Article Published in the Author Account of

Michael Gott

Tendon Phenotype Should Dictate Tissue Engineering Modality in Tendon Repair: A Review

Abstract: Advancements in the technical aspects of tendon repair have significantly improved the treatment of tendon injuries. Arthroscopic techniques, suture material, and improved rehabilitation have all been contributing factors. Biological augmentation and tissue engineering appear to have the potential to improve clinical outcomes as well. After review of the physiology of tendon repair, three critical components of tissue engineering can be discerned: the cellular component, the carrier vehicle (matrix or scaffold), and the bioactive component (growth factors, platelet rich plasma). These three components are discussed with regard to each of three tendon types: Intra-synovial (flexor tendon), extra-synovial (Achilles tendon), and extra-synovial tendon under compression (rotator cuff). Scaffolds, biologically enhanced scaffolds, growth factors, platelet rich plasma, gene therapy, mesenchymal stem cells, and local environment factors in combination or alone may contribute to tendon healing. In the future it may be beneficial to differentiate these modes of healing augmentation with regard to tendon subtype.



Introduction

Tendon injuries are encountered routinely in orthopedic practice. Treatment of these injuries has improved tremendously over the last two decades (Tang, 2005; Yamaguchi et al., 2003; Beredijiklian, 2003). Even so, the cost of tendon injuries to our society in terms of human suffering and financial burden continues to be significant. Management of tendon injury has been documented as far back as the 2nd century A.D., yet treatment protocols for many of these injuries are still actively debated (Burkhead and Habermeyer, 1996). While the advancements in basic and clinical research often lead to new therapies and treatment adjuncts, these same advancements can initiate even more controversy in the appropriateness and applicability of these new technologies. Despite the strides made in understanding tendon physiology, many of the mechanisms behind its response to injury remain unknown. Unlike bone, which has the ability to restore normal tissue after injury, tendon heals with scar that is never identical to the uninjured tissue. The goal of clinical practice is to capitalize on that scarring while attempting to limit adhesion formation in order to optimize post-injury function. Current tissue engineering techniques seek to accelerate and/or modulate and/or improve the speed and quality of the healing tendon tissue.

Although intrasynovial tendons, extrasynovial tendons, and extrasynovial tendons under compression all possess a similar biochemical composition, injuries to these tendons are generally managed differently because of the unique anatomy, physiology, function, biomechanics, healing, and post-operative rehabilitation that pertain to each. Each tendon type presents its own unique set of challenges.

Comparative Tendon Physiology

All tendons share basic structural components. Key differences exist, which aid each in its specific function. Collagen is the single most abundant structural component of tendon. Whereas water makes up 70% of its total mass, collagen constitutes 60-85% of tendon dry weight (type I - 95%, type III and IV - 5%) (O’Brien, 1997; Piez et al., 1969; Jimenez et al., 1978). Its molecular architecture provides tendon with its high tensile strength. The intrasynovial flexor tendons and the extrasynovial tendons like the Achilles and quadriceps tendon are similar in their collagen profile. Rotator cuff tendon, however, is slightly different in that it demonstrates the presence of some type II collagen, and interdigitation of some of its fibers (Clark and Harryman, 1992). The ground substance of tendon is composed largely of proteoglycans. Proteoglycans make up 1% of the dry weight of tendon, and consist of a protein core attached to many glycosaminoglycan side chains. They are large, water trapping molecules that are found in higher concentration in tendons that act in compression like the rotator cuff. This function of the rotator cuff results in this tendon possessing a higher proportion of fibroblasts which histologically resemble chondrocytes, producing both aggrecan and type II collagen (Vogel and Chevalier, 1997). Smaller proteoglycans, such as decorin, are present in purely tensile tendons, whereas larger proteoglycans are abundant in tendons that combine tension and compression (Berenson et al., 1996).

