REVIEWARTICLE

Tendon: Biology, Biomechanics, Repair, Growth

Factors, and Evolving Treatment Options

Roshan James, MS, Girish Kesturu, PhD, Gary Balian, PhD, A. Bobby Chhabra, MD

Surgical treatment of tendon ruptures and lacerations is currently the most common therapeutic modality. Tendonrepair in the hand involves a slow repair process, which results in inferior repair tissue and often a failure to obtainfull active range of motion. The initial stages of repair include the formation of functionally weak tissue that is notcapable of supporting tensile forces that allow early active range of motion. Immobilization of the digit or limb willpromote faster healing but inevitably results in the formation of adhesions between the tendon and tendon sheath, whichleads to friction and reduced gliding. Loading during the healing phase is critical to avoid these adhesions butinvolves increased risk of rupture of the repaired tendon. Understanding the biology and organization of the nativetendon and the process of morphogenesis of tendon tissue is necessary to improve current treatment modalities.Screening the genes expressed during tendon morphogenesis and determining the growth factors most crucial fortendon development will likely lead to treatment options that result in superior repair tissue and ultimatelyimproved functional outcomes. (J Hand Surg 2008;33A:102–112. Copyright © 2008 by the American Society forSurgery of the Hand.)

Key words Collagen, extracellular matrix, gene expression, growth factors, healing, tendinogenesis, repair andregeneration.

OF THE 33 MILLION MUSCULOSKELETAL injuriesreported in the United States per year, roughly50% involve injuries to the soft tissue including

tendon and ligament.1,2 As larger portions of the generalpopulation participate in physical and recreational activitiesevery year, the frequency of soft tissue injuries is likely toincrease as well, resulting in increasing health care costs andpatient morbidity. In most cases of tendon laceration orrupture, surgical intervention is required to direct the natural

From the Department of Orthopaedic Surgery, OrthopaedicResearch Laboratories, University of Virginia Health System;University of Virginia Hand Center, University of VirginiaHealth System; Department of Biochemistry and MolecularGenetics, University of Virginia Health System; andDepartment of Biomedical Engineering, University of VirginiaHealth System, Charlottesville, VA.

Received for publication April 16, 2007; accepted inrevised form September 12, 2007.

No benefits in any form have been received or will bereceived from a commercial party related directly orindirectly to the subject of this article.

Supported by research grant AR52891 from theNIAMS, NIH, and by a OREF-Zimmer CareerDevelopment Award to A.B.C.

Corresponding author: A. Bobby Chhabra, MD, 400 Ray C.Hunt Drive, Suite 330, University of Virginia,Charlottesville, VA 22908-0159; e-mail:ac2h@hscmail.mcc.virginia.edu.

0363-5023/08/33A01-0019$34.00/0doi:10.1016/j.jhsa.2007.09.007

102 � © ASSH � Published by Elsevier, Inc.

process of healing, and occasionally the damage exceeds thenatural ability to repair even with existing treatmentmodalities. Tendon repair is a slow process that iscomplicated by the need to provide appropriate and timelytension to the repair tissue. This review covers topics fromtendon biology and functionality, the normal healingprocess, and the role of polypeptide factors in the repairprocess with speculation on how these factors may improvetendon repair and surgical outcomes.

Tendon is a unit of musculoskeletal tissue that transmitsforce from muscle to bone. Lacerations, ruptures, orinflammation of the tendon cause marked morbidity andcan have a major impact on work, recreational activities,and daily needs. Normal tendon consists of soft and fibrousconnective tissue that is composed of densely packedcollagen fiber bundles aligned parallel to the longitudinaltendon axis and surrounded by a tendon sheath alsoconsisting of extracellular matrix components. Collagenconstitutes 75% of the dry tendon weight and functionschiefly to withstand and transmit large forces betweenmuscle and bone.1 The well-organized tendon architecturesupports large tensile forces and glides readily under tensionto transmit force generated by muscle contraction to thebone to cause movement.

