Regenerative Lipid Mediators for the Management of Severe Burn Wounds

用于治疗严重烧伤创面的再生脂质介质

基本信息

批准号：
10576811
负责人：
Song Hong
金额：
$ 45.58万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-20 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576811
关键词：
Acceleration Address Adipocytes Adipose tissue Adjuvant Therapy Amides Amino Acids Animals Autologous Autologous Transplantation Biomimetics Blood Vessels Bone Marrow Burn injury Cells Chronic Cicatrix Clinical Treatment Defect Dermal Endothelial Cells Esters Fatty acid glycerol esters Goals Growth Factor Homing Hour Human Hydrogel Bandage Hydrogels Impairment In Vitro Inflammation Knowledge Longevity Macrophage Mediator Mesenchymal Stem Cells Methods Oxidative Stress Patients Pericytes Phenotype Physiological Polymers Production Proliferating Proteins Regenerative capacity Reporting Role Safety Site Skin Skin Substitutes Skin graft Source Sterile coverings Suction Lipectomy Testing Tissues Treatment Efficacy Vascularization adipose derived stem cell burn therapy burn wound comorbidity cost effective therapy graft function healing hydrogel scaffold immunogenicity improved in vivo innovation insight lipid mediator lipidomics minimally invasive regeneration function regenerative regenerative cell scaffold severe burns stem cell function tissue regeneration tissue repair wound wound healing wound treatment

项目摘要

ABSTRACT The treatment of severe burns relies on autologous skin grafts, which are limited due to donor-site unavailability and substantial comorbidities. Current therapies are unable to eliminate substantial healing defects in severe burns, underscoring the urgent needs of more effective therapies. Our long-term goals are to develop better therapies for severe burns. Mesenchymal stem cells (MSCs) possess regenerative power for burn wounds. Adipose-tissue derived microvascular fragments (MVFs) are native vascularization units and a rich source of the MSCs, endothelial cells, perivascular cells, and adipocytes essential in rebuilding burn- destroyed skin. MVFs provide a better niche for MSCs, maximizing MSC regenerative power. MVFs are also easily isolated from fat tissue collected via minimally invasive liposuction. We have identified regenerative lipid mediators (ReLiMs) that increase MSC or MVF proliferation, survival, and production of growth factors, and promote tissue regeneration. ReLiM1 restored impaired vascularization and healing. However, ReLiMs have short half-lives in wounds, limiting their utility for healing burns and functionalizing MSCs. To address this problem, we developed a hydrogel that can sustain ReLiM levels in burn wounds. ReLiM release was sustained from the hydrogel of biodegradable, non-toxic amino acid-based poly(ester amide) protein-mimic polymers (AA-PEAs). The integration of a sustained-release ReLiM with an AA-PEA-hydrogel (Agel) matrix accelerated healing and promoted MSC/MVF functions. We hypothesize that sustained release ReLiMs combined with Agel scaffolds directly promote healing of severe burns and protect and guide MVF regenerative functions. Our objective is to develop ReLiM-impregnated Agels that deliver ReLiMs and provide scaffolds for healing severe burns and protecting and guiding MVF regenerative functions for better healing as well as to decipher the mechanisms via which this occurs. Aim 1. We will develop the Agel to 1A) sustain ReLiM release and to 1B) provide an optimal ReLiM-releasing biomimetic matrix for skin cell homing, vascularization, and re-epithelization, as well as for the reduction of scarring and increasing wound breaking strength. Aim 2. 2A) We will develop a construct that integrates uncultured autologous MVFs, sustained release ReLiMs, and Agel scaffolds to maximize the healing of deep burns. We predict that the achieved construct protects and guides MVF functions. We will verify results using human MVFs in vitro for better translational value. 2B) We will decipher mechanisms for efficacy of the best MVF-ReLiM-Agel. Impact: This project will provide 1) a ReLiM-Agel dressing that delivers ReLiMs and provides a matrix and covering for efficient healing, 2) a ReLiM- and MVF-carrying Agel matrix that protects and guides uncultured MVFs for more efficient healing, and 3) the underlying mechanistic knowledge. These regenerative lipid mediator functionalized dressings with nonexistent or minimal graft-donor requirements are promising adjuvant therapy to overcome the drawbacks of grafting methods or skin substitutes currently used to treat severe burns.

抽象的严重燃烧的处理取决于自体皮肤移植物，由于供体部位而受到限制不可用和大量合并症。当前的疗法无法消除大量康复严重燃烧的缺陷，强调了更有效疗法的紧急需求。我们的长期目标是为严重燃烧开发更好的疗法。间充质干细胞（MSC）具有再生能力烧伤伤口。脂肪组织衍生的微血管碎片（MVF）是天然血管化单位，A MSC，内皮细胞，血管周细胞和脂肪细胞的丰富来源，对重建燃烧至关重要破坏了皮肤。 MVF为MSC提供了更好的利基市场，从而最大程度地提高了MSC再生能力。 MVF也是很容易从微创吸脂术收集的脂肪组织中分离出来。我们已经确定了再生脂质增加MSC或MVF增殖，生存因子的生存和生产，以及促进组织再生。 RELIM1恢复了受损的血管化和愈合。但是，Relims拥有一半在伤口中的半衰期限制了它们愈合燃烧和功能化MSC的效用。解决这个问题问题，我们开发了一种可以在烧伤伤口中维持的水凝胶。 Relim释放是从可生物降解的无毒氨基酸（酯酰胺）蛋白模拟的水凝胶中持续聚合物（AA-PEAS）。与AA-PEA-HYDREGEL（AGEL）矩阵的持续释放相关性的整合加速愈合并促进了MSC/MVF功能。我们假设持续的释放依据结合艾格尔支架直接促进严重燃烧的愈合，并保护和引导MVF 再生功能。我们的目的是开发浸渍的脂肪，以提供依据并提供治愈严重燃烧，保护和指导MVF再生功能的脚手架，以更好地治愈以及破译发生的机制。目标1。我们将将agel开发为1a） Relim释放，至1B）为皮肤细胞寄养提供了最佳的释放仿生基质，血管化和重新上述以及减少疤痕和增加的伤口破裂力量。目标2。2a）我们将开发一种整合未培养的自体MVF的结构释放Relim和Agel脚手架，以最大程度地恢复深烧伤。我们预测所取得的成就构造保护和指导MVF功能。我们将在体外使用人类MVF验证结果，以更好地翻译价值。 2b）我们将破译最佳MVF-Relim-Agel功效的机制。影响：这个项目将提供1）提供依赖并提供矩阵和覆盖的依赖味有效的愈合，2）一个相关和MVF携带的agel矩阵，可保护和指导未经文化的MVF以获取更多信息有效的愈合，3）基本的机械知识。这些再生脂质介质具有不存在或最少的移植物要求的功能化调味料是有希望的辅助治疗为了克服目前用于治疗严重燃烧的嫁接方法或皮肤替代品的缺点。