Extracellular matrix hydrogels for treating ischemia

描述(申请人提供)：尽管组织工程学最近取得了进展，但仅在美国，与心血管疾病相关的缺血每年导致约500,000名心肌梗塞(MI)患者死亡，以及超过100,000名外周动脉疾病(PAD)患者的截肢。因此，我们的长期目标是开发新的、微创的组织工程疗法来治疗心肌和严重的肢体缺血。对于心肌梗死，材料被注入细胞以增加细胞保留率和存活率，或单独注射以增加内源性细胞向梗死区的迁移，包括新生血管，以增厚和支持左室壁，或两者兼而有之。在PAD和严重肢体缺血的情况下，很少有生物材料被检测，到目前为止，它们只被研究用于改善生长因子和细胞输送。目前还没有一种材料满足理想支架的所有要求，即促进新生血管以减少缺血环境，促进细胞黏附，内源性或外源性添加细胞的存活和成熟，以及可注射的能力。此外，没有一个充分模仿生化线索，这是固有的天然细胞外基质(ECM)，他们打算取代。我们的实验室已经产生了可注射的、组织特异性的ECM水凝胶，我们证明这种水凝胶具有满足理想支架的所有要求的潜力。这些可注射材料类似于活体心肌和骨骼肌细胞外环境，因为它们分别包含在心肌或骨骼肌细胞外基质中发现的各种天然生化线索。我们已经证明，这两种材料都具有招募内源性细胞促进血管形成的潜力。此外，在心肌梗死模型中注射心肌基质可以保护心功能和左室几何结构，而在后肢缺血模型中注射骨骼肌基质可以增强肌祖细胞的募集和增殖。此外，我们的体外研究表明，这些材料可以促进肌肉祖细胞的成熟。我们假设，基于细胞外基质的水凝胶来源于天然肌肉细胞外基质，含有复杂的组织特异性生化信号，可以单独输送以增加内源性细胞募集，或与外源性细胞一起输送以改善细胞存活和成熟，从而为MI和严重的PAD提供有效的治疗方法。本应用将针对以下特定目的：1)确定可注射无细胞心肌基质氢单独对心肌梗死后阴性左室重构、内源性心肌细胞存活、细胞渗透和心功能的影响；2)确定可注射无细胞骨骼肌基质水凝胶单独对肢体缺血模型中细胞的凋亡和渗透、新生血管形成和灌流的影响；3)确定可注射肌肉细胞外基质水凝胶环境中外源性肌肉前体细胞对新生血管形成、细胞移植保留、存活和成熟的影响。

DESCRIPTION (provided by applicant): Despite recent advances in tissue engineering, ischemia related to cardiovascular disease results in the death of approximately 500,000 patients per year in the case of myocardial infarction (MI) and greater than 100,000 amputations per year in the case of peripheral artery disease (PAD) in the US alone. Therefore, our long-term goal is the development of new, minimally invasive tissue-engineered therapies for the treatment of myocardial and critical limb ischemia. For MI, materials have been injected with cells in order to increase cell retention and survival, or alone to increase endogenous cell migration into the infarct area, including neovascularization, to thicken and support the left ventricular (LV) wall, or both. In the case of PAD and critical limb ischemia, very few biomaterials have been examined, and to date, they have only been studied for improving growth factor and cell delivery. No current materials meet all of the requirements of an ideal scaffold for either application, namely the ability to promote neovascularization to reduce the ischemic environment, to promote cell adhesion, survival, and maturation of endogenous or exogenously added cells, and to be injectable. Moreover, none adequately mimic the biochemical cues, which are inherent to the native extracellular matrix (ECM) that they are intended to replace. Our lab has generated injectable, tissue specific ECM hydrogels, which we show have the potential to meet all of the requirements of an ideal scaffold. These injectable materials resemble the in vivo cardiac and skeletal muscle extracellular milieu in that they contain a complex assortment of the native biochemical cues found in cardiac or skeletal muscle ECM, respectively. We have shown that both materials have the potential to recruit endogenous cells to promote vascularization. Furthermore, injection of the myocardial matrix in a MI model preserves cardiac function and LV geometry, while injection of the skeletal muscle matrix enhances the recruitment and proliferation of muscle progenitors in a hindlimb ischemia model. In addition, we show in vitro studies that these materials promote muscle progenitor maturation. We hypothesize that ECM based hydrogels, which are derived from native muscle ECM and contain complex, tissue specific biochemical cues, can be delivered alone to increase endogenous cell recruitment or with exogenous cells to improve cell survival and maturation, thereby providing effective therapies for MI and severe PAD. This application will address the following specific aims: 1) To determine the influence of an injectable acellular myocardial matrix hydrogen alone on post-myocardial infarction negative left ventricular remodeling, endogenous cardiomyocyte survival, cell infiltration, and cardiac function, 2) To determine the influence of an injectable acellular skeletal muscle matrix hydrogel alone on cell apoptosis and infiltration, neovascularization, and perfusion in a hindlimb ischemia model, and 3) To determine the effects of exogenous muscle progenitors in the milieu of injectable muscle ECM derived hydrogels on neovascularization, and cell transplant retention, survival, and maturation.