Like many tissue types in the body, tendons have a universally conserved organization. The endotenon is a thin, loose connective tissue layer that covers individual tendon bundles and fascicles. It carries neurovascular elements through the substance of the tendon, and is continuous with the overlying epitenon (Edwards, 1946). The epitenon is a layer of connective tissue that surrounds the surface of tendons. This outermost layer is specific to tendon type, aiding in its function. Tendons that glide around acute angles are encased in a synovial tendon sheath filled with synovial fluid, like the flexor tendons of the hands and feet. Tendons that travel a straight course and attach to bone with a large amount of excursion are surrounded by an areolar paratenon, like the Achilles and quadriceps tendon. The rotator cuff lacks both a synovial sheath and a paratenon. Instead, it is lined by the shoulder capsule on its articular surface and a bursa on its subacromial surface.

All tendons receive vascular supply from three sources: 1. the tendons - periosteal insertion; 2. the myotendinous junction; and 3. the surrounding soft tissues. The proportion of the blood supply from each source is not uniform across all types of tendons. The intra synovial flexor tendons have a limited direct vascular supply. The perfusion from myotendinous and periosteal vessels is minimal, and the synovial flexor sheath does not have the same rich blood supply as a paratenon. Vincular vessels from the digital arteries provide the most significant, yet still incomplete, direct blood supply to the tendon. Instead, a vital source of flexor tendon nutrition is from the diffusion of nutrients from the synovial fluid within the sheath, much like articular cartilage (Manske and Lesker, 1982; Manske and Bridwell, 1978). Extrasynovial tendons with a paratenon, like the Achilles and quadricepts tendon, receive a rich, anastomosing blood supply originating from neighboring soft tissue vessels. The Achilles tendon receives up to 35% of its supply from the paratenon (Naito and Ogata, 1983; Kvist et al., 1992). Vessels from the myotendinous junction perfuse the proximal third of the tendon, with a smaller contribution from vessels at the insertion into the calcaneus (Carr and Norris, 1989). In contrast, the rotator cuff does not have a synovial sheath or a paratenon. Instead large arterioles on its bursal surface contribute to its vascular supply (Ling et al., 1990). Larger arteries, the anterior and posterior humeral circumflex and suprascapular vessels, are largely responsible for the blood supply to the rotator cuff.

Despite receiving their blood supply from multiple different sources, many tendons have known regions of hypovascularity; these are known as watershed areas. Flexor tendons as a whole are hypovascular relative to their surrounding environments (Brockis, 1953). The Achilles tendon has a watershed area that is 2cm to 7cm proximal to its insertion (Koh et al., 2002). The presence of a watershed region in the rotator cuff is not universally accepted; however, a “critical zone” just at the insertion of the supraspinatus had been labeled as a region of vascular insufficiency (Codman, 1931; Moseley and Goldie, 1963; Rathbun and Macnab, 1970). Later reports claimed decreased perfusion was limited to the insertional surface of the distal tendon, whereas others have reported hypervascularity to the area (Tang, 2005; Ling et al., 1990). Although these regions of vascular insufficiency are commonly affected in tendon pathology, there is still little evidence to claim direct responsibility.

Tendon Healing

Tendon healing progresses through three phases, similar to bone and other tissues. The inflammatory phase is characterized by increased vascular permeability and an influx of local inflammatory cells including platelets, macrophages, monocytes, and neutrophils that release chemotactic agents to recruit blood vessels, fibroblasts, and intrinsic tenocytes. During the second, proliferative phase, fibroblasts at the injury produce collagen and matrix, and angiogenesis provides an increased local vascular supply. The third phase is the remodeling phase, in which there is a decrease in cellularity and an increase in collagen organization parallel to the axis of the tendon.

Tendon healing is believed to occur via two separate pathways: intrinsic and extrinsic. The intrinsic pathway model involves cells from the endotendon and epitendon that migrate to the area of tendon injury. In the extrinsic pathway, cells not originating from within the tendon are predominantly involved in repair. These include inflammatory cells, stem cells, and cells from other tissue compartments. Biomechanically, the intrinsic pathway of healing, or completely intratendinous healing, results in strong, more elastic tendons. The extrinsic pathway results in a healing callus, and contributes greatly to the formation of adhesions.

