Evaluation of extracellular matrix gel for adhesion prevention and tissue healing intendon surgery

项目摘要 在美国，每年约有3200万人因肌肉骨骼损伤而损失近3220亿美元(1)。经济实力雄厚 负担部分归因于术后疤痕形成(即粘连)，这是导致残疾的主要原因 肌腱手术后(4、5)。我们正在开发一种可喷雾的黏附屏障，这种屏障来自细胞外基质 (ECM喷雾)，起到机械屏障的作用，引起患者自身的愈合反应 以防止粘连的形成。每年约有150万患者遭受屈肌腱损伤，多达 其中30-40%的人会因粘连而活动范围受限(6)。当前选项 减轻粘连的方法是有限的和有缺陷的，而且对一种能够安全和 有效防止肌腱损伤后粘连的形成，维持正常的关节功能。ECM喷雾是 热响应，在涂抹的组织上形成一层薄膜水凝胶，并通过 在相邻组织之间起机械屏障的作用。ECM喷雾在手术最后一步的应用 在腹部和盆腔动物模型中，手术导致术后粘连减少70% 粘连形成。目前可用的骨科肌腱保护器/粘连屏障的主要限制是 它们是笨重的薄片，不能与修复的屈肌腱区域相吻合，因此损害 肌腱移动/滑动。有新的薄片产品可用，但外科医生称它们是有效的 就像“湿卫生纸”一样，因为它们在水合时会分解。ECM喷雾是作为液体使用的，而不是 片，以符合修复的屈肌腱和周围的屈肌腱鞘。过去的尝试 开发可喷雾粘连屏障一直没有成功，部分原因是术后组织愈合受损 申请。虽然目前还不清楚ECM喷雾对肌腱愈合有什么影响，但我们已经展示了 ECM喷雾起到了诱导性支架的作用，支持腹膜的结构性修复。基于这些 数据，本研究的目的是确定ECM喷雾剂在骨科中的安全性、有效性和可用性 屈肌腱损伤后的手术。在目标1中，我们将表征腱细胞对ECM喷雾的反应， 这将决定ECM是否具有生物相容性并支持腱细胞和滑膜细胞的生长。在目标2中，我们 将确定ECM喷雾是否在不影响肌腱粘连的情况下有效减少肌腱粘连的形成 愈合肌腱的生物力学。在目标3中，我们将演示人体解剖学中的可用性，这对 外科医生的采用和商业化。这种按设计安全的方法的结果将导致关键研究 以及在骨科手术中使用ECM喷雾所需的开发里程碑，并最终可能会改进 每年受粘连相关疾病影响的数百万人的生活。

Project Summary Approximately 32M musculoskeletal injuries in the US cost nearly $322B annually (1). The high economic burden is due in part to post-operative scar formation (i.e., adhesions), which is the leading cause of disability following tendon surgery (4, 5). We are developing a sprayable adhesion barrier derived from extracellular matrix (ECM Spray), which serves as a mechanical barrier and elicits a healing response from the patient’s own body to prevent adhesions from forming. Around 1.5M patients suffer flexor tendon injuries each year and as many as 30-40% of these individuals will subsequently have limited range of motion due to adhesions (6). Current options to mitigate adhesions are limited and flawed, and there is an unmet need for a technology which can safely and effectively prevent adhesion formation to maintain normal joint function after tendon injury. ECM Spray is thermally responsive, forming a thin film hydrogel over the tissue where applied and prevents adhesions by acting as a mechanical barrier between adjacent tissues. Application of ECM Spray as the last step of a surgical procedure resulted in >70% reduction on post-operative adhesions in abdominal and pelvic animal models of adhesion formation. A major limitation of currently available orthopedic tendon protectors / adhesion barriers is that they are bulky sheets unable to conform to the region of the repaired flexor tendon and therefore impair tendon movement / gliding. Newer thin sheet products are available, but surgeons describe them as performing like “wet toilet paper” because they disintegrate upon hydration. ECM Spray is applied as a liquid, rather than a sheet, to conform to the repaired flexor tendon and surrounding flexor tendon sheath. Past attempts at developing sprayable adhesion barriers have been unsuccessful, in part because of impaired tissue healing after application. While it remains unknown what impact ECM Spray will have upon tendon healing, we have shown that ECM Spray acts as an inductive scaffold to support constitutive repair of the peritoneum. Based upon these data, the objective of the present study is to determine ECM Spray’s safety, efficacy, and usability in orthopedic surgery following flexor tendon injury. In Aim 1, we will characterize tenocyte cellular response to ECM Spray, which will determine if ECM is biocompatible and supportive of tenocyte and synoviocyte growth. In Aim 2, we will determine if ECM Spray effective for reducing tendon adhesion formation without compromising the biomechanics of healing tendons. In Aim 3, we will demonstrate usability in human anatomy, which is critical to surgeon adoption and commercialization. Results from this safe-by-design approach will lead to key research and development milestones necessary for use of ECM Spray in orthopedic surgery and could ultimately improve the lives of the millions affected each year by adhesion-related morbidity.