Biomaterials for sequential growth factor delivery

肌肉骨骼疾病的费用平均占发达国家国内生产总值的3%， 这些国家每年在美国消费约2540亿美元。天然肌肉骨骼工程 组织代表了一种有前途的新方法，以扩大条件的范围，可以有效地 治疗。该提案的重点是开发一种再生天然骨骼组织的新方法， 其重点在于使用蛋白质生长因子暂时控制成体干细胞的活性。的 这项工作的指导假设是，工程化的生长因子可以包括在生长层的一个 无机基质，导致在材料溶解时连续的生长因子递送。增长因素将 用矿物结合序列标记，以包含在钙基矿物中， 溶解将使得能够顺序递送。每种生长因子的递送将被设计成引起不同的 间充质干细胞（MSC）反应，允许对新骨的早期生成进行时间控制 组织.在我们的方法的效用的第一个演示中，我们将释放促有丝分裂因子（FGF-2）， 成骨因子（BMP-2）。具体目标1将开发和表征一种方法， 在大孔藻酸盐水凝胶模板内生长钙基矿物质。这种做法受到启发 通过自然生物矿化过程，并采用生理加工条件， 有生物活性的生长因子。特异性目标2将设计标记有假定的 矿物结合序列纳入矿物材料，并将系统地表征生长 因子包含、释放和生物活性。重点将放在实现高水平的控制上 释放速率，同时保持生物活性。然后，我们将使用此方法按顺序发布 影响MSC活性的两种生长因子：促有丝分裂因子（FGF-2）和成骨因子（BMP-2）。 具体目标3将评估在开发的矿物质基质中时间控制的MSC活性， S.A.2，专注于优化功能性分化成骨细胞的存在。这一目标旨在 展示了我们的方法在具有重大临床意义的应用中的实用性： 功能性骨组织这一目标的结果将作为一个跳板，发展一个广泛的 研究计划集中于暂时控制生长因子向干细胞的呈递。

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.