Differences in the anatomy and physiology must be considered in the repair and healing of each tendon type. In all tendons, repair occurs by fibroblasts that are both intrinsic to the tendon (tenocytes) and by those that are extrinsic, residing in the surrounding sheath, paratenon, and/or soft tissues. Although both populations of fibroblasts are important in the repair process, it is likely that the contribution from each is different for each of the different tendon types (Chang et al., 1990). The role of extrinsic healing is relatively limited in flexor tendons, because it leads to the development of adhesions and loss of motion (Chang et al., 2000). Furthermore the presence of synovial fluid physically inhibits the ability of extrinsic growth factors to reach the intrinsic cells of a flexor tendon. In extrasynovial tendons, however, the extrinsic elements of the paratenon provide a significant fibroblastic response, by surrounding the injury in a fibrovascular callus. Furthermore, in the rotator cuff, the subacromial bursa may offer an extrinsic contribution to healing (Uhthoff and Sarkar, 1991). The extrinsic system is thought to respond earlier in the repair process; intrinsic cells of the epitenon, endotenon, and lastly the tendon core respond shortly afterwards (Soslowsky et al., 1996; Khan et al., 1998; 2000). However, the exact contribution of each repair mechanism is undetermined, as is the exact sequence of the cellular response.

The anatomy of a tendon’s injury as well as its function must be taken into consideration. In order to achieve acceptable function after injury to intrasynovial tendons, its gliding function must be restored. In these tendons, limitation of adhesion formation is paramount. In extrasynovial tendons, restoring strength is most important to the tendon’s healing due to high level forces they endure. Restoration of the tendon’s collagen organization and tendon to tendon healing may be of greatest importance in these extrasynovial tendons. In the rotator cuff, injury usually occurs at a tendon bone interface. Healing of tendon to bone must be preferentially considered when attempting to repair this tendon. Re-establishment of the specialized enthesis structure at the bone tendon interface is still a clinical challenge and focus of intense research efforts.

Tissue Engineering

Current tissue engineering techniques utilize any combination of three key components: a cellular component, a carrier vehicle/matrix or scaffold, and a bioactive component. The cellular component should consist of cells that are accessible, manipulatable, and nonimmunogenic. They should be responsive to environmental cues while maintaining a certain degree of phenotypic stability. The carrier component can act as both a delivery vehicle and a matrix scaffold. The carrier/scaffold should be biologically compatible to both the cellular component and the recipient host tissue. The carrier should allow for both in vitro and in vivo cellular seeding as well as integration into local host tissue without causing a detrimental inflammatory reaction. It should be biodegradable and biomechanically robust, acting as a temporary structural framework until its role is replaced by naturally synthesized matrix. The bioactive component should act as an inductive factor for tissue repair, augmenting chemotaxis, cell differentiation, proliferation, and/or matrix production. These include endogenous administration of synthetic growth factors and morphogens, as well as platelet rich plasma (PRP). In almost all instances the main components of tissue engineering are combined.

Animal models of tendon subtypes

Animal model systems are frequently employed to study various tissue engineering methods for orthopedic applications. Flexor tendon healing and repair has been studied primarily in rabbits, chickens, and canines. The model requires a gliding, sheathed tendon that is surgically practical to manipulate. A common model for the rotator cuff is the rat, due to their accessibility and low cost, and also because of the remarkable anatomic similarity to the human shoulder (Soslowsky et al., 1996; Derwin et al., 2006). Larger animals such as sheep, goats, and canines have also been used for their greater size and load bearing. The Achilles tendon is readily accessible in most animal models, and therefore has seen experimentation in most of the above mentioned systems.

Scaffolds

A scaffold serves as a supporting framework. Scaffolds used in tissue engineering, and specifically tendon repair are biocompatible, biodegradable structures that can mimic native extracellular matrix in both form and function. Scaffolds must be able to support and hold cells, whether these cells are implanted on them, or they are chemo-attracted to them. Furthermore, ideal scaffolds offer biomechanical properties that can support early range of motion of healing structures. Investigative interest in bioactive scaffolds is very high due to the potential convenience they offer (manufacturing, storage, and clinical application). They have been studied alone, and in conjunction with other tissue engineering components, including cells and growth factors.

