Biomaterials for sequential growth factor delivery

用于连续生长因子递送的生物材料

• 批准号: 7475383
• 负责人: WILLIAM L. MURPHY
• 金额: $ 3.01万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475383
• 关键词: 3-Dimensional; Alginates; Area; Binding; Biocompatible Materials; Biological; Bone Tissue; Calcium; Characteristics; Clinical; Condition; Developed Countries; Developing Countries; Development; Engineering; Generations; Glutamic Acid; Growth; Growth Factor; Histocompatibility Testing; Hydrogels; Interleukin-2; Localized; Mesenchymal Stem Cells; Methods; Minerals; Molecular Biology Techniques; Musculoskeletal; Natural regeneration; Osteoblasts; Physiological Processes; Polyesters; Procedures; Process; Property; Proteins; Range; Rate; Regenerative Medicine; Research; Research Design; Signal Transduction; Skeletal system; Stem cells; Study Section; Time; TimeLine; Tissues; Work; adult stem cell; base; biomineralization; bone; bone morphogenetic protein 2; clinically significant; cost; design; interest; intracellular protein transport; novel strategies; programs; protein localization location; repaired; response; tissue regeneration

Costs of musculoskeletal conditions represent an average of 3% of the gross domestic product of developed countries, consuming an estimated $254 billion annually in the V.S.. Engineering of natural musculoskeletal tissues represents a promising new approach to expand the range of conditions that can be effectively treated. This proposal focuses on development of a new approach for regenerating natural skeletal tissues, with an emphasis on temporally controlling the activity of adult stem cells using protein growth factors. The guiding hypothesis of this work is that engineered growth factors can be included into growing layers of an inorganic matrix, resulting in sequential growth factor delivery upon material dissolution. Growth factors will be tagged with a mineral binding sequence for inclusion into calcium-based minerals, and subsequent matrix dissolution will enable sequential delivery. Delivery of each growth factor will be designed to elicit a distinct mesenchymal stem cell (MSC) response, allowing for temporal control over early generation of new bone tissue. In a first demonstration of the utility of our approach, we will release a mitogenic factor (FGF-2) and an osteogenic factor (BMP-2) in sequence. Specific Aim 1will develop and characterize a method for growing calcium-based minerals within a macroporous alginate hydrogel template. This approach is inspired by natural biomineralization processes, and employs physiological processing conditions to enable inclusion of biologically active growth factors. Specific Aim 2 will engineer growth factors tagged with a putative mineral binding sequence for inclusion into mineral materials, and will systematically characterize growth factor inclusion, release, and biological activity. The emphasis will be on achieving a high level of control over release rates while maintaining biological activity. We will then use this approach to sequentially release two growth factors that influence MSC activity: a mitogenic factor (FGF-2) and an osteogenic factor (BMP-2). Specific Aim 3 will evaluate temporally controlled MSC activity within the mineral matrices developed in S.A.2, focusing on optimizing the presence of functional, differentiated osteoblasts. This aim is designed to demonstrate the utility of our approach in an application with substantial clinical significance: engineering of functional bone tissue. The results of this aim will serve as a springboard for development of an extensive research program focused on temporally controlling growth factor presentation to stem cells.

肌肉骨骼疾病的费用平均占发达国家国内生产总值的3% 据估计，VS每年的消费额为2540亿美元。天然肌肉骨骼工程 组织代表了一种很有希望的新方法，可以扩大可以有效治疗的条件的范围 治疗过了。这项提案的重点是开发一种新的再生天然骨骼组织的方法， 重点是使用蛋白质生长因子暂时控制成体干细胞的活性。这个 这项工作的指导性假设是，工程生长因子可以包括在生长层中 无机基质，导致材料溶解时连续的生长因子输送。增长因素将 用矿物结合序列标记，以包含在钙基矿物和后续基质中 溶解将使顺序交付成为可能。每一种生长因子的交付都将被设计为产生不同的 间充质干细胞(MSC)反应，允许对新骨的早期生成进行临时控制 组织。在我们方法的实用性的第一次演示中，我们将释放一种促有丝分裂因子(成纤维细胞生长因子-2)和 一种成骨因子(BMP-2)。具体目标1将开发和描述一种方法，用于 在大孔藻酸盐水凝胶模板中生长钙基矿物。这种方法是受到启发的 通过自然的生物矿化过程，并使用生理处理条件来实现包裹体 具有生物活性的生长因子。特定目标2将设计带有假定标记的增长因素 矿物结合序列，用于包含到矿物材料中，并将系统地表征生长 因子包涵体、释放和生物活性。重点将是实现高水平的控制 在保持生物活性的同时，释放速度过快。然后，我们将使用此方法按顺序发布 影响MSC活性的两个生长因子：有丝分裂因子(FGF-2)和成骨因子(BMP-2)。 具体目标3将评估在开发的矿物基质内的时间控制的MSC活性 S.A.2，重点是优化功能分化的成骨细胞的存在。这一目标旨在 展示我们的方法在一个具有重大临床意义的应用中的实用性：工程 功能性骨组织。这一目标的成果将成为发展广泛的 研究计划侧重于在时间上控制生长因子向干细胞的递送。