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.

抽象的严重烧伤的治疗依赖于自体皮肤移植，但由于供体部位的限制而受到限制不可用和严重的合并症。目前的疗法无法消除实质性治愈严重烧伤的缺陷，突显了迫切需要更有效的治疗方法。我们的长期目标是开发更好的治疗严重烧伤的方法。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）是天然血管化单位和丰富的间充质干细胞、内皮细胞、血管周围细胞和脂肪细胞来源，对于重建烧伤至关重要破坏了皮肤。 MVF 为 MSC 提供了更好的利基，最大限度地提高了 MSC 的再生能力。 MVF 还很容易从通过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、存活和生长因子产生的介质 (ReLiMs)，以及促进组织再生。 ReLiM1 恢复受损的血管化和愈合。然而，ReLiM 有伤口中的半衰期较短，限制了其治愈烧伤和间充质干细胞功能化的效用。为了解决这个问题为了解决这一问题，我们开发了一种水凝胶，可以维持烧伤创面中的 ReLiM 水平。 ReLiM 发布时间为由可生物降解、无毒的氨基酸基聚（酯酰胺）蛋白质模拟物的水凝胶维持聚合物（AA-PEA）。缓释 ReLiM 与 AA-PEA-水凝胶 (Agel) 基质的整合加速愈合并促进 MSC/MVF 功能。我们假设持续释放 ReLiMs 结合Agel支架直接促进严重烧伤愈合并保护和引导MVF 再生功能。我们的目标是开发 ReLiM 浸渍的 Agels，以提供 ReLiM 并提供用于治疗严重烧伤并保护和引导 MVF 再生功能以实现更好愈合的支架以及破译发生这种情况的机制。目标 1. 我们将开发 Agel 以 1A) 维持 ReLiM 释放和 1B) 为皮肤细胞归巢提供最佳的 ReLiM 释放仿生基质，血管化和上皮再生，以及减少疤痕和增加伤口破裂力量。目标 2. 2A）我们将开发一种整合未培养的自体 MVF 的构建体，持续释放 ReLiMs 和 Agel 支架，最大限度地促进深度烧伤的愈合。我们预测所达到的构造保护和引导 MVF 功能。我们将在体外使用人类 MVF 验证结果，以便更好地翻译价值。 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) 一种 ReLiM-Agel 敷料，可提供 ReLiM 并提供基质和覆盖物高效愈合，2) 携带 ReLiM 和 MVF 的 Agel 基质，可保护和引导未培养的 MVF 以实现更多功能有效的治疗，以及 3) 潜在的机械知识。这些再生脂质介质功能化敷料不存在或极少的移植供体需求是有希望的辅助治疗克服目前用于治疗严重烧伤的移植方法或皮肤替代品的缺点。