Healing enterocutaneous fistulas using bioengineered biomaterials

使用生物工程生物材料治愈肠皮瘘

• 批准号: 10384769
• 负责人: Ali Khademhosseini
• 金额: $ 59.16万
• 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/10384769
• 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; 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; Interventional Imaging; Intestines; 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; 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; base; biomaterial compatibility; follow-up; healing; image guided; implantation; improved; in vitro testing; in vivo; in vivo Model; mechanical properties; microCT; minimally invasive; mortality; prevent; programs; 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.

摘要 肠外瘘（ECF）是肠道和皮肤之间的异常连接。可关联 排出脓液、粪便和胃内容物，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的结果，如 漏行肠切开术或吻合口漏这可能导致肠和粪便内容物不断泄漏， 皮肤，有时每天高达许多升。肠内的污秽物对皮肤有化学刺激作用， 导致皮肤破裂和易受感染。尽管治疗取得了进展，ECFs仍然占 显著死亡率为15-20%，并与虚弱的发病率和实质上较差的生活质量相关 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的进步，ECF的成功治疗还不存在 今天目前的治疗模式是不成功的;高瘘分泌物，感染，和慢性 炎症导致高失败率和复发率。这往往导致长期重症监护病房（ICU） 这会增加医疗保健成本，每次ICU就诊可能超过50万美元。我们假设通过使用 生物工程生物材料是生物相容性，无毒，耐用，抗菌和再生，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的 通过成功闭合和治愈任何ECF，防止粪便渗漏， 大大提高患者的生活质量，减少重复干预和X射线的需要 显像我们的目标是在使用微创技术治疗可能致命的ECF方面实现范式转变。 基于血液的生物材料平台，使用开创性的可注射剪切闭合瘘管， 使富含血小板的凝胶变薄我们将设计血液来源的生物材料，包括抗菌剂，粘合剂， 再生组件，将在体外和体内进行测试（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（目的2）。最后，我们将测试这些工程生物材料， 猪ECF模型，以促进瘘管的无菌愈合（目的3）。我们将评估的愈合轨迹的 瘘管采用临床观察、透视、超声、显微CT、组织学、Helios质谱细胞仪分析 细胞群体和生物成像技术，以评估多达37个生物标志物的幻灯片， RNA测序。