Dynamic ECM-Mimicking Biomaterials for Ischemia Treatment

用于缺血治疗的动态 ECM 模拟生物材料

• 批准号: 10367736
• 负责人: Janeta Zoldan
• 金额: $ 62.22万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367736
• 关键词: 3-Dimensional; Anastomosis - action; Architecture; Behavior; Binding; Binding Sites; Biocompatible Materials; Biological; Biophysics; Blood Vessels; Blood capillaries; Blood flow; Cardiovascular system; Cells; Clinic; Clinical; Collagen; Complex; Coupled; Coupling; Crosslinker; Cues; Data; Development; Disease model; Elasticity; Endothelial Cells; Engineering; Engraftment; Extracellular Matrix; Generations; Goals; Health; Hindlimb; Human; Hyaluronic Acid; Hybrids; Hydrogels; Implant; In Situ; In Vitro; Ischemia; Lead; Mechanics; Mediating; Metalloproteases; Methods; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Outcome; Patients; Peptides; Peptoids; Perfusion; Pericytes; Peripheral; Peripheral arterial disease; Population; Predisposition; Process; Property; Reaction; Recovery; Regulation; Self-Direction; Shapes; Skin; Stimulus; Structure; Sulfhydryl Compounds; System; Testing; Therapeutic; Time; Tissue Engineering; Tissue Therapy; Tissues; Traction; Work; bioscaffold; cell assembly; cell type; computational pipelines; critical limb Ischemia; crosslink; density; endothelial stem cell; improved; in vivo; individualized medicine; induced pluripotent stem cell; limb amputation; limb ischemia; necrotic tissue; neovascular; neovascularization; non-invasive monitor; polarized cell; preservation; response; self assembly; spatiotemporal; stem cells; therapeutically effective; vasculogenesis

Dynamic ECM-Mimicking Biomaterials for Ischemia Treatment Peripheral artery disease (PAD) is the third most common cause of cardiovascular morbidity worldwide, present in 20% of the population over 65. If PAD is not treated, it can progress to critical limb ischemia, resulting in tissue necrosis and eventual limb amputation. Vasculogenesis, the process of de novo vessel formation from progenitor cells, may prove an effective therapeutic strategy. Vasculogenesis may be accomplished by delivering vascular progenitor cells derived from human induced pluripotent stem cells (hiPSCs-EPs), which have recently emerged as a promising, patient-specific therapy. However, the optimal conditions for iPSCs-EPs engraftment and anastomosis with the host vasculature are unclear, specifically, since the underlying molecular mechanisms that guide these cells' self-assembly into vascular networks are poorly understood. To overcome this hurdle, we propose to develop engineered vasculogenic hydrogels, presenting tunable cues at the cell-matrix interface, that can enhance the therapeutic vasculogenesis of iPSC-EPs for peripheral ischemia recovery and define the underlying mechanisms through which matrix properties control vasculogenesis. Previous work by us and others has shown that stable vascular network formation depends on both cell type and matrix properties such as stiffness and degradability. Highly degradable matrices such as collagen may support vasculogenesis initially, but long-term stability is challenging. Furthermore, these matrix properties are coupled and impact endothelial and perivascular cell sprouting at different time scales in neo-vascular network formation. Therefore, we hypothesize that temporal, in situ control over local matrix mechanics and degradability in synthetic matrices will synergistically regulate the vascular morphogenesis of hiPSC-EPs, lead to stable, mature vascular network formation and improve hind limb ischemia recovery. To test our hypothesis, we propose a hybrid interpenetrating hydrogel network (IPN) comprised of collagen and norbornene-modified hyaluronic acid (Coll/NorHA). This system has the advantage of combining the natural cues presented by collagen binding sites and fibrous architecture with the in situ dynamic tunability of synthetic NorHA. Our goal is to 1) elucidate the interplay between time-dependent matrix properties and mechanisms that govern vascular network development and 2) enhance therapeutic vasculogenesis for PAD. In Aim 1, we will modulate the elasticity in these hydrogels using in situ cross-linking reactions. We will study how stiffening at specific timepoints impacts the resulting vasculogenic response both in vitro and in vivo in a skin fold model. In a complementary approach to Aim 1, in Aim 2, we will isolate the effects of matrix degradability on iPSC-EPs vasculogenic potential using Coll/NorHA IPNs in which proteolytic susceptibility is tuned with matrix metalloprotease-degradable peptides. In Aim 3, we will test the synergistic impact of coupling matrix mechanics and degradability on iPSC-derived capillary plexus formation. Specifically, we will elucidate how the maturation level of the in vitro grown vascular plexus enables in vivo perfusion with host vasculature. In summary, we propose to enhance therapeutic vasculogenesis of iPSC-EPs for peripheral artery disease treatment through control of engineered matrix properties using a tunable Coll/NorHA IPN that mimics the hierarchical temporal structure of native ECM. Elucidating the interplay between matrix properties and mechanisms that govern vascular network development will identify angiogenic biomaterials that may be deployed in the clinic to improve patients' vascular health and aid in disease modeling.

