigh Abduction/Adduction

Time: 2-5 minutes

The patient moves to the corner of the pool. Facing the inside of the pool, with the arms supported by the rails, the patient lifts the legs off the floor, so that the trunk and lower limb are suspended in the water.

While maintaining knee extension, the patient abducts the thighs to their end of range, and then adducts them to neutral. Motion paused for 2 seconds at end of range.

This movement is then repeated for the desired time.

Thigh “Scissors”

Time: 2-5 minutes

The patient moves to the corner of the pool. Facing the inside of the pool, with the arms supported by the rails, the patient lifts the legs off the floor, so that the trunk and lower limb are suspended in the water. While maintaining knee extension, the patient performs a “scissor-like” movement of the legs by reciprocally flexing and extending the thighs.

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COMMENCE (5th month): Forwards Step-up Sets: Reps:

Patient stands facing the step. Proceeds to step up straight ahead with the operated leg. Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.

Retro Step-Up Sets: Reps:

Patient stands with back to step. Steps up backwards with the operated leg.

Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.

Lateral Step-up Sets: Reps:

Patient stands with operated side parallel the steps. Proceeds to step up side ways. Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.

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Continued …

Squats Sets: Reps:

Patient moves to the termination point of the entry rails to the pool. Using the rails on either side as support, the patient performs a squat movement. The trunk and back should be kept straight, with the gaze directed forward. The body is lowered by flexing the thighs and hips, until leg flexion reaches 90 degrees. The knees and thighs are then extended and the body is elevated to neutral.

Squat Lunge Variations

Sets:

Reps:

Patient stands stationary. Performs a standard lunge, followed by lunges in various directions (ie. to the side and diagonal lunges). Emphasis is placed on correct upright posture, with abdominal bracing.

“Patter” Kick Time: 2 minutes

With the aid of a floatation device, the patient executes a kicking action sufficient to maintain motion across the pool. Emphasis is placed on keeping the body horizontal.

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HFRC, UWA & Verigen Australia’s MACI Rehabilitation Protocols © 2003

MACI KNEE: CLINIC & HOME BASED EXERCISE PROGRAM

Appendix O

Phase 1: 1 to 3 weeks post surgery Static Quadriceps Sets: Reps:

Focus on quadriceps, actively contract musculature.

Hold for 5 seconds then release.

To accentuate vastus medialis, turn foot laterally 45°.

Co-contraction Sets: Reps:

Initiate hamstrings contraction, focusing on pushing heel into bed.

Subsequently, actively contract quadriceps.

Focus on maintaining both hamstring and quadricep contraction concomitantly.

Hold for 5 seconds, then release.

Passive Leg Extension – Straight Leg: Time: 5-10 minutes

A small sized roller is placed proximal to the ankle joint.

Focus on relaxing the lower limbs, as the now elevated leg passively extends the knee joint.

AROM – Leg Flexion (Plastic Bag): Time: 5-10 minutes

Tie a plastic bag around foot of operated limb.

Actively slide your heel towards your bottom until you feel the knee become “tight” (do NOT push your knee into pain).

Slowly slide your leg flat and repeat.

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Continued…

Prone Thigh Extension Sets: Reps:

Lie on your stomach.

Lift the operated leg from the bed, and hold the position for 2 seconds, then lower slowly.

Focus on maintaining knee extension, and correct orientation of the pelvis (ASISs remain aligned, flat against bed).

Straight Leg Raise Sets: Reps:

Bend knee of non-affected side to flatten lumbar spine.

Lock knee of affected side and lift leg to a height parallel to the bent knee.

Lower leg under control.

Thigh Abduction Sets: Reps:

Lie on non-affected side.

Support affected side on a roll or pillow (if necessary).

With leg straight lift thigh vertically.

Hold at top of lift for 2 seconds, and then lower slowly.

Thigh Adduction Sets: Reps:

Lie on affected side.

Place non-affected leg over and in front of affected side.

With affected leg straight, lift thigh vertically.

Hold at top of lift for 2 seconds, and then lower slowly.

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Continued…

Isometric Glutei Squeeze Sets: Reps:

Lie on your stomach.

Isolate the gluteals by actively pressing the ‘cheeks’ of the gluteals together.

Hold the contraction for 3 seconds, and then relax.

Isometric Thigh Adduction Sets: Reps: Lie on your back.

Bend both knees and place your feet flat on the bed.

Place a pillow between your knees, and squeeze the pillow by pushing both knees together.

Hold the contraction for 3 seconds, and then relax.

Seated Thigh Flexion Sets: Reps:

Begin in a sitting position, with the hips and knees flexed to 90 degrees and the feet flat on the floor.

Lift the thigh of the operated leg from the chair, and hold the position for 2 seconds.

Lower the leg under control.

Seated Calf Raise Sets: Reps:

Begin in a sitting position, with the hips and knees flexed to 90 degrees and the feet flat on the floor.

Lift the heels by contracting the calves, while the toes remain in contact with the floor.

Hold the position for 2 seconds.

Lower the leg under control.

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COMMENCE:

Arm Ergometry Time: Load:

Sit on the arm ergometer with the feet on the foot rests.

By gripping the handles, and performing a cycling motion with the arms, maintaining the set work load.

The emphasis is on cardiovascular fitness and endurance.

Thigh Adduction Sets: Reps: Load:

Sit on the machine, placing the feet in the foot rests, with the thighs pressing against the thigh pads. Grip the handles of the machine. While exhaling, pull the legs in together until they touch. Hold this position for 2 seconds before returning to the start position. Inhale as you return to the start position.

Thigh Abduction Sets: Reps: Load:

Sit on the machine, placing the feet in the foot rests, with the thighs pressing against the thigh pads. Grip the handles of the machine. While exhaling, push the legs apart as far as they can go. Hold this position for 2 seconds before returning to the start position. Inhale as you return to the start position.

Seated Leg Curls Sets: Reps: Load:

Sit on the leg flexion machine with your legs straight, and your ankles resting on the roller pad.

Lower the leg restraint over your thighs to secure them.

Grasp the handles provided on each side. Exhale as you bend your knees to move the roller pad downwards.

Inhale as you return to the starting position.

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PROGRESSIONS: Supine to ¼ Seated Leg Raise Sets: Reps:

Rest upon elbows in ¼ seated position.


Lock knee of affected side and lift leg to a height parallel to the thigh of the bent knee.


45° Side Leg Raises Sets: Reps:


Lock knee of affected side, and externally rotate the thigh by pointing the toes outwards 45 degrees.

Lift leg to a height just below the opposite the bent knee,


Seated Leg Curls (single leg) Sets: Reps: Load:

Sit on the leg flexion machine with your legs straight, and your ankles resting on the roller pad.

Lower the leg restraint over your thighs to secure them.

Grasp the handles provided on each side. Exhale as you bend the knee of the operated limb (whilst keeping the non-affected leg extended) to move the roller pad downwards.


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Phase 3: 7 to 12 weeks post surgery COMMENCE (Week 7): Thigh Extension Sets: Reps: Load:

Grasp handles of machine and place foot of non-operated limb in the centre of the footplate.

Place operated leg over the thigh pad so that it is positioned halfway between the knee joint and the hip.

Bending forward slightly, exhale and move your thigh backwards until your hip is fully extended.

Hold this position for 2 seconds before returning to the start position. Inhale as you return to the start position.

Thigh Flexion Sets: Reps: Load:

Grasp handles of machine and place foot of non-operated limb in the centre of the footplate.

Place operated leg behind of the thigh pad so that it is positioned halfway between the knee joint and the hip.

Bending forward slightly, exhale and move your thigh forwards until your hip is flexed to 90°.


Standing Calf Raises Sets: Reps:

Standing with your weight evenly distributed.

Place your toes and ball of your feet on step.

Rise up as high as you can on your toes (plantar flexion), keeping your knees extended or very slightly bent.


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COMMENCE (Week 9/10): Modified Cycle Ergometry Time: 5 minutes Load: 0.5-1.0kp/30-60 watts

Sit on the cycle with the feet in the foot straps and the arms on the arm rests.

Perform a cycling motion with the legs, maintaining an appropriate speed.

“Spider Kills” Sets: Reps:

Sit on the edge of a chair with the involved knee flexed to a comfortable position (70 to 90 degrees).

Palpate the vastus medialis

Lift the toes (ankle dorsiflexion) and apply pressure down through the heel.

Simultaneously elicit a quadriceps/hamstring co-contraction by isometrically shifting body weight backwards into chair.


Static SLR Hold with ball Sets: Reps:

Sit on the theraball.

Place the feet flat on the ground with the knees bent.

Straighten the involved knee slowly, focusing on the quadriceps.


Increase intensity by holding position for 10-20 seconds.

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COMMENCE:

Bridging Sets: Reps:

Lie on your back with the knees bent to 90 degrees, feet flat on the floor, and the arms resting by the sides.

With an exhalation, lift the pelvis and trunk from the floor, until the trunk and thighs are aligned.

Hold the position for 3-10 seconds, breathing normally.

Slowly lower the trunk and pelvis to the floor.

Increase difficulty by placing arms across chest.

Bridging with Theraball Sets: Reps:

Lie on your back, and place the heels on the top of the theraball.

Rest the arms by the sides.

With an exhalation, lift the pelvis and trunk from the floor, until the trunk and thighs are aligned.

Hold the position for 3 seconds, breathing normally.

Slowly lower the trunk and pelvis to the floor.

Increase difficulty by placing arms across chest.

Four point Thigh Extension Sets: Reps:

Begin on all fours.

Place the involved knee slightly in front of the opposite knee.

With an exhalation, push the thigh backwards and straighten the knee. Lift the thigh until it becomes parallel with the trunk.


Inhale as you return to the starting position

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Continued…. Inner Range Quads Sets: Reps: Load:

Stand facing the wall, with the involved knee slightly bent, and the tubing just above the knee.

Allow the tubing to act as resistance, and gently pull the knee back straight.


Return to the starting position.

Cycle Ergometry Time: 10 minutes Load: 1.0-2.0kp/50-100 watts

Sit on the cycle with the feet in the foot straps and the arms on the arm rests.

Perform a cycling motion with the legs, maintaining an appropriate speed.

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COMMENCE:

Wall Assisted Squat Sets: Reps:

Stand with the back against wall, and the heels placed about a thighs length from the wall. Using the wall as support, slowly lower the trunk until the thighs are parallel to the floor. Hold the position for 3 seconds

Tighten the thigh muscles as you return to the starting position.

Increase intensity by holding end position for 10 – 20 seconds.

Leg Extension - Single Legged Sets: Reps:

Sit on a chair, with your hips and knees both flexed to 90 degrees.

Slowly extend the involved knee, until it is completely straight.

The thigh should remain stationary, and only movement of the lower leg observed.

Hold the position for 2 seconds before returning to the start position.

Increase intensity by holding end position for 10 - 60 seconds. Isometric Wall Press with Theraball – Both Legs

Sets:

Reps:

Lie on your back with your feet against a wall. Place a theraball between your feet and the wall, and position yourself so your thighs and knees are flexed to 90 degrees. With an exhalation, push your feet firmly into the ball. Hold the position for 3 seconds and then relax.

Increase intensity by holding end position for 10 – 20 seconds.

WITH DUE CAUTION !

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Continued…. Isometric Wall Press with theraball – Single Legged

Sets:

Reps:

Lie on your back with your feet against a wall. Place a thereball between your feet and the wall, and position yourself so your thighs and knees are flexed to 90 degrees. Remove the uninvolved foot from the ball, and then straighten that leg and rest it on the floor, so that the ball is held with the other foot. With an exhalation, push your foot firmly into the ball. Hold the position for 3 seconds and then relax. Increase intensity by holding end position for 10 – 20 seconds.

Terminal leg extension Sets: Reps: Load:

Lie on your back on the bed.

With your knee bent over a bolster, straighten the knee by actively tightening the quadriceps.

Be sure to keep the bottom of the knee on the bolster,

Hold the position for 2 seconds, and then lower to starting position.

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Phase 6: 9 months to 1 year post surgery

COMMENCE: (Nb. All exercises to be performed with due caution)

Forwards Step-up Sets: Reps:

Patient stands facing the step (step height = 10-15cm). Proceeds to step up straight ahead with the operated leg. Step down leading with non-operated leg.


Retro Step-up Sets: Reps:

Patient stands with back to step (step height = 10-15cm). Steps up backwards with the operated leg. Step down leading with non-operated leg.


Lateral Step-up Sets: Reps:

Patient stands with operated side parallel to the step (step height = 10-15cm). Proceed to step up side ways. Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.

Squat lunge variations Sets: Reps:

Patient stands stationary. Performs a standard lunge, followed by lunges in various directions (i.e. to the side and diagonal lunges). Emphasis is placed on correct upright posture, with abdominal bracing.

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Phase 6: 9 months to 1 year post surgery Continued….

Seated Leg Press Sets: Reps:

Sit on the leg press machine positioning yourself so your thighs and knees are flexed to 90 degrees with your feet resting on the foot plate about shoulder width apart.

Grasp the handles provided on each side.

Exhale as you push firmly against the foot plate straightening your legs to 5 degrees off full extension.


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MACI KNEE: POST SURGERY PROPRIOCEPTION PROGRAM

Appendix P

1. Partial weight-bearing (Week 9-12)

• Seated with feet on rocker board, Duradisc or wobble board

- Forward/backward rocking with both legs for 2-3 minutes pain-free, - Progress to one leg.

• As above but seated on Theraball.

2. Full weight-bearing (3-6months)

• Standing on rocker board, Duradisc or wobble board (both legs)

- 2-3 minutes CW and CCW - Double leg balance for 15-20 seconds, rest 10-20 seconds, - Single leg balance

• Progressively increase complexity

- arms out in front of body - eyes closed - knee bends - bounce/catch ball

• Balance on mini trampoline (progressions as above)

- gentle bounce, toes remain in contact with trampoline - alternate heel raise in jogging motion, toes remain in contact with trampoline - side stepping Left & Right

3. Advanced Exercises and Proprioception Activities (9-12 months)

• Bounce / jog on mini trampoline with increased leg lift.

- with one-quarter turn and return - progress to half turn - increase time of jogging

• Walking on soft sand

• Power walking on grass

• Power walk on grass leading to

- Light jog forwards, backs wards, sidestep - Light jogging with change of direction (45º angle or in/out/around cones)

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PRESURGERY POSTSURGERY

TESTS Pre- 8wks Pre-1 wk 3 mo 6 mo Annually

Medical History

-

-

-

-

Quality of Life

KOOS

KPS

Anthropometric Tests

Stretch stature

Body Mass

Resting blood pressure

-

-

-

-

ROM

Knee flexion

Knee extension

Girths

Bi-lateral thigh

Isokinetic Strength

Leg flexion

Leg extension

-

-

-

-

Strength

3RM SLR

Appendix QMACI KNEE: SCHEDULE OF TESTING

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Functional Tests

6-min walk

Report to Surgeon

-

MRI

-

-

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CHAPTER FOUR

MRI AND CLINICAL EVALUATION OF COLLAGEN-COVERED AUTOLOGOUS CHONDROCYTE IMPLANTATION (CACI)

AT TWO YEARS Note 1. References cited in this chapter appear in a reference list at the end of the

chapter. Note 2. Tables and figures noted within this chapter appear at the end of the

chapter.

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Title: MRI and clinical evaluation of collagen-covered autologous chondrocyte implantation (CACI) at two years.

Keywords: Osteochondral defect, Autologous chondrocyte implantation, Correlation of outcome and MRI.

1.) W.B. Robertson MSc* ** PhD Student University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA

2.) D. Fick MBBS* PhD Student University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA

3.) D.J. Wood BSc. MBBS MS FRCS FRACS*. Professor University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA

4.) J.M. Linklater FRANZCR Musculoskeletal Radiologist Castlereagh Sports Imaging North Sydney Orthopaedic and Sports Medicine Centre 286 Pacific Hwy, CROWS NEST NSW 2065 AUSTRALIA

5.) M.H. Zheng DM., PhD., FRCPath* Professor University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA

6.) T.R. Ackland PhD FASMF**. Professor University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA

* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Nedlands, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Nedlands, WA 6009 Australia. Correspondence: Mr William Brett Robertson University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]

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mailto:[email protected]

ABSTRACT We present our experience with the collagen covered autologous chondrocyte implantation (CACI) technique. Thirty two implantations were performed in thirty one patients. Clinical outcome was measured using the KOOS score and the 6-minute walk test, as well as an MRI scoring protocol (75% of patients had a complete data set for MRI follow-up) to describe the repair tissue generated by CACI. We have also correlated our MRI results with our clinical outcome. To the authors knowledge there are no comparative studies of MRI and clinical outcome following CACI in the current literature.

Patients demonstrated an increased walk distance that improved significantly from 3 months to 24 months postoperatively (p<0.05). Analysis of the KOOS results demonstrated a significant (p<0.05) improvement in four of the five subscales from 3 months to 24 months after CACI, with the most substantial gains made in the first 12 months. Patients demonstrated an increased MRI outcome score over time that improved significantly from 3 months to 24 months postoperatively (p<0.05). We observed an 8% incidence of hypertrophic growth following CACI. We report one partial graft failure, defined by clinical, MRI and histological evaluation, at the one year time point. In contrast to the current literature we report no incidence of manipulation under anesthesia (MUA) following CACI.

This research demonstrates that autologous chondrocytes implanted under a type I/III collagen patch regenerates a functional infill material, and as a result of this procedure, patients experienced improved knee function and MRI scores. Whilst our results indicated a significant relationship between the MRI and functional outcome following CACI, MRI cannot be used as surrogate measure of functional outcome following CACI, since the degree of association was only low to moderate. That is, functional outcome following CACI cannot be predicted by the morphological MRI assessment of the repair tissue at the post surgery time points to 24 months.

