Crosslinkable Hydrogels for Growth Factor Release

用于生长因子释放的可交联水凝胶

• 批准号: 6954717
• 负责人: Robert A. Peattie
• 金额: $ 14.81万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954717
• 关键词: angiogenesis; bioengineering /biomedical engineering; biomaterial development /preparation; biomimetics; drug delivery systems; enzyme linked immunosorbent assay; extracellular matrix; fibroblast growth factor; gel; gelatin; gene expression; growth factor; heparin; hyaluronate; implant; laboratory mouse; polyethylene glycols; slow release drug; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The goal of the proposed project is to develop and evaluate novel hyaluronic acid (HA)-based hydrogel films optimized for controlled release of desired peptide growth factors (GFs) while simultaneously providing an advantageous environment for pre-seeded cell growth. Synthetic extracellular matrices (sECMs) fabricated from such biopolymer networks can serve as the foundation for tissue and organ growth both in vitro and in vivo. However, at present the clinical utility of most synthetic matrices is limited by poor regulation of the specific coordinated sequences of GF releases that typically drives tissue maturation in vivo. In the proposed project, an sECM containing small amounts of heparin (Hp), which has been shown to substantially improve control of the time course of release of sequestered GFs, will be fabricated from chemically modified HA, or HA and gelatin (Gtn). Conjugate addition chemistry will be employed to crosslink mixtures of HA-DTPH, Gtn-DTPH and Hp-DTPH, using polyethylene glycol diacrylate (PEGDA) as crosslinking agent. Vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) will be added to the HA-DTPH solution non-covalently prior to crosslinking. The relation between Hp concentration and rate of in vitro GF release from these matrices will be investigated by ELISA. Subsequently, gel samples fabricated with a minimal amount of Hp consistent with sustained GF release will be implanted in a series of mouse ear pinnas, and the angiogenic activity of released GF in vivo quantified by measurement of elicited new microvessel growth. In addition, the potential for controlling tissue phenotypic response at the gene expression level with these imlants will be studied in the same mouse model. Tissue samples will be retrieved at a series of time points post implant, and expression changes due to controlled growth factor release determined by microarray and RT-PCR analysis.

描述（由申请人提供）：拟议项目的目标是开发和评估新型透明质酸（HA）基水凝胶薄膜，该薄膜针对所需肽生长因子（GF）的受控释放进行了优化，同时为预接种提供了有利的环境细胞生长。由此类生物聚合物网络制成的合成细胞外基质（sECM）可以作为体外和体内组织和器官生长的基础。然而，目前大多数合成基质的临床应用受到对通常驱动体内组织成熟的GF释放的特定协调序列的不良调节的限制。 在拟议的项目中，含有少量肝素 (Hp) 的 sECM 将由化学改性的 HA 或 HA 和明胶 (Gtn) 制成，已被证明可以显着改善对隔离 GF 释放时间过程的控制。将使用聚乙二醇二丙烯酸酯（PEGDA）作为交联剂，采用共轭加成化学来交联 HA-DTPH、Gtn-DTPH 和 Hp-DTPH 的混合物。在交联之前，将血管内皮生长因子 (VEGF) 或碱性成纤维细胞生长因子 (bFGF) 以非共价方式添加到 HA-DTPH 溶液中。将通过 ELISA 研究 Hp 浓度与体外 GF 从这些基质中释放的速率之间的关系。随后，用与持续 GF 释放一致的最少量 Hp 制成的凝胶样品将被植入一系列小鼠耳廓中，并通过测量引发的新微血管生长来量化体内释放的 GF 的血管生成活性。此外，将在同一小鼠模型中研究这些植入物在基因表达水平上控制组织表型反应的潜力。将在植入后的一系列时间点检索组织样本，并通过微阵列和 RT-PCR 分析确定由于受控生长因子释放而导致的表达变化。