Development of materials to release bioactive lipids

描述（由申请人提供）：生物活性脂类已成为细胞内和细胞外信号传导的关键因素。生物活性脂质鞘氨醇1-磷酸（S1P）引起内皮细胞的强烈反应。S1P对内皮细胞的强大作用表明，控制S1P的递送可能有利于促进人工材料的内皮化。与蛋白质生长因子不同，S1P可以从血液中已经存在的鞘氨醇中酶促地产生。

DESCRIPTION (provided by applicant): Bioactive lipids have emerged as critical factors in intra- and extracellular signaling. The bioactive lipid sphingosine 1-phosphate (S1P) elicits powerful responses from endothelial cells. The potent effects of S1P on endothelial cells suggest that controlled delivery of S1P may be beneficial in promoting the endothelialization of artificial materials. Unlike protein growth factors, S1P can be produced within materials enzymatically, from sphingosine that is already present in blood. We have previously synthesized polyethylene glycol materials that strongly resist protein adsorption and blood cell adhesion, but allow endothelial cell adhesion due to the presence of cell adhesion peptides. The materials function as an engineered mimic of the pseudointima that is associated with endothelialization in animals. However, our coatings will not promote coagulation and thrombosis and thus could be used as a coating for small diameter vascular grafts. In the proposed studies, we will characterize the new materials, the mechanism of S1P release and the effect of S1P delivery on cell adhesion and migration. The specific aims of this research project are: Aim 1: Demonstrate that S1P release kinetics are determined by the rate of diffusion of lipid-binding proteins through the hydrogel. Aim 2: Determine if controlled delivery of S1P allows the use of higher concentrations of RGD peptides in the PEG hydrogels, which may increase long-term cell adhesion strength. Aim 3: Demonstrate that enzymatic production allows delivery of S1P from nanoscale PEG coatings. Aim 4: Evaluate the safety and efficacy of S1 P-releasing PEG coatings containing RGD-peptide in the rat carotid artery.