Characterization of the Effect of an ECM Based Adhesion Barrier on Healing of Bowel Anastomoses

项目摘要 在美国，每年有超过700万例腹部和盆腔手术，粘连是最主要的 手术后并发症的原因--近90%的患者在这些手术后出现并发症。粘连是 导致各种终生并发症(如慢性骨盆)的疤痕组织条带 疼痛、肠梗阻和不孕不育)，每年的医疗负担超过25亿美元，但目前 缓解粘连形成的选择是有限的，也是有缺陷的。基于近十年的研究，我们有 开发了一种源自细胞外基质的可喷粘屏障(ECM喷雾)，用作 引发患者自身愈合反应的机械屏障，以防止粘连和调节 组织修复。ECM喷雾具有热响应性，并在其所在的组织上形成一层薄膜水凝胶 通过在相邻组织之间起到机械屏障的作用来应用并防止粘连。在两个独立的 使用经过验证的小动物和大动物模型进行的临床前研究，术后应用ECM喷雾 导致粘连发生率和韧性降低75%。目前可用的粘接剂的主要限制 肠梗阻是禁止在涉及肠道切除和重新连接的手术中使用。 (例如，肠吻合)，因为粘连屏障已被证明抑制愈合，这可能导致 漏水。有趣的是，我们已经证明，当应用于手术损伤的腹膜时，ECM喷雾起到了 支持腹膜再上皮化和愈合的支架。然而，目前尚不清楚ECM是如何喷洒的 将与肠吻合过程中发生的更复杂的伤口愈合过程相互作用。 因此，本研究的目的是确定ECM喷雾剂对预防 粘连，同时安全地维持吻合术后的肠道愈合。在目标1中，我们将确定 ECM喷雾预防粘连的效果及ECM喷雾对肠道愈合的影响 在目标2中，我们将确定ECM喷雾是否可以促进吻合口愈合，在一个高风险的模型。 肠道修复。拟议工作的结果将导致一个关键的研究和开发里程碑 为确定ECM喷雾在腹部和盆腔手术中使用的安全性和有效性，并增加 ECM喷雾的技术和商业潜力。此外，如果我们显示ECM喷雾有可能限制 吻合口漏，这将扩大使用范围，并显著增加患者和临床影响， 以及鼓励外科医生在结直肠手术中采用。

Project Summary Over 7 million abdominal and pelvic operations are performed each year in the US and adhesions—the leading cause of post-operative morbidity—form in nearly 90% of patients following these surgeries. Adhesions are bands of scar tissue that contribute to the manifestation of myriad life-long complications (e.g., chronic pelvic pain, small bowel obstruction, and infertility) and the annual healthcare burden exceeds $2.5 billion, but current options to mitigate adhesion formation are limited and flawed. Based on nearly a decade of research, we have developed a sprayable adhesion barrier derived from extracellular matrix (ECM Spray), which serves as a mechanical barrier that elicits a healing response from the patient’s own body to prevent adhesions and regulate tissue repair. The ECM Spray is thermally responsive and forms a thin film hydrogel over the tissue where it’s applied and prevents adhesions by acting as a mechanical barrier between adjacent tissues. In two separate pre-clinical studies using validated small and large animal models, post-operative application of ECM Spray has resulted in >75% reduction in adhesion incidence and tenacity. A major limitation of currently available adhesion barriers is that they are contraindicated for use in procedures that involve a bowel resection and re-connection (i.e., bowel anastomosis) because the adhesion barriers have been shown to inhibit healing which can cause leakage. Interestingly, we’ve shown that when applied to surgically injured peritoneum, ECM Spray acts as a scaffold to support re-epithelialization and healing of the peritoneum. However, it is unknown how ECM Spray will interact with more complex wound healing processes which occur in intestinal anastomosis procedures. Therefore, the objective of the present study is to determine the efficacy of ECM Spray’s for preventing adhesions while safely maintaining bowel healing following anastomosis procedures. In Aim 1, we will determine the efficacy of ECM Spray on adhesion prevention and characterize the effect of ECM Spray on intestinal healing. In Aim 2, we will determine whether ECM Spray may promote anastomotic healing in a high-risk model of intestinal repair. Results of the proposed work will lead to a key research and development milestone necessary for establishing safety and efficacy of ECM Spray for use in abdominal and pelvic operations and increase the technological and commercial potential of ECM Spray. In addition, if we show potential for ECM Spray to limit anastomotic leaks, this will broaden the scope for use and dramatically increase the patient and clinical impact, as well as encourage surgeon adoption in colorectal surgeries.