tendinopathy, tendon healing & tendon regeneration

Tendinopathy, Tendon Healing & Tendon Regeneration

Alayna E. Loiselle, PhDAssociate Professor

IND 464 Musculoskeletal Basic Science CourseOctober 21, 2019

Outline

• Review of homeostasis• Effects of Aging• Disruptions in homeostasis• Pathogenesis of tendinopathy/ tendinitis• Mechanisms of regeneration and healing

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Tendon Cell Proliferation During Growth

Grinstein eLIFE 2019

Tendon Cell Proliferation During Growth

Grinstein eLIFE 2019

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Tendon HomeostasisYoung Aged

• Matrix composition and organization is not dramatically different• Decreased proteoglycan content• Changes in cell morphology

Functional Consequences of Aging?

Tendon is not mechanically sensitive to aging

Ackerman et al., 2017. JOR

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Collagenase Induced Tendinopathy

LD= low doseHD= high dose collagenase

Induces degenerative changes via collagen degradation

Orfei C et al. (2016) PLOS ONE 11(8): e0161590.

Mechanically Induced Tendinopathy• Fatigue loaded under anaesthesia• Uphill treadmill running• Downhill treadmill running

Neviaser A. 2012. J Shoulder Elbow Surg. N Andarawis-Puri et al., 2014. JOR

UnloadedLow levelloading

Moderateloading

High levelloading

Fatigue Loading Induces Apoptosis

Induces matrix and cellular changes

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Summary of Tendinopathy

Future Directions• Continue to identify co-morbidities that predispose or accelerate tendinopathy

• Most clinical data are from late stage pathology

• Beginning to use genetic animals models to better understand tendinopathy

Remodeling BalancePhysiological exercise increases: proliferation

collagen productiontenocytic gene expression (w/o chondro/ osteo/adipo)

Overuse/ Fatigue: Matrix DamageTenocyte apoptosis

Effects of pathology and/ or co-morbidities: promote degeneration +/- inflammationSmokingobesityhigh cholesterol

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Maximum Load at Failure

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Days Post-Surgery

Control

40-5(2*6-)7()

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Similarities between wound and tendon healing

AJ Jomas et al. 2014. Advanced Drug Delivery ReviewThiruvoth et al. 2015. Plastic and Aesthetic Research

Similarities between wound and tendon healing

Nichols, Best, Loiselle. 2019

Well-regulated inflammation is beneficial-activates healing cascade

-recruitment/activation of cellsExcessive/ Chronic inflammation is pathological

-degenerative matrix changes-fibrotic healing

Inflammation

Benefits of Anti-inflammatory therapy is controversialTiming may be key!

Generally effective at preventing excess scar formationEarly inhibition decreases mechanicsDelayed healing maintains mechanics

Cell-type specific considerations

Virchenko et al., 2004. Am J Sports Med, Geary et al. 2015. PlosOne

Proliferative/ Granulation Phase• Lasts a few weeks• Begins ~day 7 in mouse model• Proliferation of ‘fibroblasts’• Bridging on injury site• Production of ECM components (Col1/ Col3)• Rapid deposition of disorganized ECM

Day 3 Day 14

Thomopoulos et al., 2009. JOR, Thomopoulos et al., 2010. JBJS, Katzel et al. 2010. JOR, Awad Lab, Loiselle Lab

Col3a1 ISH

Tendon

ScarTissue

Remodeling Phase• Lasts many months• Begins ~day 21 in mouse model• Reorientation of ECM• Mmp-mediated remodeling

Day 21 Day 28 Day 35

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Double-edged sword of tendon healing

Matrix deposition Mechanical properties

Fibrosis

• Thickening and/or scarring of connective tissue• Typically in response to injury• In response to injury fibrosis= scar tissue• Excess matrix deposition• Disorganized matrix• Exuberant healing response

Inflammation Matrix Deposition

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Body Weight

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*Fasting Blood Glucose

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Body Weight

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Percent Body Fat

T2DM Impairs Tendon Healing

Ackerman+ PlosOne. 2017.

MTP Flexion Angle

10 14 21 280

Days Post- Repair

LFDHFD

Gliding Resistance

10 14 21 280

Days Post- Repair

Max Load at Failure

10 14 21 280

Days Post- Repair

LFD HFD **

Col3a1

3 7 10 14 21 280

Days Post-Repair

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Col1a1

3 7 10 14 21 280

Days Post-Repair

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Aging decreases fibrotic tendon healing (too much)

Ackerman et al., JOR. 2017.

Aging decreases fibrotic tendon healing (too much)

Ackerman et al., JOR. 2017.

No change in proliferative capacityDecreased matrix production on a per cell basisIs the cellular environment the same?

