A biomimetic reverse thermal gel for the treatment of myocardial infarction

描述(由申请人提供)：据估计，美国每年有635,000名冠心病患者，显然需要一种替代的治疗策略。心肌梗死(MI)是由心肌组织死亡引起的主要冠心病。目前的治疗模式主要集中在药物治疗(减少氧耗量或增加血流量)或外科干预，包括手术搭桥重建血流路径。最近的工作采取了一种更生物医学的方法，即利用梗塞部位的生长因子进行血管生成，作为一种提供血流和氧气供应的手段。虽然一些方法依赖于直接给药纯生长因子，但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，由于其反向热凝胶特性，它本身很好地适用于这一应用。这些特性使得它可以迅速且可逆地过渡。 在室温下的液体和体温下的固体之间，允许通过小口径的针头或导管直接在目标部位注射，然后在达到体温时形成粘合的固体聚合物网络。与其他基于支架的方法相比，该方法具有许多优点，包括微创部署、损伤部位的原位构象以及可调节的物理特性来模拟宿主环境。此外，该系统易于功能化，模拟天然肝素的特定生物功能，增强生长因子的稳定性和局部化表达，从而实现心肌梗死部位的局部血管生成，心功能大幅恢复。为了开发一种能够最大限度地发挥这些优势的系统，我们围绕两个特定目标构建了这一应用：1)确定合适版本的类肝素反向热凝胶(SRTG)，在体外实质上维持生长因子的表达；2)通过在体大鼠心肌梗死模型显示显著的血管生成和心肌梗死治疗效果。

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.