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INTRODUCTION

The concept of autologous chondrocyte implantation (ACI) began almost four decades

ago [1], but only recently has the technique become a viable therapeutic option [2-4].

The first evidence supporting ACI came from animal studies by Peterson et al. [2]. This

work led to human trials and subsequently, ACI using periosteal membrane (PACI) has

become a well-established technique for the treatment of articular cartilage defects, with

evidence of improved joint function and formation of hyaline or hyaline-like cartilage

[5-10]. The PACI has a number of short-comings, namely, the requirement for a large

surgical incision, peripheral graft hypertrophy [11,23], graft delamination [11-13], and

potential ectopic calcification of the periosteal patch [12,14]. Postoperatively, it has

been documented that a clinically significant percentage of patients (20-36%) present

with symptomatic “catching” of the knee joint due to hypertrophic graft edges, leading

to the need for revision arthroscopy [15,16].

Complications associated with the use of periosteum in the ACI procedure have

stimulated the search for an alternative scaffold for the containment of implanted

chondrocytes. According to Geistlich Biomaterials [17], the use of a type I/III collagen

membrane (CACI) instead of periosteum to seal the cartilage defect is a better choice,

and this membrane has been used extensively in dental and maxillofacial surgery since

1980. Recently, several studies have been published evaluating the CACI procedure

[7,16,18-22] by clinical and arthroscopic assessment. Authors of these studies

concluded that CACI produces favorable clinical and histological results [7,18-22],

which are at least comparable to PACI [16]. This paper reports non-invasive MRI in

conjunction with routine clinical assessment to evaluate the outcome of CACI with a

minimum of 2 year follow up. To the authors’ knowledge, this study provides the most

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comprehensive MRI evaluation of CACI to date and is the first to correlate MRI scores

with functional outcome measures following CACI. The study provides novel insight

into the morphological progression of the regenerative tissue produced following CACI

through the use of established MRI evaluation parameters as recommended by the

literature. The results of this study complement the currently available clinical and

histological information on CACI, with MRI assessment of the cartilage repair, a better

understanding of the outcome of ACI with a collagen membrane is afforded.

In the present study, we have evaluated the CACI graft by MRI assessment, as well as

the function of the grafted joint following surgery, in order to establish whether the

CACI procedure may produce a potentially durable repair tissue. We postulate that the

use of the type I/III collagen membrane would address the issue of graft hypertrophy

that is associated with using a periosteal membrane and thus, CACI would provide a

better capacity to facilitate cartilage regeneration compared to historical PACI data.

Furthermore, it is our intention to demonstrate that early mobilization via continuous

passive motion (CPM) following CACI is safe and leads to a lower incidence of

postoperative knee stiffness and subsequent manipulation under anaesthesia (MUA)

than the current practice of immobilization in plaster that is currently advocated in the

literature.

MATERIALS AND METHODS

Sample

Patients were selected according to the inclusion and exclusion criteria guidelines

outlined by Peterson [23]. Patients exhibiting varus or valgus deformities that required

surgical correction (<5°) were excluded from the study. Thirty two CACI surgeries

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were performed in 31 patients between March 1999 and June 2001. Thirty one

implantations survived to a minimum of 24 months, one patient was lost to follow up

after emigrating overseas, and three patients had sporadic data sets as they were poor

attendees to scheduled postoperative follow up.

The mean age at assessment of the clinical outcomes of CACI for focal chondral defects

of the knee was 37.4 years (range: 19-60 years) and mean BMI was 27.3 (range: 19-35).

All had full thickness chondral lesions, with no clinical sign of bi- or tri-compartmental

osteoarthritis as diagnosed by preoperative MRI and confirmed at arthroscopic biopsy

(range: 1.0-10.0 cm2). Of the cohort, two cases presented with bipolar defects; the

remainder had single defects. Aeitology of defects in order of frequency was trauma

(14 cases), idiopathic (12 cases) and osteochondritis dessicans (five cases). The

anatomical distribution of defects was: medial femoral condyle (20 cases), lateral

femoral condyle (two cases), patella (eight cases), and multiple defects (two cases). All

patients recruited in this series had failed prior surgical intervention and underwent

arthroscopic and MRI evaluation prior to CACI surgery. Previous procedures included

arthroscopies (n=24), partial meniscectomy (n=8), cruciate ligament reconstruction

(n=2), extensor realignment (n=2), and other (n=2). Patients were screened for joint

instability (clinically) or malalignment (>0.9 cm lateralization of the tibial tuberosity on

CAT-scan) and if present, were corrected at the time of CACI surgery. Concomitant

surgical procedures included patellar realignment (tibial tubercle transfers (n=6),

performed in accordance with Fulkerson’s principles of extensor mechanism

realignment and Hughston’s surgical technique [24]), lateral retinacular releases (n=6),

vastus medialis corrections (n=2) and two anterior cruciate ligament reconstructions.

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Surgical Technique

All surgery was performed by a single surgeon (DJW) and arthroscopic harvesting of

cartilage was performed as day surgery from the non-weightbearing supracondylar

region. Using a 4 mm concave chisel, a cartilage chip 3-4 mm long was excised (100-

150 mg cartilage), placed into nutrient media, and transported to code of good

managing practice (GMP) approved culture laboratories in Denmark (Verigen®,

Denmark Pty Ltd) with approximately 100 mls of autologous serum for cell culture.

Transportation and packaging was undertaken within strict GMP guidelines. Upon

arrival, the biopsy sample was placed in normal saline and digested with clostridial

collagenase and deoxyribonuclease, before filtration through nylon mesh. The cells

were then incubated in sterile flasks containing Ham’s F12 with HEPES buffer and

autologous patient’s serum (10 percent). Cell density (over 5 x 106 cells) was confirmed

three to four weeks later, and cells were transported (within 48 hrs) to theatre within

nutrient media for CACI surgery.

During implantation, defects were curetted to the subchondral bed to remove fibrous

tissue build-up and define vertical defect walls. Care was taken to avoid penetration of

the subchondral lamina as blood has been shown to affect chondrocyte viability [25].

The Chondro-gide® type I/III collagen membrane (Geistlich Biomaterials, Wolhusen,

Switzerland) was then shaped to match defect geometry, secured with interrupted 6.0

mm vicryl sutures at 3-4 mm intervals, before fibrin sealant (Baxter AG, Vienna,

Austria) was applied to the interface (except for a small proximal portal) to ensure a

water tight seal. The chondrocyte suspension was then carefully injected into the defect

through the proximal portal using a 1 ml syringe and 18 g cannula. The injection portal

was then sutured closed and sealed with a final application of fibrin glue. A full range

of motion of the joint was made prior to closure to assure implant stability.

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Rehabilitation

Structured rehabilitation is important to the clinical success of the CACI procedure.

The biological healing and clinical success of the graft is dependent on a controlled and

graduated return to ambulation and physical activity, and the biomechanical stimulation

of the implanted chondrocytes [26,27]. Patients participated in an eight week pre-

surgery exercise program and a 12 week post-surgery rehabilitation program. The post-

surgery program was designed to initially prevent disruption of the implanted collagen

patch (first six weeks following implantation), followed by a graduated loading phase to

give the implanted chondrocytes the necessary stimulus to cause hypertrophy and

adaptation in order to restore their natural function [26,27]. It is advocated that the

postoperative rehabilitation program following ACI be designed in accordance to defect

size, location, age of the patient, concomitant surgical procedures and in accordance to

the diverse variation that exists between patients [26,27]. The generic CACI

rehabilitation protocol was summarized as follows.

Pre-surgery Program

Preparation of patients began eight weeks prior to surgery with the goal of increasing

the muscular strength, cardiovascular fitness, and range of motion (ROM) of the knee

and lower limb. The structured preclinical program involved a twice-weekly exercise

program of 1.5 hours duration that was individually tailored to each patient. Patients

were supervised using variable resistance machines for upper and lower body strength

training as well as an aerobic fitness program. If a patient was unable to participate due

to pain or functional limitation, hydrotherapy (water-based) resistance and aerobic

programs were implemented. Patients were also given exercises to perform at home

several times a week.

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Post-surgery Rehabilitation Program

Following CACI surgery, a coordinated rehabilitation program of progressive exercise

and weight-bearing was implemented with the dual purpose of protecting the graft and

stimulating the healing process. During the early stages of the postoperative recovery

process, the primary goals were to maintain joint stability and muscle tone and to

prevent joint stiffness and excessive muscle atrophy, while adhering to all postoperative

precautions. The immediate postoperative inpatient treatment program included the

following:

1. Appropriate analgesic prescription;

2. Continuous passive motion (0 to 30 degrees) on the operated knee begun 12 to

24 hours after surgery for a minimum of 1 hour daily;

3. Postoperative ROM control brace worn 24 hours per day for three weeks to

protect the repaired cartilage surface;

4. Cryotherapy applied as standard edema control (20 minutes at least three times

daily);

5. Active dorsiflexion and plantar flexion of the ankle to encourage lower

extremity circulation;

6. Isometric contraction of the quadriceps, hamstrings, and gluteal musculature to

maintain muscle tone;

7. Breathing exercises to ensure patient uses the proper breathing technique during

therapy;

8. Proficient toe-touch ambulation allowing only 15-20 percent of body weight

transmission through the limb;

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9. Instructions on how to perform activities of daily living and functional tasks

while adhering to the postoperative precautions and proper weight-bearing

schedule.

The six phases we used in the rehabilitation of the postoperative knee during the first

year are summarized in Table 1. Along with each phase and the associated timeframe,

this table summarizes the milestones patients were expected to reach towards the end of

each phase.

(Table 1)

Patients were gradually returned to weight-bearing activities over several months, and

by postoperative week six, land-based exercises were introduced to strengthen the

stabilizing muscles of the knee. Between postoperative months three and six, full load-

bearing proprioception retraining was begun with the degree of difficulty increased as

tolerated. Between postoperative months six and nine, load-bearing exercises continued

and low impact recreational activities were introduced. In the final three months of the

first postoperative year, patients were gradually allowed to perform functional activities

such as power walking or striding, walking on soft sand, and agility drills on grass.

Outcome Measures

Functional Evaluation

Evaluation of patient function following CACI was conducted postoperatively at three,

six, 12, and 24 months. The ability to walk for distance is a cornerstone of functional

independence and can influence quality of life, as it is a fundamental component of

many activities of daily living. Functional capacity and general gait function were

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determined by the six-minute walk test (6MWT) [28], which was conducted indoors on

a flat, 25m course. This test was first introduced by Lipkin in 1986 [29] and its results

are highly correlated with those of the 12-minute walk test from which it was derived

[30] and with those of cycle ergometer and treadmill based exercise tests [31]. The

6MWT has been demonstrated to be a reliable measure of general gait function and has

been widely used for pre- and postoperative evaluation [32]. Subjects were instructed

to walk as fast as possible, trying to cover the maximum distance without over exerting

themselves. The final score was calculated as the total distance walked to the nearest

1.0 m. Quality of life and functional outcome was determined by the Knee Injury and

Osteoarthritis Outcome Score (KOOS) [33]. The KOOS score assesses pain,

symptoms, activities of daily living, sport and recreation function, and knee-related

quality of life.

Magnetic Resonance Imaging Assessment

Articular cartilage is approximately 70 percent water by weight. The remainder of the


latter contain negative charges that attract sodium ions (Na+) in intact cartilage. MRI is

an accurate and non-invasive imaging modality that can delineate signal and

morphological changes in articular cartilage [34] making it an attractive research tool in

the evaluation of chondrocyte grafting [35-39]. The correlation between MRI outcome

and graft histological outcome has yet to be determined, though recent studies have

attempted to correlate these two outcome measures with mixed results [38,40]. MRI

imaging allows non-invasive serial follow-up of patients postoperatively. It assesses the

entire graft and its integration to the subchondral bone plate and the adjacent native

articular cartilage [39]. In addition, it allows non-invasive detection of postoperative

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complications and its role in the evaluation of cartilage repair is well supported in the

literature [38-41].

MRI in this study was conducted at three, 12 and 24 months postoperatively using a 1.5

Tesla closed unit with an extremity coil (Siemens Vision; Siemens, Erlangen,

Germany). The imaging sequence protocol [41] is outlined in Table 2. A blinded

evaluation was performed by a consultant musculoskeletal radiologist. Intra-observer

reliability assessment was conducted using 20 image pairs in which a significant

(p<0.01) correlation (Spearmans Rank Order Correlation) between samples was

observed (rho=0.787) and no significant difference was recorded between test and retest

images p<0.01.

(Table 2)

The MRI scoring system employed by this study (Table 3) to describe the repair tissue

generated by CACI was based upon the international cartilage repair society (ICRS)

outcome recommendations [42] and closely followed the system reported by Trattnig et

al [43]. Due to regional discrepancies in MRI machines and sequence protocols, the

previously reported scoring system was slightly modified for this study. Each MRI

parameter (defect infill, signal intensity, surface contour, structure, border integration,

subchondral lamina, subchondral bone and effusion) was scored against a series of

sample images, ranked from 1 – “Poor” to 4 – “Excellent” then multiplied by a

weighting factor [43] to obtain the final MRI composite score (Table 3). MRI data was

also assessed in disaggregated fashion by category in accordance to the

recommendations of Marlovits et al. [44,45]. Synovitis was also recorded by the

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musculoskeletal radiologist as compared with prior MRI scans. It was graded in

accordance with the definition given by Marlovits et al. [44].

(Table 3)

Determination of Graft Failure

Graft failure was determined both clinically and radiologically. Clinically graft failure

was defined as the deterioration of the knee condition upon examination, clinical

indicators of failure included the presence of mechanical symptoms such as locking,

catching and/or associated knee joint pain. Radiological graft failure was defined by

evidence of suboptimal defect infill and/or evidence of internal derangement (such as

clefts, fissures, or basal delamination). Grafts that showed clinical and radiological

evidence of failure were referred back to the operating orthopaedic surgeon (DJW) for

patient specific management.

Histological Assessment

Failed grafts requiring revision surgery were biopsied for histological analysis. After

fixation in 4 percent parafenaldchyde, the biopsy was decalcified with 10 percent formic

acid. The biopsy was then dehydrated by a graded series of alcohol and xylene washes

and paraffin-embedded. Sections were cut to 5 µm and stained with haematoxylin and

eosin (H&E) and Alcian Blue (proteoglycan stain).

Statistical Analysis

Data were stored on Microsoft Excel spreadsheets and analyzed using SPSS (version

9.0) for Windows. Four data cells were missing at the three month time point and two

data cells were missing at the 24 month time point (MRI data only). An intention to

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treat analysis was performed using the ‘last value carried forward’ technique, and

changes between assessment time points compared using repeated measures analysis of

variance (ANOVA). Post-hoc analysis was performed using Tukey’s HSD. All

reported p-values were two-tailed and p-values less than 0.05 were considered

significant. Correlation of MRI and functional scores was undertaken using a Spearman

rank order correlation.

RESULTS

Of the 32 patients consecutively treated with CACI, 27 had data to 24 months for

analysis of clinical outcome over time. Of these 27 patients, MRI data were only

available for 24 patients due to different recording format and MRI sequencing of the

first three study patients.

Functional Outcomes of CACI

Statistical analysis of the KOOS subscales indicated that patients experienced a

significant (p<0.05) improvement in knee pain, sports and recreation function, activities

of daily living (ADLs), and knee-related quality of life from presurgery to 24 months

after CACI (Table 4).

(Table 4)

CACI patients demonstrated an increased distance covered in the 6WMT that improved

significantly from pre-surgery to 24 months postoperatively (Table 4). Post-hoc analysis

demonstrated the improvement occurred predominantly in the first 12 months (p<0.05)

and that this improvement was maintained out to the 24 month postoperative time point

(Figure 1).

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(Figure 1)

Post-hoc analysis revealed the improvement of knee pain, sports and recreation

function, and knee-related quality of life occurred predominantly in the first 12 months

following CACI then plateaued, whereas the improvement in ADLs increased linearly

to 24 months (Figure 2). The symptoms subscale of the KOOS score improved

significantly following surgery, then only marginal improvement was experienced

during the rehabilitation phase, but this was not significant (p=0.643).

(Figure 2)

MRI Assessment of CACI

CACI patients demonstrated an increased MRI composite score over time that improved

significantly from three months to 24 months postoperatively (p<0.05). Post-hoc

analysis demonstrated the improvement occurred predominantly in the first 12 months

(Figures 3 and 4).

(Figure 3)

(Figure 4)

Three months following surgery 62 percent (n=15) of the CACI patients exhibited good

to excellent filling of the chondral defect, the remaining 38 percent (n=9) exhibited fair

to poor defect infill. The signal intensity at this time point was described as good to

excellent in 50 percent (n=12) of patients. Good to excellent border integration of

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reparative tissue with adjacent native articular cartilage was evident in 67 percent

(n=16) of patients, with fair to poor integration present in the remaining 33 percent

(n=8) of cases. The surface of the reparative tissue at this stage of recovery was good to

excellent in 83 percent (n=20) of cases with the remaining 17 percent (n=4) exhibiting

fair to poor surface structure. Good to excellent subchondral lamina was evident in 96

percent (n=23) of the patient population (indicative that it was intact at the time of

surgery) and 75 percent (n=18) of the patients exhibited good to excellent resolution of

preoperative subchondral bone edema. Joint effusion was evident in 38 percent (n=9)

of the patients and 58 percent (n=14) exhibited synovitis at the three month

postoperative time point. No graft hypertrophy was reported at the three month

postoperative time point.

