Wound Repair by Stimulation of Specific Tissue Ingrowth

通过刺激特定组织向内生长来修复伤口

• 批准号: 6815470
• 负责人: WEILIAM CHEN
• 金额: $ 33.44万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815470
• 关键词: angiogenesis; angiogenesis factor; artificial membranes; artificial skin; biomaterial compatibility; biomaterial development /preparation; biomaterial evaluation; cell migration; diabetes mellitus; disease /disorder model; fibronectins; gene therapy; hyaluronate; laboratory mouse; nonhuman therapy evaluation; optical tomography; platelet derived growth factor; skin ulcer; tissue engineering; vascular endothelial growth factors; wound healing

DESCRIPTION (provided by applicant): Diabetes is the 6th leading cause of medically related death in the United States. Development of foot ulcer is one of the most serious complications, affecting up to 3% of the diabetic population each year, with 15% of all diabetic individuals experiencing one episode during their life-time. Most current treatments (e.g., off-weighting, debridement and ischemic reversal) provide only limited benefits. Recombinant human platelet derived growth factor (PDGF-BB) (becaplerrnin 0.01% gel, Regranex TM) has been approved by the FDA for topical use in treating diabetic ulcer. Compared to placebo, the incidence of complete ulcer closure was increased in some clinical trials, but not all. Non-optimal dosing was likely a major contributory factor to the discrepancy observed. We intend to engineer a biodegradable composite bioactive matrix that mimics the initial provisional matrix formed after acute wounds to achieve better healing response for chronic wounds. The initial function of this matrix is not to achieve prolonged release of bioactive agents into the wound site; rather, the therapeutic moieties will largely be confined to the matrix. This system will be constructed from Hyaluronan (HA) and a heparin stabilized cell adhesion molecule Fibronectin (FN), capable of stimulating cell migration, will be integrated into the HA structure. Both HA and FN are the main components of the provisional matrix. Additionally, heparin stabilized Vascular Endothelial Growth Factor (VEGF), with limited diffusion potential, will be incorporated to locally stimulate the endothelial cells to form blood vessels; setting the stage for granulation tissue formation. An integral component of the matrix will contain DNA encoding PDGF intended for delayed release and expression, which helps to promote the formation of robust and mature blood vessels. Migration of cells into the matrix in conjunction with blood vessel growth will precede PDGF gene transfer and subsequent PDGF expression, which will enhance granulation tissue formation. HA is truly biocompatible and does not induce inflammatory and immunogenic responses, and has mechanical properties compatible with soft tissues. Additionally, the HA matrix structure will eventually be integrated into the tissue formed during the healing process. We will first formulate and optimize these bioactive matrices using photocrosslinkable HA. The dosing information will be derived using mouse cremaster muscle models followed by a test of efficacy in diabetic mice full-thickness dermal wound models. We will use a noninvasive optical biopsy technique (Optical Coherence Tomography, OCT) to monitor the recovery of the wounds.

描述（由申请人提供）： 糖尿病是美国医学相关死亡的第六个主要原因。足球溃疡的发展是最严重的并发症之一，每年影响3％的糖尿病人群，其中15％的糖尿病患者在其一生中经历了一集。大多数目前的治疗方法（例如，不重中，清创和缺血性逆转）仅提供有限的收益。 FDA已批准重组人血小板衍生的生长因子（PDGF-BB）（Becaplerrnin 0.01％凝胶，Regranex TM），用于治疗糖尿病性溃疡。与安慰剂相比，在某些临床试验中，完全溃疡的发生率增加了，但不是全部。非最佳剂量可能是观察到差异的主要因素。 我们打算设计一种可生物降解的复合生物活性基质，该基质模仿急性伤口后形成的初始临时基质，以使慢性伤口更好地愈合反应。该基质的初始功能不是要长期释放生物活性剂到伤口部位。相反，治疗部分将在很大程度上仅限于矩阵。该系统将由透明质酸（HA）和能够刺激细胞迁移的肝素稳定细胞粘附分子纤连蛋白（FN）构建，将整合到HA结构中。 HA和FN都是临时矩阵的主要组成部分。此外，将纳入肝素稳定的血管内皮生长因子（VEGF），具有有限的扩散潜力，以局部刺激内皮细胞形成血管。为肉芽组织形成奠定了基础。矩阵的一个组成部分将包含用于延迟释放和表达的DNA编码PDGF，这有助于促进稳健和成熟的血管的形成。细胞与血管生长结合的迁移将在PDGF基因转移和随后的PDGF表达之前迁移，这将增强肉芽组织的形成。 HA确实具有生物相容性，不会诱导炎症和免疫原性，并且具有与软组织兼容的机械性能。另外，HA基质结构最终将集成到愈合过程中形成的组织中。我们将首先使用PhotoCropslinkable HA制定并优化这些生物活性矩阵。剂量信息将使用小鼠Cremaster肌肉模型得出，然后测试糖尿病小鼠全厚性皮肤伤口模型。我们将使用非侵入性光学活检技术（Optical Cooherence层析成像，OCT）来监测伤口的恢复。