Leaf-Derived Vascular Scaffolds (LeaVS): A multifunctional platform for skin regeneration

叶源血管支架（LeaVS）：皮肤再生的多功能平台

基本信息

批准号：
10579706
负责人：
GEORGE D. PINS
金额：
$ 44.79万
依托单位：
WORCESTER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579706
关键词：
3-Dimensional Acute Allografting American Animal Model Animal Sources Anti-Inflammatory Agents Autologous Autologous Transplantation Biomedical Engineering Blood Vessels Burn injury Cells Cellulose Cessation of life Characteristics Chemistry Cicatrix Clinical Data Dermal Development Elements Endothelium Engineered skin Engineering Epithelium Excision Fibrin Fibroblasts Fibrosis Functional Regeneration Future Graft Survival Growth Healthcare Hospitalization Human Immunofluorescence Immunologic Immunohistochemistry Impairment Implant In Vitro Inflammation Inflammatory Inflammatory Response Injury Laboratories Legal patent Macrophage Mechanics Modeling Morphology Natural regeneration Operative Surgical Procedures Outcome Patients Persons Phenotype Plant Leaves Plants Proliferating Protocols documentation Publishing Role Side Site Skin Skin Substitutes Skin Tissue Skin graft Skin injury Stratified Epithelium Surface Testing Thick Time Tissue Engineering Tissue constructs Tissues Traumatic injury United States Varicose Ulcer Vascular Endothelial Cell Vascular Plant Vascularization Venous Pressure level Visualization Wound models Xenograft procedure analog biocompatible scaffold burn therapy chemokine chronic wound decubitus ulcer design epithelial wound improved in vitro regeneration in vivo in vivo Model inflammatory modulation innovation keratinocyte loss of function mechanical properties mouse model neovascularization neutrophil novel preservation regenerative scaffold skin barrier skin damage skin regeneration standard of care success third degree burn tissue regeneration traumatic wound vascular bed wound

项目摘要

Each year, 3 - 4 million people in the United States require treatment for traumatic injuries, venous ulcers, and pressure sores. Current solutions, including autologous skin grafts and bioengineered skin substitutes, have shown limited success due to an inability to overcome critical limitations including prolonged revascularization rates, impaired tissue ingrowth and delayed reepithelialization at the wound site. As such, there remains a significant unmet need to develop implantable dermal scaffolds that contain vascular networks to promote rapid vascularization, downregulate inflammation and maximize functional skin regeneration. Our laboratory developed a novel decellularized leaf-derived vascular scaffold (LeaVS) with pre-existing hierarchical networks of branched, perfusable channels that remain patent and perfusable. These biocompatible scaffolds can be functionalized to support growth of a contiguous layers of keratinocytes with characteristic cobblestone morphology and progressive epithelial stratification, as well as fibroblast attachment and proliferation. From these observations, we hypothesize that LeaVS can be engineered to enhance the rate of graft neovascularization and improve the rate of pro-regenerative endothelial, dermal and epithelial tissue formation in a full thickness wound model. To systemically test our hypothesis, we propose the following specific aims: In our first aim, we will functionalize LeaVS and we will determine surface chemistries that maximize endothelialization and vascular budding within LeaVS. Then, we will investigate the LeaVS endothelialization strategy that maximizes the rate of epithelialization and neodermal formation on the scaffolds. In our second aim, we will modulate the inflammatory responses to decellularized leaf scaffolds by selectively removing extravascular elements from the LeaVS. Partially digested scaffolds will be cultured with neutrophils and macrophages to assess the LeaVS degradation strategy that minimizes inflammatory responses. In our final aim, we will determine the synergistic roles of LeaVS vascular network and inflammatory modulation on maximizing the regeneration of functional vascularized skin tissue in a full thickness wound in a small animal model. We anticipate that the results of this study will provide the first in vivo data demonstrating that functionalized LeaVS improve the rate of functional skin regeneration and scar reduction for the treatment of skin injures. Our innovative approach describes the first efforts to create a tissue engineered skin substitute on functionalized leaf-based vascular scaffolds (LeaVS). The findings from this study will enable the future development of an implantable, plant-derived scaffold to facilitate the rapid regeneration of injury skin tissue and to enable to a new standard of care for the treatment of traumatic wounds, venous ulcers and pressure sores.

每年，美国有 3 - 400 万人需要治疗外伤、静脉溃疡、和压疮。目前的解决方案，包括自体皮肤移植和生物工程皮肤替代品，已经由于无法克服包括长期血运重建在内的关键限制，显示的成功有限率、组织向内生长受损以及伤口部位的上皮化延迟。因此，仍然存在一个开发包含血管网络的可植入真皮支架的重大未满足需求，以促进快速血管化、下调炎症并最大限度地提高功能性皮肤再生。我们的实验室开发了一种新型脱细胞叶源性血管支架（LeaVS），具有预先存在的分层网络保持专利和可灌注的分支、可灌注通道。这些生物相容性支架可以功能化以支持具有特征鹅卵石的连续角质形成细胞层的生长形态和进行性上皮分层，以及成纤维细胞附着和增殖。从根据这些观察结果，我们假设 LeaVS 可以被设计来提高移植率新血管形成并提高内皮、真皮和上皮组织的促再生率全层伤口模型中的形成。为了系统地检验我们的假设，我们提出以下建议具体目标：在我们的第一个目标中，我们将对 LeaVS 进行功能化，并且我们将确定能够最大化 LeaVS 内的内皮化和血管出芽。然后，我们将研究 LeaVS 内皮化最大限度地提高支架上上皮化和新真皮形成率的策略。在我们的第二个目标中，我们将通过以下方式调节对脱细胞叶支架的炎症反应：选择性地从 LeaVS 中去除血管外成分。部分消化的支架将用中性粒细胞和巨噬细胞来评估 LeaVS 降解策略，最大限度地减少炎症反应。在我们的最终目标中，我们将确定 LeaVS 血管网络和炎症的协同作用最大限度地调节全层伤口中功能性血管化皮肤组织的再生小动物模型。我们预计这项研究的结果将提供第一个体内数据证明功能化 LeaVS 可提高功能性皮肤再生率并减少治疗中的疤痕的皮肤损伤。我们的创新方法描述了在皮肤上创建组织工程皮肤替代品的首次努力功能化叶基血管支架（LeaVS）。这项研究的结果将使未来开发可植入的植物源支架，以促进损伤皮肤组织的快速再生为治疗创伤性伤口、静脉性溃疡和压疮提供新的护理标准。