I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions

项目总结/摘要 目前，没有批准和可用的产品来预防术后心脏粘连，因此 没有标准护理。这是一个巨大的未满足的需求，因为每年有> 500，000例开胸手术（预计 到2030年将增加到> 850，000），其中> 100，000例为再次手术，约30，000例为患有 先天性心脏病心脏手术中的再次手术增加了手术风险， 粘连增加了胸骨折返的难度，阻碍了纵隔组织的可见性， 对心血管组织的潜在损伤。粘连清除时发生的损伤使 再次手术患者，增加手术时间和住院费用。这对儿科患者尤其重要 患有先天性心脏病的人一生中会经历多次手术。心脏粘连 也成为经历多次手术以修复或置换瓣膜或 接受冠状动脉血管重建手术。 有两种主要方法可以减少或试图预防心脏粘连：药物治疗 物理障碍。阻止或逆转粘附过程的药物会破坏细胞的生化途径， 炎症和纤维蛋白沉积。不幸的是，这些过程对伤口愈合也至关重要。实现 由于液体排出，在作用部位的足够药物浓度也是具有挑战性的。更可行的方法 是使用物理屏障来防止心脏与周围组织融合。障碍可以是 预成型膜或可注射水凝胶（快速胶凝液体）。预成型防粘材料需要 在应用于组织之前进行切割，并且必须缝合/包装到位以防止滑动。可注射 水凝胶允许在需要喷涂的地方自由地施加材料。前体组分是 能够快速反应，在组织表面形成保护性凝胶。虽然各种不同的 材料已经在动物和人类中进行了研究，迄今为止，没有材料能够预防 心脏手术后粘连形成。 在此，我们提出了一种使用TissueShield™预防术后心脏粘连的新方法， 由通过肟键交联的快速形成的聚（乙二醇）（PEG）水凝胶组成， 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3- 聚合物系统，可以很容易地直接喷涂到心脏上，在心脏内形成坚固的防粘连层 秒该系统已经过优化，以控制溶胀度和降解时间， 在大鼠心脏粘连模型中， 在猪模型中的初步研究。没有任何产品显示出具有我们的特征（组织粘合剂、低肿胀和 寿命）。本文的目的是优化递送体积并评估以下的初步功效和安全性： 在大型动物心脏粘连模型中的TissueShield™。这将是第一个可喷洒的防粘连剂 专门用于预防心脏粘连的产品。 Karios已经组建了一个I-Corp团队来验证我们的市场假设，完善我们的整体商业化 战略，并更好地了解市场和市场驱动因素。

PROJECT SUMMARY/ABSTRACT 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. This will be the first sprayable anti-adhesions product designed specifically for preventing cardiac adhesions. Karios has formed an I-Corp team to validate our market assumptions, refine our overall commercialization strategy, and to better understand the market and market drivers.