Biomaterials with Rationally Immobilized Growth Factors

描述（由申请人提供）：理想情况下，植入物的设计应具有促进特定生物反应的能力。在骨接触材料的情况下，这意味着在植入后，器械将立即诱导成骨细胞谱系的细胞在生物材料上或附近形成骨。植入物的稳定固定和更好地整合到组织中将是结果。本研究的总体目标是开发诱导特定细胞和组织反应的生物分子表面修饰策略。例如，组织再生的刺激（其中植入物变得整合到组织中）比修复（其中植入物通常用纤维囊隔开）更理想。据推测，骨接触材料具有表面与骨向生物分子在一个特定的介绍，可以控制在组织生物材料界面的初始细胞事件。在具体目标1中，将开发双酰肼衍生的聚（D，L-丙交酯-共-乙交酯）涂层、微球和多孔支架，用于定向固定骨生长因子。将产生具有不同长度和表面密度的双酰肼分子的表面。在具体目标2中，将设计和实施合理的方案，用于在目标1中开发的材料上定点固定生长因子。重组DNA技术将用于对胰岛素样生长因子I和骨形态发生蛋白2的氨基末端进行修饰。这些独特的位点将允许生长因子以最大化与细胞表面受体相互作用的方向固定。在具体目标3中，将确定合理改性生物材料的体外和体内生物活性。还将使用细胞培养物评估固定化生长因子对适当细胞表面受体的活化。假设生长因子的定点固定将产生更高的比生物活性，因此，与随机固定的蛋白质相比，将导致更大的细胞和组织反应（特别是骨形成）。这些研究的结果将影响具有诱导所需界面反应能力的骨接触生物材料的开发。

DESCRIPTION (provided by applicant): Ideally, implants should be designed with the ability to promote specific biological responses. In the case of bone-contacting materials, this would mean that, immediately following implantation, the devices would induce cells of the osteoblastic lineage to form bone on or in close proximity to the biomaterial. Stable fixation of the implant and better integration into the tissue would be the result. The overall goal of this research is to develop biomolecular surface modification strategies that induce specific cell and tissue responses. For example, stimulation of tissue regeneration, in which the implant becomes integrated into the tissue, is more desirable than repair, in which the implant is generally walled off with a fibrous capsule. It is postulated that bone-contacting materials possessing surfaces with osteotropic biomolecules in a specific presentation can control initial cellular events at the tissue-biomaterial interface. In Specific Aim 1, bis-hydrazide-derivatized poly(D,L-lactide-co-glycolide) coatings, microspheres, and porous scaffolds will be developed for use in site-directed immobilization of osteotropic growth factors. Surfaces with different lengths and surface densities of bis-hydrazide molecules will be produced. In Specific Aim 2, rational schemes will be designed and implemented for site-directed immobilization of growth factors on the materials developed in Aim 1. Recombinant DNA techniques will be used to introduce modifications to the amino termini of insulin-like growth factor I and bone morphogenetic protein 2. These unique sites will allow the growth factors to be immobilized in an orientation that maximizes interaction with cell surface receptors. In Specific Aim 3, in vitro and in vivo biological activity of the rationally modified biomaterials will be determined. Cell cultures will also be used to assess activation of the appropriate cell surface receptors by the immobilized growth factors. It is hypothesized that site-directed immobilization of growth factors will yield higher specific bioactivity and, therefore, will result in greater cell and tissue responses (specifically bone formation) compared to randomly immobilized protein. The findings of these studies will impact the development of bone-contacting biomaterials having the ability to induce desired interracial responses.