Twelve months following CACI good to excellent filling of the defect had increased to

79 percent (n=19) of patients. The signal intensity had increased from 50 percent

(n=12) reported as good to excellent to 71 percent (n=17). Good to excellent border

integration of reparative tissue with adjacent native articular cartilage was seen in 79

percent (n=19) of cases. The surface of the reparative tissue was intact in 83 percent

(n=20) of patients with the remaining 17 percent (n=4) fair to poor surface structure at

the twelve month postoperative time point. Good to excellent restoration of the

subchondral lamina was evident in all patients and 79 percent (n=19) of patients showed

a resolution of subchondral bone edema. Fair to poor effusion remained in 46 percent

(n=11) of the patient population and 58 percent (n=14) of cases had persistent synovitis.

There was one incidence of graft hypertrophy reported at this time point and this patient

was subsequently monitored closely as to ascertain whether further surgical intervention

was necessary.

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By 24 months following CACI surgery defect filling, signal intensity and surface

integrity had achieved a good to excellent rating in 83 percent (n=20) of cases. Effusion

was present in only 25 percent (n=6) of patients and 54 percent (n=13) had persistant

synovitis. A second case exhibited graft hypertrophy at this time point, however,

surgical intervention was not deemed necessary as the patient was asymptomatic and

the hypertropic tissue did not cause any mechanical obstruction to joint function.

Correlation of MRI scores with Functional Outcome

Low to moderate positive correlations between the MRI composite score and the

functional outcome scores were obtained for MRI and 6MWT distance (rho = 0.390,

p<0.01), MRI and KOOS pain (rho = 0.356, p<0.01), MRI and KOOS activities of daily

living (rho = 0.341, p<0.01), MRI and sport and recreation function (rho = 0.509,

p<0.01), MRI and knee related quality of life (rho = 0.246, p<0.01). No significant

correlation was obtained between the MRI composite score and the symptoms sub score

of the KOOS (rho = 0.065).

Complications

Most patients completed surgery and rehabilitation without complication. One patient

developed a deep vein thrombosis (DVT) and was anti-coagulated, while two had

superficial wound infections which were successfully treated with antibiotics.

There were three complications directly related to the CACI procedure: a focal area of

graft hypertrophy that became symptomatic, an asymptomatic case of graft hyperthropy

at the 24 month postoperative time point and a partial graft failure. The case involving

the symptomatic focal hypertrophy was successfully treated by arthroscopic

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debridement at 16 months following the initial implantation (Figure 5). The non-

symptomatic case continues to be managed conservatively.

(Figure 5)

Histological Assessment of a Failed Case

The failed case was a 12 cm2 medial femoral condyle defect that had poor infill in the

inferior half of the defect. This area was debrided to healthy bone, then implanted with a

matrix-induced autologous chondrocyte implantation (MACI) graft. Tissue from the

patient was biopsied during revision surgery and histologically processed (Figure 6).

Immediately following biopsy, the sample was placed into 4 percent paraformaldehyde

fixative.

(Figure 6)

DISCUSSION

The CACI technique addresses many of the problems associated with PACI by

replacing the perisoteum with an inert collagen membrane. As a result, the operative

technique is simplified, anaesthetic time is reduced, and periosteal harvesting is

abolished. Also, the incidence of tissue hypertrophy is minimized because unlike

periosteum, the collagen membrane is acellular. Graft hypertrophy incidence after

PACI has been reported as being as high as 20-36 percent in the literature [15,16], yet

we observed only two cases (8 percent incidence) of hypertrophic growth in this study.

This result is consistent with others reported in the literature [16,20]. Related literature

also revealed a 3-8 percent incidence of retarded knee flexion following CACI,

requiring manipulation under anesthetic [7,16,20,21]. Further investigation identified

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that immobilization of the operated knee joint for 10-14 days was routine in numerous

studies irrespective of defect location [7,16,18-22]. This is in contrast with the

recommendation of Hambly et al. [27] who stated that immobilization led to decreased

joint ROM, followed by adaptation of articular structures to the immobilized

circumstance. We observed no incidence of knee stiffness requiring manipulation under

anesthetic in this study and, therefore, advocate early mobilization via CPM in

conjunction with a rehabilitation protocols that incorporate all of the complexities

associated with each individual case [36,37].

Several studies investigating the CACI procedure are reported in the literature [18-22].

All used clinical and histological evaluation postoperatively to measure durability and

outcome of the CACI procedure. The results generally indicate improved functional

outcome from pre-operative scores following CACI and a lower rate of postoperative

graft hypertrophy, with reported incidences ranging from 6-9 percent compared with the

20-36 percent reported in PACI [15,16]. Arthroscopic evaluation was performed using

the ICRS grading system and biopsy samples were obtained at one year “whenever

possible” [16, 20-22]. It is important to note that only two of these studies collected

biopsy data on the entire sample [18,19]. On average, the remaining studies reported

biopsy data on 44 percent of the sample (range: 32-62 percent) [16,20-22].

Furthermore, the use of “gold standard” biopsies has been stated by one author to render

MRI evaluation of “limited” benefit [21]. However, durability of the implanted tissue

remains undetermined due to limited biopsy data taken in the majority of studies at the

1-year post-surgery time point [16,20-22].

Clinical follow-up is reported ranging from 2-7 years, but it is questionable if clinical

follow-up alone has sufficient sensitivity to accurately reflect graft durability.

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Arthroscopic examination and biopsy as routine follow-up is controversial, and

provides an inconsistent measure of durability, especially considering biopsy is not

always possible [7,16]. Many consider it unethical to subject ACI patients to routine

‘second-look’ arthroscopy and biopsy when the ACI graft is considered to be

functioning well from a clinical perspective. Also, the high incidence of inadequate

biopsies (55 percent as reported by ICRS Histological Endpoint Committee [42])

precludes meaningful interpretation in the majority of specimens that are obtained

arthroscopically. The majority of biopsy specimens obtained in these studies were

collected at the one year postoperative time point, despite the general consensus in the

literature that the neocartilage regenerated by ACI continues to remodel and mature up

until 24 months postoperatively [5,7]. Our biopsy data were obtained opportunistically

at revision of a failed case, and we would only consider arthroscopic assessment or

biopsy of the graft in instances where further surgical intervention was deemed

appropriate.

MRI evaluation of the defect infill and tissue regeneration following CACI revealed a

similar maturation pathway to other studies of PACI and CACI procedures [38-

40,44,45]. The present study demonstrated an increased MRI composite score over

time that improved significantly from three to 24 months postoperatively (p<0.05).

Post-hoc analyses revealed the improvement occurred predominantly in the first 12

months, then plateaued, but did not decline. This indicated that regenerated graft tissue

following CACI maintains its maturity and function up to the 24 month postoperative

time point, a result that is comparable to the PACI procedure [8].

The regeneration process following CACI does not appear complete until at least the 12

month postoperative time point; a result that is consistently reported in the literature

133

[8,36,45]. A consistent pattern was also observed in the evolution of the MRI scores

from the CACI grafts. In the early postoperative phase (first three months), the grafts

were uniformly hyperintense relative to native hyaline articular cartilage. The degree of

fill was usually more than 50 percent of the thickness of native hyaline articular

cartilage. Linear signal hyperintensity at the interface between the graft and native

cartilage was observed, often without breach of the graft surface. Signal hyperintensity

at the basal layer of the graft was typical in the early postoperative phase. In most

patients, the subchondral plate lamina was intact at three months post-surgery,

suggesting it had been intact at the time of surgery. Subchondral bone marrow edema

was common in the early postoperative phase.

Several consistent changes were observed on the follow-up scans at 12 and 24 months.

The graft signal intensity typically decreased from that observed at the three month

MRI, to become isointense or hypointense relative to native hyaline articular cartilage.

In most patients there was a reduction in the extent of subchondral bone marrow edema.

Resolution of the linear signal intensity was observed at the interface between the graft

and native hyaline articular cartilage, and at the interface between the graft and the

subchondral plate.

The incidence and natural history of chondral defects has been well documented [46-

48]. In many patients, the degeneration of the articular cartilage and the subsequent

alterations in knee function and loading cause pain and loss of motion in the affected

joint. Knee function was assessed via the KOOS, a superset of the Western Ontario and

MacMaster Universities osteoarthritis index (WOMAC) [50], which has been

previously validated for the assessment of knee pain and function during daily

activities. This survey tool has proven to be reliable, responsive to surgery and physical

134

therapy, and evaluates the course of knee injury and treatment outcome [33]. At the

three month time point following surgery, the poor knee function, as evidenced in the

KOOS, was primarily due to the postoperative restraints placed on the patient in order

to protect the integrity of an immature graft [26,27].

Subjective knee function in the CACI patients improved over time in parallel with the

maturation process of the regenerating graft. At the 12 month time point, the KOOS

results reported in our study were comparable to those by Marlovitis et al. [51].

Patients in our study experienced significant improvement in knee pain, sports and

recreation function, activities of daily living, and knee-related quality of life from three

to 24 months. The majority of this improvement, and that observed for the MRI results,

occurred in the first 12 months. The 24 month KOOS results from our study were also

comparable to those reported by Marlovitis et al. [45], thereby indicating that

improvements following surgery were maintained over time.

The ability to walk for a distance is a cornerstone of functional independence and

greatly influences patients’ quality of life since it is a fundamental component of many

activities of daily living. Prior to surgery, the average 6MWT distance was 492 m. This

capacity decreased to 434 m at the three month postoperative time point (p<0.05), most

probably the result of the trauma of surgery and early postoperative restraints [26,27].

Following this initial decrease, 6MWT distance improved significantly (p<0.005) to the

12 month postoperative time point, and this capacity was maintained through to 24

months.

Even though our results indicated a significant relationship between the MRI and

functional outcome following CACI, MRI grading alone should not be used as

135

surrogate measure of functional outcome following CACI, since the degree of

association was only low to moderate. That is, functional outcome following CACI

cannot be predicted by the morphological MRI assessment of the repair tissue at the

post-surgery time points to 24 months.

The partially failed case observed in this series has helped to highlight the possibly

detrimental effect of suturing both collagen membrane and periosteum to the defect

boundary. The cleft observed in the recovered biopsy of this case suggests that

superficial graft integration may be hindered by suturing and the creation of micro-

defects in the anchoring cartilage. Whilst good integration of this series was seen under

MRI, it is possible that small clefts at the interface of repair and healthy tissues may

leave the treated area susceptible to surface degeneration and cell leakage.

In summary, this study demonstrated that autologous chondrocytes implanted under a

type I/III collagen patch (CACI) regenerate functional infill material, and as a result of

this procedure, patients experienced improved knee function and MRI scores in the

short to mid-term. Further investigation of the relationship between MRI and clinical

outcome following chondrocyte implantation is imperative as it remains to be

determined whether the native ultra structure of cartilage needs to be restored in order to

achieve good, durable, clinical results.

ACKNOWLEDGEMENTS

This study was funded by a research grant provided by The National Health and

Medical Research Council (ID Number: 254622), and was administered by the council

on behalf of the Australian Government. Unless otherwise specified, the data given in

this review are based on work carried out at the University of Western Australia. We

136

would like to acknowledge Mr Craig Willers for his assistance in the description of the

biological aspects of CACI.

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Table 1. Rehabilitation Phases Following CACI Surgery

Rehabilitation Phase

Postoperative Time Point Expected Outcome by Phase End

1 1 to 3 weeks 1. Pain free knee active ROM of ≥60°; 2. Heel toe gait with toe touch pressure (≤20% body weight) using 2

crutches and knee brace; 3. Reduced oedema and pain; 4. Full passive extension; and 5. Able to generate a quadriceps contraction.

2 3 to 6 weeks 1. Pain-free active knee ROM of ≥90°; 2. Proficient straight leg raise; and 3. Pain-free gait using one crutch, knee brace and 50% body weight

pressure.

3 6 to 12 weeks 1. Pain free knee active ROM of ≥130° 2. Pain-free 6-minute walk test with or without walking aids 3. Use cycle ergometers pain-free without knee brace 4. Full passive extension; 5. Ability to generate a voluntary quadriceps contraction

4 3 to 6 months 1. Normal gait pattern without pain and without walking aids 2. Return to work (depending on demands of job) 3. Perform proprioception activities: 30 second single leg balance on

trampette

5 6 to 9 months 1. Able to tolerate walk distances of up to 5 kms 2. Able to negotiate stairs and mild gradients 3. Able to effectively traverse uneven ground 4. Able to return to preoperative low impact recreational activities

6 9 to 12 months 1. Able to perform all activities of daily living 2. Able to commence return to running program, for example:

walk/jog, jog/run, run on soft surface 3. Resume dynamic recreational activities (however, sports with

high knee loading and twisting or shear forces are to be avoided.)

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Table 2: MRI cartilage sequence

Sequence Coronal T2 Fat

Saturated (COR T2 FS)

Coronal Proton Density (COR PD)

Sagittal Proton Density (SAG PD)

Sagittal T2 Fat

Saturated (SAG T2 FS)

Axial Proton Density

Fat Saturated (AX PD FS)

Time to Repetition (TR) 4650.0 2060.0 2720.0 3400.0 3000.0 Time to Echo (TE) 81.0 34.0 32.0 72.0 38.0 Turbo Factor (echo train) 11.0 3.0 7.0 9.0 5.0 Acquistions 2.0 1.0 2.0 2.0 1.0 Bandwidth (hertz per pixel) 100.0 100.0 150.0 130.0 130.0 Slice Thickness (mm) 3.0 3.0 4.0 4.0 3.0 Distance Factor (%) 40.0 40.0 25.0 25.0 30.0 Field of view in the Frequency Direction (Read FOV)

140.0 140.0 140.0 140.0 150.0

Matrix – frequency axis 256.0 512.0 512.0 320.0 256.0 Phase Resolution (%) 75.0 45.0 50.0 70.0 100.0 Scan Time 3m48s 4m 4m4s 3m49s 3m41s

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Table 3: MRI composite score: parameters, grading, points and weighting scale. Parameter Score Rating Description Weighting 1. Signal 1 = Poor Fluid signal / Hyperintense diffuse 2 = Fair Hyperintense basal layer >50% / < 50% 3 = Good Hypointense 4 = Excellent Isointense

*0.30

2. Infill 1 = Poor Subchondral bone exposed 2 = Fair <50% height of adjacent cartilage 3 = Good >50% height of adjacent cartilage 4 = Excellent Complete

*0.20

3. Border 1 = Poor Incomplete border, visible defect 2 = Fair Incomplete border, split visible 3 = Good Complete border, minor split 4 = Excellent Complete integration

*0.15

4. Surface 1 = Poor Ulceration, delamination, full thickness 2 = Fair Fair <50% fibrillation 3 = Good Good focal changes only 4 = Excellent Excellent smooth

*0.10

5. Structure 1 = Poor Heterogenous, clefts 2 = Fair Heterogenous, no clefts 3 = Good >50% homogenous 4 = Excellent >75% homogenous

*0.10

6. Subchondral Lamina 1 = Poor No visible lamina 2 = Fair <25% intact 3 = Good >50% intact 4 = Excellent Fully reconstituted

*0.05

7. Subchondral Bone 1 = Poor Cysts, sclerosis, edema 2 = Fair Edema >1cm from lamina 3 = Good Edema <1cm from lamina 4 = Excellent Intact no significant edema

*0.05

8. Effusion 1 = Poor Severe 2 = Fair Moderate 3 = Good Mild 4 = Excellent None

*0.05

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Table 4: Descriptive Statistics and ANOVA Summary for CACI patients (n=27). Postoperative time point (months)

Variable Pre - surgery 3 6 12 24 F P

6-min walk (m) Mean 492acd 434e 482f 575 597

SD 97 76 106 116 114 29.4 p<0.001

KOOS - subscales Pain Mean 50.6abcd 67.2e 73.9 76.5 77.0 SD 13.9 13.6 17.8 14.2 16.0 22.7 p<0.001

Symptoms Mean 50.4 abcd 73.9 75.4 79.7 76.0 SD 19.4 16.8 15.8 12.7 18.4 18.1 p<0.001

Activities of Mean 61.5 abcd 72.3e 79.0f 85.5 83.4 daily living SD 16.1 18.2 15.2 13.2 16.0 17.1 p<0.001

Sport & Mean 8.8bcd 4.3e 22.6f 35.8 38.0 recreation SD 12.8 9.0 30.4 31.9 31.6 13.3 p<0.001

Function Knee related Mean 23.5 abcd 32.1e 41.4 45.7 48.2 quality of life SD 14.5 18.4 18.6 20.8 21.6 10.2 p<0.001

a = significant difference (p<0.05) presurgery vs 3 months b = significant difference (p<0.05) presurgery vs 6 months c = significant difference (p<0.05) presurgery vs 12 months d = significant difference (p<0.05) presurgery vs 24 months e = significant difference (p<0.05) 3 months vs 6 months f = significant difference (p<0.05) 6 months vs 12 months g = significant difference (p<0.05) 12 months vs 24 months

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Fig. 1. Changes in six-minute walk distance (m) at pre- and post-surgery assessment time points ( x ± SE, n = 27).

Fig. 2. Changes in the five sub domains of KOOS at pre- and post-surgery assessment time points ( x ± SE, n = 27). Total KOOS scores (0 = extreme knee problems and 100 = no knee problems), ADL = activities of daily living, Sport&Rec = sport and recreation function, KQOL = knee-related quality of life.

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Fig. 3. Changes in MRI composite score at post-surgery assessment time points ( x ± SE).

Fig. 4. Sagittal proton density fast spin echo magnetic resonance image of a CACI graft (depicted between the two arrow heads) to the medial femoral condyle in a patient who had a previously full thickness chondral defect. A. At three months post-surgery the graft is hyperintense and of reduced thickness when compared with the adjacent normal articular cartilage. B. One year post-surgery the CACI graft has a heterogeneous appearance and is of similar thickness to the adjacent normal cartilage. C. At two years post-surgery, the CACI graft remains intact and demonstrates equivalent signal characteristics to the adjacent normal cartilage. Border integration is smooth with no radiological evidence of fissures or clefts between the graft and the native cartilage.

