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.
