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

• 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
• 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

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300万至400万人需要治疗创伤性损伤、静脉溃疡， 和褥疮目前的解决方案，包括自体皮肤移植和生物工程皮肤替代品， 由于无法克服包括延长血运重建在内的关键限制， 速率，受损的组织向内生长和延迟的伤口部位的上皮再生。因此，仍然有一个 开发含有血管网络的可植入真皮支架以促进快速生长的显著未满足的需求 血管化，下调炎症和最大化功能性皮肤再生。本实验室 开发了一种新的脱细胞叶衍生血管支架（LeaVS），具有预先存在的分层网络 分支的、可灌注的通道保持开放和可灌注。这些生物相容性支架可以是 功能化以支持具有特征性鹅卵石的角质形成细胞的邻接层的生长 形态学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可以被工程化以提高移植率， 促进血管新生，提高内皮、真皮和上皮组织的促再生率 在全厚度伤口模型中形成。为了系统地检验我们的假设，我们提出以下建议 具体目标： 在我们的第一个目标中，我们将功能化LeaVS，我们将确定表面化学， LeaVS内的内皮化和血管出芽。然后，我们将研究LeaVS内皮化 该策略最大化支架上的上皮形成和新皮肤形成的速率。 在我们的第二个目标中，我们将通过以下方式调节脱细胞叶片支架的炎症反应： 选择性地从LeaVS中移除血管外成分。部分消化的支架将与 嗜中性粒细胞和巨噬细胞，以评估使炎症反应最小化的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。 调节对最大程度地再生全层伤口中的功能性血管化皮肤组织的作用 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 功能化的LeaVS提高了治疗的功能性皮肤再生和疤痕减少的速度， 皮肤损伤。 我们的创新方法描述了第一次努力创造一个组织工程皮肤替代品， 功能化叶基血管支架（LeaVS）。这项研究的结果将使未来 开发可植入的植物衍生支架，以促进受损皮肤组织的快速再生， 从而为创伤性伤口、静脉溃疡和压疮的治疗提供新的护理标准。