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3-400万人需要治疗创伤性伤害，静脉溃疡，和压疮。当前的解决方案，包括自体皮肤移植物和生物工程的皮肤替代品，具有由于无法克服关键局限性，包括长时间的血运重建，其成功有限速率，组织向内生长受损和伤口部位的延迟再上皮化。因此，仍然有一个开发含有血管网络以促进快速的可植入的皮肤支架的巨大未满足的需求血管化，下调炎症并最大化功能性皮肤再生。我们的实验室开发了一种新型的脱细胞叶片衍生的血管支架（LEAVS），并具有现有的层次网络保持专利和灌注的分支，灌注通道的。这些生物相容性的脚手架可以是功能化以支持具有特征性鹅卵石的角质形成细胞连续层的生长形态和进行性上皮分层以及成纤维细胞的附着和增殖。从这些观察结果，我们假设可以对LEAV进行设计以提高移植的速率新生血管形成并提高促增再生内皮，皮肤和上皮组织的速度在全厚的伤口模型中形成。为了系统地检验我们的假设，我们提出以下具体目的：在我们的第一个目的中，我们将使LEAV功能化，并确定最大化的表面化学成分 LEAV中的内皮化和血管萌芽。然后，我们将研究LEAVS内皮化最大化脚手架上上皮化和新肤色形成速率的策略。在我们的第二个目标中，我们将通过通过有选择地从LEAV中去除血管外元素。部分消化的脚手架将与中性粒细胞和巨噬细胞评估最小化炎症反应的LEAVS降解策略。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调节功能性血管化皮肤组织的再生在一个全厚的厚度中小动物模型。我们预计这项研究的结果将提供第一个证明的体内数据该功能化的LEAV提高了治疗功能性皮肤再生的速度和疤痕减少的速度皮肤损伤。我们的创新方法描述了创建组织工程皮肤替代品的首次努力基于官能化的叶子支架（LEAVS）。这项研究的发现将使未来开发可植入的植物衍生支架，以促进损伤皮肤组织的快速再生为了治疗创伤性伤口，静脉溃疡和压疮的新标准。