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TH E JO U R NA L OF BONE & JOINT SURGER Y · JBJS .ORG

VO LU M E 85-A · NU M B ER 3 · MARCH 2003BIOLOG I C AS P E C T S OF FLEXOR TENDON LA CER A T I ON A N D REPAIR

response observed clinically is a combination of extrinsic andintrinsic mechanisms (Fig. 4)1.

The differences between the extrinsic and intrinsic mech-anisms extend beyond the site of origin of the healing cells. Theextrinsic mechanism appears to be active earlier in the healingsequence, whereas the intrinsic mechanism is often delayed10,11.Some studies have demonstrated that the synovial sheath reactswith a greater proliferative and inflammatory response com-pared with the endotenon and tendon proper12. Other studieshave shown the synovial fibroblasts to be more reactive to cy-tokines and to have a greater capacity for degradation of theextracellular matrix11. In addition, it is thought that predomi-nance of the extrinsic mechanism of healing leads to increasedcollagen content at the injury site as well as to a reduction inthe level of collagen organization and material properties of thereparative tendon tissue13,14. For these reasons, it is believed thatthe predominance of the extrinsic mechanism of healing leadsto scar formation and adhesions between the tendon and sur-rounding peritendinous structures.

Modulating the healing process to enhance the intrinsicpathway (and augment end-to-end tendon healing) whilesuppressing the extrinsic pathway (and diminishing adhesionsof the tendon to surrounding tissues) could lead to improve-

ments in the treatment of these injuries. While investigationsinto the biology of tendon healing have shed some light on themechanisms by which tendon tissue heals, there has been rela-tively little progress toward the biologic enhancement of thehealing process after injury and repair. As a result, modulationof the process by which tendons heal remains an appealing,but not currently practicable, concept.

Biologic Solutions to Adhesion Formation: Historical PerspectiveIt is well recognized that motion prevents scar formation1,7,15-17.There is not a specific amount of motion that is needed, onlya relative amount�that is, enough to overcome the problemsof scarring and adhesion formation. If one could decrease theamount of scarring associated with a given amount of mo-tion, less motion would be required. This approach wouldeliminate the need for aggressive postoperative motion pro-tocols that place the tendon repair site at risk for dehiscence.If the ideal scar inhibitor could be found, the patient couldbe treated with postoperative immobilization in a cast orsplint until the tendon healed, allowing the repair to heal in amechanically protected environment without concern aboutadhesions.

Historically, prevention of adhesion formation has beenattempted on two fronts. The first method has been to place aphysical and mechanical barrier between the healing tendonand the surrounding tissues. The rationale for this approachis that limiting contact between the tendon and its sheathdiminishes the amount of adhesions around the repaired ten-don�that is, the tendon is allowed to heal to itself but not tothe sheath and surrounding tissues. The various barrier ma-terials that have been tried include silicone18, polyethylenemembranes19, alumina sheaths20, polytetrafluoroethylene21, andchondroitin sulfate-coated polyhydroxyethyl methacrylate mem-branes22, among many others. In spite of the many differentmaterials studied for this purpose, none are in routine clinicaluse at this time.

In a similar approach, many authors have attempted touse chemical modulation to diminish the amount of scar for-mation after repair. The chemical agents that have been usedin these efforts include local23,24 and parenteral25,26 corticoste-roids, dimethyl sulfoxide27, beta-aminoproprionitrile28, hyalu-ronic acid29,30, and 5-fluorouracil31,32, among many others. Thecommon principle of these methodologies is reduction of in-flammation. In the case of the corticosteroids and hyaluronicacid, the goal is to diminish inflammation by inhibiting lym-phocyte migration, proliferation, and chemotaxis as well asmacrophage motility. Similarly, 5-fluorouracil, an antimetab-olite, suppresses scar formation by inhibiting contraction ofcollagen lattice and proliferation of inflammatory cells31,32.

Researchers using barrier and chemical techniques havereported some degree of adhesion reduction in laboratory andclinical studies of tendon repair18,20,21,23,25,29,31,32. In spite of thesefindings, these methods are not widely used in clinical prac-tice. This suggests that none of them have been demonstratedto be effective in most clinical settings.

Fig. 4

Schematic representation of extrinsic (A) and intrinsic (B) pathways of tendon healing. (Adapted from: Gelberman RH, Vande Berg JS, Lund-borg GN, Akeson WH. Flexor tendon healing and restoration of the glid-ing surface. An ultrastructural study in dogs. J Bone Joint Surg Am. 1983;65:78-79.)

on October 7, 2006 www.ejbjs.orgDownloaded from

TH E JO U R NA L OF BONE & JOINT SURGER Y · J BJ S .ORG

VO LU M E 85-A · NU M B ER 3 · MARCH 2003BI O LO G I C AS P E C T S OF FLEXOR TENDON LA CER A T I ON A N D REPAIR