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Fig. 5. Sagittal proton density fast spin echo magnetic resonance image of a CACI graft to the lateral femoral condyle in a patient who had a previously full thickness chondral defect. A. Focal graft hypertrophy was detected at the 12 month post-surgery time point (indicated by the arrow head). B. Following arthroscopic debridement at the 16 month postoperative time point, the 24 month MRI of the graft revealed a reduction in the height of the graft at the lateral femoral condyle and with the graft demonstrating a similar height to adjacent native cartilage.

Fig. 6. A. Photomicrograph taken of an obvious cleft (arrow) abutting the repair-healthy interface (dashed line) created by suturing the collagen membrane to the adjacent cartilage during surgery. B. Alcian Blue staining showed that the repair tissue was positive for proteoglycan (blue). The repair tissue was composed of a mixture of hyaline islands of chondrocyte within lacunae groups (C), and isolated chondrocytes within a hyaline-like matrix (D).

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CHAPTER FIVE

MRI AND CLINICAL EVALUATION OF MATRIX-INDUCED AUTOLOGOUS CHONDROCYTE IMPLANTATION (MACI)

AT TWO YEARS Note 1. References cited in this chapter appear in a reference list at the end of the


chapter.

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Title: MRI and clinical evaluation of matrix-induced autologous chondrocyte implantation (MACI) at two years. Keywords: Osteochondral defect, Autologous chondrocyte implantation, Correlation of outcome and MRI.


2.) Craig Willers M. (Med) Sc* PhD Student University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA





* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Crawley, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Crawley, WA 6009 Australia. Correspondence: Mr William Brett Robertson University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]

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ABSTRACT

This study presents MRI and clinical outcomes for 31 matrix-induced autologous chondrocyte implantations (MACI) over 24 months post surgery. Following MACI knee surgery, patients underwent a coordinated rehabilitation program of progressive exercise and graduated load bearing to protect then stimulate the healing process. In contrast to the current literature we report no incidence of manipulation under anesthesia following MACI.

Clinical outcomes were measured using the KOOS score and the six-minute walk test, whereas an MRI scoring protocol described the quality and quantity of the repair tissue. Patients demonstrated an increased walk distance that improved significantly from three months to 24 months postoperatively (p<0.001). Analysis of the KOOS results demonstrated a significant (p<0.001) improvement in all of the five subscales from three months to 24 months after CACI, with the most substantial gains made in the first 12 months. Patients also demonstrated an increased MRI composite score over time that improved significantly from three months to 24 months postoperatively (p<0.001). Post-hoc analysis demonstrated the improvement occurred predominantly in the first 12 months, then plateaued at 24 months postoperatively. A 10 percent incidence of hypertrophic growth following MACI was observed.

The MACI technique addresses many of the problems associated with use of a periosteum cover by replacing this with an inert collagen membrane. As a result, the operative technique is simplified, anaesthetic time is reduced, and periosteal harvesting is abolished. This study provides novel insight into the morphological progression of the regenerative tissue produced following MACI through the use of established MRI evaluation parameters. These results supplement the clinical, radiological and histological information on MACI, so that a better understanding of the outcome of ACI with a collagen membrane is afforded.

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INTRODUCTION:

Conventional autologous chondrocyte implantation (ACI) was the first surgical

technique to highlight the therapeutic potential of autologous cell therapy in the field of

orthopaedics [7,36]. However, the original surgical technique described by Peterson et

al. [7], required the use of a periosteum cover (PACI), which was successful in the

majority of patients but associated with numerous postoperative complications such as

extensive surgical incision, graft hypertrophy, delamination and potiential ectopic

calcification of the periosteal membrane [7,13,24,35,50]. Use of a collagen membrane

in place of perisoteum has been advocated recently [8-11], and related studies indicated

that ACI using a type I/III collagen membrane (CACI) produced clinical, histological

and radiographical results that were at least comparable to PACI [18,19,26,41].

Importantly, the favorable outcomes gained through CACI were obtained with a

decreased incidence of postoperative complications.

Although CACI had been shown to exhibit commendable postoperative outcomes, its

surgical technique remains cumbersome. A large surgical incision is required in order

to suture the membrane to the circumference of the chondral defect - a tedious task that

increases the length and technical difficulty of the surgical procedure. Furthermore,

concern remains regarding the uneven distribution of chondrocytes within the fluid

suspension, possible leakage of suspension fluid through the graft-cartilage interface,

and creation of microdefects in the native cartilage by the suturing process [10,41,48].

The associated complications with the PACI and CACI procedures have resulted in the

search for alternative bioscaffolds that are thought to be less problematic. Naturally-

derived bioscaffolds such as collagen, hyaluronan, fibrin glue, chitosan and various

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polysaccharides have been investigated to act as three-deminsional templates for

cellular propagation and growth factor seeding [52]. Matrix-induced autologous

chondrocyte implantation (MACI) has applied the concept of direct cell inoculation

onto a collagen scaffold for implantation. In this procedure the chondrocytes are no

longer injected under a collagen membrane into a sealed defect compartment. Instead,

they are directly seeded onto the type I/III collagen membrane and delivered into the

chondral defected as a cell-scaffold construct. This modified delivery method, obviates

the need for periosteal harvest and is generally suture free. Once prepared, the cell-

seeded membrane can be secured to the base of the recipient defect using a thin layer of

fibrin glue. The MACI procedure can be performed through mini-arthrotomy or

arthroscopically depending upon the defect location [44], and since the first introduction

of the MACI technique in 1998, more than 3000 patients have been treated across

Europe, Australia and Asia. Figure 1 outlines the paradigm of MACI cartilage

regeneration.

(Figure 1)

A prospective clinical investigation was conducted to evaluate the efficacy of the MACI

procedure over time (two year follow-up). The morphologic characteristics of the

MACI graft were assessed by MRI, as was the function of the grafted joint following

surgery, in order to establish whether the MACI procedure produced a potentially

durable repair tissue. It was hypothesized that use of the cell-seeded type I/III collagen

membrane would reduce the incidence of graft hypertrophy that is often associated with

using a periosteal membrane [24,32]. Thus, MACI could be regarded as providing a

better capacity to facilitate cartilage regeneration than PACI. Furthermore, it was our

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intention to demonstrate that early mobilization via continuous passive motion (CPM)

following MACI is safe and leads to a lower incidence of postoperative knee stiffness

and subsequent need for manipulation under anesthesia (MUA) than the practice of

immobilization in plaster that has been advocated by some in the literature [3].

MATERIALS AND METHODS:

Sample

A consecutive series of 31 procedures in 28 patients (18 male; 10 female) between

August 2001 and March 2004. Thirty-one implantations survived to a minimum of 24

months, however, one claustrophobic patient was excluded from MRI evaluation. The

mean age at assessment of the clinical outcomes of MACI for focal chondral defects of

the knee was 36.5 years (range: 13-60 years) and mean BMI was 25.9 (range: 17.2–

33.9). All subjects suffered from persistent pain associated with full thickness chondral

lesions (Outbridge grade III or IV [36], range: 1.5–9.6 cm2), with no clinical sign of bi-

or tri-compartmental osteoarthritis as diagnosed by preoperative MRI and confirmed at

arthroscopic biopsy. Patient demographics are described further in Table 1.

(Table 1)

Patient Selection

Patients were recruited based on the following inclusion/exclusion criteria:

• Age: 13–60 years;

• Defect location: medial or lateral femoral condyle, trochlea, or patella (non-

opposing lesions only);

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• Area and depth: < 10cm2, down to stable subchondral bone plate;

• Aetiology: trauma or osteochondritis dessicans;

• Joint condition: absence of progressive inflammatory disease or osteoarthritis;

• Joint stability: absence of full menisectomy or instability;

• Abnormal weight-bearing: absence of significant varus/valgus abnormality (>5°),

patella maltracking, or obesity (body mass index >35); and

• Sensitivities: no history of gentamycin sensitivity.

Membrane

The membrane employed in this study was a type I/III collagen membrane composed of

a purified collagen fibrous network. It was produced from porcine peritoneal membrane

using controlled manufacturing processes. Starting materials for the production of the

membrane were harvested in European Union certified slaughterhouses under strict

veterinary controls from animals declared fit for human consumption. The membrane

complied with the relevant provisions of Schedule 3 – Part 1.6 of the Therapeutic

Goods (Medical Devices) Regulations 2002 and had a TGA conformity assessment

certificate (Certificate Number: AU DE00026/01). The bi-layered structure had an

outer flat layer with relatively low friction and closely aggregated fibres, while the inner

surface was rough with a loose arrangement of collagen fibres. This presents a larger

surface area for chondrocyte adhesion [52]. Manufacture involved moving excess flesh

and fat, washing with a NaOH, treating it with hydrochloric acid, saline and sodium

bicarbonate. This was followed by dehydration, degreasing and lyophilisation. The

membrane was then sterilized by gamma radiation (minimum dose 25 kGy). Clinical

and preclinical [51] studies revealed that selected collagen membranes are

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biocompatible, well tolerated and effective. They have been used extensively in the

clinical setting, including guided bone repair, cartilage repair, skin care and skin

surgery. This acellular membrane shows no evidence of genotoxicity and, on

broadband viral testing, is designated virus free.

Chondrocyte Characterization

The chondrocytes were harvested in a similar way to the traditional PACI and CACI

techniques. At day case arthroscopic surgery, a small volume of normal articular

cartilage was harvested from the medial femoral condylar ridge, usually at the junction

between the patellofemoral and tibiofemoral joints. The site, geometry, containment of

the defect, ligamentous stability, and meniscus health were also evaluated during

primary surgery to determine the condition of the joint. Approximately 1x105 cells

were obtained at biopsy and expanded to 12x106 cells in a laboratory over a period of

four to six weeks. Initially, the cells were treated in normal saline for transport to the

GMP laboratory where there were lysed with chlostridial collagenase. They were

cultured at 37ºC in an atmosphere of CO2 with HEPPS buffer and hemes medium in

autologous patient’s serum. Three days prior to implantation, the cells were seeded

onto the collagen membrane, held ‘rough-side-up’ and stabilized with a plastic ring.

The inoculation of chondrocytes onto the porous surface of the collagen membrane has

been shown to increase chondrocyte differentiation and proliferation within the three-

dimensional scaffold [10,17,28].

Fibrin Glue

Initially, there was some concern that fibrin glue may alter the differentiation or the

viability of chondrocytes [8], however, we have demonstrated that the glue is chemo-

attractant to chondrocytes, the cells penetrate and migrate through fibrin glue and retain

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their chondrocyte phenotype [15,51,52]. Fibrin glue has also been shown to be a

suitable adhesive for MACI grafts, as determined by MRI [32].

Surgical Technique

A single surgeon performed all surgery. The defect site was accessed via a medial or

lateral parapatellar arthrotomy approach in a tourniquet-controlled field. If additional

realignment or ligament reconstruction was required, the surgical approach was

modified accordingly. The defect was prepared by removing all damaged and loose

cartilage down to, but not through, the subchondral plane. Care was taken to avoid

bleeding, as blood has been shown to affect chondrocyte viability [53]. Adrenaline

soaked patches or fibrin glue may have been used for haemostasis. Vertical walls of

normal cartilage should exist at the periphery of the defect and the MACI membrane

was secured into this contained area. Once a thin layer of fibrin glue was applied and

the membrane pressed into the defect, 30 s was allowed for the glue to set and a further

two minutes for the fibrin glue to cure. The knee was put through a full range of

passive motion five to 10 times in order to test graft stability. Any evidence of de-

lamination or instability was corrected with strategic 6/0 vicryl sutures. Meticulous

layer closure was then performed. The synovial membrane was closed as a separate

layer to the capsule with 2/0 vicryl. The capsule was closed using 1/0 vicryl and the

skin closed according the surgeon’s preference.

Rehabilitation

Following MACI knee surgery, patients underwent a coordinated rehabilitation program

of progressive exercise and graduated weight bearing to protect and stimulate the

healing process (Figure 2). Continuous passive motion was routinely commenced one

day after surgery and patients were gradually returned to weight bearing activity over

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the ensuing months by participation in a graduated rehabilitation program designed

specifically for MACI [42].

(Figure 2)

Structured exercise sessions (which included extensive education regarding the MACI

procedure) commenced prior to surgery in order to prepare patients physically and

pscyhologically for a traumatic surgery and the lengthy post-operative recovery.

Following surgery, patients underwent an intensive, individually tailored MACI

rehabilitation program. The underlying principle for this program was to encourage and

maximize the chondrocyte maturation process, whilst minimizing the risk of graft

failure through overload or delamination.

Outcome Measures – Functional Assessments

Six-Minute Walk Distance Test

Functional capacity and general gait function (cadence and stride length) were

determined by the six-minute walk test (6MWT) [1,41], which was conducted indoors

on a flat, 25 m course. Subjects were instructed to walk as fast as possible, trying to

cover the maximum distance without over exertion. The final score was calculated as

the total distance walked to the nearest 1.0 m. The 6MWT has been demonstrated to be

a reliable measure of general gait function and has been widely used for pre- and

postoperative evaluation [14,41].

The Knee Injury and Osteoarthritis Outcome Score

Subjective knee function was assessed pre- and postoperatively using the knee injury

and osteoarthritis outcome score (KOOS), a knee-specific instrument developed by

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Roos et al. [46]. The KOOS evaluates both short-term and long-term consequences of

knee injury, is self-administered, and is responsive to changes over time and between

groups [45]. The questionnaire comprises 42 items within five domains: Pain (nine

items), Symptoms (seven items), Function in activities of daily living (ADL, 17 items),

Function in sport and recreation (Sport/Rec, five items), and Knee-related quality of life

(KQOL, four items) [46].

Outcome Measures - MRI Assessment

MRI scans were conducted at three, 12 and 24 months postoperatively using a 1.5 Tesla

closed unit with an extremity coil (Siemens Vision; Siemens, Erlangen, Germany),

employing an established cartilage imaging sequence protocol [5,41]. A blinded

evaluation was performed by a consultant musculoskeletal radiologist using a

previously described scoring system [41]. Each MRI parameter (defect infill, signal

intensity, surface contour, structure, border integration, subchondral lamina,

subchondral bone and effusion) was scored against a series of sample images, ranked

from 1=“Poor” to 4=“Excellent” then multiplied by a weighting factor [41] to obtain the

final MRI composite score. MRI data was also assessed in disaggregated fashion by

category in accordance to the recommendations of Marlovits et al. [31,33]. Synovitis

was recorded and graded separately in accordance with the definition given by

Marlovits et al. [33]. Intra-observer reliability assessment was conducted using 20

image pairs in which a significant (p<0.01) correlation (Spearmans Rank Order

Correlation) between samples was observed (rho=0.787) and no significant difference

was recorded between test and retest images p<0.01.

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Graft failure was determined both clinically and radiographically. Clinically, graft

failure was defined as the deterioration of the knee condition upon examination, with

indicators that included the presence of mechanical symptoms such as locking, catching

and/or associated knee joint pain. Radiographically, graft failure was defined by

evidence of suboptimal defect infill and/or evidence of internal derangement (such as

clefts, fissures, or basal delamination). Any that showed clinical and radiographical

evidence of failure would be referred back to the surgeon for patient-specific

management.



10.0) for Windows. One cell was missing at the three month time point, three at the 12

month and two data cells were missing at the 24 month time point. An intention to treat

analysis was performed using the ‘last value carried forward’ technique (five percent of

data cells), and changes between postoperative time points compared using repeated

measures analysis of variance (ANOVA). Post-hoc analysis was performed using

Tukey’s HSD. All reported p-values were two-tailed and p-values less than 0.05 were

considered significant.

RESULTS:

Functional Outcomes of MACI

Statistical analysis of the functional outcome variables indicated that patients

experienced a significant (p<0.001) improvement in 6MWT distance and KOOS

subscales - knee pain, symptoms, ADLs, sports and recreation function, and knee-

related quality of life from pre-surgery to 24 months after MACI (Table 2).

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(Table 2)

Though MACI patients demonstrated an increased distance covered in the 6MWT from

pre-surgery to 24 months postoperatively, scores on this parameter were artificially

suppressed at the three month time point due to the weight bearing constraints of the

rehabilitation protocols. Post-hoc analysis demonstrated the improvement occurred

predominantly in the first 12 months (p<0.05) and that this improvement was

maintained out to the 24 month postoperative time point (Figure 3).

(Figure 3)

Post-hoc analyses also revealed the improvement of knee pain, symptoms and ADLs

occurred predominantly in the first 12 months following MACI then plateaued, whereas

the improvement in sport and recreation function increased linearly from three to 24

months (Figure 4). The knee related quality of life subscale of the KOOS score

improved significantly from three to 12 months following surgery, then only marginal

improvement was experienced from 12 to 24 months (p>0.05).

(Figure 4)

MRI Assessment of MACI

MACI patients demonstrated an increased MRI composite score over time that

improved significantly from three to 24 months postoperatively (p<0.001). Post-hoc

analysis demonstrated the improvement occurred predominantly in the first 12 months

(Figures 5 and 6), then plateaued at 24 months postoperatively.

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(Figure 5)

(Figure 6)

At three months following surgery, 45 percent (n=13) of the MACI grafts exhibited

good to excellent filling of the chondral defect, the remaining 55 percent (n=16)

exhibited fair to poor defect infill. The signal intensity at this time was described as

good to excellent in 28 percent (n=8) of grafts. Good to excellent border integration of

reparative tissue with adjacent native articular cartilage was evident in 76 percent

(n=22) of grafts, with fair to poor integration present in the remaining 24 percent (n=7)

of cases. The surface of the reparative tissue at this stage of recovery was good to

excellent in 83 percent (n=24) of cases with the remaining 17 percent (n=5) exhibiting

fair to poor surface structure. Good to excellent subchondral lamina was evident in 96

percent (n=28) of the cases (indicative that it was intact at the time of surgery) and 83

percent (n=24) of the cases exhibited good to excellent resolution of preoperative

subchondral bone edema. Joint effusion was evident in 24 percent (n=7) of cases and

55 percent (n=16) exhibited synovitis at the three month postoperative time point. No

graft hypertrophy was reported at this time.

