Biologics in Rotator Cuff Repair

Biologics in Rotator Cuff Repair

Salma Chaudhury and Scott A. Rodeo

Chapter Synopsis

• High failure rates after rotator cuff repairs have encouraged the search for biologics that may stimulate improved healing. This chapter will consider a number of different biologic approaches to augmenting rotator cuff repairs. Key cytokine and growth factors that play important roles are identified as potential targets for biologic therapies. The efficacy and limitations of a number of commercially available biologic treatments are considered, including drug therapies, platelet-rich plasma, structural support with scaffolds, and more novel cellular therapies. Techniques to indirectly modulate the biologic milieu of rotator cuff tendons are also considered, such as encouragement of neovascularization and mechanical loading.

Important Points

• Modulation of cytokines and growth factors in the biologic milieu surrounding rotator cuff tendons may enhance healing.

• A number of drugs have been identified that potentially impair tendon healing, such as cyclooxygenase 2 inhibitors and fluoroquinolones; their judicious use after rotator cuff surgeries is advised.

• The role of platelet-rich plasma in rotator cuff repairs remains unproven and requires further investigation.

• Concerns persist about the efficacy of a number of synthetic and biologic scaffolds for augmenting rotator cuff repairs.

• Stem cell therapies alone have failed to result in improved rotator cuff healing. Enhanced stem cell function and tendon healing may occur through modulation of cell cytokine expression.

Rotator cuff pathologies are among the most common causes of shoulder pain. The incidence of rotator cuff tears is known to increase with age, particularly over the age of 50 years. Torn rotator cuff tendons are associated with increased pain and poorer shoulder function. A significant proportion of torn rotator cuff tendons retear after surgical repairs, and failure rates of 30% to 70% are frequently reported. The biologic milieu that precedes and follows rotator cuff tears has been shown to contribute to rotator cuff tear pathogenesis. The increasing health burden of rotator cuff tears has encouraged investigation into biologic adjuncts that may be used to augment surgical repairs of rotator cuff tendons with the aim of ultimately reducing high failure rates. It is hoped that biologic adjuncts will encourage regeneration of functional tendon tissue rather than mechanically inferior scar tissue that usually forms at the healing rotator cuff enthesis (Fig. 37-1).¹

Figure 37-1 A, Histologic sections of a normal supraspinatus tendon insertion site demonstrates the four zones of a direct insertion: tendon (T), unmineralized fibrocartilage (U-Fc), mineralized fibrocartilage (M-Fc), and bone (B). B, This histologic section of the tendon-bone attachment site 4 weeks after supraspinatus tendon repair in a rat model shows the site is characterized by a fibrovascular scar tissue interface (IF) without formation of an intermediate zone of fibrocartilage between tendon (T) and bone (B). (From Kovacevic D, Rodeo SA. Biological augmentation of rotator cuff tendon repair. Clin Orthop Relat Res. 2008;466:622-633.)

This chapter explores a number of biologic approaches used to treat rotator cuff tears in addition to surgical repairs, such as drug, scaffold, and cellular therapies, as well as mechanical modulation of the healing environment. Drugs and systemic factors that impair tendon-bone healing also are considered.

Drug Treatments That Improve Healing

Modulating Cytokines and Growth Factors

The biologic milieu surrounding healing rotator cuff tears is complex and affected by a number of factors that can be both helpful and detrimental to tendon regeneration. Manipulation of this biologic environment may tip the balance to favor tendon healing rather than tendon breakdown. A number of growth factors and cytokines related to extracellular matrix (ECM) regulation and turnover have been shown to play a role in rotator cuff tear pathogenesis. Modulation of these growth factors is proposed to enhance tendon healing, and a number of biologic moieties have been delivered to rotator cuff repair sites in an attempt to augment the rotator cuff tendon-bone interface.

