Healing enterocutaneous fistulas using bioengineered biomaterials

使用生物工程生物材料治愈肠皮瘘

• 批准号: 10532787
• 负责人: Ali Khademhosseini
• 金额: $ 57.29万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532787
• 关键词: Adhesives; Biocompatible Materials; Biological Markers; Biomedical Engineering; Blood; Blood Banks; Blood Platelets; Catheters; Chemicals; Chronic; Clinic; Clinical; Collaborations; Colon; Colorectal; Complex; Coupled; Creativeness; Data; Engineering; Ensure; Enteral; Enterocutaneous Fistula; Extravasation; Failure; Family suidae; Feces; Fibrin; Fistula; Fluoroscopy; Formulation; Gel; Growth Factor; Health Care Costs; Histology; Hydrogels; Image; Imaging technology; In Vitro; Incontinence; Infection; Inflammation; Injectable; Intensive Care Units; Intervention; Intestines; Intra-abdominal; Irritants; Lead; Literature; Magnetic Resonance Imaging; Malnutrition; Medical; Mental Depression; Modeling; Morbidity - disease rate; Morphologic artifacts; Neck; Operative Surgical Procedures; Organ; Outcome Measure; Pain; Pancreatic enzyme; Patients; Peptide Hydrolases; Performance; Population; Postoperative Period; Pre-Clinical Model; Predisposition; Property; Proteins; Pus; Quality of life; RNA; Radiation; Rattus; Recurrence; Rodent; Roentgen Rays; Silicates; Skin; Slide; Small Intestines; Stomach Content; Surgeon; Surgical complication; Techniques; Testing; Therapeutic Effect; Thinness; Time; Tissues; Treatment Efficacy; Visit; X-Ray Computed Tomography; X-Ray Medical Imaging; adhesive polymer; animal data; antimicrobial; biomaterial compatibility; follow-up; healing; image guided; implantation; improved; in vitro testing; in vivo; in vivo Model; mechanical properties; microCT; minimally invasive; mortality; nano; prevent; regenerative; seal; skills; subcutaneous; transcriptome sequencing; ultrasound; wound care

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.

抽象的 肠外瘘（ECF）是肠道和皮肤之间的异常连接。它可以与 脓液、粪便和胃内容物的排出，甚至可能导致失禁。 ECF 被称为 文献中的手术悲剧，高达85%是腹腔内手术并发症造成的，例如 错过肠切开术或吻合口漏。这可能导致肠道和粪便内容物不断泄漏 皮肤，有时每天可达数升。肮脏的肠内容物对皮肤有化学刺激作用， 导致皮肤破损和感染倾向。尽管治疗取得了进步，ECF 仍然占 死亡率高达 15-20%，并且与衰弱的发病率和生活质量显着下降有关 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。 尽管手术技术和术后管理取得了进步，但 ECF 尚无成功的治疗方法 今天。目前的治疗模式并不成功；瘘管分泌物高、感染和慢性 炎症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 持续增加医疗费用，每次 ICU 就诊可能超过 500,000 美元。我们假设通过使用 生物工程生物材料具有生物相容性、无毒、耐用、抗菌和再生性，我们将 改变 ECF 方法中的医疗实践标准。这种创造性的方法可能会减少世界范围内 通过成功封堵和治愈任何 ECF，防止粪便渗漏，降低发病率和死亡率；它还会 显着改善患者的生活质量并减少重复干预和 X 射线的需要 成像。我们的目标是使用微创治疗可能致命的 ECF 进行范式转变 基于血源生物材料的平台，使用突破性的可注射剪切来闭塞瘘管 稀释富含血小板的凝胶。我们将设计血液衍生的生物材料，使其包括抗菌剂、粘合剂和 将在体外和体内测试再生组件（目标 1），我们将评估优化的 生物材料与已建立的啮齿动物瘘管模型（目标 2）。最后，我们将测试这些工程生物材料 猪 ECF 模型促进瘘管无菌愈合（目标 3）。我们将评估患者的康复轨迹 使用临床观察、透视、超声、显微 CT、组织学、Helios 质谱流式细胞仪分析来诊断瘘管 细胞群和 Hyperion 成像技术可评估载玻片上多达 37 种生物标志物 RNA测序。