At 12 months following MACI, good to excellent filling of the defect had increased to

76 percent (n=22) of grafts. The signal intensity had improved from 28 percent

reported as good to excellent at three months to 93 percent (n=27) by 12 months post-

surgery. Good to excellent border integration of reparative tissue with adjacent native

articular cartilage was seen in 79 percent (n=23) of cases. The surface of the reparative

tissue was intact in 86 percent (n=25) of grafts with the remaining 14 percent (n=4) fair

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to poor surface structure at the 12 month postoperative time point. Good to excellent

restoration of the subchondral lamina was evident in all cases and 93 percent (n=27) of

cases showed a resolution of subchondral bone edema. Joint effusion improved from 24

percent down to only three percent (n=1) of cases, though 28 percent (n=8) of cases had

persistent synovitis. Minor graft hypertrophy was reported in two cases.

By 24 months following MACI surgery, defect signal intensity and graft structure had

achieved a good to excellent rating in 86 percent (n=25) of cases. There was no change

in infill from the 12 to 24 month time point. Good to excellent border integration of

reparative tissue with adjacent native articular cartilage was seen in 83 percent (n=24)

of cases. The surface of the reparative tissue was intact in 83 percent (n=24) of grafts

with the remaining 17 percent (n=5) fair to poor surface structure at the 24 month

postoperative time point. Effusion was present in only one case and synovitis had

improved from 28 percent down to 20 percent (n=6) of sample. A third case exhibited

graft hypertrophy at this time point.

Complications

Most patients completed surgery and rehabilitation without complication. Five patients

developed a deep vein thrombosis (DVT) and were anti-coagulated.

There were four complications directly related to the MACI procedure including three

cases of graft hypertrophy. Surgical intervention was not deemed necessary in any of

the reported cases of hypertrophy, as all patients were asymptomatic and the

hypertropic tissue did not cause any mechanical obstruction to joint function. These

cases continue to be managed conservatively. The fourth complication involved a

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patient who was diagnosed with patella tendonitis of severe intensity that was probably

related to MACI and the tibial tubercle transfer surgical procedure. This patient

underwent physiotherapy and injection of corticosteroids, which alleviated the majority

of symptoms. This case continues to be managed conservatively.

A traumatic graft delamination was detected at the three month post-surgery time point.

An MRI scan revealed the MACI graft had become detached and was lodged near the

head of the gastrocnemeus. Upon clinical review, the patient revealed an incidence of

accidental non-compliance to postoperative rehabilitation due to inebriation in the tenth

postoperative week. The detached graft was removed arthroscopically and assessment

of the graft revealed residual tissue infill approximating 25 percent of the height of the

adjacent native cartilage. This patient had exhibited good to excellent infill upon MRI

examination at the 12 month postoperative time point. A possible explanation for such

a positive result at the 12 month time point is that the cell migration of chondrocytes

from the cambium surface of the membrane was practically complete at the time of

delamination. Thus the delamination of the membrane only dislodged the superficial

layer of the graft, leaving residual reparative tissue intact in the base of the defect,

which continued to develop and mature over time.

DISCUSSION

The MACI technique addresses many of the problems associated with PACI by

replacing the perisoteum with an inert collagen membrane. As a result, the operation is

simplified, anaesthetic time is reduced, and periosteal harvesting is abolished. Also, the

incidence of tissue hypertrophy is minimized because unlike periosteum, the collagen

membrane is acellular. Graft hypertrophy incidence, requiring arthroscopic

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debridement, after PACI has been reported in the literature [18,34] to be as high as 20-

36 percent of patients, yet only three cases (10 percent incidence, no debridement

required) of minor hypertrophic growth were noted in this study. This result is

consistent with others reported in the literature [3] for ACI using a type I/III collagen

membrane.

A review of the literature revealed a 6-8 percent incidence of retarded knee flexion

following MACI, requiring MUA [3]. Further investigation identified that

immobilization of the operated knee joint, irrespective of defect location, for 10-14 days

was advocated by some authors in the current literature [3]. This view is in contrast

with the recommendation of Hambly et al. [20] who stated that immobilization led to

decreased joint ROM, followed by adaptation of articular structures to the immobilized

circumstance. No incidence of knee stiffness requiring MUA was observed in this

study. Therefore, the results support early mobilization via CPM in conjunction with

rehabilitation protocols that incorporate all of the complexities associated with each

individual case [20,42].

The biological longevity and clinical success of the graft is dependent on a controlled

and graduated return to ambulation and physical activity, and the resultant

biomechanical stimulation of the implanted chondrocytes. This has been evidenced at a

cellular level with various studies showing the relationship between cartilage matrix

synthesis and biomechanical stimuli [9,16,47,49]. Dynamic compression of cartilage

stimulates matrix biosynthesis dependent on loading frequency and amplitude, whereas

increased static compression by mechanical or osmotic stress has been shown to

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decrease matrix biosynthesis in a dose-dependent manner [9,47,49]. Using CPM also

improves matrix biosynthesis postoperatively by controlled dynamic compression [43].

The rehabilitation protocol adopted in this study [42] was well tolerated by all patients;

however, the single incidence of graft delamination highlights the clinical importance of

a protection phase coupled with patient compliance during the first three months

following implantation. The cellular regeneration, matrix production and adaptation of

the regenerating tissue to natural function involves a combination of time and

appropriate biomechanical stimulus. Therefore, it is not only important to encourage

successful maturation of the implanted graft, but it is vital that the integrity of the graft

be appropriately protected during all phases of the postoperative rehabilitation process.

Whilst structured rehabilitation cannot guarantee clinical success following MACI,

results from this study show that the introduction of biomechanical stimuli through

controlled postoperative rehabilitation may indeed act to enhance cartilage matrix

synthesis and aid both qualitative and quantitative aspects of cartilage repair.

Arthroscopic examination and biopsy as routine follow up is controversial. Also, the

high incidence of inadequate biopsies (55 percent as reported by ICRS [29]) precludes

meaningful interpretation in the majority of specimens. We consider it unethical to

subject ACI patients to routine ‘second-look’ arthroscopies and biopsy when the ACI

graft is considered to be functioning well clinically. Therefore, we have sought to

examine the potential for MRI assessment as a postoperative measure of graft outcome

and durability. MRI allows evaluation of articular cartilage thickness, graft

incorporation and congruity of the articular surface. Post-operative complications such

as delamination, arthrofibrosis, fissure formation and hypertrophy of implant material

can be reliably assessed with this technology, along with the signal characteristics of the

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subchondral bone. Thus, MRI allows non-invasive, serial follow-up of patients and

detection of postoperative complications. Its role in the evaluation of cartilage repair is

well supported in the literature [2,11,39,40].

MRI evaluation of the defect infill and tissue regeneration following MACI revealed a

similar maturation pathway to that reported by previous studies of the PACI and CACI

procedures [3,21,23,34]. The present study demonstrated an increased MRI composite

score over time that improved significantly from three to 24 months postoperatively.

Post-hoc analyses revealed the improvement occurred predominantly in the first 12

months, then plateaued, but did not decline. This indicated that regenerated graft tissue

following MACI maintains its maturity and function from the 12 to 24 month

postoperative time point, a result that is comparable to the PACI and CACI procedures

[19,41].

The incidence and natural history of chondral defects has been well documented

[12,22]. In many patients, degeneration of the articular cartilage and the subsequent

alterations in knee function and loading cause pain and loss of motion in the affected

joint. Knee function was assessed via the KOOS [45], which has been validated

previously for the assessment of knee pain and function during activities of daily living.

This survey tool has proven to be reliable, responsive to surgery and physical therapy,

and evaluates the course of knee injury and treatment outcome [45]. At the three month

time point following surgery, the poor knee function, as evidenced in the KOOS, was

primarily due to the postoperative restraints placed on the patient in order to protect the

integrity of an immature MACI graft [20,42].

166

Subjective knee function among MACI patients improved over time in parallel with the

maturation process of the regenerating graft. At the 12 month time point, the KOOS

results reported here were comparable to those by Marlovitis et al. [30]. Patients in our

study experienced significant reduction in knee pain, and improvements in sports and

recreation function, activities of daily living, and knee-related quality of life from three

to 24 months, with the majority of this improvement, occurring in the first 12 months.

The 24 month KOOS results from our study were also comparable to those reported by

Marlovitis et al. [31], thereby indicating that improvements following surgery were

maintained over time.



activities of daily living. Prior to surgery, the average 6MWT distance was 542 m. This

capacity decreased to 444 m at the three month postoperative time point, most probably

the result of the trauma of surgery and early postoperative restraints [20,41]. Following

this initial decrease, six-minute walk distance improved to the 12 month postoperative

time point, and this capacity was maintained through to 24 months.

CONCLUSION

Initially, collagen membrane was simply used to replace the periosteal patch which

sealed the cell solution into the chondral void. This was termed collagen-covered ACI.

Although CACI has exhibited commendable histological and clinical outcomes, its

surgical efficiency is impeded by the need to microsuture the membrane to the defect

border, a tedious task that increases the length and technical difficulty of the operation.

Furthermore, concerns surrounding cell delivery, the possibility of cell leakage through

the graft-cartilage interface, and the creation of microdefects by suturing remain [40].

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The MACI technique involves direct cell inoculation onto a collagen scaffold for

implantation. Instead of an injection of chondrocytes under the collagen membrane into

the sealed defect compartment (CACI), chondrocytes are directly inoculated onto type

I/III collagen membrane and delivered as a cell-scaffold construct for implantation.

This study demonstrated that the MACI approach with complementary rehabilitation

yields regenerated functional infill material, and patients experienced improved knee

function and MRI scores in the short to mid-term. The development of MACI

decreases operative time, allows a smaller surgical incision, and facilitates postoperative

recovery. These data also show that the MACI procedure reduces the incidence of

postoperative complications, especially the incidence of tissue hypertrophy.


and graduated return to ambulation and physical activity, as well as the biomechanical

stimulation of the implanted chondrocytes. Therefore, reduced cartilage thickness

and/or matrix synthesis observed in some patients may be related to a lack of

biomechanical stimulation of the graft. The introduction of biomechanical stimuli

through controlled postoperative rehabilitation in the first three months may enhance

cartilage matrix synthesis and aid both qualitative and quantitative aspects of cartilage

repair.

This study provides novel insight into the morphological progression of the regenerative

tissue produced following MACI through the use of established MRI evaluation

parameters. These results supplement the clinical, radiographical and histological

information on MACI, so that a better understanding of the outcome of ACI with a

collagen membrane is afforded. Further investigation of the relationship between MRI

168

and clinical outcome following chondrocyte implantation is imperative as it remains to

be determined whether the native ultra structure of cartilage needs to be restored in

order to achieve good, durable, clinical results.

ACKNOWLEDGEMENTS


Medical Research Council (ID Number: 254622), it was administered by the council on

behalf of the Australian Government. Unless otherwise specified, the data given in this

review is based on work carried out at the University of Western Australia.

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Table 1. Patient demographics: anatomical site, aetiology of chondral defects and prior surgical interventions. Patient Demographics Number (%) Anatomical site Medial femoral condyle 17 (55) Lateral femoral condyle 4 (13) Patella 6 (19) Trochlea 4 (13) Aetiology Trauma 14 (45) Chondromalacia patella 6 (19) Osteochondritis dessicans 4 (13) Disease 3 (10) Idiopathic 3 (10) Failed prior intervention 1 (3) Prior Surgical Interventions Arthroscopes

-Diagnostic & lavage 10 (34) -Menisectomy 9 (32) -Chondroplasty 2 (7) -Lateral release 2 (7) -Debridement 1 (3)

Anterior cruciate ligament reconstruction 4 (14) Patellofemoral reconstruction 1 (3)

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Table 2. Descriptive Statistics and ANOVA Summary for Functional Outcome Variables (n=28). Postoperative time point (months)


6-min walk (m) Mean 542acdef 444e 549f 620 601

SD 102 91 97 89 102 32.4 p<0.001

KOOS - subscales Pain Mean 56.7abcdef 66.5e 72.4f 80.0 80.1 SD 16.1 16.7 17.7 16.0 16.0 16.2 p<0.001

Symptoms Mean 61.7abcd 72.0 78.5 83.4 84.0 SD 16.7 16.1 18.0 14.0 15.0 14.2 p<0.001

Activities of Mean 65.0bcdef 68.3e 80.3f 89.0 88.7 daily living SD 18.0 18.1 18.0 13.4 13.0 19.4 p<0.001

Sport & Mean 18.4adefg 3.2 15.8f 32.0g 51.4 recreation SD 21.3 7.0 23.4 30.0 34.7 17.9 p<0.001

function Knee related Mean 21.4bcde 26.2e 38.8 42.7 47.7 quality of life SD 18.0 23.5 26.1 25.5 26.0 18.8 p<0.001

a = significant difference (p<0.05) presurgery vs 3 months b = significant difference (p<0.05) presurgery vs 6 months c = significant difference (p<0.05) presurgery vs 12 months d = significant difference (p<0.05) presurgery vs 24 months e = significant difference (p<0.05) 3 months vs 6 months f = significant difference (p<0.05) 6 months vs 12 months g = significant difference (p<0.05) 12 months vs 24 months

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Fig. 1. Paradigm of matrix-induced autologous chondrocyte implantation (MACI) cartilage regeneration. 1) Implantation of chondrocyte seeded membrane (blue) into the fibrin sealant-covered (pink) base of the debrided chondral defect (day of implantation). 2) Cell migration of chondrocytes from the cambium surface of the membrane into the fibrin sealant matrix. Host resorption of the collagen membrane has also commenced (2-5 days following implantation). 3) Matrix production by implanted autologous chondrocytes. Type II collagen, aggrecan and other matrix proteins important for healthy articular cartilage function are synthesised by the newly implanted cells (1-9 months following implantation). 4) Matrix maturation and hyaline-like/hyaline cartilage formation. Cartilage infill is complete, chondrocyte morphology and surrounding matrix appears healthy (or similar to surrounding native tissue) and graft cartilage is well integrated with the adjacent cartilage (12-24 months following implantation).

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Fig. 2. The graduated return to weight-bearing administered to patients during functional rehabilitation following their MACI surgery. Gradual loading of the joint is conducted to stimulate hypertrophy and adaptation of hyaline-like cartilage in-fill tissue through physiologically induced maturation of chondrocyte biosynthesis.

Fig. 3. Changes in six-minute walk distance (m) at pre- and post-surgery assessment time points (x ± SE, n = 28).

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Fig. 4. Changes in the five sub domains of KOOS at pre- and post-surgery assessment time points (x ± SE, n = 28). Total KOOS scores (0 = extreme knee problems and 100 = no knee problems), ADL = activities of daily living, Sport&Rec = sport and recreation function, KQOL = knee-related quality of life.

Fig. 5. Changes in MRI composite score at post-surgery assessment time points (x ± SE).

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Fig. 6. Sagittal proton density fast spin echo magnetic resonance image of a MACI graft to the medial femoral condyle in a patient who had a previously full thickness chondral defect. B. At three months post-surgery the graft is hyperintense and of reduced thickness when compared with the adjacent normal articular cartilage. C. One year post-surgery the MACI graft has a heterogeneous appearance and is of similar thickness to the adjacent normal cartilage, it is interesting to note the reconstitution of the sub-chondral bone plate from three to 24 months (depicted by red arrow heads). D. At two years post-surgery, the MACI graft remains intact and demonstrates heterogeneity in graft signal compared to the adjacent native cartilage. Border integration is smooth with no radiological evidence of fissures or clefts between the graft and the native cartilage.

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CHAPTER SIX

COMBINED HIGH TIBIAL OSTEOTOMY AND MATRIX-INDUCED AUTOLOGOUS CHONDROCYTE IMPLANTATION (MACI)

FOR EARLY OSTEOARTHRITIS OF THE KNEE Note 1. References cited in this chapter appear in a reference list at the end of the


chapter.

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Title: Combined high tibial osteotomy and matrix-induced autologous chondrocyte implantation (MACI) for early osteoarthritis of the knee.

Keywords: Osteochondral defect, Autologous chondrocyte implantation, Tibial

osteotomy.


2.) R.J.K Khan FRCS, FRACS* Senior Lecturer University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA





* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Crawley, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Crawley, WA 6009 Australia. Correspondence: Mr William Brett Robertson Schools of Surgery & Pathology and Human Movement & Exercise Science University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]

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ABSTRACT Early symptomatic osteoarthritis (OA) of the knee poses a difficult challenge to orthopaedic surgeons, particularly in the presence of lower limb malalignment. Most surgical options are palliative. Our aim was to assess combined high tibial osteotomy (HTO) and matrix-induced autologous chondrocyte implantation (MACI) as a treatment option. Patients with localised medial compartment OA and varus malalignment were identified. Diagnosis was supported with radiographs and MRI, and suitability for ACI confirmed at arthroscopy; where a cartilage specimen for culture were obtained. HTO and MACI procedures were performed in one sitting by a single surgeon. The HTO was performed through an inverted hockey-stick incision. The MACI procedure was performed via a small medial arthrotomy; the defect was debrided to subchondral bone and graft applied. Patients received three months rehabilitation and function was assessed preoperatively and at three-monthly intervals. MRI and radiographs were repeated at three months and then annually to the 24 month time point. Fifteen patients were identified: 12 were male and the average age was 46 years (27-58). Mean varus deformity was 6 degrees. As well as medial compartment OA two patients had evidence of osteochondritis dissecans, and two early patello-femoral OA. Eight patients had previous surgery to the knee. Average time between cartilage harvest and implantation was six weeks. Fourteen patients had a lateral closing wedge osteotomy; a medial opening wedge was performed in a case of leg shortening. Mean operation duration was 72 minutes (range 60-90 minutes). The graft was fixed with fibrin glue in all cases, and augmented with stitches or vicryl pins in five cases. Mean defect size was 6.2cm2 (range 2-12 cm2). There were three complications: one DVT, a haemarthrosis and a graft detachment; the latter was successfully treated with a second procedure. MRI scans at three months showed oedematous tissue at the defect sites, contrasting with the fluid filled defects seen preoperatively. Scans at one year showed hyaline-like cartilage infill with similar signal characteristics to native hyaline cartilage. Six minute walk test and knee injury and osteoarthritis outcome score (KOOS) indicated improved functional capacity at six months and one year when compared to preoperative scores. This is the first series of HTO and MACI published in the literature. Preliminary results suggest a significant functional improvement, supported by radiologic evidence of deformity correction and filling-in of articular defects on MRI. Definitive conclusions will be made with longer term follow-up.

