A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions

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例心内直视手术 （预计到2030年将增加到85万例），其中10万例为再次手术，约3万例为儿童手术 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减少 预防心脏粘连：药物治疗和物理屏障。预防或逆转 粘附过程破坏炎症和纤维蛋白沉积的生化途径。可惜这些 过程对于伤口愈合也是至关重要的。在作用部位达到足够的药物浓度也是 由于液体引流而具有挑战性。更可行的方法是使用物理屏障来防止 心脏周围组织。屏障可以是预成型的膜或可注射的水凝胶（快速）。 胶凝液体）。预成型防粘材料在应用于组织之前需要切割，并且必须 缝合/包装到位以防止滑动。可注射的水凝胶允许自由地施加材料， 需要喷雾。前体组分能够快速反应，在表面上形成保护性凝胶。 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， 迄今为止，还没有材料能够防止心脏手术后的粘连形成。在此我们 提出了一种使用TissueShield™预防术后心脏粘连的新方法，该方法由以下组成 一种快速形成的聚（乙二醇）（PEG）水凝胶，其通过肟键交联并包括组织 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3-聚合物系统， 可以很容易地直接喷涂到心脏上，在几秒钟内形成坚固的防粘连层。该系统 已经进行了优化，以控制溶胀程度和降解时间，防止粘连， 在大鼠心脏粘连模型中干扰心脏功能，以及在猪模型中进行的初步小规模试点研究。 没有产品显示出我们的特征（组织粘合剂、低膨胀和寿命）。本文的目的 是为了优化输送量，并评估TissueShield™的初步有效性和安全性， 动物心脏粘连模型。随访把握度研究将比较该体积与腹部产品。 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。

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.