动态ECM模拟生物材料用于缺血治疗 周围动脉疾病（PAD）是全球心血管发病率的第三大原因，目前 在20％以上的人口中，如果没有治疗PAD，则可以发展为临界肢体缺血，导致组织 坏死和最终肢体截肢。血管生成，祖先从头形成的过程 细胞可能证明是一种有效的治疗策略。血管生成可以通过输送血管来实现 源自人类诱导的多能干细胞（HIPSCS-EPS）的祖细胞，这些细胞最近出现了 作为一种有希望的特定于患者的治疗。但是，IPSCS-EPS植入的最佳条件和 宿主脉管系统的吻合术不清楚，因为它的基本分子机制是 这些细胞的自组装为血管网络的理解很少。 为了克服这一障碍，我们建议开发工程设计的血管生成水凝胶，可调节 细胞矩阵界面的提示，可以增强IPSC-EPS的治疗性血管生成 外围缺血恢复并定义了基质特性的基本机制 控制血管生成。 我们和其他人的先前工作表明，稳定的血管网络形成取决于细胞类型和 矩阵特性，例如刚度和降解性。高度降解的矩阵（例如胶原蛋白）可能会支持 血管生成最初，但长期稳定性是具有挑战性的。此外，这些矩阵属性是耦合的 以及在新的血管网络形成的不同时间尺度上撞击内皮和血管周围细胞的发芽。 因此，我们假设对局部基质力学的原位控制和降解性 合成矩阵将协同调节嘻哈的血管形态发生，导致稳定，成熟 血管网络形成并改善后肢缺血恢复。为了检验我们的假设，我们提出了一个 由胶原蛋白和诺尔伯烯改性透明质酸组成的混合互穿水凝胶网络（IPN） （Coll/Norha）。该系统的优点是结合胶原蛋白结合位点提出的自然提示 和纤维结构，具有合成Norha的原位动态可调性。我们的目标是1）阐明 依赖时间依赖的矩阵属性和控制血管网络发展的机制之间的相互作用 2）增强PAD的治疗性血管生成。在AIM 1中，我们将调节这些水凝胶中的弹性 使用原位交联反应。我们将研究在特定时间点上的僵硬如何影响由此产生的 在皮肤折叠模型中，体外和体内的血管生成反应。在AIM 1的补充方法中 AIM 2，我们将使用COLL/NORHA隔离基质降解性对IPSC-EPS血管生成潜力的影响 蛋白水解易感性的IPN用基质金属蛋白酶降解肽调节。在AIM 3中，我们 将测试耦合矩阵力学和降解性对IPSC衍生的毛细管丛的协同影响 形成。具体而言，我们将阐明体外生长的血管丛的成熟水平如何使 带有宿主脉管系统的体内灌注。 总而言之，我们建议增强IPSC-EPS治疗性血管生成用于周围动脉疾病 通过使用可调的Coll/Norha IPN来控制工程基质特性的处理 天然ECM的分层时间结构。阐明矩阵属性和 控制血管网络开发的机制将识别可能是的血管生成生物材料 部署在诊所中，以改善患者的血管健康并有助于疾病建模。