The use of scaffolds alone in flexor tendons has not been highly studied, but they have been combined with tenocytes in an effort to engineer an autologous tendon graft. Leghorn hen flexor tendon tenocytes were harvested, seeded onto polyglycolic acid (PGA) scaffolding shaped as a tendon, and cultured. These grafts were then used to repair 3-4cm flexor tendon defects, demonstrating superior histologic and biomechanical repairs when compared to PGA scaffolding alone (Cao et al., 2002; Adams et al., 2006). However, the use of scaffolds in flexor tendon repairs may have a detrimental effect on tendon gliding, due to their size, and the lack of space within a repaired synovial sheath.

Scaffolds for both the Achilles tendon and the rotator cuff have been investigated both as structural supports and as delivery systems for other tissue engineering modalities. Four of the matrix scaffolds that are commercially available for rotator cuff repair (GraftJacketTM, TissueMendTM, RestoreTM, and CuffPatchTM) were compared in their biomechanical properties to canine infraspinatus tendons. Derwin et al. (2006) found the elastic moduli of these scaffolds to be an order of magnitude less than actual canine tendon, suggesting that these scaffolds may not be used as a means of strengthening an immediate repair. Separately, a dermal matrix graft was able to produce a biomechanical repair equal to that of an autologous tendon graft by twelve weeks in full-thickness canine rotator cuff tears (Adams et al., 2006). Another study comparing different commercially available scaffold patches demonstrated the varying ways they failed under tension (Barber et al., 2006). In a clinical trial, rotator cuff tears that were augmented with porcine small intestine submucosa failed to demonstrate improved healing rates or clinical scores when compared to traditional repair (Iannotti et al., 2006). In goat infraspinatus tendons, polylactic acid (PLA) scaffolds used in conjunction with surgical repair failed to demonstrate a biomechanical advantage, although an earlier study looking at initial repair strength in sheep infraspinatus tears suggested a 25% increase over control repairs (MacGillivray et al., 2006; Koh et al., 2002).

In the Achilles tendon, Brodie et al. (2011) were able to improve the biomechanical properties of Achilles tendon repairs using a bio-adhesive coated scaffold. They used a porcine cadaveric model where suture repair alone was used in one group and in a second experimental group the suture repair was augmented with a tissue scaffold of either pericardium or dermal tissue that was augmented with a bioadhesive coating. In biomechanical testing the experimental group showed an improvement in stiffness, load to failure, and energy expenditure to failure.

Growth factors

Growth factors act as mitogens in tissue repair, and their local administration has been the focus of many investigations. Some of the growth factors that have been identified as having an effect in flexor tendon repair are transforming growth factor β (TGF-β), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblastic growth factor (bFGF2). Consistent with the potent mitogenic role that IGF has with many other tissues, it has been shown to increase collagen, proteoglycan, and tenocyte proliferation in rabbit flexor tendons, and has improved healing in a flexor tendonitis model (Abrahamsson et al., 1991; Dahlgren et al., 2002). Simultaneous administration of PDGF-β, IGF-1, and FGF-2 show a synergistic effect on tenocyte proliferation in vitro (Costa et al., 2006). TGF-β is a ubiquitous growth factor, with effects that are largely determined by the individual cell type. In vitro studies have shown increased concentration of this growth factor in injured tendon, and increased collagen synthesis in response to TGF-β administration (Thomopoulos et al., 2007; Klein et al., 2002). However, in vitro and in vivo investigations using a rabbit model demonstrated decreased type-I collagen synthesis and increased range of motion after surgical repair when TGF-β was inhibited, suggesting its potential role in adhesion formation (Bidder et al., 2000; Bates et al., 2006). A knockout study that inhibited the effects of TGF-β showed that adequate tendon healing can still occur in its absence (Tsuboneet et al., 2006). PDGF is one of the earliest responding growth factors following tendon injury. Its presence was upregulated in healing canine flexor tendons, and has been associated with increased collagen and proteoglycan synthesis and tenocyte DNA synthesis in vitro and in vivo (Duffy et al., 1995; Yoshikawa and Abrahamsson, 2001; Thomopoulos et al., 2007). Although VEGF has been found in higher concentrations in healing flexor tenocytes than in uninjured tendon, there are no studies that report results of experimental manipulations of flexor tendon repairs with VEGF (Bidder et al., 2000; Boyer et al., 2001).