Tendon is stronger per unit area than muscle, and itstensile strength equals that of bone, although it is flexibleand slightly extensible. The parallel arrangement of tendoncollagen fibers resists tension so that contractile energy is notlost during transmission from muscle to the bone. Tendonstrength, however, does not allow for a wide margin of

safety; forces generated by muscle during various power-

TENDON DEVELOPMENT, REPAIR, AND REGENERATION 103

intensive activities may approach the maximum transmittabletendon force and lead to rupture, tear, or degeneration.

Tendon repair or replacement begins with thereestablishment of tendon fiber continuity and the glidingmechanism. Injury initiates several signaling events thatrecruit fibroblasts and stimulate the local tenocyte populationto synthesize collagen and other extracellular components,establishing physical continuity at the site. With furtherappropriate stimuli, such as mechanical stress and strain,remodeling restores partial or close-to-normal function. Therepair process is slow and characterized by a scar withmechanically inferior tissue, at least initially. Lack of use ormorbidity leads to extensive scarring and adhesions; these inturn impede tendon gliding and have a negative impact onflexor tendon repair in the digit. Excessive stress duringhealing can cause tendon rupture. To improve the results oftendon repair, this complex process will require a healingresponse that is enhanced by a combination of treatments,including growth factors, mechanical stimulation, tissueengineering, and/or gene therapy. These treatmentmodalities may improve tissue healing, tendon gliding,mechanical strength, and return to normal function whilepreventing tendon gapping, ruptures, and extensiveadhesions.

TENDON BIOLOGYThe musculotendinous unit is composed predominately ofcollagen fibers and rod- or spindle-shaped fibroblast-likecells (tenocytes) within a well-ordered extracellular matrix(ECM)3,4 (Fig. 1). Collagen is synthesized by the tenocytesand constitutes the basic structural unit of tendon. Thecollagen polypeptides form a triple helix, which self-assembles into collagen fibrils with intermolecular cross-linksthat form between adjacent helixes.5,6 The parallelorganization of the collagen helixes into fibrils and theintermolecular cross-linking leads to an increase in tendontensile strength. The collagen polypeptides and the ensuingtriple helix are synthesized inside the cell, secreted into theECM, and assembled into the microfibrillar units thatconstitute the collagen fibers. The major fibrillar componentof tendon is type I collagen predominately, whereas type IIIcollagen is present in the endotenon and epitenon. Duringthe process of repair, collagen fiber diameter is notablysmaller, thus reducing the tensile strength of tendon.7,8 TypeIII collagen synthesis increases during the early phase ofrepair and remodeling and decreases as type I collagenproduction increases and becomes highly organized intofibrillar structures of the ECM (SL Woo, JA Buckwalter,presented at the AAOS/NIH/ORS workshop, 1987).9,10

Collagen type V is cross-linked to other collagen types andregulates the characteristics of fibrillar structures intendon.11,12

The ECM contains other proteins and proteoglycanssuch as decorin and aggrecan. Water representsapproximately 55% of the weight of tendon, is present

mostly in the ECM, and is believed to reduce friction,

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facilitating the gliding of fibrils in response to mechanicalloading.13 Elastin fibers and several glycoproteins are alsointegral parts of tendon ECM and provide functionalstability to the collagen fibers.

