Outline

Tissue engineering is a field that aims to apply our expanding basic knowledge of tissue biology to the design of engineered tissue substitutes. Despite advances in tendon repair, many patients still experience poor outcomes that can lead to lifelong disability. Tendon tissue engineering and bioactive sutures are well suited to address this clinical need. In injuries to the hand that require interposition tendon grafts, the need for autograft material may outstrip the supply in a given patient, or the available autograft material may lead to suboptimal outcomes for the patient. A tissue-engineered tendon would be readily available as an off-the-shelf product designed to optimize the healing process and to recapitulate normal function. Design of such a tendon requires a detailed understanding of the tendon healing process as well as normal tendon function and biology, including its structure and composition, cells and their role in tendon function, and biomechanical properties of tendons. This understanding can then be applied to the four primary components of a tissue-engineered tendon: cells, scaffolds, growth factors, and mechanical manipulation. Injuries requiring suture repair, whether or not an interposition graft is necessary, often have poor outcomes despite advances in suture techniques and materials. Current research into bioactive sutures loaded with growth factors or cells offers a new strategy for strengthening and improving suture repairs of tendons.

Despite recent advances in flexor tendon repair surgery, many patients still experience poor outcomes following repair. This is often due to severe adhesion formation, which may require tenolysis procedures to improve motion. Additional causes of poor outcomes include tendon rupture or failure at the repair site, due to either suture pull-through, suture breakage, knot slippage, or gapping at the repair site.

When graft material is required, repairs are currently limited to autografts such as the palmaris longus, plantaris, and toe extensor tendons. Limitations of autograft harvesting include donor site morbidity and additional anesthesia and operative time. In cases of mutilating injuries to the hand (Figure 7-1), the demand for graft material may outstrip the autograft supply in a patient, leaving these patients without a good solution for restoring hand function.

Figure 7-1 Mutilating injury to the forearm and hand with significant soft tissue loss, including tendon damage. This patient required extensive reconstruction and would have benefited from a tissue-engineered tendon.

Although synthetic graft materials such as Dacron grafts and Silastic rods have been used for tendon reconstruction, outcomes are generally poor, and the life span of these grafts tends to be short. Failure is typically due to mechanical wear or rupture of the tendon–graft interface. These synthetic materials are designed to replace tendon tissue, rather than to regenerate it. Thus, the resulting repair does not heal with tendon tissue properly and does not support the ingrowth of cells to promote biodegradation and remodeling of the implant.

Tissue Engineering

One of the earliest articles broadly defining tissue engineering was a 1993 Science article by Langer and Vacanti.¹ In this article, they defined the nascent field of tissue engineering as “an interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function.” They described three general strategies of tissue engineering: (1) cells or cell substitutes, (2) tissue-inducing substances such as growth factors and delivery vehicles, and (3) cell-seeded scaffolds. These principles have been applied to clinical needs in hand surgery, resulting in commercially available products including engineered skin substitutes² and allogeneic nerve grafts.³ However, a tissue-engineered tendon is not yet available.

Tendon Biology

At their simplest, tendons can be thought of as thick collagen ropes that transmit forces from muscles to act across joints to move and stabilize them. Development of a tissue-engineered tendon requires a much deeper understanding. The mechanical properties of tendons crucial to their proper functioning rely not only on the structure and organization of its major collagen constituents but also on the other extracellular matrix components. At steady state, tendons are relatively hypocellular and have low metabolic demands. During times of injury and healing, cells and their nutritional pathways play a critical role, and their activity is a major determinant of tendon healing.

Structure and Anatomy

Collagen is the basic structural unit of tendons.^4,⁵ It is organized into a hierarchical structure of progressively larger and more organized subunits to form the crimped or sinusoidal pattern visible by light microscopy.

While collagen is the major constituent of tendons, proteoglycans are critical to the biological and mechanical functioning of tendons.⁶ Proteoglycans promote hydration through hydrophilic subunits and mediate interactions between structural units of the tendon, which are important determinants of the viscoelastic properties of tendons. Another important function of proteoglycans is their role in promoting cell signaling to mediate growth, proliferation, and migration.

Synovial sheaths around tendons are found in areas subjected to mechanical stress in which efficient gliding is mediated by synovial lubrication. Examples of tendons of the hand with intrasynovial portions include the flexor digitorum superficialis and flexor digitorum profundus tendons. These tendons have an intrasynovial region in their more distal portions within the hand and an extrasynovial region in their more proximal portions. In addition to assisting with gliding in areas of high mechanical stress, the synovial sheath also provides nutrition by diffusion through synovial fluid. Extrasynovial tendons are covered by the paratenon, a loose connective tissue that carries the blood supply. This distinction is important because although overall outcomes are generally unsatisfactory with injuries to intrasynovial tendons and graft reconstruction, particularly in zone 2, better outcomes are achieved when reconstruction is performed with intrasynovial autografts rather than extrasynovial autografts.

Brockis and others made early observations about the vascular supply to flexor tendons.⁷ They observed that tendons receive their blood supply through the musculotendinous junction, the paratenon surrounding the tendon in the extrasynovial region, the vincula within the intrasynovial region, and the osteotendinous insertion. In addition to vascular nutrition, the intrasynovial portion of the tendon receives nutrition by diffusion through the synovial fluid.^8,⁹

Cells

Tenocytes, the primary cell type in tendons, are spindle-shaped fibroblast-like cells oriented along the long axis of tendons that are responsible for the production and maintenance of the extracellular matrix of the tendon. As they mature, their metabolic activity and energy demand decrease. This enables tendons to carry loads and maintain tension for long periods of time without becoming ischemic and necrotic. However, during injury and repair, this slow metabolic rate leads to prolonged healing.

Tendon Healing

Tendons heal slowly because of their hypocellularity, hypovascularity, and low metabolic rates.¹⁰ This prolonged healing process requires immobilization to reduce the risk of tendon rupture or gap formation. The duration of this immobilization must be balanced against the risk of adhesion formation. Modulating this healing process to create a strong tendon repair with minimal adhesion formation requires an understanding of the three stages of tendon healing: inflammatory, proliferative, and remodeling.^4,¹⁰

The inflammatory stage occurs within the first 24 hours and is characterized by recruitment of inflammatory cells. The proliferative stage begins as tenocytes are recruited to the site of injury and begin to produce extracellular matrix components, including collagen type III. After several weeks, the remodeling stage begins. The randomly organized extracellular matrix produced during the proliferative stage is organized into parallel fibrils, while the collagen type III production decreases and collagen type I production increases. As healing is completed, tenocyte number and metabolism then begin to decrease.

Extrinsic Versus Intrinsic Healing

It was originally thought that tendons must heal by an extrinsic process in which ingrowth of new cells occurred through vascularized adhesions to surrounding tissue.¹¹ It was later demonstrated that intrasynovial tendons could heal by a process mediated by cells intrinsic to the tendon.^12,¹³ This suggested that adhesion formation might not be necessary for tendon healing if cells within the damaged tendon are available to mediate repair.