In Situ Skin Regeneration and Angiogenesis for Full-Thickness Burns

全层烧伤的原位皮肤再生和血管生成

• 批准号: 10587297
• 负责人: Mahmood Khan
• 金额: $ 65.8万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587297
• 关键词: Adhesions; Allogenic; Animal Model; Area; Autologous; Autologous Transplantation; Biopolymers; Burn injury; Cell Adhesion; Cell Survival; Cells; Chemicals; Cicatrix; Collagen; Collagen Type I; Data; Dermal; Dermis; Development; Emerging Technologies; Engineered skin; Engraftment; Environment; Epidermal Ridges; Epidermis; Epithelium; Family suidae; Goals; Growth Factor; In Situ; Infection prevention; Lasers; Length; Length of Stay; Life; Liquid substance; Mechanics; Modeling; Myofibroblast; Natural regeneration; Nutrient; Oxygen; PDGFA gene; Patients; Pattern; Perfusion; Platelet-Derived Growth Factor; Predisposition; Procedures; Proliferating; Publications; Quality of life; Regenerative Medicine; Risk Reduction; Role; Sepsis; Silk; Skin; Skin graft; Speed; Surface; Technology; Testing; Thick; Tissue Donors; VEGFA gene; Vascular Endothelial Growth Factors; Vascularization; Width; angiogenesis; burn model; burn wound; design; functional improvement; improved; improved outcome; in vivo; infection risk; keratinocyte; manufacture; mortality; mouse model; nanoparticle; new technology; novel; paracrine; platelet-derived growth factor BB; porcine model; regenerative; release factor; scaffold; second degree burn; skin regeneration; stemness; survival outcome; third degree burn; tongue papilla; wound; wound closure; wound healing

Prompt closure of wounds is critical to prevention of infection and sepsis in patients suffering massive burn injuries. The most common challenge associated with treating these patients is the lack of available donor skin. Although new technologies are emerging to treat deep partial thickness burns, only one is commercially available for the treatment of full-thickness burns (cultured epithelial autografts, CEAs). CEAs are a life-saving treatment option; however, they are extremely fragile, prone to damage and require > 3 weeks to manufacture. As early wound closure reduces the risk of infection, fluid loss, mortality and scarring, strategies to quickly and permanently close full-thickness wounds are needed to increase survival and improve outcomes. The current obstacles to rapid in situ regeneration of full-thickness wounds using cell sprays include the lack of viable dermis, low engraftment efficiency and variable survivability of spray-on cells. Our team recently developed allogeneic dermal substitutes with laser ablative dermal papillae that significantly enhanced keratinocyte proliferation. This regenerative platform, consisting of freshly isolated autologous cell sprays and an off-the-shelf, allogeneic dermal template with laser micropatterned dermal papillae and growth factor loaded rapid release nanoparticles, is proposed to facilitate rapid, permanent wound closure via enhanced adhesion and survival of spray-on skin cells and rapid angiogenesis. In Aim 1, spray-on skin cell engraftment and survivability will be examined as a function of the form of the laser micropatterned dermal papillae (width, length, angle). Aim 2 seeks to further enhance spray-on skin cell survivability and epidermal regeneration via enhanced angiogenesis. The role of vascular endothelial growth factor (VEGF)/ platelet-derived growth factor (PDGF)-releasing, high surface area to volume polydopamine (PDA) nanoparticles on the rate and extent of angiogenesis and downstream epidermal regeneration will be assessed in a mouse model followed by a highly translational porcine model. In Aim 3, gradient collagen-silk scaffolds will be fabricated to reduce contraction of the wounds while providing a physical and chemical environment that promotes epidermal regeneration. Finally, the efficacy of the fully optimized laser micropatterned dermal template (dermal papillae form, VEGF/PDGF-PDA loading and concentration and scaffold mechanics) will be examined in a porcine burn model compared to standard autografting and spray-on skin cells alone. The proposed studies leverage the expertise in regenerative medicine, vascularization and large animal models to develop a novel, immediate use technology that can dramatically transform treatment for patients suffering from massive burn injuries and improve outcomes and quality of life.

大面积烧伤后及时缝合创面是预防感染和脓毒症的关键 受伤与治疗这些患者相关的最常见挑战是缺乏可用的供体皮肤。 虽然治疗深二度烧伤的新技术不断出现，但只有一种技术是商业上可利用的 用于治疗全层烧伤（培养的上皮自体移植物，CEA）。CEA是一种挽救生命的治疗方法 但是，它们非常脆弱，容易损坏，并且需要> 3周的制造时间。早 伤口闭合降低了感染、体液流失、死亡率和瘢痕形成的风险， 需要永久闭合全层伤口以增加存活率和改善结果。当前 使用细胞喷雾的全层伤口的快速原位再生的障碍包括缺乏有活力的真皮， 移植效率低和喷雾细胞的存活率可变。我们的团队最近开发了同种异体 具有激光消融性真皮乳头的真皮替代物显著增强角质形成细胞增殖。这 再生平台，包括新鲜分离的自体细胞喷雾和现成的同种异体真皮 具有激光微图案化真皮乳头和加载生长因子的快速释放纳米颗粒的模板， 建议通过增强喷涂皮肤细胞的粘附和存活来促进快速、永久的伤口闭合 和快速血管生成。在目标1中，将检查喷雾皮肤细胞植入和存活性作为功能 激光微图案化真皮乳头的形式（宽度、长度、角度）。目标2旨在进一步加强 喷雾皮肤细胞存活性和通过增强的血管生成的表皮再生。血管的作用 内皮生长因子（VEGF）/血小板衍生生长因子（PDGF）-释放，高表面积体积比 聚多巴胺（PDA）纳米颗粒对血管生成和下游表皮细胞增殖的速率和程度的影响 将在小鼠模型中评估再生，随后是高度转化的猪模型。在目标3中， 将制造梯度胶原-丝支架以减少伤口的收缩，同时提供物理的 和促进表皮再生的化学环境。最后，充分优化的激光器的功效 微图案化的真皮模板（真皮乳头形式，VEGF/PDGF-PDA负载和浓度， 支架力学）将在猪烧伤模型中与标准自体移植和喷涂进行比较 单独的皮肤细胞。拟议的研究利用再生医学，血管化和大型 动物模型开发一种新的，立即使用的技术，可以显着改变治疗， 患者遭受大面积烧伤，并改善结果和生活质量。