Nanolayer Assemblies for Temporal Cytokine Therapy in Diabetic Ulcer Healing

描述（由申请人提供）：与一般人群相比，慢性伤口对糖尿病患者的影响不成比例。据预测，四分之一的糖尿病患者在其一生中会出现慢性伤口，复发率接近70%。许多慢性伤口的严重程度不断恶化，12%的复发性慢性伤口导致截肢。虽然生长因子疗法已证明促进伤口愈合的能力有限，但目前的治疗方式不能准确地重建自然伤口愈合过程。本项目的目的是开发新的治疗性伤口敷料，更准确地再现体内观察到的自然伤口愈合动力学。该提议的中心假设是，逐层（LbL）技术可用于产生分层的静电组件，该静电组件在时间上调节慢性伤口中的局部细胞因子水平并刺激愈合过程。为了验证这一假设，Aim 1将开发特异性结合细胞因子的“亲和聚合物”，以调节时间释放曲线。随后将制造具有两种不同治疗策略的LbL构建体：（1）释放血管内皮生长因子（VEGF），随后释放血小板衍生生长因子（PDGF）以促进血管生成和上皮再生，和（2）持续释放CX 3CL 1以将治疗性细胞募集到伤口床。体外表征将用于优化敷料的细胞因子负载、释放特征和生物活性。以下 敷料开发，目标2将检查时间调节的细胞因子递送促进糖尿病小鼠模型中伤口愈合的能力。总的来说，这些目标将揭示通过协调细胞因子递送产生的协同信号传导促进慢性伤口愈合的能力的新见解。这项工作随后将为开发治疗慢性伤口患者的新临床策略奠定基础。

DESCRIPTION (provided by applicant): Chronic wounds disproportionately affect diabetic individuals compared to the general population. One in four diabetic individuals are predicted to develop a chronic wound during their lifetime, with a recurrence rate close to 70%. Many chronic wounds progress in severity, with 12% of recurrent chronic wounds resulting in amputation. While growth factor therapy has demonstrated a limited ability to promote wound healing, the current therapeutic modalities do not accurately recreate the natural wound healing process. The objective of this project is to develop new therapeutic wound dressings that more accurately recreate the natural wound healing dynamics seen in vivo. The central hypothesis of this proposal is that layer-by-layer (LbL) technology can be used to create stratified electrostatic assemblies that temporally modulate local cytokine levels in chronic wounds and stimulate the healing process. To test this hypothesis, Aim 1 will develop 'affinity polymers' that specifically bind cytokines to enable tuning of the temporal release profile. LbL constructs will be subsequently fabricated that possess two different therapeutic strategies: (1) the release of vascular endothelial growth factor (VEGF) followed by the release of platelet derived growth factor (PDGF) to promote angiogenesis and reepithelialization, and (2) the sustained release of CX3CL1 to recruit therapeutic cells to the wound bed. In vitro characterization will be used to optimize the cytokine loading, release profile, and biological activity of the dressings. Following dressing development, Aim 2 will examine the ability of temporally modulated cytokine delivery to promote wound healing in a diabetic mouse model. Collectively, these aims will uncover new insights into the ability to promote chronic wound healing via the synergistic signaling that arise from coordinated cytokine delivery. This work will subsequently lay the foundation for developing a new clinical strategy for treating patients suffering from chronic wounds.