DESCRIPTION (provided by applicant): Flexor tendon injuries are one of the most common and difficult-to-treat hand traumas causing considerable functional loss and economic burden. Hand traumas are estimated to account for over 10% of total emergency department visits. For the past half-century, flexor tendon reconstruction has been a major surgical procedure to restore hand function following flexor tendon injuries. However, clinical outcomes remain frustratingly unsatisfactory and are marred by a high rate of complications, including adhesion and poor digit function following reconstruction. These unacceptable outcomes often result in multiple surgical revisions or even finger amputations that further prolong patient disability and increase medical costs. The overall goal of this project is to develop a clinically-applicable engineered tendon graft that could become an off-the-shelf, functionally superior alternative to the conventional tendon graft. In the first award period, we have developed strategies to improve the surface quality of the graft tendons using carbodiimide derivatized hyaluronic acid and lubricin, two important lubricating molecules. We found that this modification enhanced tendon gliding ability, decreased adhesions, and improved digit function using either extrasynovial autograft (clinical standard) or intrasynovial allograft (attractive alternative) transplantation. Encouragingly, our experiments in an in vitro model have allowed us to successfully enhance graft tendons using chemically modified native synovial fluid (SF) from joints, which is readily available and clinically applicable. Therefore, in this renewal, we will advance our project to test our hypothesis that synovialization of extrasynovial autograft using chemically modified autologous SF will improve the outcome of flexor tendon reconstruction in a clinically-relevant canine in vivo model as proposed in Specific Aim 1. If successful, this technique can be quickly translated to clinical practice, since both chemical modification and autologous synovial fluid can be safely applied clinically to tendon autograft. This technique can also be adopted in transplantation of other organs where adhesions are problematic. Furthermore, in an ex vivo model, we have developed a novel cell-based therapy that has potential to accelerate allograft regeneration, overcoming the slow revitalization we have encountered in the first funding period. Therefore in Specific Aim 2, we will combine chemical and tissue engineering approaches to synovialize and revitalize intrasynovial allograft tendon to generate a functionally superior alternative to the conventional tendon graft for flexor tendon reconstruction. If successful, these techniques can also be rapidly applied to clinical application since allograft tendons could be available off-the-shelf and revitalized and synovialized from patient's own joint fluid and cells. Considering the clinical significance of flexor tendon reconstruction, our novel and feasible approaches, supportive preliminary studies, reasonable hypotheses, and measurable outcomes, we are confident this proposal will be successful and has a significant clinical impact.
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