Biomaterials for sequential growth factor delivery

用于连续生长因子递送的生物材料

• 批准号: 7189073
• 负责人: WILLIAM L. MURPHY
• 金额: $ 6.99万
• 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/7189073
• 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; 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

DESCRIPTION (provided by applicant): 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 1 will 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.

描述（由申请人提供）：肌肉骨骼状况的成本平均占发达国家国内生产总值的3％，估计每年在V.S中消耗约2540亿美元。天然肌肉骨骼组织的工程代表了一种有希望的新方法来扩展可以有效治疗的条件范围。该提案的重点是开发一种新方法来再生天然骨骼组织，重点是使用蛋白质生长因子在时间上控制成年干细胞的活性。这项工作的指导假设是，可以将工程生长因子包括在无机基质的增长层中，从而导致材料溶解后的顺序生长因子递送。生长因子将用矿物结合序列标记，将其纳入基于钙的矿物质，随后的基质溶解将实现顺序递送。将设计每个生长因子的递送，以引起独特的间充质干细胞（MSC）反应，从而可以对新骨组织的早期产生时间控制。在首次展示我们方法的实用性时，我们将按顺序释放有丝分裂因子（FGF-2）和成骨因子（BMP-2）。特定的目标1将开发并表征一种在大孔藻酸盐水凝胶模板中生长基于钙的矿物的方法。这种方法受到自然生物矿化过程的启发，并采用生理加工条件来纳入生物活性生长因子。具体目标2将设计用推定的矿物结合序列标记的生长因子，以纳入矿物质材料，并将系统地表征生长因子包含，释放和生物学活性。重点将是在维持生物学活动的同时，在释放率上获得高水平的控制。然后，我们将使用这种方法顺序释放影响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S.A.2中开发的矿物矩阵内的时间控制的MSC活性，重点是优化功能性，分化的成骨细胞的存在。该目标旨在证明我们方法在具有实质性临床意义的应用中的实用性：功能性骨组织的工程。该目标的结果将作为开发广泛研究计划的跳板，该计划着重于时间控制生长因子向干细胞的呈现。