Increasing cell numbers and their proliferation is proposed to increase tendon healing. One such cytokine that stimulates tendon regeneration is transforming growth factor β₁ (TGF-β₁), through its effects on cell replication and hyperplasia. However, a number of cytokines affect multiple pathways and can result in negative as well as positive effects on tendon healing. TGF-β₁ also increases smooth muscle actin (SMA) levels, which are thought to contribute to tendon retraction after tears.

Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases [TIMPs]) control the balance between synthesis and degradation of the ECM. The most important regulators of the ECM include MMPs 1, 2, 3, 9, and 10 as well as TIMPs 2, 3, and 4. Manipulation of MMP-related pathways are proposed to encourage tendon regeneration. Tetracyclines inhibit collagenase via an interleukin (IL)-1β–mediated release of MMP-3. One such example, doxycycline, was reported to improve the histology and mechanics of rotator cuff tendon healing in a rat model.²

Recapitulating embryonic tendon differentiation may help to replicate the scarless healing process that is seen in the embryo. TGF-β₃ plays a role in wound healing and embryonic tendon development, and therefore a number of studies have investigated the effects of localized TGF-β₃ delivery to healing tendon sites.3,4 TGF-β₃ delivery resulted in improved collagen I expression, vascularity, cellularity and cell proliferation. Improvements in histology and mechanical properties were also noted (Fig. 37-2).

Figure 37-2 Representative safranin O–stained tissue sections of the healing enthesis at 2 weeks after surgery. There is more fibrocartilage present in the experimental groups compared with the control group. T, Tendon; IF, interface; B, bone. (From Kovacevic D, Fox AJ, Bedi A, et al. Calcium-phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair. Am J Sports Med. 2011;39:811-819.)

Effects of some growth factors may be temporally mediated and depend on the phase of healing during which they are delivered. For example, fibroblast growth factor 2 (FGF-2) delivered both with and without scaffolds was found to improve the histology and biomechanical properties of healing supraspinatus tears in rats at early rather than later time points.5,6 Another cytokine that is thought to be detrimental to rotator cuff healing is the proinflammatory mediator tumor necrosis factor α (TNF-α), and its effects appear to be affected by timing. A study of the effects of TNF-α blockade found an early improvement in mechanical properties only at 2 and 4 weeks, but the improvement was no longer present at 8 weeks.⁷

Ultimately, the effectiveness of cytokine- or growth factor–mediated enhancement of rotator cuff healing may be determined by a number of factors related to delivery, such as concentration, timing of delivery, and delivery modality. One interesting approach taken was to coat sutures with platelet-derived growth factor (PDGF-BB), and although it improved the histology of the rotator cuff, there was no effect on mechanical properties.⁸ Biologic and synthetic scaffolds are increasingly used as a delivery vehicle for growth factors, to ensure localized delivery and retention. Targeted delivery can be achieved by seeding transduced cells that express desired factors to the site of the rotator cuff repair.

Another approach to ensure higher levels of growth factor and cytokine delivery is to use concentrated autologous platelets as a delivery vehicle in the form of platelet-rich plasma (PRP), which is classified as an autologous blood product rather than a drug (Fig. 37-3). Few randomized controlled trials have studied PRP application to rotator cuff repairs, and these studies have failed to demonstrate an improvement in healing after PRP treatment, which calls into question the efficacy of PRP use for rotator cuff tears. Two randomized controlled trials looking at the effects of platelet-rich fibrin matrix in 88 and 79 patients found there was no significant difference in clinical outcomes or healing rates compared with primary closures alone.^9,10 However, a smaller randomized controlled trial in 20 patients reported a significant increase in blood flow in the PRP group, but this did not translate to improved clinical scores.¹¹ Questions remain about the ideal concentration system, cellular content, platelet count, and timing of delivery.

Figure 37-3 Arthroscopic image of platelet-rich fibrin matrix augmentation during rotator cuff repair, fixed with sutures.

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Sep 11, 2016 | Posted by admin in SPORT MEDICINE | Comments Off

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