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: 10540794
• 负责人: Janeta Zoldan
• 金额: $ 62.3万
• 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/10540794
• 关键词: 3-Dimensional; Anastomosis - action; Architecture; Behavior; 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; Endothelium; 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; Progenitor Cell Engraftment; Property; Reaction; Recovery; Regulation; Self Direction; Shapes; Skin; Stimulus; Structure; System; Testing; Therapeutic; Time; Tissue Engineering; Tissue Therapy; Tissues; Traction; Vascularization; Work; bioscaffold; cell assembly; cell type; computational pipelines; critical limb Ischemia; crosslink; density; dithiol; 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.

用于缺血治疗的动态仿ECM生物材料 外周动脉疾病（PAD）是全球心血管疾病发病率的第三大常见原因， 在65岁以上的人群中占20%。如果不治疗PAD，它可以发展为严重的肢体缺血，导致组织坏死。 最终导致肢体坏死和截肢血管发生，从祖细胞重新形成血管的过程 细胞，可能证明是一种有效的治疗策略。血管生成可以通过递送血管生成因子来实现。 来源于人诱导多能干细胞（hiPSCs-EPs）的祖细胞，其最近出现 作为一种有前景的针对患者的治疗方法。然而，iPSCs-EP移植的最佳条件和 特别是，与宿主血管系统的吻合尚不清楚，因为潜在的分子机制， 如何引导这些细胞自我组装成血管网络还知之甚少。 为了克服这一障碍，我们建议开发工程血管生成水凝胶， 细胞-基质界面的提示，可以增强iPSC-EP的治疗性血管发生， 外周缺血恢复，并确定通过基质性质 控制血管生成。 我们和其他人以前的工作表明，稳定的血管网形成取决于细胞类型和 基质性能如硬度和降解性。高度可降解的基质，如胶原蛋白， 血管生成最初，但长期稳定性是具有挑战性的。此外，这些矩阵属性耦合 并在新生血管网络形成的不同时间尺度上影响内皮细胞和血管周围细胞发芽。 因此，我们假设，时间，在原位控制局部基质力学和降解性， 合成基质将协同调节hiPSC-EP的血管形态发生，导致稳定的、成熟的 血管网的形成和改善后肢缺血的恢复。为了验证我们的假设，我们提出了一个 由胶原和聚乙烯改性透明质酸组成的混杂互穿水凝胶网络（IPN） (Coll/NorHA）。该系统具有结合胶原蛋白结合位点所呈现的自然线索的优点 和纤维结构与合成NorHA的原位动态可调性。我们的目标是1）阐明 时间依赖性基质性质与控制血管网发育机制之间的相互作用 和2）增强PAD的治疗性血管生成。在目标1中，我们将调节这些水凝胶的弹性 使用原位交联反应。我们将研究特定时间点的硬化如何影响结果， 血管生成反应在体外和体内的皮肤褶皱模型。作为对目标1的补充， 目的2，我们将使用科尔/NorHA分离基质降解性对iPSC-EPs血管生成潜力的影响 其中蛋白水解敏感性用基质金属蛋白酶可降解肽调节的IPN。在目标3中，我们 将测试偶联基质力学和降解性对iPSC衍生的毛细血管丛的协同影响 阵具体来说，我们将阐明如何在体外生长的血管丛的成熟水平， 用宿主脉管系统进行体内灌注。 总之，我们建议增强iPSC-EP用于外周动脉疾病的治疗性血管生成， 通过使用可调的科尔/NorHA IPN控制工程化基质性质的处理， 原生ECM的分层时间结构。阐明基质性质与 控制血管网络发育的机制将确定可能 部署在诊所，以改善患者的血管健康并帮助疾病建模。