Collagen fibrils, 100–500 nm in diameter, are bundledinto large fibers that are evident throughout the tendon,visible under light microscopy as a crimped or a sinusoidalpattern that facilitates a 1% to 3% elongation of thetendon.8,14–16 This elongation of the individual fibers servesto buffer the tendon from sudden mechanical loading.Interactions between collagen fibrils at the macromolecularlevel leading to the fiber unit architecture dictate thestrength of tendon. Spindle-shaped tendon fibroblasts arearranged between collagen fibers and synthesize andmaintain the ECM. The collagen fiber structural units arebound into bundles by the endotenon to give higherstructural units called fascicles, which in turn are boundtogether by epitenon to form the tendon.4,13,15 Theendotenon contains the vascular, lymphatic, and neuraltransmission routes to maintain tendon fibroblasts, and theepitenon binds the fascicles together and supplies bloodvessels and tracts for the lymphatics and nerves.17 In thehand, tendons bend sharply around the joints and areenclosed by a tendon sheath and a pulley system. Thissheath is covered with synovial cells that lubricate and assistthe enclosed tendons and reduce sliding friction. Tendonsnot enclosed within a sheath with synovial fluid move in astraight line and are surrounded by a continuous paratenon(eg, Achilles’ tendon). Paratenon is a loose connective tissuethrough which blood vessels enter and vascularize theendotenon and epitenon.

TENDON FORCE CURVEBiomechanical properties of tendons during their repair andregeneration have been studied extensively and theirproperties compared with normal tendon. These tests haveshown that current procedures used for repair produce atissue with biomechanical properties that are inferior tothose of normal tendon. Attempts at improving themechanical properties of repair tissue has led to the designand testing of new therapies, including tissue-engineeringtechniques, followed by biomechanical testing of theregenerate tissue. Mechanical testing involves separate clampsto grip the muscle-tendon complex at one end and thebone at the other end ensuring that the ends are held firmlywithout slippage, the tendon is loaded along its longitudinalaxis, and the force and displacement are recorded until thetissue fails.18 The data from biomechanical tests arenormalized to the initial cross-sectional area and plottedagainst the strain or percentage elongation of the tendon.

A typical stress-strain curve has 3 distinctive regions19–21

(Fig. 2): (1) A toe region that corresponds with the straighteningof the zigzag pattern or crimp that is visible by polarized lightmicroscopy of the collagen fiber bundles. This pattern

disappears under tension and then reappears when the stress is

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104 TENDON DEVELOPMENT, REPAIR, AND REGENERATION

released. Elastin fibers present in the ECM may be partlyresponsible for bringing the stretched collagen bundles back tothe resting state. (2) Immediately after the toe region is the linear

FIGURE 1: Growth factors released by tenocytes in response to local ssynthesis. Collagens and proteoglycans are components of the ECM cmicrofibrils that are bundled together to attain macroscopic structurehigher-order structure (fascicles) that constitute tendons. A loose conencloses each fiber bundle and tendon.

region. The slope of this region is constant and is referred to as

JHS �Vol A, Ja

Young’s modulus, or stiffness. At this point, the collagen fiberbundles are no longer crimped. (3) Beyond the linear region,collagen fibers fail in an unpredictable fashion; tears occur in the

li modulate signaling events that lead to gene expression and proteinl to tendinogenesis. The triple helical collagen molecules formlagen fibers) with a crimped pattern. These bundles give rise to ae tissue sheath that is rich in blood vessels and has a nerve supply

timuriticas (colnectiv

tendon leading to rupture.

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TENDON DEVELOPMENT, REPAIR, AND REGENERATION 105

The mechanical properties of tendon may be correlatedat the molecular level with the mechanical characteristics ofthe collagen fibers.22 Tendon viscoelastic behavior,20,23

which is the result of complex interactions between variouscomponents, is dependent on age and activity. Tendons donot usually fail or rupture under normal conditions;therefore, it is more appropriate to quantify the physicalproperties within the linear region, including stressrelaxation, creep, hysteresis loop, and viscoelasticity. Therate of elongation that the tendon is subjected to modulatesthe amount of load transferred. This necessitates the designof functional parameters based on in vivo function ratherthan on a comparison of parameters such as stiffness andmaximum force. This approach to the problem of tendonrepair may better define the biomechanical characteristics ofthe regenerate tissue.