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INTRODUCTION

The knee joint is required to withstand large forces over a wide range of daily activities.

On weight bearing the medial compartment of the knee is exposed to 70% of the knee

joint load generated [1]. Subsequently, the hyaline articular cartilage of the medial

compartment is prone to degeneration. Among active individuals, osteoarthritis (OA)

compromises activities of daily living and participation in sport and recreational

activities.

Hyaline articular cartilage is a terminally differentiated tissue with an inability to

regenerate. It consists of chondrocytes embedded in a matrix of proteoglycan and

collagens. This tissue can withstand high levels of mechanical stress and continuously

renews its extracellular matrix. Despite this durability, mature articular cartilage is

vulnerable to injury and disease processes that cause irreparable tissue damage. It has a

limited capacity of repair and does so through the formation of fibrocartilage.

Early unicompartmental osteoarthritis (OA) of the knee in the young and active patient

groups poses a treatment challenge, particularly in the presence of lower limb

malalignment, since preservation of native joint structures where possible is highly

desirable. Until recently, surgical options were limited to arthroscopic lavage and

debridement, marrow-tapping techniques, osteotomy and arthroplasty [2,3]. Research

into newer, alternative techniques has included osteochondral grafts [4], periosteal and

perichondral grafts [5-7], autologous chondrocyte implantation (ACI) [8], meniscal

transplant [9,10] and gene therapy [11].

Arthroscopic lavage and debridement has been shown to be of limited benefit in the

absence of mechanical symptoms [12]. Results from marrow-stimulation techniques

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(abrasion arthroplasty, subchondral drilling and microfracture) have been partially

successful in that they may reduce pain and improve mobility, but only for a limited

period [13], probably due to the inferior biomechanical properties of the fibrocartilage

produced [3,13]. These techniques may also be less effective in patients over 40 years

because of poor intrinsic healing capacity [14]. A recent randomised trial with 2 year

follow-up comparing micro-fracture and ACI (using periosteum), reported improvement

in terms of pain, Lysholm score, macroscopic and microscopic appearances but no

difference between the groups [8]. However, SF-36 (physical component) scores were

significantly higher with micro-fracture (p=0.004). Longer-term results are yet to be

published.

Periosteal and perichondral grafts have achieved good short-term results, but long-term

results are less favourable [5-7]. Results of autologous osteochondral plug transfer

(‘mosaicplasty’) are encouraging [4], although there are concerns about donor site

morbidity. Gene therapy and meniscal transplant techniques remain experimental.

Autologous chondrocyte implantation has been developed over the past four decades

[15], but only in the last 10 years has become a viable therapeutic option for the

treatment of chondral defects of the knee [16]. Histological analysis supports the

formation of hyaline or hyaline-like cartilage [8,16-21]. There are two main techniques

for implantation: a) cells injected under a flap of periosteum (PACI) or collagen (CACI)

that is sutured to adjacent chondral surfaces, or b) cells cultured on a collagen matrix

(Matrix-induced autologous chondrocyte implantation, MACI, Verigen®) fixed in place

with fibrin glue. The use of periosteum has the disadvantages of donor site morbidity,

hypertrophy of periosteum requiring re-operation and incorporation of periosteal

remnants in the cartilage [20,22]. Although using a collagen membrane (CACI) avoids

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these problems [23,24], methods involving injection of cells under a membrane are

technically more challenging with increased operating time, difficulty obtaining a seal,

and possible suture failure [7,18,23]. The MACI technique obviates many of these

difficulties [3,25]. Furthermore, it allows treatment of uncontained defects, although in

these cases matrix fixation is augmented with vicryl pins. This technique may also be

performed through a smaller incision or arthroscopically [26].

Malalignment causes progression of OA, and it is argued that correction may prevent or

slow this process [27,28]. High tibial osteotomy (HTO) may also relieve symptoms by

unloading the forces on the subchondral bone [29] and reducing intraosseous venous

pressure [30]. Success rates of HTO depend upon patient selection, meticulous surgery

and definition of ‘failure’. With conversion to total knee replacement as the end-point,

10-year survival rates of 51% to 75% have been reported in well-selected patients [31-

33]. With moderate to severe pain as the definition of failure, 10-year survival rates

vary from 28% to 66% [31,34,35]. Proponents generally agree that young, active

patients are better suited to osteotomy rather than arthroplasty, so their high levels of

activity may be maintained [2,36,37]. The degree of correction, however, is in debate.

Naudie et al. [32] reported significantly better survival when the deformity was

corrected to valgus (0-5 degrees) and maintained at one year (p<0.016). Others support

over-correction to 7-10 degrees of valgus [31,38].

Unicompartmental total knee arthroplasty (UKA) has evolved since the 1970s. Ten-

year survival figures have steadily improved from 70–85% [39,40] to 95–98% [41,42]

with the development of better quality implants and better patient selection. The use of

UKA in relatively young or active patients, however, is controversial because it

contravenes the preservation of native joint surfaces, and because of the high loads

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placed on the prosthesis [36,43,44]. Survival figures in this group are estimated to drop

significantly [43]. UKA may be indicated for young patients when HTO is

contraindicated [45].

The aim of this study was to assess combined HTO and MACI as a therapeutic option

for young patients with medial compartment OA and varus malalignment. The rationale

was to establish whether by off-loading the medial compartment, the hostile loading

environment of the arthritic knee was assuaged, allowing chondrocyte regeneration to

occur. Based on our extensive experience with MACI in the absence of malaligment

[46] we hypothesised that patients would demonstrate significant improvements in

functional and radiological scores for 12 months postsurgery, and that these

improvements would be maintained.

METHODS

Sample Patients under 60 years of age, with symptomatic medial compartment degeneration

associated with varus malalignment, were considered for inclusion. Exclusion criteria

included tricompartmental OA, previous infection or ligamentus deficiencies. Patients

were investigated pre-operatively with long-leg alignment radiographs (Maquet view)

and magnetic resonance imaging (MRI). Patient function was assessed using the six-

minute walk test (6MWT) [47] and the Knee Injury and Osteoarthritis Outcome Score

(KOOS) [48].

Fifteen suitable patients were identified for the study, including 12 males and three

females, with an average age of 46 years (range: 27-58 years), and mean BMI of 27

(range: 23-33). As well as medial compartment OA, two patients had evidence of

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osteochondritis dissecans, and two presented with early patello-femoral OA. All

patients had chronic knee problems, with a 5 year median duration of symptoms. Nine

patients had undergone previous surgery to the knee including medial meniscectomy (3

patients), arthroscopic debridement (5 patients) and arthroscopic washout (1 patient).

Mean defect size was 4 cm2 (range: 2-10 cm2), and varus deformity 6 degrees (range: 5-

8 degrees).

Surgical Technique

Arthroscopic Biopsy

Cartilage specimens were obtained arthroscopically for culture as a day-case procedure.

Specimens were taken from a non-weight bearing area of the proximal medial femoral

condyle and placed in a nutrient tube for transport to the laboratory. The cartilage was

treated enzymatically to separate chondrocytes from their matrix. Cell culture over a

period of 3-4 weeks increased cell volume to between 10-20 million cells, which were

then seeded directly onto and into the type I/III collagen membrane of 1 mm thickness

(up to 3-4 cell layers thick).

Implantation and High Tibial Osteotomy

At a mean of 6 weeks after the biospy, combined MACI and HTO procedures were

performed in one theatre session. All procedures were performed by a single surgeon.

The MACI (Figure 1a) was performed via a short medial parapatellar arthrotomy

(Figure 1b). The articular lesion was circumscribed with a scalpel to reveal healthy

cartilage. The defect was cleared of all tissue down to, but not through, subchondral

bone. A piece of the matrix cut to size was then fixed into the defect with fibrin glue in

all cases, and augmented with stitches or vicryl pins in five cases. Firm pressure was

applied to the graft for 30 seconds. After 2 minutes, the knee was put through 10 full

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range of motion manipulations to confirm stability of the graft. HTO was performed

through an inverted ‘hockey stick’ incision (Figure 1b). Eleven patients had a lateral

closing wedge osteotomy. A single medial opening wedge was performed in one

patient with leg shortening from a previous injury. The proximal tibio-fibular joint was

disrupted and the osteotomy was fixed with a compression plate in all cases (Figure 1c).

Malalignment was corrected to neutral or slight valgus, and the average operation

duration was 72 minutes (range: 60-90 minutes). Metal ware from the HTO procedure

was removed at 9 months in all patients.

(Figure 1)

Rehabilitation

Structured exercise sessions commenced prior to surgery in order to prepare patients

physically and mentally for the rigors of surgery and the lengthy post-operative

recovery. Following surgery, patients underwent a 3 month, intensive, specialised

MACI rehabilitation programme that took into consideration healing at the osteotomy

site. The underlying principle for this program was to encourage and maximise the

chondrocyte maturation process, whilst minimising the risk of graft failure through

overload or delamination [25].

Outcome Measures – Functional Assessments

Functional capacity and general gait function were determined by the 6MWT [47],

which was conducted indoors on a flat, 25 m course. Subjects were instructed to walk

as fast as possible, attempting to cover a maximum distance without over-exertion. The

final score was calculated as the total distance walked to the nearest 1.0 m. The 6MWT

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has been demonstrated to be a reliable measure of general gait function and has been

widely used for pre- and postoperative evaluation of orthopaedic patients [23,25,48].

Subjective knee function was assessed preoperatively and at regular postoperative

intervals using the KOOS, a knee-specific instrument developed by Roos et al. [49].

The KOOS evaluates both short and long-term consequences of knee injury, is self-

administered, and is responsive to changes over time and between groups [50]. The

questionnaire comprises 42 items within five domains: Pain (nine items), Symptoms

(seven items), Function in activities of daily living (ADL, 17 items), Function in sport

and recreation (five items), and Knee-related quality of life (four items) [49].

Outcome Measures - MRI Assessment

MRI scans were conducted at 3, 12 and 24 months postoperatively using a 1.5 Tesla


employing an established cartilage imaging sequence protocol [23,51]. Blinded


previously described scoring system [23]. Eight MRI parameters (defect infill, signal


subchondral bone and effusion) were scored against a series of sample images, ranked

from 1 (“Poor”) to 4 (“Excellent”) and then multiplied by a weighting factor to obtain

the final MRI composite score that ranged from 1 (worst) to 4 (best) [23]. MRI data

were also assessed in a disaggregated fashion by category, and synovitis recorded and

graded separately, as described by Marlovits et al. [52]. Intra-observer reliability

assessment was conducted using 20 image pairs in which a significant (p<0.01)

correlation (Spearmans rank order correlation) between samples was observed

188

(rho=0.787) and no significant difference was recorded between test and retest

occasions p<0.01.




indicators that included the presence of mechanical symptoms such as locking, catching

and/or associated knee joint pain. Radiologically, graft failure was defined by evidence

of suboptimal defect infill and/or evidence of internal derangement (such as clefts,

fissures, or basal delamination). Any patient that showed clinical and/or radiological

evidence of failure was referred back to the surgeon for patient-specific management.



12.0) for Windows. Three data cells were missing at the 3 month, one at the 12 month

and three at the 24 month assessment time points. An intention to treat analysis was

performed using the ‘last value carried forward’ technique (7% of data cells), and

changes between postoperative time points compared using repeated measures analysis

of variance (ANOVA). Post hoc analysis was performed using related-samples t-tests.

All reported p-values were two-tailed and p-values less than 0.05 were considered

significant.

189

RESULTS

Functional Outcomes of MACI

Statistical analysis of the functional outcome variables indicated that patients

experienced a significant (p<0.001) improvement in 6MWT and KOOS subscales -

knee pain, symptoms, ADLs, sports and recreation function, and knee-related quality of

life from pre-surgery to 24 months after MACI and HTO (Table 1).

(Table 1)

Though the combined MACI and HTO patients demonstrated an increased distance

covered in the 6MWT from pre-surgery to 24 months postoperatively, scores on this

parameter were artificially suppressed at the 3 month time point due to the weight

bearing constraints of the rehabilitation protocols. Post hoc analysis demonstrated the

improvement continued to the 24 month postoperative time point (p<0.05, Figure 2).

(Figure 2)

Post hoc analyses also revealed the improvement of knee pain, symptoms and ADLs

occurred predominantly in the first 12 months following combined MACI and HTO

then plateaued, whereas the improvement in sport and recreation function increased

‘steadily’ from 3 to 24 months (Figure 3). The knee related quality of life subscale of

the KOOS score improved significantly from 3 to 12 months following surgery, then

only marginal improvement was experienced from 12 to 24 months (p>0.05).

(Figure 3)

190

MRI Assessment of MACI

Patients demonstrated an increased MRI composite score over time that improved

significantly from 3 to 24 months postoperatively (p<0.05). Post hoc analysis

demonstrated the improvement occurred predominantly in the first 12 months (Figure

4), then plateaued at 24 months postoperatively.

(Figure 4)

At 3 months following surgery, one patient (8%) exhibited good to excellent filling of

the chondral defect, the remaining 11 (92%) exhibited fair to poor defect infill. The

signal intensity at this time was described as good to excellent in six patients (50%).

Good to excellent border integration of reparative tissue with adjacent native articular

cartilage was evident in three patients (25%), the remaining nine patients (75%)

exhibiting fair to poor integration. The surface of the reparative tissue at this stage of

recovery was good to excellent in three patients (25%), with the remaining nine patients

(75%) exhibiting fair to poor surface structure. Good to excellent subchondral lamina

was evident in all cases (indicating that it was intact at the time of surgery) and six

patients (50%) exhibited good to excellent resolution of preoperative subchondral bone

edema. Joint effusion and synovitis was evident in nine patients (75%) at the 3 month

postoperative time point. No graft hypertrophy was reported at this time.

At 12 months following combined MACI and HTO, good to excellent filling of the

defect had increased from one to four patients (33%) (Figure 5). Good to excellent

signal intensity was evident in 11 patients (92%) by 12 months post-surgery. Border

integration of reparative tissue with adjacent native articular cartilage was reported as

good to excellent in four patients (33%). The surface of the reparative tissue was intact

191

in five patients (42%) with the remaining seven (58%) exhibiting fair to poor surface

structure at the 12 month postoperative time point. Good to excellent restoration of the

subchondral lamina was again evident in all cases and five patients (42%) showed a

resolution of subchondral bone edema. The level of joint effusion and synovitis

remained unchanged from the 3 month post-operative time point.

(Figure 5)

There was no change in graft infill or signal intensity from the 12 to 24 month time

point. Six patients (50%) achieved a good to excellent rating for graft structure and

good to excellent border integration of reparative tissue with adjacent native articular

cartilage was seen in four patients (33%). The surface of the reparative tissue was intact

in six patients (50%) with the remaining grafts exhibiting fair to poor surface structure

at the 24 month postoperative time point. Effusion was persistant in six patients (50%)

(n=6), whilst synovitis had improved in a further three patients.

Complications

There were three complications related to this study. One patient developed an above-

knee deep vein thrombosis (DVT) that required anti-coagulation. Another patient had a

haemarthrosis that required evacuation. A third patient sustained a graft detachment at

2 weeks that was evident clinically and confirmed on MRI (Figure 6). This was

successfully treated with a second surgical procedure, where the graft fixation was

augmented with vicryl pins. The patient remained in the trial. There were no

complications related to the HTO. There was one unrelated death in our series; 18

months following surgery. This patient sustained a fatal closed head injury in a

mountain biking accident.

192

(Figure 6)

DISCUSSION

Chondral lesions are common: a survey of 31,516 knee arthroscopies reported their

presence in 63% of knees, with an average of 2.7 lesions per knee [53]. They may be

primary (of unknown aetiology), or secondary to trauma or osteochondritis dissecans

(OCD). Malalignment in OA may be related to trauma, previous meniscectomy or

progression of soft tissue imbalance. Symptomatic lesions tend to be those greater than

2-3 cm2, located on the load-bearing surface and with poor peripheral cartilage support

(i.e. ‘cartilage shoulders’) [13]. These tend to deteriorate rapidly, particularly in the

presence of malalignment [13,36], though early diagnosis and treatment may minimise

progression to OA [13,16,36,53,54]. Until recently, treatment options have been limited

to non-biological methods [2]. The ideal treatment involves restoration of normal knee

function by regenerating hyaline cartilage [20]. The rationale for this study was to

achieve this by optimising the environment for chondrocyte implantation by combining

it with a corrective osteotomy.

