Molecularly regulated release of angiogenic factors from superporous hydrogels

超孔水凝胶中血管生成因子的分子调控释放

• 批准号: 9276516
• 负责人: Yong Wang
• 金额: $ 42.96万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276516
• 关键词: Affinity; Angiogenic Factor; Architecture; Attention; Binding; Biocompatible Materials; Biological Assay; Blood Vessels; Bolus Infusion; Cell Survival; Cells; Chemicals; Chronic; Competitive Binding; Complex; Data; Development; Diabetic wound; Disease; Disease model; Dose; Exhibits; Future; Generations; Growth; Growth Factor; Hybrids; Hydrogels; Implant; In Vitro; Injectable; Injection of therapeutic agent; Investigation; Ischemia; Kinetics; Lead; Link; Localized Disease; Methods; Molecular; Mus; Myocardial Infarction; Nucleic Acids; Organ; Oxygen; Physical Stimulation; Polymers; Procedures; Process; Property; Site; Specificity; Stroke; Structure-Activity Relationship; System; Technology; Testing; Time; Tissue Engineering; Tissue Survival; Tissues; Transport Process; Ultrasonography; Vascularization; Work; angiogenesis; aptamer; base; cell growth; controlled release; design; dosage; improved; in vivo; injured; novel; novel strategies; nutrition; platelet-derived growth factor BB; public health relevance; release factor; repaired; response; systemic toxicity; therapeutic angiogenesis

 DESCRIPTION: Vascularization is important for the treatment of various ischemic diseases and the survival of tissue-engineered constructs. Thus, the development of angiogenesis strategies has continuously attracted great attention in various fields. However, the realization o successful angiogenesis is challenging, because vascular formation and maturation involve multiple growth factors at different stages. Moreover, while insufficient angiogenic factors do not induce effective angiogenesis, excess angiogenic factors can lead to the formation of defective and leaky blood vessels. Thus, therapeutic angiogenesis requires not only multiple growth factors, but also mechanisms for modulating the time, dosage, and sequential order of growth factor delivery. While bolus injections are the simplest way to control the time, dosage, and sequential order of growth factor delivery, this mode of delivery requires very high levels of growth factors. It can lead to severe systemic toxicity. By contrast, polymeric delivery systems hold great promise for localized delivery of growth factors with reduced systemic toxicity. However, it is challenging to develop a polymeric system to control the release time, dosage and sequential order of multiple growth factors. The objective of this application is to develop a novel molecularly controlled release mechanism and a hydrogel-based polymeric system that can release multiple angiogenic factors with differential and independent timing and dose control, hence regulating angiogenesis in a dynamic manner. The central hypothesis is that multiple growth factors would be sequestered within the same hydrogel by specific binding to hydrogel-linked nucleic acid aptamers, and released specifically by competitive binding of complementary sequence (CS) triggers. To test this hypothesis, we will work on three specific aims: 1) to synthesize aptamer-functionalized superporous hydrogels (AS-gels) for high-capacity sequestration and retention of multiple growth factors; 2) to design and optimize aptamer and CS sequences and to determine molecularly regulated growth factor release from AS-gels in vitro; and 3) to investigate molecularly regulated growth factor release from AS-gels and angiogenesis in mice. We have performed preliminary studies and acquired compelling data showing that AS-gels can sequester growth factors and release them in the presence of CS triggers. More importantly, AS-gels can be triggered to release growth factors to stimulate angiogenesis in vivo. Therefore, the accomplishment of this project will lead to a novel strategy for on-demand delivery of multiple growth factors. It will benefit the treatment of various ischemic diseases such as repair of internal organs where it is too harmful or impossible to repeatedly inject growth factors directly into the tissue.

 描述：血管形成对于治疗各种缺血性疾病和组织工程构建体的存活至关重要。这，血管生成策略的发展继续吸引各个领域的引起极大的关注。但是，实现成功的血管生成是具有挑战性的，因为血管形成和成熟涉及不同阶段的多种生长因子。此外，虽然血管生成因子不足 诱导有效的血管生成，超过血管生成会导致形成有缺陷和漏水的血管。这不仅需要多种生长因子，而且还需要调节生长因子递送的时间，剂量和顺序顺序的机制。虽然注射推注是控制时间，剂量和顺序的生长因子传递顺序的最简单方法，但这种交付方式需要非常高的生长因子。它可能导致严重的全身毒性。相比之下，聚合物输送系统对局部递送的生长因子具有降低的全身性毒性的局部递送。但是，开发一个聚合系统以控制多种生长因子的释放时间，剂量和顺序顺序是挑战。该应用的目的是开发一种新型的分子控制释放机制和基于水凝胶的聚合系统，该系统可以释放具有差分和独立时机和剂量控制的多个血管生成因子，因此以动态方式调节血管生成。中心假设是，通过特异性结合与水凝胶连接的核酸适体，将在同一水凝胶中测序多个生长因子，并专门通过互补序列（CS）触发器的竞争结合而释放。为了检验这一假设，我们将针对三个特定的目的：1）合成APATMER官能化的超孢子水凝胶（AS-GELS），以实现高容量序列并保留多种生长因子； 2）设计和优化APATMER和CS序列并确定分子调节的生长因子在体外从AS-GELS释放； 3）研究分子调节的生长因子从AS-凝胶和小鼠中的血管生成释放。我们已经进行了初步研究，并获得了令人信服的数据，表明AS-GEL可以在CS触发器的存在下隔离生长因子并释放它们。更重要的是，可以触发AS凝胶释放生长因子以刺激体内血管生成。因此，该项目的实现将导致一种新的策略，以按需多种增长因素提供。它将有益于对各种缺血性疾病的治疗，例如修复内脏的修复，在这种内部器官中，它对组织过于有害或不可能直接将生长因子直接注入组织。