Molecular Engineering of Bioactive Hydrogels

生物活性水凝胶的分子工程

• 批准号: 7471860
• 负责人: DAVID V SCHAFFER
• 金额: $ 21万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471860
• 关键词: Address; Adverse effects; Affinity; Animals; Binding; Biological; Biology; Biomedical Engineering; Brain; Cell Count; Cell Culture System; Cell Differentiation process; Cell physiology; Cell-Free System; Cells; Cellular biology; Clinical; Coculture Techniques; Collection; Complex; Condition; Conditioned Culture Media; Congestive Heart Failure; Development; Diabetes Mellitus; Disease; Engineering; Engraftment; Environment; Epitopes; Extracellular Matrix; Extracellular Matrix Proteins; Goals; Grant; Heart; Human; Hydrogels; Immune; In Vitro; Injury; Ligands; Liver; Medicine; Methods; Molecular; Molecular Biology; Mus; Muscle; Numbers; Pancreas; Parkinson Disease; Patients; Peptides; Personal Satisfaction; Population; Process; Production; Proteins; Public Health; Range; Regenerative Medicine; Reproducibility; Science; Serum; Signal Transduction; Source; Stem cells; Surface; System; Technology; Tissue Engineering; Tissues; Treatment Efficacy; base; bone; cell behavior; cell type; human embryonic stem cell; immunogenic; in vivo; leukemia; novel; pathogen; reconstruction; scale up; self-renewal; synthetic peptide; therapy design; transmission process

Description (provided by applicant): Human embryonic stem cells (hESCs) have strong potential as sources of cells for the treatment for disease and injury (e.g. tissue engineering and reconstruction, diabetes, Parkinson's Disease, leukemia, congestive heart failure, etc.). The successful integration of hESC into such therapies will hinge upon three critical steps: their expansion without differentiation (i.e., self-renewal), their differentiation into a specific cell type or collection of cell types, and the promotion of their survival and functional integration into existing tissue. However, controlling cell behavior during each of these steps will require precise control over the cellular microenvironment. This poses a major challenge ex vivo in current hESC culture systems, which range from co-culture with feeder cells to serum-free systems where cells are cultured on complex extracellular matrix proteins. All such systems involve animal or human proteins, which pose problems for pathogen transmission, immune rejection, limited reproducibility, and scale up to a clinical process. To achieve the intended goals of regenerative medicine, methods for the precise control of the survival, proliferation, and differentiation of stem cell populations in vitro and in vivo are necessary. Here, we propose to develop a completely synthetic environment to precisely control hESC self-renewal in culture. Specifically, we will engineer a tunable and well-defined environment presenting a completely "synthetic extracellular matrix" (ECM) and chemically-defined media to control the self-renewal/expansion of hESCs. Furthermore, we will develop high throughput approaches to identify synthetic peptide ligands for functionalization to the synthetic ECM and promotion of hESC self-renewal. If hESCs can be derived and maintained within this fully synthetic microenvironment, then it will be possible to eliminate pathogen transmission associated with mouse or human feeder layers, provide a scalable basis for large-scale production of hESCs, and provide a precise base for further development to control hES cell differentiation. Furthermore, the result will be a technology platform that can be generally applied to numerous stem cell populations and used to investigate the basic biological/developmental mechanisms underlying self-renewal. Public Health Relevance: The development of novel, bioactive materials has significant potential for exerting precise control over cell function, both for fundamental biological studies and applications in tissue engineering and regenerative medicine. For example, developing synthetic, bioactive material systems to promote the self-renewal and expansion of human embryonic stem cells will have numerous biomedical applications including the design of therapies for disease or injury in the muscle, bone, brain, heart, liver, pancreas, and other tissues. The novel blend of stem cell biology, materials science, molecular biology, and bioengineering described in this proposal will be well suited to addressing an important problem, i.e. stem cell control, at the interface of biology, engineering, and medicine

描述（由申请人提供）：人类胚胎干细胞（HESC）作为疾病和损伤治疗的细胞来源（例如组织工程和重建，糖尿病，帕金森氏病，白血病，充血性心力衰竭等）具有强大的潜力。 HESC成功整合到此类疗法中将取决于三个关键步骤：它们的扩展没有分化（即自我更新），它们分化为特定细胞类型或细胞类型的收集，以及促进其生存和功能整合到现有组织中。但是，在每个步骤中控制细胞行为都需要精确控制细胞微环境。这在当前的hESC培养系统中构成了一个重大的挑战，范围从与进料细胞共培养到无血清系统，在复杂细胞外基质蛋白上培养细胞。所有此类系统均涉及动物或人类蛋白质，这对病原体传播，免疫排斥，有限的可重复性构成问题，并扩展到临床过程。为了实现再生医学的预期目标，必须在体外和体内精确控制干细胞种群的生存，增殖和分化的方法。在这里，我们建议开发一个完全合成的环境，以精确控制文化中的hESC自我更新。具体而言，我们将设计一个可调且定义明确的环境，呈现一个完全“合成的细胞外基质”（ECM）和化学定义的介质，以控制hESC的自我更新/扩展。此外，我们会的 开发高吞吐量方法，以鉴定合成肽配体，以对合成ECM的功能化并促进hESC自我更新。如果可以在这种完全合成的微环境中得出和维持hESC，那么可以消除与小鼠或人类喂食器层相关的病原体传播，为大规模生产hESC提供可扩展的基础，并为进一步的发展提供了进一步的发展以控制HES细胞分化。此外，结果将是一个技术平台，通常可以应用于众多干细胞群体，并用于研究自我更新的基本生物学/发育机制。公共卫生相关性：新型生物活性材料的开发具有对细胞功能的精确控制的重要潜力，包括基础生物学研究以及在组织工程和再生医学中的应用。例如，开发合成的生物活性材料系统来促进人类胚胎干细胞的自我更新和扩展，将具有许多生物医学应用，包括肌肉，骨骼，大脑，心脏，肝脏，胰腺和其他组织的疾病或损伤疗法设计。干细胞生物学，材料科学，分子生物学和本建议中描述的生物工程的新型混合物非常适合解决重要的问题，即干细胞控制，在生物学，工程和医学的界面上