CHAPTER 34
Advances in Understanding of Tendon Healing and Repairs and Effect on Postoperative Management

PETER C. AMADIO, MD*

Significance of Tendon Injuries

Upper extremity injuries are common, representing approximately one third of all traumatic injuries. Tendon injuries are among the most severe upper extremity injuries. The number of tendon injuries is difficult to quantify because epidemiologic studies have not been done, but estimates suggest that roughly 40,000 inpatient tendon repairs are done each year in the United States.1 A much larger number of tendon surgeries are done on an outpatient basis. More importantly, these injuries occur almost exclusively in a young, working-age population and result in considerable disability. The typical tendon injury requires 3 to 4 months of rehabilitation, during which time the affected hand is unavailable for work use. Failure rates or residual impairment remain disturbingly high, in the 20% to 30% range in most series, despite ongoing attention to the problem. From 1976 to 1999, consistently between 7% and 8% of the articles in the Journal of Hand Surgery focused on tendon injuries.² Despite this evident importance and ongoing interest, translation of research results into meaningful clinical improvements have been limited. By most accounts,³ the most significant improvement in tendon rehabilitation remains the institution of early passive motion therapy by Kleinert in the early 1970s.⁴ Since then, quality improvements have been incremental. Tendon rupture rates continue to be cited at an incidence of 5% to 10%. These failures require complex secondary tendon reconstruction surgeries.^5-8 Better methods for improving intrinsic tendon healing and minimizing tendon adhesions are still needed so we can improve upon clinical outcomes, with the ultimate goal being the production of an adhesion-free tendon repair.

Tendon Healing

The extracellular matrix (ECM) is the principal component of tendon tissue and is responsible for its material properties.9-11 The major constituents of the ECM are type I collagen; proteoglycans, principally decorin, but also aggrecan in the gliding regions;^12-15 fibronectin; and elastin. This matrix is synthesized by tendon cells, or tenocytes (Fig. 34-1). These cells are surrounded by the dense matrix; thus, although they are metabolically active, they do not participate much in the tendon-healing process. Instead, undifferentiated cells in the epitenon do the heavy lifting for tendon healing, and proliferating, migrating into the gap between the tendon ends, and finally uniting the cut tendon ends^16,17 (Fig. 34-2). Unfortunately, this process presents a bit of a dilemma; if these same cells migrate away from the tendon, toward the tendon sheath, they form adhesions that restrict tendon motion. Often this is indeed the case, as the relatively ischemic tendon is surrounded by better vascularized tissue, which sends out vascular buds under the stimulation of vascular endothelial growth factor (VEGF).^18-21

After tendon injury, the ECM undergoes significant changes due to synthesis of new elements, such as type III collagen, by the tenocytes,22-24 degradation of existing elements by various matrix metalloproteinases (MMP), and remodeling of the resulting combination, under the influence of cytokines such as transforming growth factor beta (TGF-β) as well as mechanical forces. Manipulation of these processes, to augment their action between the tendon ends while reducing them at the tendon’s gliding surface, is the goal of much research, as described later.

Pharmacologic Manipulation of Tendon Healing

Various pharmacologic agents have been used in the past in an attempt to modify adhesion formation. Steroids, antihistamines, and β-aminoproprionitrile have not been shown to decrease scar formation clinically.25,26 Ibuprofen and indomethacin, however, have been found to have a small beneficial effect.²⁷

The ideal pharmacologic agent should have no systemic side effects, should be limited to a single application, and should be directed at growth factor expression and ECM production. Such a drug may be 5-fluorouracil (5-FU), an antimetabolite used not only as a cancer chemotherapeutic agent but also to prevent adhesions in glaucoma filtration surgery. The exposure of a surgical field to 5-FU produces a focal inhibition of scarring. Blumenkranz and colleagues have found that 5-FU inhibits the proliferation of fibroblasts in cell cultures and reduces retinal scarring.^28,29 Single exposures to 5-FU, for as short duration as 5 minutes, can have antiproliferative effects on fibroblasts for several days. The suppression of fibroblast proliferation has been observed for up to 36 hours without signs of cell death.^30,31 This time frame may be adequate to inhibit tendon adhesions prior to beginning postoperative motion protocols. Reversible prolonged inhibition of fibroblast function is attributed to the drug’s inhibition of DNA and messenger RNA (mRNA) synthesis through thymidylate syntheses. More importantly, these effects appear to be focal to the site of application and titratable in terms of length of action.^32-34 A 5-minute exposure to 5-FU has been shown to significantly decrease postoperative flexor tendon adhesions in chicken and rabbit models.^35,36 This beneficial effect is felt to be due to the down-regulation of TGF-β and modulation of MMP-2 and MMP-9 production.^37,38 The effect on surface lubrication is unknown. No adverse effect was noted on tendon healing in these studies. It is presumed therefore that the topical 5-FU does not penetrate to affect the cells below the tendon surface. Topical 5-FU may well have a role in improving the outcomes in selected cases of tenolysis.

