Engineering Tendon Grafts for Better Outcomes

描述（由申请人提供）：屈肌腱损伤是一种常见的致残性临床问题。如果受损肌腱不能立即直接修复或初次修复失败，则需要肌腱移植。然而，临床结果表明肌腱移植后并发症发生率高，粘连形成和手指功能差。临床和动物模型表明，滑膜内自体移植物比滑膜外自体移植物提供更好的结果，但用作肌腱自体移植物的滑膜内肌腱的临床来源有限。虽然我们以前的工作已经表明，一个工程化的滑膜外移植物表面，碳二亚胺衍生的HA（cd-HA）改性，改善肌腱滑动和减少术后粘连，导致手指功能仍然远远低于正常福尔斯。虽然使用滑膜内肌腱的同种异体移植物来源是可能的，但用于同种异体移植物制备和保存的程序会损伤肌腱表面并降低其滑动能力。令人鼓舞的是，我们最近的初步研究表明，表面处理与cd-HA改善滑膜内同种异体移植物的摩擦性能和减少粘连形成。更值得注意的是，即使在瘢痕肌腱床中使用经处理的同种异体移植物时，也注意到这些改善，瘢痕肌腱床是一种比用于研究屈肌腱重建的通常动物模型更具临床相关性的模型，即，一个正常的，以前未操作的手指。最近，我们开发了一种新的化合物，通过添加润滑素，一种粘液糖蛋白，到cd-HA（cd-HA-润滑素）的肌腱表面改性。我们在体外的初步研究表明，cd-HA-润滑素进一步改善滑膜外肌腱的润滑，达到与滑膜内肌腱相当的水平。我们的总体目标是开发一种临床适用的肌腱移植替代品，一种表面用cd-HA润滑素润滑的工程同种异体移植物，可以成为一种现成的，功能上级传统肌腱移植的替代品。考虑到润滑素已知的抗粘连特性，我们假设在体内用cd-HA-润滑素处理的同种异体移植物可以获得比传统的滑膜外自体移植物更好的结果。如果我们的目标得以实现，并且cd-HA-lubricin修饰的移植物提供了上级结局，则将来将提出临床转化研究。我们还将能够使用我们的新型工程表面改性来研究肌腱移植的其他应用，其中粘连预防是重要的，例如肩袖。

DESCRIPTION (provided by applicant): Flexor tendon injury is a common and disabling clinical problem. If the damaged tendon cannot be immediately and directly repaired or primary repairs fail, a tendon graft is indicated. However, clinical outcomes have demonstrated high rates of complications after tendon graft, with adhesion formation and poor digit function. Clinical and animal models have shown that intrasynovial autografts provide better results than extrasynovial autografts, but clinical sources of intrasynovial tendons for use as tendon autografts are limited. Although our previous work has shown that an engineered extrasynovial graft surface, modified with carbodiimide derivatized HA (cd-HA), results in improved tendon gliding and decreased postoperative adhesions, resulting digit function still falls far short of normal. While allograft sources using intrasynovial tendon are possible, procedures used for allograft preparation and preservation damage the tendon surface and decrease its gliding ability. Encouragingly, our recent pilot studies have shown that surface treatment with cd-HA improved intrasynovial allograft frictional properties and decreased adhesion formation. More encouragingly, these improvements were noted even when the treated allografts were used in a scarred tendon bed, a much more clinically relevant model than the usual animal model used to study flexor tendon reconstruction, i.e., a normal, previously unoperated digit. More recently, we have developed a new compound for tendon surface modification by adding lubricin, a mucinous glycoprotein, to the cd-HA (cd-HA-lubricin). Our preliminary studies in vitro have shown that cd-HA-lubricin further improves the lubrication of extrasynovial tendon to a level comparable to intrasynovial tendon. Our overall goal is to develop a clinically applicable tendon graft alternative, an engineered allograft with a surface lubricated with cd-HA-lubricin that could become an off-the-shelf, functionally superior alternative to conventional tendon grafting. Given the known anti-adhesive properties of lubricin, we hypothesize that outcomes better than conventional extrasynovial autografting can be achieved with cd-HA-lubricin treated allografts in vivo. If our goals are achieved and the cd-HA-lubricin modified graft provides superior outcomes, clinical translation studies will be proposed in the future. We will also be able to use our novel engineered surface modification to study other applications of tendon grafting where adhesion prevention is important, such as for the rotator cuff.