It is commonly accepted that underlying malalignment at the knee must be corrected

prior to implantation of a chondrocyte graft [13,16,18,36,56]. Only one author has

reported data on a series of patients with combined HTO and ACI, in which a

significant improvement in the Cincinnati Knee Score (p=0.02) was documented at the

12 month follow-up [57]. However, the indications for HTO were varied and

comparisons with our research, in which HTO was performed purely for varus

deformity, is difficult. Wide variations in the extent of disease also adds to the

difficulty of comparing results between studies. A standardised classification system

193

was therefore proposed by Minas [13]. Patients were divided into three groups: simple

(unipolar lesions), complex (including multifocal lesions, OCD, uncontained defects

and associated malalignment), or salvage reconstruction (bipolar lesions and early OA).

However, as conceded by the author in a later publication [57] this system may be

overly broad, since it is not clear in which category our current group of patients fall as

they all exhibited both malalignment and early OA, and in some cases, uncontained

defects.

Knee function was assessed via the KOOS [49], which has been validated for the

assessment of knee pain and function during activities of daily living. This survey tool

has proven to be reliable, responsive to surgery and physical therapy, and evaluates the

course of knee injury and treatment outcome [50]. At the 3 month time point following

surgery, the poor knee function, as evidenced in the KOOS, was primarily due to the

postoperative restraints placed on the patient in order to protect the integrity of an

immature MACI graft [25].

Subjective knee function among our patients improved over time in parallel with the

maturation process of the regenerating graft. Patients in our study experienced

significant reduction in knee pain, and improvements in sports and recreation function,

activities of daily living, and knee-related quality of life from 3 to 24 months, with the

majority of this improvement, occurring in the first 6 to 12 months. The 24 month

KOOS results from our study indicated that these early improvements following surgery

were maintained over time.



194

activities of daily living. Prior to surgery, the average 6MWT distance was 577 m.

This capacity decreased to 456 m at the 3 month postoperative time point; most

probably the result of the trauma of surgery and early postoperative restraints [24].

Following this initial decrease, walk distance improved to the 24 month postoperative

time point, and this capacity improved incrementaly at each of the post-operative test

points.

The present study demonstrated an increased MRI composite score over time that

improved significantly from 3 to 24 months postoperatively. Post hoc analyses revealed

the improvement occurred predominantly in the first 12 months, then plateaued, but did

not decline. This indicated that regenerated graft tissue following combined MACI and

HTO maintains its maturity and function from the 12 to 24 month postoperative time

point, a result that is comparable to the PACI, CACI and MACI procedures [21,23,46].

However, several of the MACI and HTO cases in this series exhibited graft infill of the

majority of the defect, with a small residual Outerbridge Grade IV defect. All of the

grafts were scored according to the worst appearance area of the graft. Subsequently,

this limited the ability of the scoring system to accurately represent the status of the

graft. The area of residual Grade IV change was located at the non-contained notch

margin of the graft in the majority of cases. No cases of graft hypertrophy were seen in

this series.

Our study has a number of limitations, including a small sample size (n=15), and

perhaps more importantly, we did not have a control group for comparison. The latter

limitation makes establishment of the relative benefit of the individual procedures

performed impossible. Ideally we would perform a randomised controlled trial, but the

limited number of patients suitable for this treatment precludes this. However, we have

195

commented on the presence and quality of the graft at 24 months and believe it is

reasonable to attribute some of the clinical improvement to the combined intervention.

CONCLUSION

Young and active patients with OA associated with varus deformity of the knee are a

difficult patient group to treat, and to date no defined protocols exist. We describe the

first series treated with combined MACI and HTO. Results show a significant

functional improvement, supported by radiographic evidence of deformity correction.

This study also provides novel insight into the morphological progression of the

regenerative tissue produced following combined MACI and HTO through the use of

established MRI evaluation parameters.

ACKNOWLEDGEMENTS

The studies presented in this thesis were funded by a research grant provided by The

National Health and Medical Research Council (ID Number: 254622), administered by

the Council on behalf of the Australian Government. Unless otherwise specified, the

data given in this thesis is based on work carried out at the University of Western

Australia.

196

Table 1. Descriptive Statistics and ANOVA Summary for Functional Outcome Variables (n=15). Postoperative time point (months)


6-min walk (m) Mean 577 456a 552b 594c 612 d

SD 111 117 135 90 96 16.6 p<0.001

KOOS - subscales Pain Mean 52.3 74.2a 71.0 76.0 77.5 SD 20.8 12.0 15.2 15.8 18.3 11.2 p<0.001

Symptoms Mean 60.0 80.3 a 78.4 80.0 79.1 SD 21.0 11.2 13.1 15.3 13.2 7.5 p<0.001

Activities of Mean 61.2 81.0a 81.0 87.0 89.0 daily living SD 19.0 8.4 12.0 16.5 10.5 17.1 p<0.001

Sport & Mean 14.5 5.0 17.5b 40.1c 48.5 d

recreation SD 17.0 9.0 19.2 27.4 32.0 14.4 p<0.001

function Knee related Mean 18.1 32.4a 34.0 41.3 43.0 quality of life SD 10.0 17.0 13.1 22.5 25.0 7.6 p<0.001

a = significant difference (p<0.05) presurgery vs 3 months b = significant difference (p<0.05) 3 months vs 6 months c = significant difference (p<0.05) 6 months vs 12 months d = significant difference (p<0.05) 12 months vs 24 months

201

1.

2.2.

1.

2.

Fig. 1.A. Schematic diagram of the MACI surgerical technique (picture curtesy of Verigen Australia). B. Surgical incision sites 1. MACI incision site (medial parapatellar) 2. HTO ‘inverted hockey stick’ incision site. C. Postoperative fluroscope of HTO insitu.

Fig. 2. Changes in six-minute walk distance (m) at pre- and post-surgery assessment time points (x±SE, n = 15).

202

Fig. 3. Changes in the five sub domains of KOOS at pre- and post-surgery assessment time points (x±SE, n=15). Total KOOS scores (0 = extreme knee problems and 100 = no knee problems), ADL = activities of daily living, Sport&Rec = sport and recreation function, KQOL = knee-related quality of life.

Fig. 4. Changes in MRI composite score at post-surgery assessment time points (x±SE).

203

Fig. 5.A. Coronal proton density fast spin echo magnetic resonance image of a combined HTO and MACI patient one year following surgery. The graft (depicted between the two arrow heads) is hypointense compared to surrounding native tissue. B. The Saggital view reveals that the graft approximates the height of the surrounding native tissue. The signal intensity is hypointense when compared to the native tissue, however, border integration is smooth and the preoperative subchondral bone oedema that was present preoperatively has resolved.

Fig. 6.A. Sagittal proton density fast spin echo magnetic resonance image of a delaminated MACI graft 3 days post implantation (arrow). B. Sagittal proton density fast spin echo magnetic resonance image of the MACI graft following reattachment augmented with Vicryl pins).

204

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CHAPTER SEVEN

SUMMARY, RECOMMENDATIONS

AND CONCLUSIONS

SUMMARY

In Australia, there was a sequential evolution of the ACI technique from the

conventional periosteum covered ACI (PACI), to the use of a porcine collagen type I/III

membrane sutured as a periosteal substitute (CACI). The CACI technique was then

further modified to the current practice of a): first seeding the cultured autologous

chondrocytes onto the cambium layer of the type I/III membrane and then, b):

implanting the cell-seeded membrane as a single construct via the matrix-induced

autologous chondrocyte implantation technique (MACI). This thesis has concentrated

on the CACI and MACI techniques, since the PACI method has been shown to involve

a number of short comings [21,30,40,54,55,81].



To address these problems, a biodegradable type I/III collagen membrane was

developed for use in conjunction with ACI. This membrane comprised highly purified

porcine collagen and exhibited excellent biocompatibility and low immunogenicity.

The membrane was designed to reproduce the physiological barrier functions of the

periosteum. Prior to the commencement of this thesis, definitive evidence regarding the

role of the membrane in enhancing chondrocyte-mediated cartilage regeneration was

sparse. There also existed discrepancies in the literature with regard to the

quantification of the ACI surgical outcome. The effectiveness of this new treatment

was often limited to clinical evaluation and opportunistic arthroscopic examination.

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Arthroscopic examination and biopsy as routine follow-up remains controversial.

Clinical evaluation is important to track the patient symptoms, however, it is yet to be

correlated with arthroscopic or MRI data. This thesis provides novel insight into the

morphological progression of the regenerative tissue produced following CACI and

MACI through the use of established MRI evaluation parameters [50,51]. The results

compliment the currently available clinical and histological information on CACI and

MACI, and with MRI assessment of the cartilage repair, a better understanding of the

outcome of ACI with a collagen membrane is afforded.

At the point in time that CACI was introduced into Australia (February 1999),

information pertaining to the most appropriate post-operative rehabilitation pathway

following implantation was scarce, while that for the newer MACI technique was non-

existent. As no guidelines other than those pertaining to PACI existed, it was necessary

to develop a specific rehabilitation protocol for collagen covered and matrix induced

ACI that was based on biological principles underlying postoperative biomechanical

stimulation of chondrocyte biosynthesis. Whilst structured rehabilitation cannot

guarantee clinical success following MACI, results from this series of studies

demonstrate that the introduction of biomechanical stimuli through controlled

postoperative rehabilitation may indeed act to enhance cartilage matrix synthesis and

aid both qualitative and quantitative aspects of cartilage repair.

Rehabilitation

The biological principle underlying our rehabilitation protocol for MACI is based on

postoperative biomechanical stimulation leading to chondrocyte biosynthesis. That is,

the rehabilitation protocol is designed to activate the cell-mediated progression of

206

regenerative cartilage into physiologically functional articular cartilage. The

neocartilage formed following MACI surgery is characterised by tissue that is high in

cell density, water, and type II collagen content, but of weak biomechanical resilience.

After cell cultivation and surgical technique, the key to the therapeutic success of MACI

is the maturation of neocartilage to functional cartilage through healthy extracellular

matrix production by chondrocytes post-implantation, a process heavily reliant on

effective rehabilitation.

The rehabilitation protocol presented in this thesis (Chapter three) was well tolerated by

all patients; however, the single incidence of graft delamination (Chapter five)

highlights the clinical importance of a protection phase coupled with patient compliance

during the first three months following implantation. The cellular regeneration, matrix

production and adaptation of the regenerating tissue to natural function involves a

combination of time and appropriate biomechanical stimulus. Therefore, it is not only

important to encourage successful maturation of the implanted graft, but it is vital that

the integrity of the graft be appropriately protected during all phases of the

postoperative rehabilitation process. Additionally, the results support early mobilisation

via CPM (rather than immobilisation) in conjunction with rehabilitation protocols that

incorporate all of the complexities associated with each individual case [81,83].

Magnetic Resonance Imaging

Routine arthroscopic examination and biopsy is costly and it is often difficult to gain the

patient’s consent to a third invasive procedure. Also, the high incidence of inadequate

biopsies (55% as reported by ICRS [38]) precludes meaningful interpretation in the

majority of specimens. We consider it unethical to subject ACI patients to routine

207

‘second-look’ arthroscopies and biopsy when the ACI graft is considered to be

functioning well from a clinical perspective. Therefore, we have sought to examine the

potential for MRI assessment as a postoperative measure of graft outcome and

durability. Its role in the evaluation of cartilage repair is well supported in the literature

[4,20,63,84]. This series of studies provided novel insight into the morphological

progression of the regenerative tissue produced following CACI and MACI through the

use of established MRI evaluation parameters. These results supplement the clinical,

radiographical and histological information on MACI, so that a better understanding of

the outcome of ACI with a collagen membrane is afforded.

Substitution of Periosteum with a Type I/III Collagen Membrane

Results from these studies also revealed that many of the problems associated with

PACI could be addressed by replacing the periosteum with an inert collagen membrane.

Additional benefits of the collagen membrane include simplification of the operative

technique, reduced anaesthetic time, and the abolishment of periosteal harvesting. Our

results also indicated that the incidence of tissue hypertrophy was minimised, because

unlike periosteum, the collagen membrane is acellular. This result is consistent with

others reported the literature [31] for ACI using a type I/III collagen membrane.

RECOMMENDATIONS FOR FUTURE RESEARCH

This thesis provides novel insight into the morphological progression of the

regenerative tissue produced following CACI and MACI through the use of established

MRI evaluation parameters. The development of our graduated load-bearing

rehabilitation protocol has been specifically targeted to provide an appropriate

biomechanical stimulus over the first postoperative year to maximise chondrocyte-

208

mediated defect regeneration. However, the problem still faced is what constitutes

‘optimal’ postoperative rehabilitation?

Current rehabilitation protocols are based on theoretical models since randomised,

controlled trials investigating various postoperative rehabilitation protocols following

ACI have yet to be reported. This is because, historically, the primary focus in the

literature has been on surgical technique, modification of delivery systems, histological

versus radiological assessments and chondrocyte biology. Whilst the role of

postoperative rehabilitation has been acknowledged, it has taken a ‘back seat’ to the

aforementioned topics.

From a rehabilitation clinician’s point of view, this lack of knowledge is extremely

frustrating, as we have been effectively forced to ‘fly blind’. Postoperatively, if we

push the patient too aggressively, we risk graft delamination and subsequent graft

failure. However, if we progress too conservatively, we risk affecting the regeneration

of tissue due to inadequate loading stimuli. In turn, this may lead to the associated

problems of muscle atrophy, interarticular adhesions, gait abnormalities and thus

generate a subsequent pain-inactivity spiral. Every patient is unique as they present

with different defect locations and inherent individual regenerative capacity.

Rehabilitation therapists require defect-specific rehabilitation protocols guided by

accurate, non-invasive methods of graft assessment that are predictive of functional

capacity. This will allow the patient safe progression of functional activity, which will

be of direct benefit to patient outcome and to clinical practice. Additionally,

randomised controlled trials investigating current versus alternative methods of load

bearing are required in order to provide evidence-based treatment parameters. Further

209

research into the role of postoperative rehabilitation following ACI is required, as

current practice has not kept pace with the recent advances in the field of cartilage

repair.

Young and active patients with OA associated with varus deformity of the knee are a

difficult patient group to treat, and to date no defined protocols exist. Most surgical

options are palliative. Within this thesis, the first patient series treated with combined

MACI and HTO was described. Results show a significant functional improvement,

supported by radiographic evidence of deformity correction. The data provide novel

insight regarding the morphological progression of regenerative tissue produced

following combined MACI and HTO through the use of established MRI evaluation

parameters. However, several of the MACI and HTO cases in this series exhibited graft

infill of the majority of the defect, with a small residual Outerbridge Grade IV defect.

All of the grafts were scored according to the worst appearance area of the graft.

Subsequently, this limited the ability of the scoring system to accurately represent the

status of the graft.

Further investigation of the relationship between MRI and clinical outcome following

chondrocyte implantation is imperative as it remains to be determined whether the

native ultra structure of cartilage needs to be restored in order to achieve good, durable,

clinical results. The current focus needs to shift from morphological assessment of the

ACI graft, to the development of reliable, in vivo measures of the quality of regenerated

tissue. Advanced MRI techniques such as T2 mapping have the capability to map the

distribution of collagen throughout the articular surface. Alternatively, the distribution

of cartilage glycosaminoglycan (GAG) can now be measured by delayed Gadolinium

210

Enhanced MRI of Cartilage (dGEMRIC). The ability to monitor GAG content in a

cartilage repair site will assist in determining the physiological state of the repair tissue.

The information provided by these advanced MRI protocols will complement the

current morphological assessment techniques and have the potential to bridge the

current gap between histological and radiological outcome following ACI.

CONCLUSIONS

Initially, collagen membrane was simply used to replace the periosteal patch which

sealed the cell solution into the chondral void. This was termed collagen-covered ACI.

Although CACI has exhibited commendable histological and clinical outcomes, its

surgical efficiency is impeded by the need to microsuture the membrane to the defect

border, a tedious task that increases the length and technical difficulty of the operation.

Furthermore, concerns remain surrounding cell delivery, the possibility of cell leakage

through the graft-cartilage interface, and the creation of microdefects by suturing [84].

The MACI technique involves direct cell inoculation onto a collagen scaffold for

implantation. Instead of an injection of chondrocytes under the collagen membrane into

the sealed defect compartment (CACI), chondrocytes are directly inoculated onto type

I/III collagen membrane and delivered as a cell-scaffold construct for implantation. This

study demonstrated that the MACI approach with complementary rehabilitation yields

regenerated functional infill material, and patients experienced improved knee function

and MRI scores in the short to mid-term. The development of MACI decreases

operative time, allows a smaller surgical incision, and facilitates postoperative recovery.

These data also show that the MACI procedure reduces the incidence of postoperative

complications, especially the incidence of tissue hypertrophy.

211

Based on our experience with MACI to the medial femoral condyle, we have reported

the first patient series treated with combined MACI and HTO. Our aim was to assess

combined HTO and MACI as a therapeutic option for young patients with medial

compartment OA and varus malalignment. The rationale was to establish whether by

off-loading the medial compartment, the hostile loading environment of the arthritic

knee was assuaged, allowing chondrocyte regeneration to proceed. Results showed a

significant functional improvement, supported by radiographic evidence of deformity

correction. However, this study had a number of limitations, including a small sample

size (n=15), and perhaps more importantly, we did not have a control group for

comparison. The latter limitation makes establishment of the relative benefit of the

individual procedures performed impossible. Ideally, we would have performed a

randomised controlled trial, but the limited number of patients suitable for this

treatment precluded such a research design. However, we have commented on the

presence and quality of the graft at 24 months and believe it is reasonable to attribute

some of the clinical improvement to the combined intervention.


and graduated return to ambulation and physical activity, as well as the biomechanical

stimulation of the implanted chondrocytes. Therefore, reduced cartilage thickness

and/or matrix synthesis observed in some patients may be related to a lack of

biomechanical stimulation of the graft. The introduction of biomechanical stimuli

through controlled postoperative rehabilitation in the first three months may enhance

cartilage matrix synthesis and aid both qualitative and quantitative aspects of cartilage

repair.