REPAIR AND REGENERATIONThe restoration of normal tendon function after injuryrequires reestablishment of tendon fibers and the glidingmechanism between tendon and its surroundingstructures.24–26 The initial stage of repair involves formationof scar tissue that provides continuity at the injury site27;however, lack of mechanical stimulus on the tendon willcause proliferation of scar tissue and subsequent adhesionsthat are undesirable and harmful because they impedenormal tendon function, particularly in the hand. Althoughstability to the injury site is necessary, mobility is critical, andmechanical loading that is associated with motion of thehealing tendon decreases the formation of postoperativeadhesions and increases the strength. After tendon injury, thebody initiates a cascade of distinct events or phasesdistinguishable by the cellular and biochemical processes thatoccur. The sequence of repair involves a progressionthrough 3 stages: tissue inflammation, cell proliferation, andremodeling28–36 (Fig. 3).

Inflammatory Stage

Injuries sustained by blood vessels that are in the tendon

FIGURE 2: Stress-strain curve of normal tendon failed in tension.(Reprinted with permission from the Annual Review of BiomedicalEngineering, Volume 6, © 2004 by Annual Reviewswww.annualreviews.org.)

sheath cause the formation of a hematoma. The resultant

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clot activates the release of various chemotactic factors suchas vasodilators and proinflammatory molecules that attractinflammatory cells from the surrounding tissue. Erythrocytes,platelets, neutrophils, monocytes, and macrophages migrateto the wound site where the clot, cellular debris, and foreignbody matter are engulfed and resorbed by phagocytosis.Fibroblasts recruited to the site begin to synthesize variouscomponents of the extracellular matrix.37 Angiogenic factorsare released during this phase and initiate the formation of avascular network.38 These processes include an increase inDNA and in ECM, which establishes continuity and partialstability at the site of injury.

Proliferative Stage

The continued recruitment of fibroblasts and theirrapid proliferation at the wound site are responsible forthe synthesis of collagens, proteoglycans, and othercomponents of the ECM. These components areinitially arranged in a random manner within theECM, which at this point is composed largely of typeIII collagen.39 An extensive blood vessel network ispresent, and the wound has a scar-like appearance.40

At the end of the proliferative stage, the repair tissue ishighly cellular and contains relatively large amounts ofwater and an abundance of ECM components.

Remodeling Stage

Remodeling begins 6–8 weeks after injury. This phase ischaracterized by a decrease in cellularity, reduced matrixsynthesis, decrease in type III collagen, and an increase intype I collagen synthesis. Type I collagen fibers areorganized longitudinally along the tendon axis and areresponsible for the mechanical strength of the regeneratetissue.41 During the later phases of remodeling, interactionsbetween the collagen structural units lead to higher tendonstiffness and consequently greater tensile strength; however,the repair tissue never achieves the characteristics of normaltendon. Two distinct models have been proposed to explainthe mechanism of tendon healing.

Extrinsic healing: One hypothesis is that fibroblasts andinflammatory cells move from the periphery or externaltissue sources to invade the healing site and initiate, and laterpromote, repair and regeneration. This process includes theinitial formation of adhesions and requires a well-establishedvascular network for the tissue to heal effectively.

Intrinsic healing: Intrinsic healing occurs through amechanism that entails the migration and proliferation ofcells from the endotenon and epitenon into the injury site;these cells establish an extracellular matrix and an internalneovascular network.

In most cases, both mechanisms are involved in thehealing phenomenon that is dependent on several factors,including tendon location, extent of trauma, andpostoperative motion. The extrinsic mechanism, activated

earlier than the intrinsic mechanism, is responsible for the

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106 TENDON DEVELOPMENT, REPAIR, AND REGENERATION

formation of adhesions that occur initially, the disorganizedcollagen matrix with high cellularity, and high water contentof the injury site. By contrast, the intrinsic mechanism isresponsible for the reorganization of the collagen fibers andmaintenance of fibrillar continuity.

