Engineering Tendon Grafts for Better Outcomes

描述（由申请人提供）：屈肌腱损伤是最常见和最难治疗的手部创伤之一，造成相当大的功能丧失和经济负担。手部创伤估计占急诊总访问量的10%以上。在过去的半个世纪里，屈肌腱重建一直是屈肌腱损伤后恢复手部功能的主要手术方法。然而，临床结果仍然令人沮丧地不满意，并受到高并发症的损害，包括粘连和重建后手指功能差。这些不可接受的结果往往导致多次手术修复甚至手指截肢，从而进一步延长患者的残疾并增加医疗费用。该项目的总体目标是开发一种临床应用的工程肌腱移植物，它可以成为传统肌腱移植物的现成的、功能优越的替代品。在第一阶段，我们研究了利用碳二亚胺衍生透明质酸和润滑素这两种重要的润滑分子来改善移植物肌腱表面质量的策略。我们发现这种改良增强了肌腱的滑动能力，减少了粘连，并改善了手指功能，无论是使用滑膜外自体移植物（临床标准）还是滑膜内同种异体移植物（有吸引力的替代方案）移植。令人鼓舞的是，我们在体外模型中的实验使我们能够使用来自关节的化学修饰的天然滑液（SF）成功地增强移植物肌腱，这很容易获得并且临床上适用。因此，在本次更新中，我们将推进我们的项目来验证我们的假设，即使用化学修饰的自体SF对滑膜外自体移植物进行滑膜化将改善临床相关犬体内模型中屈肌腱重建的结果，如Specific Aim 1中提出的那样。如果成功，该技术可以迅速转化为临床实践，因为化学修饰和自体滑液都可以安全地应用于临床自体肌腱移植。这种技术也可以用于其他器官的移植，其中粘连是有问题的。此外，在离体模型中，我们已经开发出一种新的基于细胞的治疗方法，有可能加速同种异体移植物的再生，克服我们在第一个资助期遇到的缓慢再生。因此，在具体目标2中，我们将结合化学和组织工程方法来滑膜化和恢复滑膜内同种异体肌腱，以产生一种功能优越的替代传统肌腱移植物用于屈肌腱重建。如果成功，这些技术也可以迅速应用于临床，因为同种异体肌腱可以现成获得，并且可以从患者自身的关节液和细胞中再生和滑膜化。考虑到屈肌腱重建的临床意义，我们新颖可行的方法，支持性的初步研究，合理的假设，以及可测量的结果，我们相信这个建议会成功并具有显著的临床影响。

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.