Growth Factors

Growth factors are the chemical signals that direct the migration and proliferation of the tendon fibroblast during the healing process. The role of growth factors has been examined extensively in cutaneous wounds and other soft tissue processes, yet we are only beginning to know the specifics involved in flexor tendon healing.11,39 The factors that appear to be involved include TGF-β, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), and VEGF.^21,40,41 These same growth factors have also been shown to optimize tissue-engineered constructs used for tendon repair.^21,40-44 Growth differentiation factor-5 (GDF-5), a member of the TGF-β superfamily, has also been shown to accelerate tendon healing in multiple animal models.^45-47

TGF-β stimulates the formation of the ECM. It signals fibroblasts to produce collagen and fibronectin, decreases protease production, and increases the formation of integrins, which promote cellular adhesions and matrix assembly. In normal tissue, TGF-β becomes inactivated once wound healing is complete; however, it may remain active in tendon adhesion formation, continuing the cycle of matrix accumulation.^48,49 Excessive expression of TGF-β is detrimental to many tissues, resulting in tissue fibrosis in the heart, kidney, and liver.⁴⁹ Modulation of TGF-β has been reported to reduce the fibrotic process in glomerulonephritis, dermal wounds, and arthritis as well as decreasing peritendinous adhesions in a rabbit tendon model.^49-52 TGF-β levels can remain elevated for up to 8 weeks after tendon injury.^53,54

Neuropeptides may also play a role in tendon healing.^55-58 During the early phases of healing, tendons exhibit nerve fiber ingrowth.⁵⁵ This nerve ingrowth is associated with the temporal release of substance P (SP). SP promotes tendon regeneration through the stimulation and proliferation of fibroblasts.^59-62 Further studies have found that tendon motion helps to modulate the release of SP.⁵⁶ The injection of SP into the peritendinous region of ruptured rat tendons improves healing and increases tendon strength.⁶³ Similarly, GDF-5 has a potential to stimulate bone marrow-derived stem cell (BMSC) proliferation and regulate BMSC differentiation to tenocytes.⁶⁴ Recent experiments have shown a beneficial effect of GDF-5 on tendon healing as well.^19,46,65

Tendon Grafting

At one time, most flexor tendon injuries were treated with tendon grafts,66,67 but today primary repair is used almost exclusively, with grafts being used primarily to reconstruct otherwise unbridgeable tendon gaps. This is a good thing, since tendons in the hand are intrasynovial and have a specialized gliding surface, whereas most tendon grafts, such as the palmaris or plantaris, are extrasynovial and have no such specialized surface.^68,69 The result is much more adhesion formation than would be the case if intrasynovial grafts were available. As noted later, in the future it may be possible to engineer such grafts to reduce friction and improve healing.

Augmentation of Intrinsic Tendon Healing with Stem Cells

Healing of flexor tendons in zone 2 depends on the ability of the injured tendon to recruit fibroblasts and other cellular components to the site of injury.70 Normally these are circulating or locally derived undifferentiated (i.e., stem) cells that are recruited to the injury site by the expression of cytokines in the wound.^18,21,71-73 Cytokine stimulation is also important in converting these undifferentiated cells into the tendon phenotype, characterized by the expression of markers such as tenomodulin and scleraxis.^74,75 BMSC can also enter and participate in soft tissue healing.^76-78 BMSCs delivered on collagen sponges improve healing in animal models of tendon repair,^42,79 and stem cells from other origins have been shown to be effective in enhancing repair in several other tendon injury models.^80-83 Current research is focused on optimizing the isolation and differentiation of stem cells into the tendon phenotype. In the future, it is likely that cells derived from the patient’s own bone marrow, fat, skin, or muscle will be used to augment tendon repair and to populate engineered tendon graft substitutes (Fig. 34-3). My colleagues and I are pursuing one such option in our laboratory now: a decellularized flexor digitorum profundus tendon allograft, reconstituted with stem cells from the patient’s own tissues and lubricated with an engineered surface containing hyaluronic acid (HA) (Fig. 34-4) and lubricin.^84-87 Such a graft could be used to bridge flexor tendon defects and, finally, to replace like with like.