Growth factors have been extensively investigated in Achilles tendon repairs. Injecting vascular endothelial growth factor (VEGF) into healing Achilles tendons has demonstrated increased tensile strength during repair after two weeks, with no difference in the two groups after four weeks (Zhang et al., 2003). Growth and differentiation factor 5 (GDF-5) coated sutures improved histologic quality of repair and biomechanical tensile strength and load to failure in rat Achilles surgical defects during the early stages of tendon healing (3 weeks) (Dines et al., 2007). An earlier study using sutures similarly coated with GDF-5 also described a stronger repair during early healing (2 weeks) in rat Achilles tendons (Rickert et al., 2001). Recent studies, by our group, investigated sutures coated with PDGF to augment rat Achilles tendon repairs. We observed significant improvements in load to failure at earlier time points compared to controls.

The rotator cuff specifically has become a popular model for the study of local growth factor application. The more commonly studied bioactives include members of the transforming growth factor superfamily, such as TGF-β and the several bone morphogenic proteins (BMP); growth factors such as platelet derived growth factor-beta (PDGF-β), insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF) have also been explored. As the number of investigations looking at the local milieu of tendinopathy and tendon repair continues to increase, it is probable that additional bioactive factors will be discovered and will appear in the literature. In a sheep model, a construct that contained a combination of growth factors (BMP 2-7 and TGF-β 1-3) in conjunction with a type I collagen carrier was used to increase load to failure in infraspinatus tendon to bone repair. It was noted, by the author, however, that the improved repair strength could have been due to an observed increased quantity of repair tissue, not an actual improvement in quality of repair tissue (Rodeo, 2007). Cartilage derived morphogenic protein 2 (CDMP-2), also known as growth and differentiation factor 5 (GDF-5) was utilized in a different study to improve biomechanical and histologic quality of repair in rat rotator cuff tears (Murray et al., 2007). Recently studies have been directed towards sustained release of growth factor to the rotator cuff. Manning et al. (2011) used a heparin-fibrin based delivery system. They found that when combining TGFβ-3 to their delivery system and using it in repaired rat rotator cuffs they were able to see both histological and biomechanical improvements in healing up to 56 days post repair.

Platelet Rich Plasma

The use of plasma rich plasma (PRP) by orthopedic surgeons and others has grown rapidly, stimulated in part because of the potential for improved healing that might occur as a result of the extraordinarily high concentration of the various factors within PRP as well as the ease of preparation and low cost. Eppley et al. (2004) found a 6.2-fold increase of VEGF, a 5.1-fold increase PDGF-β, a 3.9-fold increase in EGF, and a 3.6-fold increase in TGFβ-1 in activated PRP. PRP not only contains increased levels of growth factor found in its alpha granules, it also contains elevated amounts of fibrin, fibronectin, and vitronectin. These are important for cell adhesion and epithelial migration (Eppley et al., 2004). In vitro studies using PRP have been promising. Schnabel and his colleagues examined gene expression patterns, cell proliferation, and collagen content of equine flexor digitorum superficialis tendon explants cultured in media consisting of PRP or other blood products (blood, plasma, platelet poor plasma, bone marrow aspirate). The results of this experiment showed that tendons cultured in 100% PRP showed the most significant enhancement of mRNA expression of the matrix molecules COL1A1 (collagen type I), COL3A1 (collagen type 3), and COMP (cartilage oligomeric matrix protein) with no concomitant increase in the catabolic molecules MMP-3 and MMP-13 (Schnabel et al., 2007). Another study found a specific enhancement of the extrinsic healing pathway by PRP. In this study, rat tendon injuries, in which local PRP was injected, were found to have increased levels of circulatory derived cells infiltrating the repair site. These cells included circulating inflammatory cells, as well as cells derived from the bone marrow. This increase in repair site infiltration led to the conclusion that PRP can have an effect on not only intrinsic healing, but also the extrinsic pathway (Kajikawa et al., 2008).