MOLECULAR MECHANISMSDuring tendon repair, several growth factors areinvolved in the activation and regulation of the cellularresponses. These factors or cytokines bind to specificreceptors that are present on the cell surface andactivate specific signaling events within the cell. Thisinitiates a cascade of pathways leading to thetranscription of specific regulatory genes. Theinitiation or release of these factors is stimulated bycells that are located at the site of injury and, duringthe remodeling phase, by mechanical loading of theinjured tendon (Table 1).

Transforming growth factor-� (TGF-�) is a product ofmost cells that are involved in the healing process; its 3isoforms give rise to distinct spatial responses leading to itsdiverse effects that regulate several events. During the initialinflammatory phase after trauma, TGF-� expression iselevated and stimulates cellular migration and proliferation,as well as interactions within the repair zone.42 Synthesis ofcollagen type I and collagen type III is increased greatlyduring the later phases. One of the isoforms of the growthfactor, TGF-�1, is responsible for the initial scar tissue thatforms to establish tissue continuity at the wound site. In thelater phases of wound healing, increased expression of TGF-

FIGURE 3: Stages of tendon healing after m

�1 leads to scar proliferation and reduced functionality.

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Transforming growth factor-�3 acts as a negative regulatorof scarring at the wound site.43,44 Transforming growthfactor-� also serves to regulate the synthesis of collagen intendon mechanically during physical exercise.45

During the initial repair process and the inflammatoryphase, upregulation of growth factors and cytokines such asinsulin-like growth factor-1 (IGF-1) stimulate themigration and proliferation of fibroblasts andinflammatory cells to the wound site.46,47 Insulin-likegrowth factor-1 may be stored as an inactive precursorprotein in normal tendon and, upon injury, enzymesrelease the growth factor to exert its biological activity.During the later phases such as remodeling, IGF-1stimulates synthesis of collagen and other extracellularmatrix components; studies in vitro have shown that theeffects of IGF-1 on matrix metabolism are dosedependent.48–50 Investigations with equine flexor tendoninjury models have shown that both cell proliferation andcollagen content increase on treatment with IGF-1.These changes are accompanied by increased stiffness inthe treated tendon.51

Platelet derived growth factor (PDGF) induces theexpression of other growth factors such as IGF-1during the initial repair phase. In addition, the deliveryof PDGF to tendon injuries in animal models increasescell proliferation and stimulates the synthesis ofcollagen and other ECM components in a dose-dependent manner during the remodeling phase.52–56

Some studies have shown that a phased delivery ofPDGF over a longer duration may be desirable to

bstance injury. GAG, glycosaminoglycans.

idsu

obtain repair that leads to a regenerate tissue that is

nuary

ation

TENDON DEVELOPMENT, REPAIR, AND REGENERATION 107

functionally closer to normal tendon.57,58 Experimentsconducted in vivo and in vitro attest to the mitogenicactivity of basic fibroblast growth factor (bFGF), apotent factor that is involved in cell migration andangiogenesis in addition to cell proliferation.59 Basicfibroblast growth factor has been immunolocalizedduring tendon repair and is expressed by fibroblast andinflammatory cells.60 Wound healing models showeddistinctly faster wound closure on treatment withincreasing doses of bFGF.61– 63 In this regard, bonemarrow stromal cells (BMSCs) treated with low dosesof bFGF have exhibited increased cell proliferation andsubsequent expression of specific extracellular matrixcomponents suggesting a potential role formesenchymal cells from marrow in tendonregeneration.64

Vascular endothelial growth factor (VEGF) is critical for

TABLE 1: Events During Tendon Repair*

Repair Phase Activity

Inflammatory Stimulates recruitment of fibroblasts anto the injury site

Regulation of cell migration

Expression and attraction of other grow

Angiogenesis

Proliferative Cell proliferation (DNA synthesis)