Tendon Lubrication: Hyaluronic Acid and Lubricin

In addition to collagen and structural proteoglycans, such as decorin, the tendon ECM also contains important lubricants for efficient flexor tendon motion (see Fig. 34-1). The synovial cells of the flexor tendon sheath secrete HA into the ECM, which may serve as a surface lubricant.⁸⁸ HA, a polysaccharide, is found in all vertebrate tissues and body fluids. Various physiologic functions have been assigned to HA, including lubrication, water homeostasis, filtering effects, and regulation of plasma protein distribution.⁸⁹ HA is found in increased amounts during the first week after tendon repair.⁹⁰ After a tendon is treated with a hyaluronidase solution, which destroys HA, the gliding resistance between the tendon and pulley increases significantly.⁹¹ This suggests that HA on the surface of the flexor tendons may play a role in the surface lubrication of the tendon–pulley system. In vivo results have demonstrated that HA may inhibit the proliferation of rabbit synovial cells, thus preventing cell adhesion between the sheath and the tendon.^92,93

Recent studies indicate that lubricin, a proteoglycan found in the superficial zone of articular cartilage, may play an important role in preventing cellular adhesions in addition to providing the lubrication necessary for normal joint function.^94-97 Lubricin was originally isolated from articular cartilage.⁹⁸ It has since been identified on the surface of tendons^97,99-101 and plays an important role in tendon lubrication.⁸⁵ However, lubricin also inhibits cellular adhesion and so has the undesirable effect of inhibiting tissue repair.¹⁰²

The expression of lubricin is modulated by interleukin-1 (IL-1), tumor necrosis factor (TNF-α) and TGF-β.⁹⁷ Little else is known about the expression or regulation of lubricin within digital flexor tendons, but its modulation may have a profound effect on the restoration of the flexor surface and the prevention of adhesions after tendon injury and repair (Fig. 34-5) and perhaps as a coating on a tissue-engineered tendon graft or tendon graft substitute, as discussed later.

Engineering the Tendon Surface

The effect of HA on flexor tendon repair has been investigated in animal and clinical studies.103-107 Exogenously applied HA may prevent adhesion formation between the flexor tendon and surrounding tissue following tendon repair without affecting tendon healing,^108-111 although in vivo results have been contradictory.^93,106,112 As the half-life of HA in tissue is short, native HA is probably eliminated too rapidly to maintain a long-lasting physical barrier between opposing tissues.¹¹³ Moreover, abrasion during tendon gliding constantly threatens to physically remove HA from the tendon surface.¹¹⁴ Therefore, extending HA half-life and strengthening HA binding ability on the tendon surface are important to enhancing the clinical effect of exogenously administered HA.

The carbodiimide derivatization, a chemical modification of HA, has been developed recently for clinical use.^115-117 This modification of HA decreases the water solubility of HA, increases its intermolecular binding strength, and therefore increases tissue residence time.¹¹⁸ Clinical studies of a proprietary form of this derivatized HA (Seprafilm or Seprafilm II, Genzyme Corp, Cambridge, MA, or Hyaloglide; ACP gel, Fidia Advanced Biopolymers, Abano Terme, Italy), fabricated as a cross-linked sheet to be inserted as a barrier between opposing surfaces where adhesion is undesirable, have shown that it can reduce postsurgical adhesions in gynecologic and abdominal surgery.^118-121 A variation on this theme, by doing the cross-linking reaction in situ to fix the HA directly to the tendon surface, using collagen as an intermediary (carbodiimide derivatized HA, or cd-HA), has had promising preliminary results in animal studies in vitro and in vivo.¹²² The combination of HA and lubricin appears to have an additive effect.⁸⁵ Recent work has also shown, though, that although physicochemical and pharmacologic interventions can reduce adhesion formation, in both tendon grafts and tendon repairs,^122-124 there is a cost in terms of delayed or impaired tendon healing after tendon repair. Newer investigations are considering how to combine adhesion reduction and improved healing through the use of growth factors and stem cells.

Tendon Repair

Over the past 50 years, novel repair techniques have resulted in improved clinical outcomes following flexor tendon surgery.125-129 The details of clinical tendon repair are covered in Chapter 35, but this chapter focuses on the effect of repair constructs on tendon healing and tendon kinematics.

