Improving the safety and effectiveness of adhesion prevention following colorectal procedures with high risk of cancer or infection

项目摘要 术后长期并发症的主要原因是粘连，近95%的患者会发生粘连 手术后。粘连是疤痕组织的带，有助于表现出无数的终身 并发症（例如小肠梗阻、不孕症和慢性疼痛）。每年的医疗负担， 粘连超过30亿美元，但减轻粘连形成的选择是有限的和有缺陷的。所有 在腹部手术中，结直肠手术中粘连相关并发症发生率最高。而 由粘连引起的病理可能需要数月甚至数年才能在临床上显现， 经常并发感染（例如，脓肿形成或脓毒症）和癌症肿瘤发生。的目标 该建议是为了确定我们新开发的可喷涂水凝胶技术对粘附的影响 在被细菌或癌细胞污染的高风险手术环境中进行结肠直肠手术的预防。 TYBR在生物材料开发和流体动力学方面的专业知识为可喷涂 来源于细胞外基质的粘连屏障（ECM喷雾），作为机械屏障， 来自患者自身的愈合反应，以防止粘连并调节组织修复。ECM喷雾 是热响应性的并且（在与组织接触时）形成薄膜水凝胶以防止 邻近组织作为机械屏障。ECM喷雾已被证明是>75%的有效减少 广泛接受的小型和大型动物手术模型中粘连的发生率和韧性。这些有前途的， 数据显示，ECM喷雾剂可有效减少粘连，保持无菌性，但不清楚ECM如何 喷雾剂将在受污染的手术中使用，这是一个没有有效治疗的高危患者群体， 竞争产品在很大程度上禁忌用于受污染的手术。感染风险是关键 粘附屏障的转化挑战，过去失败的产品突出了这一点，包括 Intergel在超过100例感染问题报告（包括3例死亡）后被撤出市场。 因此，本研究的目的是确定ECM喷涂是否能防止粘连形成 而不会增加污染手术中肿瘤发生或腹腔脓肿的风险。在目标1中，我们 确定ECM喷雾剂对细菌生长的影响。在目标2中，我们将确定ECM喷雾对 癌症肿瘤发生。建议的工作成果将直接导致一个关键的研究和发展 迈向商业化的里程碑。这些结果将提交给FDA，以确定安全性和有效性 用于肿瘤切除手术和非无菌手术的ECM喷雾剂，并增加技术和 ECM Spray的商业潜力。此外，如果我们展示ECM喷雾剂减少感染的潜力， 扩大使用范围，显著增加患者和临床影响，并鼓励 外科医生在受污染区域的手术中采用。

Project Summary The leading cause of long-term post-operative morbidity is adhesions—which form in nearly 95% of patients following surgery. Adhesions are bands of scar tissue that contribute to the manifestation of myriad life-long complications (e.g. small bowel obstruction, infertility, and chronic pain). The annual healthcare burden from adhesions exceeds $3 billion, but options to mitigate adhesion formation are limited and flawed. Among all abdominal surgeries, the highest rate of adhesion-related complications occurs in colorectal surgery. While pathologies caused by adhesions may take months or even years to manifest clinically, colorectal surgery is also often complicated by infection (e.g., abscess formation or sepsis) and cancer tumorigenesis. The objective of this proposal is to determine the effect of our newly developed sprayable hydrogel technology for adhesion prevention in colorectal surgery within high risk surgical environments contaminated by bacteria or cancer cells. TYBR’s expertise in biomaterial development and fluid dynamics has informed the development of 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 (upon contact with tissue) forms a thin film hydrogel to prevent adhesions between adjacent tissues by acting as a mechanical barrier. ECM Spray has proven to be >75% effective at reducing the incidence and tenacity of adhesions in well-accepted small and large animal surgical models. These promising, data show effective adhesion reduction with ECM Spray where sterility is maintained, but it is unknown how ECM Spray will perform in contaminated surgeries—an at risk patient population without an effective therapy because competitor products are largely contraindicated for use in contaminated surgeries. Infection risk is a key translational challenge for adhesion barriers, which has been highlighted by past failed products, including Intergel which was removed from the market after over 100 reports of infection problems, including 3 deaths. Therefore, the objective of the present study is to determine if ECM Spray will prevent adhesion formation without increasing risk of tumorigenesis or abdominal abscess in a contaminated surgeries. In Aim 1, we will determine the effect of ECM Spray on bacterial growth. In Aim 2, we will determine the effect of ECM Spray on cancer tumorigenesis. Results of the proposed work will directly lead to a key research and development milestone towards commercialization. These results will be presented to the FDA to establish safety and efficacy of ECM Spray for use in tumor resection surgeries and non-sterile surgeries and increase the technological and commercial potential of ECM Spray. In addition, if we show potential for ECM Spray to reduce infection, this will broaden the scope for use and dramatically increase the patient and clinical impact, as well as encourage surgeon adoption in surgeries with a contaminated field.