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

基本信息

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
项目类别：
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

项目摘要

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.

摘要：目前，还没有批准和可用的产品来预防术后心脏粘连。因此，没有标准的护理，这是一个巨大的未满足的需求，因为每年有超过 500,000 例心脏直视手术。（预计到 2030 年将增长到超过 850,000 例），其中超过 100,000 例为再次手术，约 30,000 例为儿童患有先天性心脏缺陷的心脏手术中的再次手术会增加由于心脏原因而导致的手术风险。粘连，增加胸骨折返的难度，阻碍纵隔组织的可见度，并增加去除粘连时对心血管组织的潜在损伤使死亡率增加三倍。再次手术患者，增加手术时间和住院费用，这对于儿科患者尤其相关。患有先天性心脏病的人一生中会经历多次手术心脏粘连。对于经历多次手术来修复或更换瓣膜或存在两种主要方法来减少或尝试进行冠状动脉血运重建手术。预防心脏粘连：预防或逆转的药物治疗和物理障碍。不幸的是，粘附过程会破坏炎症和纤维蛋白沉积的生化途径。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很重要。由于液体排放而具有挑战性，一种更可行的方法是使用物理屏障来防止融合。心脏与周围组织的屏障可以是预制膜或可注射水凝胶（快速）。预制的抗粘连材料在应用于组织之前需要进行切割，并且必须经过切割。缝合/包装到位以防止滑动。可注射水凝胶允许在任意位置自由施加材料。前体成分能够快速反应，在其上形成保护凝胶。虽然已经在动物和人类身上研究了各种不同的材料，迄今为止，还没有材料能够预防心脏手术后粘连的形成。提出了一种使用 TissueShield™ 预防术后心脏粘连的新方法，该方法由一种快速形成的聚乙二醇 (PEG) 水凝胶，通过肟键交联并包含组织结合部分，以确保产品保持粘附在心脏上。我们的方法是一种 3 聚合物系统。该系统可以轻松地直接喷射到心脏上，在几秒钟内形成坚固的防粘连层。已经经过优化来控制溶胀程度和降解时间，以防止粘连，而不是干扰大鼠心脏粘连模型中的心脏功能以及猪模型中的初步小型试点研究。没有任何产品被证明具有我们的特点（组织粘合剂、低膨胀和使用寿命）。是为了优化输送量并评估 TissueShield™ 在大范围内的初步功效和安全性动物心脏粘连模型。后续动力研究将将此体积与腹部产品进行比较。这将是第一个专门为预防心脏粘连而设计的可喷雾防粘连产品。