Image Guided Delivery of Bioresponsive Hydrogels

总结 心肌梗死（MI）引起局部功能障碍，使心脏的远端区域处于局部缺血状态。 机械缺陷导致长期不利的左心室（LV）重塑和并发症 充血性心力衰竭（CHF），其在西方世界仍然是发病和死亡的主要原因。 目前的项目将集中在评估和调节基质金属蛋白酶的关键平衡 (MMP)和基质金属蛋白酶的组织抑制剂（TIMP），其已知发挥重要作用 在心肌梗死后的重塑过程中已经提出了许多药理学和手术疗法来限制 心肌梗死后重塑，包括：心肌内给予生物材料。这些聚合物疗法 在减少梗死面积、增加血管生成、改善局部缺血性脑血管病等方面， 功能，并限制心肌梗死后重塑的临床前研究，并已在最近翻译给患者。 我们已经建立了新的非侵入性混合SPECT/CT方法，用于评估局部病变的变化。 心肌灌注、血管生成、MMP激活，沿着超声心动图成像方法， 定量评价局部心肌应变和心室重构。当前的多PI提案 将集中于：1）开发一种用于MI后治疗的新型可成像MMP响应性治疗诊断水凝胶 和跟踪输送和水凝胶保留的系列评价，2）多模态非侵入性的应用 解剖学、生理学和分子成像方法，用于指导和评估经皮 MMP-响应性水凝胶的心肌内递送，和3）评价MMP-响应性水凝胶的心肌内递送的机制， 这些释放局部TIMP的可注射MMP响应性水凝胶改变心肌力学并限制后 心肌梗死重构。我们假设，局部释放MMP-反应性水凝胶的心肌内递送， MI后早期释放TIMP-3将导致：1）调节局部MMP-TIMP平衡和炎症反应， MI内的反应，2）局部和整体心肌力学的改变，3）改善 血管生成和心肌灌注，以及4）减少不利的整体MI后重塑。我们也 假设我们的多模态成像方法将促进治疗诊断水凝胶的最佳递送， 并且允许跟踪关键的解剖学、生理学和分子事件沿着治疗功效。 因此，我们具体建议：1）开发可成像的MMP响应性治疗诊断水凝胶 对于MI后治疗，2）应用多模态成像指导和评价经皮图像引导 使用MI后重构的临床相关猪模型进行这些水凝胶的心肌内递送，以及3） 评价疗效机制。发展起来的诊断和治疗方法 拟议的项目将直接转化为MI后患者的管理。

Summary Myocardial infarction (MI) causes regional dysfunction placing remote areas of the heart at a mechanical disadvantage resulting in long term adverse left ventricular (LV) remodeling and complicating congestive heart failure (CHF), which remains a leading cause of morbidity and death in the Western world. The current project will focus on evaluating and modulating the critical balance of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) which is known to play an important role during remodeling post-MI. A number of pharmacological and surgical therapies have been proposed to limit post-MI remodeling, including; the intramyocardial administration of biomaterials. These polymeric therapies have demonstrated mixed success in reducing infarct size, increasing angiogenesis, improving regional function, and limiting post-MI remodeling in pre-clinical studies, and have been recently translated to patients. We have established novel noninvasive hybrid SPECT/CT approaches for evaluation of changes in regional myocardial perfusion, angiogenesis, MMP activation, along with echocardiographic imaging approaches for quantitative evaluation of regional myocardial strain and ventricular remodeling. The current multi-PI proposal will focus on; 1) development of a novel imageable MMP-responsive theranostic hydrogel for post-MI therapy and tracking delivery and serial evaluation of hydrogel retention, 2) application of multimodality non-invasive anatomical, physiological and molecular imaging approaches for directing and evaluating the percutaneous intramyocardial delivery of MMP-responsive hydrogels, and 3) the evaluation of the mechanisms by which these injectable MMP-responsive hydrogels that release local TIMP alter myocardial mechanics and limit post- MI remodeling. We hypothesize that the intramyocardial delivery of MMP-responsive hydrogels that locally release TIMP-3 early post-MI will result in; 1) modulation of the local MMP-TIMP balance and the inflammatory response within the MI, 2) alteration of regional and global myocardial mechanics, 3) improvement in angiogenesis and myocardial perfusion, and 4) a reduction of adverse global post-MI remodeling. We also hypothesize that our multimodality imaging approach will facilitate optimal delivery of a theranostic hydrogel, and allow tracking of critical anatomical, physiological and molecular events, along with therapeutic efficacy. Accordingly, we propose to specifically: 1) development an imageable MMP-responsive theranostic hydrogels for post-MI therapy, 2) apply multimodality imaging to direct and evaluate percutaneous image-guided intramyocardial delivery these hydrogels using clinically relevant porcine models of post-MI remodeling, and 3) evaluate the mechanisms of therapeutic efficacy. The diagnostic and therapeutic approaches developed in the proposed project will be directly translatable to the management of patients following MI.