Postoperative adhesion is a major debilitating yet still unsolved complication of autograft flexor tendoplasty. Previous studies have shown that adhesions are modulated, at least in part, by TGF-2 signaling to the live tendon or autograft tenocytes as part of the initial inflammatory response to the surgery. Interestingly, while fibrosis in a variety of pathologies is associated with TGF-21 induction of plasminogen activator inhibitor-1 (PAI-1) that prevents activation of MMPs, TGF-23 has anti-scarring effects in cutaneous wound healing. However, the mechanisms by which TGF-2 isoforms modulate tendon scarring remain poorly understood, and biologic therapeutics to prevent adhesions are not available. To address these questions, a novel mouse model of flexor tendoplasty that involves the implantation of intercalary live autograft or freeze-dried allograft is implanted in the distal flexor digitorum longus (FDL) tendon of the hind paws was developed. In this model, the range of metatarsophalangeal (MTP) joint flexion was lower with autografts than allografts and this was associated with more fibrotic scarring at 14 and 28 days post-surgery. Early expression of Tgfb1 was associated with suppression of Mmp9 and scar formation, while late expression of Gdf5 was associated with delayed upregulation of Mmp2 and Mmp14, and subsequent improvement in the MTP joint flexion. Furthermore, local and transient Gdf5 gene delivery via freeze-dried allografts significantly reduced adhesions and restored the MTP joint flexion following flexor tendoplasty. Recent data using an in vitro tenocyte-seeded collagen gel model of scar tissue suggest that GDF-5 suppresses TGF-21 induced contraction of the gel and rescues MMP gene expression. Therefore, this proposal seeks to test the following hypotheses: 1) Acellular allografts, which cannot respond to endogenous TGF-21 signals, are effective delivery scaffolds for therapeutics in flexor tendoplasty;and 2) Inhibition of TGF-21/PAI-1 induced suppression of MMPs using rAAV/allograft-mediated over expression of Gdf5 or Tgfb3 reduces scarring and adhesions in flexor tendoplasty. This application proposes a series of complimentary studies to test these hypotheses and develop a tissue engineering solution for flexor tendon adhesions.
Specific Aim 1 seeks to formally challenge the current paradigm in flexor tendoplasty that favors the use of live autografts by determining the role of the live graft tenocytes and endogenous TGF-2 signaling in flexor tendoplasty adhesions. Towards the development of a mechanistically- driven tissue engineering solution for flexor tendon adhesions, Specific Aim 2 seeks to investigate the effects of TGF-2 and GDF-5 on MMP-mediated remodeling of an in vitro scar tissue model. Finally, Specific Aim 3 will investigate how over-expression of Tgfb3 and Gdf5 using rAAV-loaded FDL tendon allografts influences adhesion in the mouse flexor tendoplasty model. An experienced multi-disciplinary team has been assembled to conduct these studies that will test an innovative mechanistically-driven paradigm in flexor tendon tissue engineering with significant clinical implications.
This proposal seeks to develop a tissue engineered-based solution to debilitating adhesions frequently encountered with flexor tendon reconstructive surgery. It will evaluate the interplay between pro- and anti- adhesion factors to identify therapeutic targets for this problem. The studies will demonstrate the efficacy of using allografts (tissues from deceased donors) and gene therapy in eradicating adhesions and restoring the joint's range of motion.
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