212

This thesis provides new insight into the morphological progression of the regenerative

tissue produced following CACI, MACI and combined HTO and MACI through the use

of the established MRI evaluation parameters. These results supplement the clinical,

radiological and histological information on ACI, so that a better understanding of the

outcome of ACI with a collagen membrane is afforded. Further investigation of the

relationship between MRI and clinical outcome following chondrocyte implantation is

imperative as it remains to be determined whether the native ultra structure of cartilage

needs to be restored in order to achieve good, durable, clinical results.

213

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APPENDIX ONE

COMBINED ANTEROMEDIALISATION TIBIAL TUBERCLE OSTEOTOMY AND AUTOLOGOUS CHONDROCYTE IMPLANTATION (C-ACI & MACI) FOR THE TREATMENT OF ISOLATED CHONDRAL DEFECTS OF THE

PATELLOFEMORAL JOINT.

Note 1. References cited in this appendix appear in a reference list at the end of

the paper. Note 2. Tables and Figures noted within this appendix appear at the end of the

paper.

Title: Combined anteromedialisation tibial tubercle osteotomy and autologous chondrocyte implantation (C-ACI & MACI) for the treatment of isolated chondral defects of the patellofemoral joint. Keywords: Osteochondral defect, Autologous chondrocyte implantation, Patellofemoral joint.

1.) M. Ledger MBBS* University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA


3.) D. Fick MBBS* PhD Student University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA




* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Nedlands, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Nedlands, WA 6009 Australia. Correspondence: Mr William Brett Robertson University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]


ABSTRACT Despite initial failures, Autologous Chondrocyte Implantation (ACI) treatment for patellofemoral cartilage defects has improved more recently when combined with attention to, and surgical correction of patellofemoral pathomechanics. ACI technology has also progressed to collagen-covered (C-ACI) and matrix-induced ACI (MACI) 16 patients with 17 patellofemoral cartilage defects were treated with either C-ACI or MACI and realignment procedures when indicated. 6-minute walk test, Knee Injury and Osteoarthritis Outcome Scores (KOOS), and Magnetic Resonance Imaging studies were obtained at regular intervals to 24 months. Changes between pre- and post-operative time points were compared using repeated measures analysis of variance. As a combined group, 6-minute walk test significantly improved from pre-surgery to 24 months (p<0.001). There was also significant improvement across all five KOOS subscales (p<0.05). There was no significant difference detected in functional outcomes between the C-ACI or MACI groups. There were no graft failures and MRI composite graft scores improved significantly from 3 months to 24 months postoperatively (p<0.05).

INTRODUCTION

Patients with chondral defects involving the articulating surfaces of the patellofemoral

joint are a difficult group to treat. This is because these defects are usually secondary

to pathological abnormalities or imbalances between the static (osseous and

ligamentous) elements or dynamic (neuromuscular) factors contributing to

patellofemoral function [1]. Autologous chondrocyte implantation (ACI) for the

repair of articular cartilage defects in the knee has gained increasing acceptance in the

last decade as a useful treatment modality, however, the initial results of ACI for

repair of patella defects were poor [2]. With time, the results for patella ACI have

improved, with attention to patella maltracking, realignment of the extensor

mechanism where indicated, and a subsequent reduction in abnormal forces across the

patellofemoral joint likely to cause graft failure [3-6].

There are few studies examining the outcomes of newer techniques of collagen-

covered autologous chondrocyte implantation (C-ACI) and matrix-induced

autologous chondrocyte implantation (MACI) in patients with isolated patellofemoral

cartilage defects. Further complicating matters, the success of anteromedialisation

tibial tubercle osteotomy alone without ACI has been shown to correlate the anatomic

location of the patella defect [7]. This potentially obscures a review of combined ACI

/ patellofemoral realignment procedures and many previous studies reviewing the

success of patellofemoral ACI have not allowed for this.

We present our functional and MRI outcome measures of C-ACI and MACI

techniques applied to the treatment of anatomically defined cartilage defects in the

patellofemoral joint.

MATERIALS AND METHODS

Sample

Patients were selected according to the inclusion and exclusion criteria guidelines

outlined by Peterson [8]. Seventeen patellofemoral ACI surgeries were performed in

16 patients (8 male and 8 female) between December 1999 and June 2005. All

implantations survived to a minimum of 24 months. Preoperative assessment

included a clinical examination with particular attention to patellofemoral tracking, a

patellofemoral computerized topography (CT) geometry scan, and an magnetic

resonance imaging (MRI) scan.

The mean age at time of surgery was 37.5 years (range: 23-57 years). All had full

thickness chondral lesions as diagnosed by preoperative MRI and confirmed at

arthroscopic biopsy with a mean of 4.3 cm2 (range: 1.0-9.0 cm2). Of the cohort, one

case presented with a concomitant medial femoral condyle lesion; the remainder had

single defects. The etiology of defects in order of frequency was patellofemoral

arthritis associated with maltracking (11 cases), traumatic patella dislocation (4 cases)

and defect post-septic arthritis (one case). According to Faulkerson [11], the

anatomical distribution of defects was: inferior pole-4, lateral facet-2, medial facet-3,

proximal-1, panpatellar-5 and trochlear groove-2. Ten patients had not had prior

surgery specifically for their patellofemoral cartilage defect. Two patients had

previous extensor realignment by tibial tubercle transfer and a further five patients

previously underwent arthroscopy with patellofemoral chondroplasty, lateral release,

or both. One patient previously had a medial femoral condyle cartilage defect treated

with MACI three years prior to the patellofemoral treatment. In the cohort, 10

patients underwent MACI (8 patella, 2 trochlea) and 7 patients underwent C-ACI (7

patella).

Surgical Technique

All surgery was performed by the senior author (DJW). Autologous chondrocytes

were harvested arthroscopically six weeks prior to implantation via C-ACI or MACI

techniques described previously [9,10]. Either a medial or lateral parapatellar

approach was utilised. Tibial tubercle anteromedialisation according to Faulkerson

[11] was performed if there was clinical evidence of maltracking or the preoperative

CT scan demonstrated tubercle lateralization of greater than 9 mm [12]. A lateral

release according to Hughson [13] was performed if there was evidence of lateral

patellar retinacular tightness contributing to maltracking or subluxation.

Outcome Measures

Functional assessment was performed at 3,6,12 and 24 months. The previously

validated 6 minute walk test (6MWT) [14] and Knee Injury and Osteoarthritis

Outcome Score [15] was measured.

MRI scans were conducted at 3, 12 and 24 months postoperatively using a 1.5 Tesla


employing an established cartilage imaging sequence protocol[9,16]. A blinded


previously described scoring system [9]. Each MRI parameter (defect infill, signal


subchondral bone and effusion) was scored against a series of sample images, ranked

from 1=“Poor” to 4=“Excellent” then multiplied by a weighting factor [9] to obtain

the final MRI composite score. MRI data was also assessed in disaggregated fashion

by category in accordance to the recommendations of Marlovits et al. [17]. Synovitis

was recorded and graded separately in accordance with the definition given by

Marlovits et al. [17]. Intra-observer reliability assessment was conducted using 20

image pairs in which a significant (p<0.01) correlation (Spearman’s Rank Order

Correlation) between samples was observed (rho=0.787) and no significant difference

was recorded between test and retest images (p<0.01).




indicators that included the presence of mechanical symptoms such as locking,

catching and/or associated knee joint pain. Radiographically, graft failure was

defined by evidence of suboptimal defect infill and/or evidence of internal

derangement (such as clefts, fissures, or basal delamination). Any that showed

clinical and/or radiographical evidence of failure would be referred back to the

surgeon for patient-specific management.

Statistical Analylsis


12.0) for Windows. Missing data were addressed by performing an intention to treat

analysis using the “last value carried forward” technique (less than five % of data),

and changes between pre and postoperative time points compared using repeated

measures analysis of variance (two factor ANOVA). Post-hoc analysis was

performed using dependant variable t-test. All reported p-values were two-tailed and

p-values less than 0.05 were considered significant.

RESULTS

Functional Outcomes (Table 1)

There was significant improvement over time from pre-surgery to 24 months post

implantation for the 6MWT for all patients (p<0.001). There was no significant

difference was detected between C-ACI and MACI groups (Figure 1).

(Figure 1)

Significant improvement over time from pre-surgery to 24 months post implantation

was observed in all of the five KOOS domain subscales for all patients (p<0.05).

There was no significant difference between MACI and C-ACI groups with the

exception of the symptoms subscale pre-operatively (Figure 2).

(Figure 2)

MRI Assessment of Patella ACI Grafts

Patients demonstrated an increased MRI composite score over time that improved

significantly from 3 months to 24 months postoperatively (p<0.05). Post-hoc analysis

demonstrated the improvement occurred linearly from three to 12 months and from 12

to 24 months post-surgery (Figure 3).

(Figure 3)

Three months following surgery, 38% (n=5) of the patient cohort exhibited good to

excellent filling of the chondral defect, the remaining 62% (n=8) exhibited fair to

poor defect infill. The signal intensity at this time point was described as good to

excellent in only 7% (n=1) of patients. Good to excellent border integration of

reparative tissue with adjacent native articular cartilage was evident in 62% (n=8) of

patients, with fair to poor integration present in the remaining 38% (n=5) of cases.

The surface of the reparative tissue at this stage of recovery was good to excellent in

69% (n=9) of cases with the remaining 31% (n=4) exhibiting fair to poor surface

structure. Good to excellent subchondral lamina was evident in 85% (n=11) of the

patient cohort (indicative that it was intact at the time of surgery) and 62% (n=8) of

the patients exhibited good to excellent resolution of preoperative subchondral bone

edema. Joint effusion was evident in 70% (n=9) of the patients and 85% (n=11)

exhibited synovitis at the 3 month postoperative time point. No graft hypertrophy

was reported at the 3 month postoperative time point.

Twelve months following surgery, good to excellent filling of the defect had

increased to 46% (n=6) of patients. The signal intensity had increased from 7% (n=1)

reported as good to excellent to 62% (n=8). Good to excellent border integration of

reparative tissue with adjacent native articular cartilage was seen in 62% (n=8) of

cases. The surface of the reparative tissue was intact in 69% (n=9) of patients with

the remaining 31% (n=4) fair to poor surface structure at the 12 month postoperative

time point. Good to excellent restoration of the subchondral lamina was evident in

92% of patients (n=11) and 77% (n=10) of patients showed a resolution of

subchondral bone oedema. Fair to poor effusion remained in 54% (n=7) of the patient

population and 62% (n=8) of cases had persistent synovitis. No hypertrophy was seen

at this time point.

By 24 months following surgery, defect infill had improved from 46% (n=6) to 62%

(n=8), signal intensity improved to 77% (n=10) good to excellent reported in the

patient population. Graft structure had achieved a good to excellent rating in 85%

(n=11) of cases. Good to excellent border integration of reparative tissue with

adjacent native articular cartilage was seen in 69% (n=9) of cases. The surface of the

reparative tissue was intact in 77% (n=10) of grafts with the remaining grafts

exhibiting fair to poor surface structure at the 24 month postoperative time point.

Effusion was present in 25% (n=2) of case and synovitis had improved from 62 %

down to 38 % (n=5) of the patient sample.

DISCUSSION

Articular cartilage is approximately 70% water by weight. The remainder of the


latter contain negative charges that attract sodium ions (Na+) in intact cartilage. MRI

is an accurate and non-invasive imaging modality that can delineate signal and

morphological changes in articular cartilage [18] making it an attractive research tool

in the evaluation of chondrocyte grafting [19-23]. The correlation between MRI

outcome and graft histological outcome has yet to be determined, though recent

studies have attempted to correlate these two outcome measures with mixed results

[22,24]. MRI imaging allows non-invasive serial follow-up of patients

postoperatively. It assesses the entire graft and its integration to the subchondral bone

plate and the adjacent native articular cartilage [23]. In addition, it allows non-

invasive detection of postoperative complications and its role in the evaluation of

cartilage repair is well supported in the literature [18-22].

The first techniques of ACI involved injecting a suspension of cultured chondrocytes

into a debrided chondral defect under a locally harvested periosteal cover (P-ACI).

Problems relating to the periosteal cover such as graft hypertrophy, calcification,

delamination, and morbidity relating to the periosteal harvest brought the

development of C-ACI, which utilises a biodegradable porcine-derived typeI/typeIII

collagen cover. Concerns over uneven distribution of chondrocyte cells implanted as

a suspension and the potential for leakage have been overcome by matrix-induced

autologous cartilage implantation (MACI). Here, a biodegradable scaffold as a

membrane impregnated with chondrocyte cells is held in place with fibrin glue

without the need for suturing the graft. We have found this technique technically less

demanding and associated with a shorter surgical time.

We believe that the overall improvement in functional outcomes and MRI graft

evaluation over time seen in this patient group support the use of C-ACI and MACI

for chondral defects in the patellofemoral joint. We found a greater percentage

functional improvement in the subset of patients with lateral facet and inferior pole

lesions, which approached statistical significance in the overall KOOS score (p=0.09),

however Minas and Bryant [3] have suggested corrective osteotomy without ACI for

this patient group in their treatment algorithm. Whilst it is certain that corrective

osteotomy in this group unloads the damaged patella, it is possible that restoring

articular homeostasis also has an independent, additive treatment effect.

No patients in this study suffered from graft failure. The most recently published

series of patients treated with patellofemoral P-ACI had a graft failure rate of 18% at

a minimum of 2 years [3]. Whether this difference is due to the use of newer ACI

techniques and absence of a periosteal patch is unknown.

Whilst there were no significant differences between the two ACI techniques, the

numbers in each group were small. Whilst both groups are generally similar, it is

worth noting that there were no worker’s compensation cases in the MACI group as

opposed to the C-ACI group and this is probably reflected in the differences seen in

the pre-operative pain KOOS subscale. We have also not included control subjects in

this study, which may have been helpful in quantifying the effect of realignment

procedures without ACI.

The results of patellofemoral P-ACI out to 9 years have been released with good to

excellent results in 76% of cases [5]. The early results of advanced patellofemoral

ACI techniques utilised in this study are encouraging and will require follow-up in the

long term.

ACKNOWLEDGEMENTS


Medical Research Council (ID Number: 254622), it was administered by the council

on behalf of the Australian Government. Unless otherwise specified, the data given in

this review is based on work carried out at the University of Western Australia.

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Descriptive Statistics and ANOVA Summary for CACI&MACI Patella Patients (n=17).

Postoperative time point (months)


6-min Walk Distance Mean 545 438 529 581 590a Combined (n=17)

6-min walk (m) SD 166 88 112 124 105 12.5 p<0.001

Mean 509 440 526 574 592 CACI (n=7)

6-min walk (m) SD 148 74 140 175 142 Mean 580 436 531 589 590 MACI (n=10)

6-min walk (m) SD 74 106 90 66 68

0.8 NS

KOOS - subscales

Mean 59 69 70 75 72 Combined (n=17)

Pain SD 20 14 22 16 22 2.5 p<0.05

Mean 49 68 74 73 73 CACI (n=7)

Pain SD 13 13 23 22 22 Mean 69 70 67 77 70 MACI (n=10)

Pain SD 21 16 22 19 24

2.6 NS

Mean 60 78 79 79 78a Combined (n=17)

Symptoms SD 18 11 12 15 19 10.2 p<0.001

Mean 47* 74 79 79 73 CACI (n=7)

Symptoms SD 9 10 13 17 20 Mean 72* 81 79 84 84 MACI (n=10)

Symptoms SD 16 10 11 11 17

3.2 p<0.05

Mean 63 72 78 80 77 Combined (n=17)

Activities of daily living SD 19 15 17 15 23 3.6 p<0.05

Mean 53 70 81 76 76 CACI (n=7)

Activities of Daily Living SD 10 16 13 16 22 Mean 73 74 74 86 78 MACI (n=10)

Activities of Daily Living SD 21 17 21 13 25

1.8 NS

Mean 24 5 14 24 37 Combined (n=17)

Sport&Recreation Function SD 26 10 20 27 33 5.0 p<0.05

Mean 10 8 20 23 40 CACI (n=7)

Sport&Recreation Function SD 15 14 28 35 40 Mean 38 3 8 26 35 MACI (n=10)

Sport&Recreation Function SD 28 5 7 20 27

2.1 NS

Mean 25 32 37 44 45 a Combined (n=17)

Knee related quality of life SD 16 22 24 29 28 3.5 p<0.05

Mean 20 32 40 43 54 CACI (n=7)

Knee related quality of life SD 7 12 18 27 26 Mean 29 33 34 45 35 MACI (n=10)

Knee related quality of life SD 22 30 30 32 28

1.4 NS

a = significant difference (p<0.05) presurgery vs 24 months

400

450

500

550

600

Presurgery Post+3 Post+6 Post+12 Post+24

Time (months)

Dis

tanc

e w

alke

d in

six

min

utes

(m)

650

CACI&MACI Patella Patients (n=17, p<0.05) CACI Patella Patients (n=7) MACI Patella Patients (n=10)

Fig. 1. Six minute walk test. (Combined, with CACI mean, n=7 & MACI

ean n=10)

m

igure 2. Knee Injury and Osteoarthritis Outcome Scores (by subscale, n=17)

F

0

2

4

6

8

10

Presurgery Post+3 Post+6 Post+12 Post+24Time (months)

Tran

sfor

med

Sco

re (0

=wor

st, 1

00=b

est)

0

0

0

0

0

Pain Symptoms ADL's Sport & Rec KQOL

Fig. 3. Changes in MRI composite score at post-surgery assessment time points (x ± SE).

functional and radiological evaluation of … · functional and radiological evaluation of...

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