PRP augmentation of repair has been investigated in animal models of flexor tendon injuries. In an equine model, digital flexor tendons were surgically cut and repaired. One group of tendons received a single injection of PRP, while the control group received an injection of saline. The PRP group of tendons had a higher strength to failure and elastic modulus as compared to the controls (Bosch et al., 2010). To date no human trials using PRP in human flexor tendon injuries have been studied.

PRP augmentation of Achilles tendon ruptures has been controversial. Sanchez et al. (2007) looked at Achilles tendon repairs in athletes that were augmented with PRP. He then compared their clinical outcomes with matched cohort that did not have PRP augmentation. They observed that the athletes who received the PRP recovered their range of motion earlier (7 ± 2 weeks vs. 11 ± 3 weeks), showed no wound complication, and took less time to take up gentle running (11 ± 1 week vs. 18 ± 3 weeks) and to resume training activities (14 ± 0.8 weeks vs. 21 ± 3 weeks). In addition, the cross-sectional area of the PRP treated tendon increased less. In a clinical study from the Netherlands comparing the use of PRP injection versus saline injection administered to patients with chronic Achilles tendinopathy, the PRP treated patients did not have any greater improvement in pain and activity than the saline treated patients (de Vos et al., 2010). More recently in a randomized single blinded study PRP was shown to have no effect on Achilles tendon rupture healing in humans (Schepull et al., 2011).

PRP augmented rotator cuff repairs have also been investigated. Recently a randomized controlled trial in arthroscopic rotator cuff repairs using or not using a PRP matrix to augment the repair showed no differences in outcomes between the two groups (Castricini et al., 2011).

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are multipotent cells that are known to be the progenitor cells of fibroblasts in tendon healing sites. Autografting of MSCs to tendon repair sites have been investigated. In vitro studies have shown similar positive results as PRP and growth factor augmentation.

MSC augmentation of flexor tendon repairs has shown improvements in repair histology in an in vivo horse flexor tendon model; however, there were no improvements in the biomechanics between the two groups (Schnabel et al., 2009).

MSC repair augmentation in an extrasynovial tendon models has been more successful than in intrasynovial tendons. Histologic quality and biomechanical strength of repair were improved in early Achilles tendon healing (3 weeks) in a rabbit model system with the use of marrow derived mesenchymal stem cells in a fibrin carrier system (Chong et al., 2007). Results from separate projects using MSCs to repair 1cm Achilles tendon defects in rabbits also showed an increased biomechanical advantage (Young et al., 1998; Ouyang et al., 2003). Other groups even reported some histological success in using MSCs to create tissue engineered tendon grafts (Long et al., 2005; Calve et al., 2004).

In a rat rotator cuff model, MSCs were added to repair sites. These tendons were then looked at histologically and biomechanically. No improvements in peak stress to failure or stiffness were found between the group of rats in which MSCs were added to the repair sites and those without (Gulotta et al., 2009).

Gene Therapy for Tendon Repair

Gene therapy is the insertion of genetic material into the genome of a cell or groups of cells that can intrinsically change the cells’ function. This therapeutic modality has been studied in tendon repair as a way to modify the cells in injured tendons to heal more efficiently and effectively.

Similar to other aspects of tissue engineering, gene therapy has been utilized to augment the application of growth factors in flexor tendon repair. In a rat flexor tendon model, transduced by plasmids containing PDGF-β, treated tendons produced a significantly greater amount of type I collagen DNA than control tendons in vitro (Wang et al., 2004). Similarly, rat flexor tenocytes transduced with bFGF using a viral vector increased type I and III collagen DNA synthesis in vitro (Wang et al., 2005).