Stimulates synthesis of collagen and EC

Stimulates cell-matrix interactions

Collagen type III synthesis

Remodeling ECM remodeling

Termination of cell proliferation

Collagen type I synthesis

*Tendon repair phases with biological characteristics and ensuing mole

TABLE 2: Genes InvolvedWith Tendon Development an

Gene Function in

Scleraxis72,93–97 Transcription factoselectively expres

Tenomodulin96,98 Regulators of cell p

Tenascin99 ECM protein evide

Collagen III41,100,101 Early ECM collage

Collagen I1,14,102,103 Mature and highly

Decorin and aggrecan84,104 Proteoglycan intera

Smad8105 Tenocyte differenti

neovascularization,65 and in the later phases, VEGF is

JHS �Vol A, J

essential to the establishment and maintenance of thevasculature present in the endotenon and epitenon.Postoperatively, VEGF expression in healing tendons showsa biphasic expression by a majority of the cells within therepair site.66,67

Delivery of bone morphogenetic protein (BMP) -12,-13, and -14 (also known as growth/differentiation factor[GDF] -7, -6, and -5 or cartilage derived morphogeneticprotein [CDMP] -3, -2, and -1, respectively) to ectopic sitesleads to the formation of tendon-like connective tissue. Inanimal models, treatment of tendon injuries with GDFs alsoincreases tendon callus. Growth/differentiation factorsregulate the synthesis of ECM components and expressionof collagen type I and collagen type III.68–74 Thesepolypeptide factors regulate the expression of specific genesthat are found in common among tendons and ligaments,and the expression of these genes serve as markers of

Growth Factor

flammatory cells IGF-180–82

TGF-�42,83–86

actors (eg, IGF-1) PDGF56,87,88

VEGF, bFGF61–63,89–92

IGF-1 and PDGF, TGF-�, bFGF,GDF-5, -6, and -768–70,72,74

omponents IGF-1 and PDGF, bFGF

TGF-�, bFGF

TGF-�, GDF-5, -6, and -7

IGF-1

TGF-�

TGF-�, GDF-5, -6, and -7

events that are regulated by several cytokines or growth factors.

pair

velopment, Repair, and Tissue Regeneration

cifically detected in tendon cell precursor populations andn later stages

eration, differentiation, and collagen fibril maturation

uring embryonic and tendon development

nized collagen fibrils

s modulating collagen fibril orientation and alignment

, phenotype modulation, and intracellular signaling

d in

th f

M c

cular

d Re

De

r spesed i

rolif

nt d

n

orga

ction

tendinogenesis (Table 2).

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108 TENDON DEVELOPMENT, REPAIR, AND REGENERATION

TENDON INJURY ANIMAL MODELThe development of biomaterials for orthopedic applicationsand the discovery of growth factors that influence tendonrepair have influenced the approaches for the treatment oftendon injuries. In addition, biodegradable materials thatmay be implantable as a medical device to enhance tissuerepair or regeneration require rigorous testing in order toestablish the efficacy of these new therapeutic techniques.The combination of novel biomaterials with the emergingtechniques of gene transfer and therapy further increase thepossibilities of restoring tendon to its normal function. Inconcert with these developing techniques is the need for invitro evaluation of parameters to establish biocompatibility,mechanical properties, cell proliferation, biochemical analysisof tendon extracellular matrix and gene expression, and toextend these measurements to an appropriate animal modelin vivo before applications to clinical situations.75–77

Although specimens from cadavers have helped developtechniques for a limited number of research problems, use ofcadaveric parts is not suitable for investigations of variouspathologic states. Some therapies do not reach the point ofclinical trials because baseline information on the potentialeffect on humans is lacking.

