Engineering Tendon Grafts for Better Outcomes

描述(申请人提供)：屈肌腱损伤是一个常见的和致残的临床问题。如果受损的肌腱不能立即直接修复或一期修复失败，则需要肌腱移植。然而，临床结果显示肌腱移植后并发症发生率高，粘连形成，手指功能差。临床和动物模型表明，滑膜内自体移植比滑膜外自体移植有更好的效果，但临床上用于自体肌腱移植的滑膜内肌腱来源有限。尽管我们以前的工作表明，用碳化二亚胺衍生化HA(CD-HA)修饰的工程化滑膜外移植物表面可以改善肌腱滑动，减少术后粘连，但所产生的手指功能仍远远低于正常。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准备和保存的程序会损害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，CD-HA表面处理改善了滑膜内同种异体移植物的摩擦性能，减少了粘连形成。更令人鼓舞的是，即使在伤痕累累的肌腱床上使用经过处理的同种异体肌腱，这些改善也被注意到，这是一个比通常用于研究屈肌腱重建的动物模型更具临床相关性的模型，即以前未手术的正常手指。最近，我们开发了一种用于肌腱表面修饰的新化合物，通过在CD-HA(CD-HA-Luluin)中添加一种粘性糖蛋白来进行修饰。我们的体外初步研究表明，CD-HA-Luluin进一步改善了滑膜外肌腱的润滑，达到了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，一种表面由CD-HA润滑剂润滑的工程化同种异体肌腱移植，可能成为一种现成的、功能上优于传统肌腱移植的替代品。鉴于润滑剂已知的抗粘连特性，我们假设CD-HA-润滑素处理的同种异体移植物在体内可以达到比传统的滑膜外自体移植更好的效果。如果我们的目标得以实现，并且CD-HA-润滑素修饰的移植物提供了更好的结果，那么临床翻译研究将在未来被提出。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，在防止粘连方面非常重要，例如用于肩袖。

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.