Despite these advances in repair technique, adhesions continue to occur, and results can be less than adequate, particularly when the injury occurs in zone 2, the so called no-man’s land, where the tendon resides within a fibro-osseous pulley system. Critical features related to tendon repair include a strong, minimally reactive repair that maintains strong tendon coaptation while permitting tendon gliding.^130-134 Two major problems continue to occur within the clinical setting: gapping with rupture at the repair site and adhesion formation within the flexor sheath.^70,135-137 Despite attempts at modifying rehabilitation, whether through increased levels of applied load or increased rates, tendon excursion methods have failed to increase early tendon core strength.^138-141

Repair Biomechanics

The ideal tendon repair is strong, easy to perform, and does not interfere with either tendon healing or tendon gliding. Current methods are moderately strong and able to withstand the normal forces of light motion.142-147 However, some of these constructs, especially those with multiple loops or knots on the anterior tendon surface,^133,148,149 also generate high-friction forces with movement and may abrade the pulley surface over time¹⁵⁰ (Fig. 34-6). Newer suture designs have incorporated features such as fewer surface loops, loops on the lateral rather than anterior tendon surfaces, and knots inside the repair rather than on the surface; all these features help reduce friction while having little effect on breaking strength.¹⁵¹ Newer suture materials, such as FiberWire, a composite suture consisting of a monofilament polyethylene core surrounded by a braided polyester jacket (Arthrex, Naples FL), combine higher breaking strength, so that a smaller-diameter suture can be used, as well as providing low friction.^146,152

The Effect of Friction on the Results of Tendon Repair

Animal studies over the past decade have shown convincingly that high-friction repairs result in abrasion of the tendon sheath (Fig. 34-7) and adhesion formation, even when factors such as rehabilitation method are optimized.^150,153,154 Thus, the goal should be to use a high-strength, low-friction repair construct and a low-friction suture material. Most recently I have been using 3-0 Ethibond and a modified Pennington design, but the recent data noted earlier on FiberWire is certainly intriguing.

Effect on Postoperative Management

Until the mid-1960s, most flexor tendon repairs were immobilized postoperatively for 3 weeks. This policy was based on the research of Mason and Allen,155 who had shown that canine flexor tendon repairs decreased in tensile strength for 3 weeks postoperatively. Subsequent clinical work by Verdan,¹⁵⁶ Kleinert and Verdan,¹⁵⁷ and Duran and associates¹⁵⁸ showed that human flexor tendon repairs could be safely mobilized with a combination of active extension and passive flexion.

The use of early mobilization after tendon repair has resulted in improved outcomes.^{4,156,158-161} In animal models,^153,162-167 earlier mobilization results in better final tendon gliding and tensile strength. More recently, the fine details of mobilization have been studied, specifically the effect of timing^168-170 and the effect of differential motion of the wrist and finger joints on tendon loading and tendon gliding during the healing period.^153,171,172 Active motion protocols have also been used, although, interestingly, the clinical results are not reliably better than passive protocols.^{5,125,173,174} Moreover, the addition of loading to motion in animal models has been shown to have little effect on the final result in terms of strength and motion.^166,172,175 Thus, the available evidence suggests that motion, not load, is the critical factor.

Of course, there must be some load on the tendon if it is going to move; at the very least, the load must be sufficient to overcome the forces of friction. It is for this reason that low-friction repairs are important—they minimize the load needed to initiate movement. Friction, though, is not the only concern. The force needed to overcome joint stiffness and to flex traumatized, edematous tissues must also be considered, as well as the weight of the distal digit itself; often these latter forces far outweigh the frictional ones in magnitude, especially in injured digits. So, the minimum force needed to load the tendon is a combination of the frictional force and the force needed to move the joints and soft tissues. This combination is often called the “work of flexion” of the unloaded digit.^169,176,177

One might imagine that the maximum load that could be applied is the load that represents the breaking strength of the tendon, but that would be incorrect: long before the tendon breaks, it begins to gap, and gapping also increases friction, setting up a vicious cycle that can lead to later rupture. So, really, the upper bound is not breaking strength but the force needed to create a gap, which is usually much less.^161,178-187 The difference between the two forces—the unloaded work of flexion and the gapping force—represents the “safe zone” in which rehabilitation can occur¹⁵¹ (Fig. 34-8). Early on, this safe zone is bounded by strictly mechanical parameters related to the anatomy and biomechanics of the repair. Over time, though, the effects of tendon healing are added in; the general effect is usually to gradually widen the safe zone, enabling the rational use of a graded resistance program as outlined by Groth.¹⁸⁸ The details of such programs are reviewed in Chapter 36.

Summary

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* Disclosure: The author has, with others, applied for a patent relating to the tissue engineering of tendon surfaces to reduce friction, but has no financial or other relationships with any commercial entities related to the subject of this chapter.