FRACTURE UNION AND RECENT ADVANCES

Prepared by:Dr Dipendra MaharjanFirst year resident

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• Fracture is defined as a – break in the continuity of bone– results in loss of its mechanical stability – partial destruction of blood supply.

• But following fracture a scar is not formed, instead a bone has formed

• bone healing the appropriate nomenclature would be BONE REGENERATION

What is Fracture?

What is a Fracture Healing?

• A complex process that requires the recruitment of appropriate cells

• the subsequent expression of the appropriate genes at the right time and in the right anatomical location.

• A fracture initiates a sequence of inflammation, repair, and remodeling that can restore the injured bone to its original state or near original state.

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There are 3 major phases with sub divisions:

• Reactive Phase– Fracture and inflammatory phase– Stage of hematoma formation– Granulation tissue formation.

• Reparative Phase:– Cartilage Callus formation.– Lamellar bone deposition.

• Remodeling Phase:– Remodeling to original bone contour.

STAGES OF FRACTURE HEALING

FACTURE UNION

• Union is incomplete repair and the ensheathing callus is calcified.

• Clinically the fracture site is still a little tender, the bone moves in one piece, attempted angulation is painful.

• X-Rays show the fracture line still clearly visible, with fluffy callus around it.

• Repair is incomplete and it is not safe to subject the unprotected bone to stress.

• Clinical union – occurs when progressively increasing stiffness and

strength provided by the mineralization process makes the fracture site stable and pain free.

• Radiographic union – present when plain radiographs show bone

trabeculae or cortical bone crossing the fracture site.

• Radioisotope studies have shown increased activity in fracture sites long after painless function has been restored and radiographic union is present, indicating that the remodeling process continues for years.

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• Local factors• Chemical factors• Vascular factors• Systemic factors• Electromagnetic factors• Treatment factors

INFLUENCING FACTORS

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A.Type of boneB. Degree of TraumaC.Vascular InjuryD. Degree of ImmobilizationE. Type of FracturesF. others: Bone death caused by

radiation thermal chemical burns infection.

LOCAL FACTORS

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1.MESSENGER 2.GROWTH 3.PERMEABILITYSUBSTANCES FACTORS FACTORS-Serotonin -Transforming GF -Proteases-Prostaglandins -Fibroblast GF -Polypeptides-Histamines -Platelet derived GF -Amines-Thromboxane -Insulin like GF -Bone morphogenic proteins(BMP)

2.CHEMICAL FACTORS

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• MESSENGER SUBSTANCE:CYTOKINES-

IL-1,4,6,11, macrophage and granulocyte/macrophage stimulate bone resorption.

IL-1 ,6 synthesis is decreased by estrogen

PROSTAGLANDINS-Stimulate osteoblastic bone formation and inhibit activity of isolated osteoclasts.

LEUKOTRINES-Stimulate osteoblastic bone formation and enhance the capacity of isolated osteoclasts to form resorption pits.

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GROWTH FACTORS A.Transforming growth factor(TGF):

-Act on serine/threonine kinase cell wall receptors - Promotes proliferation and differentiation of osteoblasts,

osteoclasts and chondrocytes - Stimulates both endochondral and intramembranous

bone formation and collagen type 2 synthesis.

B.Fibroblast growth factors(FGF):-Increase proliferation of chondrocytes and osteoblasts-Enhance callus formation & stimulates angiogenesis.

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C.Platelet derived growth factor(PDGF):

•Stimulates bone cell growth•Increases type I collagen synthesis by increasing the number of osteoblasts.•PDGF-B stimulates bone resorption.

D.Insulin like growth factor(ILGF):

•Stimulates bone collagen & matrix synthesis and replicates osteoblasts . •It also inhibits collagen degradation.

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• E.Bone Morphogenic Proteins (BMP):

BMP are Osteoinductive proteins initially isolated from demineralized bone matrix.•FUNCTIONS:

–Induce cell differentiation : BMP 3(osteogenin).–Promote endochondral ossification: BMP 2 & 7.–Regulate extracellular matrix production :BMP1.–Increase fusion rates in Spinal fusions (anterior lumbar interbody fusion): BMP 2–Non unions: BMP 7 as good as bone grafting .

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• 3.PERMEABILITY FACTORS:

-Protease – Plasmin , Kalikrein, Globulin permeability factor.-Polypeptides –leucotaxime, Bradykinin, Kallidin-Amines – Adrenalin, nor-adrenalin, Histamine.

These factors work in ways that :– Increase capillary permeability– Alteration in diffusion mechanism in intracellular matrix– Cellular migration– Proliferation & differentiation– New blood vessel formation– Matrix synthesis– Growth & development.

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3.VASCULAR FACTORS

•A. Metalloproteinases:

–Degrade cartilage and bones to allow

invasion of vessels

•B Angiogenic factors:

-Vascular-endothelial growth factors mediate neo-

angiogenesis & endothelial-cell specific mitogens.

•C. Angiopoietin (І & ІІ)

–Regulate formation of larger vessels and branches.

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A.Age: Young patients heal rapidly and have a remarkable ability to remodel V/S old .

B.Nutrition: An adequate metabolic stage with sufficient carbohydrates and protein is necessary.

C.Systemic Diseases: an immunocompromised state will likely delay healing. Illnesses like Marfan’s syndrome and Ehlers-Danlos syndrome cause abnormal musculoskeletal healing.

4.SYSTEMIC FACTORS

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D.HORMONES:– Estrogen

• Stimulates fracture healing through receptor mediated mechanism.

– Thyroid hormones• stimulate osteoclastic bone resorption.