Adenovirus particles carrying growth and differentiation factor-5 that were injected into transected rat Achilles tendons demonstrated a significantly thicker repair site than controls, but only a trend towards greater tensile strength (Rickert et al., 2005). Whereas, local administration of adenovirus expressing BMP-14 into rat Achilles defects demonstrated an increase in both tenocyte proliferation and repair site tensile strength (Bolt et al., 2007).

PDGF-β and IGF-1 transduced fibroblasts combined with a PGA scaffold were shown to improve tenocyte proliferation and collagen synthesis in vitro, and histologic repair in a rat rotator cuff repair model. The same IGF-1 transduced constructs also improved the biomechanical strength of repair in this model system (Dines et al., 2007; Uggen et al., 2005).

Combination of Tissue Engineering Techniques

All of the aforementioned tissue engineering techniques described have been investigated in conjunction with one another, in addition to being investigated alone. Scaffolds have been impregnated with stem cells, and stem cells have been engineered to express greater levels of certain growth factor.

Influence of Local Environment

As the differences in each of the methods of tendon repair augmentation become more apparent, the question arises whether there is an identifiable difference in these tendon types that makes their responses to methods of augmentation more predictable. One aspect that may be important is the local environment of the tendon itself. As outlined in Table 1, the three representative tendon types (flexor, Achilles, and rotator cuff) have different blood supplies, local environments, and primary repair methods. While the synovial based tendons appear to utilize an intrinsic repair method, the non-synovial tendons, which tend to get the majority of their blood supply by direct vascularization from surrounding paratenon and bursa, seem to utilize more of an extrinsic method of repair. This suggests that extra-synovial tendons may be more likely to respond to augmentation techniques that supply the surrounding environment with enhanced growth factors and cellular markers for repair than synovial tendons. These include scaffolds, mesenchymal stem cells, and possibly PRP. Synovial tendons, in contrast, which seem to rely on intrinsic methods of repair, may be more likely to respond to augmentation techniques, such as gene therapy, and locally delivered growth factors that affect the intrinsic healing potential. Furthermore, enhancements of the extrinsic healing pathway in intrasynovial tendons may also be detrimental. Enhanced extrinsic healing may cause increased scarring and adhesions which may inhibit tendon gliding.

Anatomical differences in each tendon type may also contribute to the tissue engineering modality better suited for repair in that tendon. In flexor tendons, the repair is most reliant on tendon to tendon healing, whereas in repairs of rotator cuff injuries bone to tendon healing is most important. The use of growth factors, such as those in the BMP superfamily, have been shown to enhance tendon to bone healing (Rodeo, 2007).

Delivery of the each engineering modality to the three different types of tendons also must be taken into consideration (Table 1). Intra-synovial tendons are bathed in synovial fluids. This fluid turns over frequently. Injecting growth factor or PRP may be problematic. The growth factor may not be present in the local environment long enough to have an effect on healing. Delivery systems are being developed, however, that can keep these growth factors in the local healing milieu long enough to have an effect. These include suture coating and binding systems (Dines et al., 2007; Eppley et al., 2004). Gene therapy can change the healing capacity of a cell after one dose thereby bypassing the necessity for it to have to be present for a long period of time.

While there have been many advances in tissue engineering and tendon repair in experimental settings, translation of this work is required to make this technology practical and applicable in clinical settings. While the currently available methods of tendon repair are encouraging, each has its own limitations that will need to be improved. An understanding of specific tendon anatomy and physiology and the predominant healing pathway found in that tendon aids in directing which tissue engineering modality will be most successful to enhance healing.

Disclosure

The authors report no conflicts of interest.

Corresponding Author

Daniel A. Grande, Ph.D., Orthopedic Research Laboratory, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(62):75-84, July 2011. Copyright © Discovery Medicine. All rights reserved.]

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