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.

Keywords: cell therapy; critical limb ischemia; gene delivery; growth factor; nanomaterials; nanomedicine; nanoparticles; peripheral vascular disease; stem cells; therapeutic angiogenesis; tissue engineering; vascular graft.

Figure 1

Schematic illustration of nanoscale strategies in the treatment of peripheral vascular disease or critical limb ischemia.

Figure 2

PEGylated Cy5.5-labeled silica nanoparticles (Cy-SiNPs) preferentially accumulated in ischemic tissue upon intravenous injection in mouse, as evidenced by fluorescent imaging on the front side (a) and the opposite side (b) of limb tissue as well as the fluorescent images of cryosectioned tissue (c), where NPs were red and nuclei were stained blue. Notably, same targeting effects were not observed with bare NPs. Reprinted with permission from ref . Copyright 2011 American Chemical Society.

Figure 3

Graphene oxide nanoparticles (GO) loaded with VEGF by physical adsorption and conjugated to IR800, a commonly used near-infrared fluorescent dye, for VEGF delivery and imaging. (a) Schematic structure of IR800-VEGF-GO; (b) atomic force microscopy (AFM) images and (c) the height profile of IR800-GO (without VEGF); (d) absorption and (e) emission spectrum of various GO NPs. In vitro tube formation assay with (f) GO-IR800, (g) free VEGF, and (h) GO-IR800-VEGF, using human umbilical vascular endothelial cells (HUVECs). Reprinted from ref with permission. Copyright 2013 Royal Society of Chemistry.

Figure 4

(A) Schematic diagram of syndecan-4 and FGF-2 co-delivery using liposomes into ischemic tissue for effective revascularization. (B) Laser Doppler images of the rat ischemic hind limbs 14 days after induction of ischemia through femoral artery ligation. The quantification of blood flow at days 0, 7, and 14 are shown below. *Statistically different from all other groups (P < 0.05). (C) Quantification of large vessel number per field of view. Quantification of capillary number per field of view. *Statistically different from FGF group (P < 0.05). **Statistically different from all other groups (P < 0.05). Reprinted from ref with permission. Copyright 2012 National Academy of Sciences of the United States of America.

Figure 5

Small diameter (2.2 mm) vascular graft with coaxial-electrospun double-layered membrane encapsulating VEGF/PDGF on the inner/outer layer respectively to enhance the growth of vascular endothelial cells (vECs) and vascular smooth muscle cells (vSMCs). SEM images of the vascular graft (A) and the cross section of the nanofibrous membrane (B). Reprinted from ref with permission. Copyright 2013 Elsevier Ltd.