– Glucocorticoids• increased osteoclastic bone resorption.

– Parathyroid Hormone• Accelerates callus formation (+osteoprogenitor cells) with

enhanced remodeling & biomechanical properties of healing #

– Growth Hormone• Increases callus formation and fracture strength

• In vitro bone deformation produces piezoelectric currents and streaming potentials.

• Electromagnetic (EM) devices are based on Wolff’s Law that bone responds to mechanical stress: Exogenous EM fields may simulate mechanical loading and stimulate bone growth and repair

• TYPES ARE :– Ultrasound.– Direct electrical current.– Pulsed electromagnetic fields (PEMF).

5.ELECTROMAGNETIC FACTORS

A.Ultrasound therapy:

• Modulates signal transduction,

increases gene expression

(aggrecan ), increases blood flow,

enhances bone remodeling and

increases callus torsional strength in

animal models.

• Low-intensity ultrasound is approved

by the FDA for stimulating healing of

fresh fractures.

• Direct Electrical current:– Electric stimulation of

bone has been taught to be an effective and non invasive method for fracture healing and treating fracture non union. Studies shows that electric field generated helps in proliferation of bone cells.

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C. Pulsed electromagnetic fields (PEMF).

• Approved for the

treatment of non-unions

• Efficacy of bone

stimulation appears to be

frequency dependant

– are most effective (15 to

30 Hz range)

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RECENT ADVANCESBone graft

Autogenous (iliac crest, prox. tibia, distal femur)Scaffold for osteoconductionHas bone matrix proteins osteoinductionHas progenitor stem cells osteogenesis(free vascular fibular graft for absent radius/ long bone)

Allogenic (from cadaver)

Synthetic (demineralized bone matrix, collagen, ceramics, cements, polymers- Si, PMMA)

2 emerging productsTricalcium PO4 composite (VITROSS, CORTOSS)Hydroxyapatite compound (pro osteon) – marine coral

•Bone Marrow Aspirate• bone marrow contains mesenchymal stem cells and circulating

progenitors

• Mesenchymal stem cells can differentiate into osteoblasts, chondrocytes, and other connective tissue cells in vitro under appropriate conditions.

• circulating endothelial progenitors that can contribute to adult vasculogenesis.

• some of the effects of bone marrow aspirate on fracture healing could be due to the local application of osteochondrogenic cells and/or endothelial progenitor cells during bone healing.

• Use of Serological Bone Formation Markers

– Current serum markers of bone formation activity include • bone-specific alkaline phosphatase (ALP)• procollagen type-I N-terminal propeptide (PINP) • procollagen type-I C-terminal propeptide (PICP)• osteocalcin (OC)

– to Monitor Callus Development and Fracture Healing

– PINP is superior in reflecting bone formation processes when compared with ALP, PICP, and OC. PINP can also be characterized as an index of collagen synthesis, a marker of the early stages of bone formation, and a marker of callus formation.

• Laser Photobiomodulation on Bone– Laser Phototherapy (LPT) is an effective tool to stimulate

bone. – results show that the use of IR laser results on increased

bone neo-formation. – LPT effect depends not only on the total dose, but also on

both irradiation time and mode. – Energy density and intensity are biologically independent

and accounts for the success and the failure of the treatment.

Percutaneous vertebroplasty: – Vertebroplasty is a minimally invasive, image-guided

therapy used to relieve pain from a vertebral body fracture.– It has been used for osteoporotic or malignant fractures. – Vertebroplasty can increase patient mobility, decrease

narcotic needs, and prevent further vertebral collapse.– Percutaneous vertebroplasty (PVP) usually involves

percutaneous injection of a cement, polymethylmethacrylate (PMMA), into the vertebral bodies.

– Occasionally, PMMA has been placed manually into vertebral lesions during open surgical operations.

Percut. Inj. (Fibroblast GF-2 + hyaluronon) callus formation & mechanical strength

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• OTHER RECENT ADVANCES:

• GROWTH FACTOR THERAPY Due to their ability to stimulate proliferation and

differentiation of mesenchymal and osteoprogenitor cells they have shown great promise for their ability to promote fracture repair .

• APPLICATION OF PLATELET RICH PLASMAPRP improves cellular proliferation and chondrogenesis during early

fracture healing and increases the mechanical strength of callus during late fracture healing

Injecting platelet rich plasma at fracture site helps in fracture healing .

• TISSUE ENGINEERING, STEM CELLS AND GENE THERAPIES

In past decade tissue culture and stem cells have been implicated in enhancing fracture healing and articular cartilage regeneration.

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• Fracture healing is influenced by many variables including mechanical stability,

electrical environment, biochemical factors and blood flow etc…

• Our ability to enhance fracture healing will increase as we better understand the

interaction between these variables.

SUMMARY

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Thank You

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• CAMPBELL TEXTBOOK OF ORTHOPAEDICS 11TH EDITION..• APLEYS PRINCIPLE OF ORTHOPAEDICS• REVIEW OF ORTHOPAEDICS BY MILLER• Orthopaedic Knowledge Update 10• Recent Developments in the Biology of Fracture Repair• Recent Advances in the Use of Serological Bone Formation

Markers to Monitor Callus Development and Fracture Healing Marlon O. Coulibaly1, Debra L.

• Recent Advances on the Use of Laser Photobiomodulation on Bone. A. Pinheiro

• Gene therapy for in vivo bone formation: recent advances W. LATTANZI1*, E. POLA2*

• The evidence of low-intensity pulsed ultrasound for in vitro, animal and human fracture healingPilar Martinez de Albornoz†, Anil Khanna‡,

BIBLIOGRAPHY