It is widely accepted that there is no model in which allpotential therapies may be tested appropriately; however, it hasbecome essential to have an animal model matched to theclinical pathology prior to initiating a clinical trial. Whenselecting an appropriate animal model, the salient criteria toconsider are a closely matched anatomic structure and the easewith which the treatment can be translated to a clinicalsetting.78 A study of adhesions formed after injury to the flexortendon in the primate was found to have the closestresemblance to humans in both surgical technique and physicalattributes of the matching tissues and organs.79 Use of dogs andchickens has been ruled out primarily because their physical andanatomic features do not match the human anatomy. This isessential for research translation from an animal model to thehuman situation. In short, testing materials, biological factors,and surgical techniques in an animal model that mimics thepathogenic condition in humans is ideal because it will facilitateresearch translation to humans. Murine models that simulatevarious disease states, such as genetic disorders, growth factordeficiencies, cancers, and immunodeficiency are available tomany investigators. Animal models have given a major boost tothe design of research tools and are available for thedevelopment and validation of novel therapies prior to humantrials. These models are used to test procedures quantitativelyand to determine the ease and effectiveness of surgicalprocedures, and they allow for statistically significant studies inmice, rats, and rabbits. In addition, larger animals, such as goats,sheep, as well as porcine and equine models, have been utilizedin appropriate circumstances. The choice of the animal model isalso determined by the outcomes sought by the investigators.Most animal models are appropriate for the determination ofhistology, cell proliferation, and biochemical analysis in order to

determine the effectiveness of surgical or therapeutic treatment

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procedures. The need to have a technically reproducible andmechanically stable tendon injury model is paramount to theultimate utility of the animal model. In addition, the availabilityof techniques that will measure the strength of the regeneratetissue is necessary with most musculoskeletal components.These considerations set the lower limit to the anatomic sizeand morphologic features within the experimental model. Inchoosing an animal model, an important consideration is theability to compare results with the existing literature to betterassess the effects of a therapy that leads to the desired outcome.

EVOLVING TREATMENT OPTIONSAlthough our understanding of tendon biology and thebiological processes that regulate repair have progressedtremendously, many challenges need to be addressed tobring about a successful treatment strategy. Progress indeciphering how the temporal and spatial biochemical cueseffect repair and regenerate tissue, combined withdevelopment of a suitable biomaterial that will providemechanical support, shows great promise in formulating atissue-engineering treatment option. Growth factorsregulate the repair process in a spatial and temporalmanner; however, the exact mechanisms on thedownstream pathways are lacking. Recent studies haveshown that growth factors can modulate stromal cells intospecific lineages. Recently, adipose-derived stromal cellshave been shown to differentiate into multiple lineagesunder appropriate chemical cues. In addition,subpopulations exist within the stromal cells that exhibitphenotypic and surface markers leading to a specific celltype. Treatment options involving growth factors, aloneor in combination with a stromal population, may formfunctional repair or regenerate tendon faster than existingtreatment modalities. The delivery of necessary factors atthe required dosages in a temporal and spatial patternover the repair phase is critical to a successful treatment.The appropriate delivery option may deliver and maintainsuitable stromal cells at the repair site to effect a fasterrepair process. The repair or regenerate functional tissuemust form in synchronization with degradation of thedelivery vehicle. Depending on the application,biomaterials can be modulated to have the desiredproperty (factor delivery and biomimetic). Tendons andligaments must be loaded in tension during the repairphase to prevent scarring and adhesion formation withthe surrounding tissues. The biomaterial must transmittensile forces from muscle to bone to support digitmovement after treatment. Recent studies haveinvestigated the potential of polymeric scaffolds formusculoskeletal applications. The choice of biomaterialand processing technique can be used to modulate thephysical properties of the tissue-engineering implant, andnanoarchitecture on the scaffold surface elicits ECMdeposition and organization. Treatment strategies usingthese various parameters are extremely promising fortendon tissue-engineering applications. The challenge is

to consolidate the progress in various areas (role of

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TENDON DEVELOPMENT, REPAIR, AND REGENERATION 109

chemical cues, biomechanics, biomaterials, and suitablestromal cells) to overcome the current obstacles inachieving a functional repair or regenerate tendon.

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