A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions

一种可喷雾的组织结合水凝胶，用于防止术后心脏粘连

• 批准号: 10546558
• 负责人: Gregory Grover
• 金额: $ 99.82万
• 依托单位: KARIOS TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546558
• 关键词: Abdomen; Adhesions; Adhesives; Adult; Animal Model; Animals; Autopsy; Binding; Biochemical Pathway; Blood; Bypass; Cardiac; Cardiac Surgery procedures; Cardiac Tamponade; Cardiovascular system; Catechols; Cell Adhesion; Child; Clinical Chemistry; Coagulation Process; Congenital Heart Defects; Coronary; Data; Deposition; Dose; Drainage procedure; Ensure; Excision; Fibrin; Freedom; Gel; Heart; Heart Ventricle; Hemorrhage; Histology; Hospital Costs; Human; Hydrogels; Immunohistochemistry; Incidence; Inflammation; Injectable; Injury; Length; Liquid substance; Literature; Longevity; Magnetic Resonance Imaging; Measures; Mediastinal; Membrane; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Oximes; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Pleural; Polymers; Prevention; Procedures; Process; Property; Proteins; Puncture procedure; Rattus; Repeat Surgery; Resistance; Safety; Severities; Site; Small Business Innovation Research Grant; Structure of parenchyma of lung; Surface; Surgical sutures; Swelling; System; Testing; Thoracotomy; Time; Tissues; Urine; adhesion process; animal efficacy; biomaterial compatibility; chemical stability; clinically relevant; crosslink; design; effectiveness evaluation; efficacy study; ethylene glycol; experience; follow-up; heart function; inflammatory marker; mortality; novel; novel strategies; operation; pediatric patients; pericardial sac; peripheral blood; porcine model; pre-clinical; prevent; repaired; response; standard of care; surgical risk; treatment group; wound healing

Summary. Currently, there are no approved and available products to prevent postsurgical cardiac adhesions and hence no standard of care. This is a large unmet need since there are >500,000 open-heart surgeries/year (projected to grow to >850,000 by 2030) and >100,000 of these are reoperations and ~30,000 are on children with congenital heart defects. Reoperations in cardiac surgery have increased surgical risks due to cardiac adhesions, which increase the difficulty of sternal reentry, hinder visibility of mediastinal tissues, and increase potential injury to cardiovascular tissues. Injuries occurring to adhesion removal triples the mortality of reoperation patients, increase operation time and hospital costs. This is especially relevant for pediatric patients with congenital heart defects who will experience multiple surgeries over their lifetime. Cardiac adhesions have also become a common problem in adults who experience multiple surgeries to repair or replace valves or to undergo coronary revascularization procedures. Two main approaches exist for reducing or attempting to prevent cardiac adhesions: pharmacological therapy and physical barriers. Drugs that prevent or reverse adhesion processes disrupt biochemical pathways of inflammation and fibrin deposition. Unfortunately, these processes are also vital for wound healing. Achieving adequate drug concentration at the site of action is also challenging due to fluid drains. A more viable approach is the use of a physical barrier to prevent fusion of the heart to surrounding tissues. The barriers can be either preformed membranes or injectable hydrogels (fast gelling liquids). Preformed anti-adhesive materials need to be cut before application to the tissue, and must be sutured/packed into place to prevent slippage. Injectable hydrogels allow the freedom of applying material where needed with spraying. The precursor components are capable of quickly reacting, forming a protective gel on the surface of the tissue. While a variety of different materials have been investigated in animals and humans, no materials, to date, have been capable of preventing adhesion formation post-cardiac surgery. Herein, we propose a new approach to prevent postsurgical cardiac adhesions using TissueShield™, which is composed of a rapidly forming poly(ethylene glycol) (PEG) hydrogel that is cross-linked by oxime bonds and includes a tissue binding moiety to ensure the product remains adhered to the heart. Our approach is a 3-polymer system that can be easily sprayed directly onto the heart forming a robust anti-adhesion layer within seconds. This system has already been optimized to control the degree of swelling and degradation time to prevent adhesions and not interfere with cardiac function in rat cardiac adhesions models and an initial small pilot study in a porcine model. No product has been shown to have our features (tissue binder, low swelling, and lifespan). The objective herein is to optimize the delivery volume and evaluate preliminary efficacy and safety of TissueShield™ of in a large animal cardiac adhesions model. Follow up powered study will compare this volume with abdominal products. This will be the first sprayable anti-adhesions product designed specifically for preventing cardiac adhesions.

概括。目前，尚无批准和可用产品来防止外科术后心脏粘附 因此没有护理标准。这是一个巨大的未满足需求 （预计到2030年将增长到> 850,000），其中> 100,000是重新运行，大约30,000个儿童 先天性心脏缺陷。心脏手术的重新手术增加了由于心脏而增加的手术风险 粘附，增加了胸骨再入的难度，阻碍了纵隔组织的可见性并增加 心血管组织的潜在损伤。依从性删除的伤害三倍 重新食用患者，增加手术时间和医院费用。这与小儿患者特别相关 先天性心脏缺陷将在一生中进行多次手术。心脏粘连具有 在成年人中，经历了多项手术以维修或更换阀门或进行多次手术的成年人或 接受冠状动脉血运重建程序。有两种主要方法用于减少或尝试 预防心脏广告：药物治疗和物理障碍。预防或逆转的药物 粘附过程破坏炎症和纤维蛋白沉积的生化途径。不幸的是，这些 过程对于伤口愈合也至关重要。在作用部位达到足够的药物浓度也是 由于流体排水而挑战。一种更可行的方法是使用物理屏障来防止融合 心脏到周围的组织。障碍物可以是预制的膜或可注射水凝胶（快速 胶凝液体）。在施用组织之前，需要切割预先形成的抗粘附材料，必须是 缝合/包装到位，以防止打滑。注射水凝胶允许使用材料的自由 喷涂需要。前体的成分能够快速反应，形成保护性凝胶 组织的表面。虽然已经在动物和人类中研究了各种不同的材料，但 迄今为止，迄今为止尚无材料能够预防心脏后手术后的粘合剂形成。这里，我们 提出一种使用TissueShield™防止外科心脏粘附的新方法，该方法由 快速形成的聚（乙二醇）（PEG）水凝胶，由氧键交联并包括组织 结合部分以确保产品保持粘附在心脏上。我们的方法是一个三聚合物系统 可以在几秒钟内轻松地将其直接喷射到心脏上，形成坚固的抗粘附层。这个系统 已经进行了优化以控制肿胀和降解时间以防止粘附而不是 在大鼠心脏粘合剂模型中干扰心脏功能和猪模型中最初的小型初步研究。 尚无产品具有我们的特征（组织粘合剂，低肿胀和寿命）。这里的目的 是优化较大的TissueShield™的递送量并评估初步效率和安全性 动物心脏广告模型。后续研究将将这一卷与腹部产品进行比较。 这将是第一个专门用于预防心脏粘合剂的可喷涂抗粘附产品。