Nanostructured Hydrogel Surfaces for Artificial Extracellular Matrix

用于人工细胞外基质的纳米结构水凝胶表面

基本信息

批准号：
10373590
负责人：
Shelley Ann Claridge
金额：
$ 18.4万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10373590
关键词：
3-Dimensional Accidents Address Adhesions Adopted Aging Area Behavior Benchmarking Binding Biological Carbohydrates Cartilage Cell Adhesion Cell Transplantation Cell surface Cells Chemical Structure Chemicals Chemistry Chondrogenesis Clinical Collagen Cues Deposition Differentiation and Growth Disease Elements Environment Extracellular Matrix Fiber Film Future Gel Generations Geometry Goals Health Human Hydrogels Hypoxia Implant Individual Injury Instruction Length Ligands Lysine Mechanics Mesenchymal Stem Cells Modification Modulus Mus Myoblasts Nanostructures Organ Organ Transplantation Osteogenesis Pattern Peptides Perfusion Printing Property Regenerative Medicine Resolution Side Signal Transduction Site Smooth Muscle Myocytes Specific qualifier value Stem cell transplant Structure Surface Surface Properties Technology Testing Thick Thinness Tissues Transplantation Transplantation Surgery United States Waiting Lists angiogenesis base biomaterial compatibility bone cell growth chemical property design experimental study flexibility functional loss functional restoration improved in vivo innovation lipid biosynthesis mechanical properties mechanical signal polyacrylamide polydiacetylene polydimethylsiloxane prevent prototype regenerative tissue repaired scaffold stem cell growth stem cells stemness success tissue regeneration tissue support frame transplantation therapy volumetric muscle loss wound healing

项目摘要

PROJECT SUMMARY Scaffolded stem cell transplantation has the potential to provide structured chemical and mechanical cues to guide cell growth into functional tissues for regenerative medicine. However, significant challenges have limited the clinical success of this approach. Cells implanted in large scaffolds often have limited viability due to hypoxic conditions in the host, while cells injected individually or in small clusters often suffer from poor retention at the site of injury. Hydrogels are commonly utilized as stem cell scaffold materials because they confer substantial flexibility in terms of chemical composition and ligand integration. However, hydrogels are also typically amorphous, limiting control over ligand presentation (important for adhesion and signaling), and lacking structural cues such as fibers that are present in biological ECM, which impacts mechanical strength. We have recently demonstrated that it is possible to generate stable, 1-nm-resolution functional patterns on amorphous polyacrylamide and polydimethylsiloxane surfaces, using sub-nm-thick films of highly ordered polydiacetylenes (PDAs) that are preassembled and covalently transferred to the hydrogel surface. Our approach potentially addresses both chemical and mechanical challenges associated with hydrogel stem cell scaffolds, enabling generation of cell-instructive hydrogel tapes that can be shaped to create 3D scaffolds. However, to be useful in clinical settings, this strategy will need to be validated with: (1) commonly used hydrogel stem cell scaffold materials, (2) hydrogel moduli matching the range commonly associated with tissues, and (3) films thin enough for adequate perfusion to prevent hypoxia and enable normal secretome interactions. Here, we develop a platform technology based on cell-instructive hydrogel tapes, benchmarking their chemical and mechanical properties, and their impacts on human mesenchymal stem cells (hMSCs). In Aim 1, we evaluate the hypothesis that PDA surface functionalization can improve chemical control over surfaces of hydrogels common in regenerative medicine, orienting and spatially clustering ligand presentation, to modify stem cell growth in a predictable fashion. We test this by culturing hMSCs on surfaces designed to maintain stemness or to induce specified differentiation behavior (angiogenesis, adipogenesis, chondrogenesis), benchmarking against common stochastic hydrogel modification strategies. In Aim 2, we evaluate the hypothesis that our PDA surface-functionalization approach can improve the mechanical and handling properties of thin, soft hydrogel films, enabling creation of cell-instructive hydrogel tapes. We generate and test impacts of paired tapes as cell sandwich scaffolds and 3D constructs that provide structured chemical surfaces and mechanical environments, while maximizing perfusion to and from cells. Overall, this proposal develops a modular surface functionalization strategy that can be easily integrated with many existing hydrogels for tissue scaffolds, providing structured ligand presentation and mechanical strength aimed at improving utility in clinical cell transplantation therapies.

项目摘要脚手架干细胞移植具有提供结构化的化学和机械线索的潜力将细胞生长引导到功能组织中，以进行再生医学。但是，重大挑战有限这种方法的临床成功。大型支架中植入的细胞通常由于宿主中的低氧条件，而单独注射或小簇中注射的细胞通常患有较差在受伤部位保留。水凝胶通常用作干细胞支架材料，因为它们在化学组成和配体整合方面具有很大的灵活性。但是，水凝胶是也通常是无定形的，限制对配体呈现（对于粘附和信号传导很重要）的控制缺乏生物ECM中存在的纤维等结构线索，从而影响机械强度。我们最近证明，可以在使用高度有序的sub-nm厚膜聚二乙烯（PDA）被预组装并共价转移到水凝胶表面。我们的方法可能解决与水凝胶干细胞相关的化学和机械挑战脚手架，使能够形成以创建3D脚手架的细胞结构水凝胶磁带的产生。但是，要在临床环境中有用，需要对此策略进行验证：（1）常用水凝胶干细胞支架材料，（2）水凝胶模量与通常相关的范围组织，（3）薄膜足够稀薄，足以灌注以防止缺氧并启用正常分泌组互动。在这里，我们开发了一种基于细胞结构水凝胶磁带的平台技术，基准测试它们的化学和机械性能及其对人间充质干细胞（HMSC）的影响。在AIM 1中，我们评估了PDA表面功能化可以改善化学控制的假设在再生医学中常见的水凝胶表面，定向和空间聚类配体呈现，以可预测的方式修饰干细胞生长。我们通过在旨在的表面上培养HMSC来对此进行测试保持干性或诱导特定的分化行为（血管生成，脂肪生成，软骨发生），针对常见的随机水凝胶修饰策略进行基准测试。在AIM 2中，我们评估了我们的PDA表面官能化方法可以改善的假设薄的软水凝胶膜的机械和处理特性，从而创建细胞教学水凝胶磁带。我们将配对磁带的影响和测试影响作为细胞三明治支架和3D构造提供结构化的化学表面和机械环境，同时最大程度地提高细胞的灌注。总体而言，该建议制定了一个模块化的表面功能化策略，可以轻松地与许多现有用于组织支架的水凝胶，提供结构化的配体表现和机械强度旨在改善临床细胞移植疗法的效用。