A biomimetic reverse thermal gel for the treatment of myocardial infarction

描述（由申请人提供）： 据估计，每年有635，000名美国人患有冠状动脉疾病（CAD），显然需要替代治疗策略。心肌梗死（MI）是由心肌组织死亡引起的主要CAD。目前的治疗模式主要集中在药物（减少氧需求或增加血流量）或手术干预，包括外科搭桥术，以重建血流通道。最近的工作采取了更多的生物医学方法，其中使用生长因子在梗死部位的血管生成作为一种手段，以提供血流和氧气供应为目标。虽然一些方法依赖于直接施用纯生长因子，但在更广泛的心血管组织工程领域的经验告诉我们，基于支架的方法可能是最有前途的策略。我们最近开发了一种聚合物可注射生物材料，由于其具有反向热胶凝特性，该材料本身很好地用于该应用。这些特性使它能够快速而可逆地转变 在室温下的液体和体温下的固体之间，允许通过小规格针或导管直接在目标部位注射，然后在达到体温时形成粘性固体聚合物网络。这种方法与其他基于支架的方法相比具有许多优点，包括微创部署、对损伤部位的原位构象和可调节的物理性质以模拟宿主环境。此外，该系统可以容易地功能化以模拟天然肝素的特异性生物功能，从而增强生长因子的稳定性和局部表达，从而实现MI部位的局部血管生成，并使心脏功能基本恢复。为了开发能够最大化这些优点的系统，我们围绕两个特定目标构建了该应用：1）确定在体外基本上维持生长因子表达的肝素模拟反向热凝胶（SRTG）的适当形式和2）通过体内大鼠MI模型证明实质性血管生成和MI治疗效果。

DESCRIPTION (provided by applicant): With an estimated 635,000 Americans with coronary artery disease (CAD) each year, there is a clear need for an alternative treatment strategy. Myocardial infarction (MI) is a leading CAD caused by the death of heart muscle tissues. The current treatment paradigm is focused on pharmacological (reducing oxygen demand or increasing blood flow) or surgical intervention including surgical bypass to reconstruct blood flow path. Recent work has taken a more biomedical approach in which angiogenesis using growth factors in infarction site is targeted as a means to provide blood flow and oxygen supply. While some approaches are dependent on direct administration of pure growth factors, experience in the wider field of cardiovascular tissue engineering has taught us that a scaffold-based approach may be the most promising strategy. We have recently developed a polymeric injectable biomaterial that serves itself well to this application owing to is reverse thermal gelling properties. These properties allow it too rapidly and reversibly transition between a liquid at room temperature and a solid at body temperature, permitting injection through a small gauge needle or catheter directly at the target site and then formation of a cohesive solid polymer network upon reaching body temperature. This approach has many advantages over other scaffold-based approaches including minimally- invasive deployment, in situ conformation to the injury site and tunable physical properties to mimic the host environment. In addition, this system can be readily functionalized to mimic specific biofunction of natural heparin to enhance stability and localized expression of growth factors, and thereby achieve localized angiogenesis in MI site with substantial recovery of heart function. Towards developing a system that can maximize these advantages, we have constructed this application around two specific aims: 1) determine appropriate version of heparin-mimicking reverse thermal gel (SRTG) that substantially sustains growth factor expression in vitro and 2) demonstrate substantial angiogenesis and MI treatment effect by in vivo rat MI model.