Healing enterocutaneous fistulas using bioengineered biomaterials

摘要 肠皮肤瘘(ECF)是肠道和皮肤之间的一种异常连接。它可以关联到 排出脓液、粪便和胃内容物，甚至可导致大小便失禁。ECF被称为 文献中的手术悲剧高达85%是腹部手术并发症的结果，例如 漏诊的肠切开术或吻合口漏。这会导致肠道和粪便内容物从 皮肤，有时高达每天许多公升。肮脏的肠道内容物对皮肤起到化学刺激物的作用， 导致皮肤破裂和易受感染。尽管在治疗方面取得了进展，但ECFS仍占 死亡率高达15%-20%，并与使人衰弱的发病率和极低的生活质量有关 由于复杂的伤口护理、严重的营养不良、频繁的感染并发症、疼痛和抑郁。 尽管外科技术和术后管理取得了进步，但尚无成功的治疗方法。 今天。目前的治疗模式是不成功的；高瘘管出院、感染和慢性 炎症会导致高失败率和复发率。这通常会导致重症监护病房(ICU)时间延长。 持续增加的医疗保健费用，每次ICU就诊可能超过500,000美元。我们假设通过使用 生物工程材料是生物兼容、无毒、耐用、抗菌和可再生的，我们将 在ECF的方法上改变医疗实践的标准。这种创造性的方法可能会在世界范围内减少 通过成功闭塞和治愈任何ECF，防止粪便渗漏；它还将 大幅提高患者的生活质量，减少重复干预和X光检查的需要 成像。我们的目标是在治疗潜在致命的ECF方面进行范式转变，使用一种微创 基于血源性生物材料的平台，使用突破性的可注射剪切剂封堵瘘管- 稀释富含血小板的凝胶。我们将对血液衍生生物材料进行改造，以包括抗菌剂、粘合剂和 将在体外和体内进行测试的再生成分(目标1)，我们将评估优化的 已建立啮齿动物瘘管模型的生物材料(目标2)。最后，我们将测试这些工程生物材料在 一种促进瘘管无菌愈合的猪ECF模型(目标3)。我们将评估骨折的愈合轨迹 应用临床观察、透视、超声、显微CT、组织学、Helios质量细胞仪分析 和Hyperion成像技术来评估玻片上多达37个生物标记物 RNA测序。

Abstract Enterocutaneous fistula (ECF) is an abnormal connection between the bowel and skin. It can be associated with discharge of pus, feces, and stomach contents and can even lead to incontinence. ECFs are referred to as surgical tragedies in the literature, as up to 85% are the result of intraabdominal surgical complications, such as missed enterotomies or anastomotic leaks. This can lead to constant leakage of enteric and fecal contents from the skin, sometimes up to many liters per day. The foul enteric contents act as a chemical irritant to the skin, leading to skin breakdown and predisposition to infection. Despite advances in treatment, ECFs still account for significant mortality of 15-20% and are associated with debilitating morbidity and substantially poor quality of life due to complex wound care, severe malnutrition, frequent infectious complications, pain, and depression. Despite advances in surgical techniques and postoperative management, no successful treatment of ECF exists today. The current treatment paradigm is unsuccessful; high fistula discharge, infection, and chronic inflammation lead to high failure and recurrence rates. This often results in prolonged intensive care unit (ICU) stays increasing health care cost which can be over $500,000 per ICU visit. We hypothesize that by using a bioengineered biomaterial that is biocompatible, non-toxic, durable, antimicrobial and regenerative, we would change the standard of medical practice in the approach to ECF. This creative approach may reduce world-wide morbidity and mortality by successfully occluding and healing any ECF, preventing fecal leakage; it will also substantially improve the quality of life of the patient and reduce the need for repeated interventions and X-ray imaging. We aim to make a paradigm shift in the treatment of potentially fatal ECF using a minimally invasive blood-derived biomaterial-based platform to occlude the fistulous tract using groundbreaking injectable shear- thinning platelet-rich gels. We will engineer the blood derived biomaterial to include antimicrobial, adhesive, and regenerative components that will be tested in vitro and in vivo (Aim 1) and we will evaluate the optimized biomaterial with established rodent fistula models (Aim 2). Finally, we will test theses engineered biomaterials in a porcine ECF model to promote aseptic healing of fistulas (Aim 3). We will evaluate healing trajectories of the fistulas using clinical observation, fluoroscopy, ultrasound, micro-CT, histology, Helios mass cytometer analysis of the cellular populations and the Hyperion imaging technology to evaluate up to 37 biomarkers on slides and RNA sequencing.