Nanoscale Strategies: Treatment for Peripheral Vascular Disease and Critical Limb Ischemia

Abstract

Peripheral vascular disease (PVD) is one of the most prevalent vascular diseases in the U.S. afflicting an estimated 8 million people. Obstruction of peripheral arteries leads to insufficient nutrients and oxygen supply to extremities, which, if not treated properly, can potentially give rise to a severe condition called critical limb ischemia (CLI). CLI is associated with extremely high morbidities and mortalities. Conventional treatments such as angioplasty, atherectomy, stent implantation and bypass surgery have achieved some success in treating localized macrovascular disease but are limited by their invasiveness. An emerging alternative is the use of growth factor (delivered as genes or proteins) and cell therapy for PVD treatment. By delivering growth factors or cells to the ischemic tissue, one can stimulate the regeneration of functional vasculature network locally, re-perfuse the ischemic tissue, and thus salvage the limb. Here we review recent advance in nanomaterials, and discuss how their application can improve and facilitate growth factor or cell therapies. Specifically, nanoparticles (NPs) can serve as drug carrier and target to ischemic tissues and achieve localized and sustained release of pro-angiogenic proteins. As nonviral vectors, NPs can greatly enhance the transfection of target cells with pro-angiogenic genes with relatively fewer safety concern. Further, NPs may also be used in combination with cell therapy to enhance cell retention, cell survival and secretion of angiogenic factors. Lastly, nano/micro fibrous vascular grafts can be engineered to better mimic the structure and composition of native vessels, and hopefully overcome many complications/limitations associated with conventional synthetic grafts.

Biomaterials and Nanotherapeutics for Enhancing Skin Wound Healing

“…This was tested in a diabetic mouse model and showed improved diabetic wound healing (Das et al, 2016a,c) and enhanced ischemic revascularization (Jang et al, 2012; Das et al, 2014, 2016b; Monteforte et al, 2016)(Figure 5). There are various other lipid NPs, which have shown promise for treating peripheral vascular disease and critical limb ischemia, reviewed elsewhere (Tu et al, 2015). Solid lipid nanoparticles (SLN) are a new pharmaceutical delivery system with a solid lipid core stabilized by surfactants, which can solubilize lipophilic molecules.…”

Multifunctional Transmembrane Protein Ligands for Cell-Specific Targeting of Plasma Membrane-Derived Vesicles

“…Creating PMVs that target eGFP‐tagged receptors provides an opportunity to evaluate the absolute specificity of PMVs for target cells, since cells lack endogenous eGFP expression. Further, the ability to target PMVs to cells that express eGFP‐tagged receptors could be useful for molecular delivery to engineered cell lines in complex contexts such as engineered tissues and cell implantation studies, where engineered cells are surrounded by other cell types …”

Current Phase II drugs under investigation for the treatment of limb ischemia

“…Future perspectives include currently, promising adipose-derived MSCs therapy (Table 1) and another emerging field of research in CLI, nanomedicine (e.g., medical application of nanotechnologies). Versatility of nanoparticles and nanofibers could further facilitate targeted delivery of growth factors and stem cells within the ulcerative tissue with nano-facilitated cell therapy and nano-scale gene delivery [64]. Moreover, combined therapies using revascularization procedures which improve macrocirculation and therapeutic angiogenesis involving different stem cells or stem cells and growth factors, which enhance ischemic tissue perfusion in the microcirculatory level, could further improve limb salvage [65].…”