Hydrogels for Local Gene Delivery and Therapeutic Angiogenesis

描述(申请人提供)：能够在组织形成的不同时间传递生物活性信号的治疗策略对于复杂组织的再生至关重要，例如成熟的血管系统。在正常的伤口愈合过程中，导致成熟血管形成的事件是一系列严格调控的事件的结果，这些事件随着环境的变化而顺序发生。因此，为了产生成熟和稳定的血管，需要不止一个生物活性信号，并且这些信号在不同的时间需要。这项建议的重点是设计、合成和测试(体外和体内)非病毒基因递送策略，可以顺序地递送多个DNA。在我们的方法中，一种由微孔(5孔)缓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可酶降解水凝胶将在不同的时间输送包裹的DNA纳米颗粒。目的1探索设计和合成双组分水凝胶支架，在体内外以两种不同的速率释放DNA纳米颗粒。目的2探索优化的双组分水凝胶在体外和体内实现时间控制的基因转移的能力。目的3探讨在创伤愈合环境中，我们的双组分水凝胶系统能够以不同的速率释放包裹的促血管生成复合体和生长因子，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.