Hydrogels for Local Gene Delivery and Therapeutic Angiogenesis

描述（由申请人提供）：能够在组织形成过程中不同时间传递生物活性信号的治疗策略对于复杂组织（如成熟的脉管系统）的再生至关重要。在正常的伤口愈合过程中，导致成熟血管形成的事件是由一系列严格调控的事件引起的，这些事件随着环境的变化而依次发生。因此，为了成熟稳定的血管的生成，需要不止一种生物活性信号，并且这些信号在不同的时间需要。这一建议的重点是设计，合成和测试（在体外和体内）的非病毒基因传递策略，可以传递多个DNA顺序。在我们的方法中，一种由微孔（5孔）慢降解水凝胶和纳米孔（n孔）快速降解水凝胶组成的双组分酶降解水凝胶将在不同时间递送被封装的DNA纳米颗粒。目的1将探索设计和合成在体外和体内以两种不同速率释放DNA纳米颗粒的双组分水凝胶支架。目的2将探索优化后的双组分水凝胶在体外和体内暂时控制基因转移的能力。目的3将探讨在伤口愈合环境中，我们的双组分水凝胶系统可以以不同的速率释放包裹的促血管生成复合物和生长因子，从而促进血管生成和随后的伤口愈合。

DESCRIPTION (provided by applicant): Therapeutic strategies that can deliver bioactive signals at different times during tissue formation are essential for the regeneration of complex tissues such as a mature vasculature. During normal wound healing, the events that lead to mature blood vessel formation result from a series of tightly regulated events, which occur sequentially upon environmental changes. As a result, for the generation of mature and stable blood vessels more than one bioactive signal is needed and these signals are needed at different times. This proposal focuses on the design, synthesis and testing (in vitro and in vivo) of a non- viral gene delivery strategy that can deliver multiple DNA sequentially. In our approach, a two component, enzymatically degradable hydrogel composed of a micro porous (5-pore) slow degrading hydrogel and nano-porous (n-pore) fast degrading hydrogel will be used deliver encapsulated DNA nanoparticles at different times. Aim 1 will explore the design and synthesize two component hydrogel scaffolds that can release DNA nanoparticles at two different rates in vitro and in vivo. Aim 2 will explore the ability of the optimized two-component hydrogels to result in temporally controlled gene transfer in vitro and in vivo. Aim 3 will explore the hypothesis that within the wound-healing environment our two-component hydrogel system can release the encapsulated pro-angiogenic polyplexes and growth factors at different rates and result in enhanced angiogenesis and subsequent wound healing.