Proangiogenic Microstructured Hydrogels for Chronic Wound Treatment

项目总结(李，项目负责人) 慢性创面影响了650多万患者，并造成了重大的社会和经济损失 负担，美国每年伤口治疗的总费用超过250亿美元 只有一个州。慢性伤口不遵循正常的伤口愈合过程，因为 血管肉芽组织的形成异常，临时基质由 多种细胞类型和细胞派生的ECM矩阵。未能形成有功能的血管系统是 通常与基质重塑缓慢和组织愈合延迟有关，这与 对许多病理情况，如缺血。尽管有各种各样的治疗方法 包括生长因子输送、细胞输送、支架材料或伤口敷料 以前用于治疗慢性伤口，肉芽组织形成的结果和 创面血管生成仍然有限。这项建议的总目标是促进 血管肉芽组织在促血管生成和微结构水凝胶中的应用 总结有效的细胞外微环境，以改善慢性伤口愈合。至 为了实现这一目标，我们的目标是使用一种简单的一步液-液相分离方法来 通过化学反应捕捉相分离过程，形成微结构 具有促血管生成因子和可调节微区的受控释放的水凝胶。是这样的 生物材料系统提供了独特的机会来了解细胞外 微环境线索调节促进血管生成和慢性创面的细胞行为 治愈。我们还将建立体外人性化的创伤损伤和闭合模型体系，以 捕获血管化肉芽组织新生组织并评价微创治疗的效果 结构域和血管内皮生长因子对组织血管生成和伤口闭合的影响。这个 可注射微结构生物材料作为真皮替代物的发展 伤口血管生成将扩大我们对水凝胶微结构和组织 血管形成有助于伤口愈合。可调谐生物材料与一种新型材料的集成 体外三维创面损伤与闭合模型构建自下而上的仿生系统 生化信号和生物物理线索之间的协同效应最小 增强伤口血管生成所需的成分。这一综合性的体外培养平台 3D多细胞培养系统将识别伤口愈合和修复的关键基质属性 可用于未来与慢性伤口相关的病理情况的调查。

PROJECT SUMMARY (Li, Project Lead) Chronic wounds affect more than 6.5 million patients and cause a significant social and economic burden, with an overall cost for wound treatment exceeding $25 billion annually in the United States alone. Chronic wounds do not follow the normal wound healing process due to the abnormalities in the formation of a vascularized granulation tissue, a provisional matrix composed of multiple cell types and cell-derived ECM matrices. Failure to form a functional vasculature is often associated with slow matrix remodeling and delayed tissue healing, which is highly linked to many pathological conditions such as ischemia. Although a variety of therapeutic approaches including growth factor delivery, cell delivery, scaffolding materials, or wound dressings have previously been applied to treat chronic wounds, the outcome of granulation tissue formation and wound angiogenesis remains limited. The overall goal of this proposal is to promote the formation of a vascularized granulation tissue in pro-angiogenic and micro-structured hydrogels that better recapitulate the effective extracellular microenvironment for improved chronic wound healing. To achieve this goal, we aim to employ a simple, one-step liquid-liquid phase separation method to capture the phase separation process via chemical reactions, to formulate micro-structured hydrogels with controlled release of pro-angiogenic factors and tunable micro-domains. Such biomaterial system offers unique opportunities to understand how extra-cellular microenvironmental cues regulate cellular behavior in promoting angiogenesis and chronic wound healing. We will also establish a humanized in vitro system of wound injury and closure model to capture the de novo formation of vascularized granulation tissue and evaluate the effect of micro- domains and vascular endothelial growth factors on tissue angiogenesis and wound closure. The development of injectable micro-structured biomaterials as dermal replacements that enhance wound angiogenesis will expand our understanding of how hydrogel microstructure and tissue vascularization contributes to wound healing. The integration of tunable biomaterials with a novel in vitro 3D wound injury and closure model builds a bottom-up biomimetic system to explore the synergistic effects between biochemical signals and biophysical cues with the minimum components required for enhanced wound angiogenesis. This comprehensive in vitro platform of a 3D multicellular culturing system will identify the key matrix properties for wound healing and can be used for future investigation of pathological conditions associated with chronic wounds.