Therapeutic strategies for enhancing angiogenesis in wound healing

Abstract

The enhancement of wound healing has been a goal of medical practitioners for thousands of years. The development of chronic, non-healing wounds is a persistent medical problem that drives patient morbidity and increases healthcare costs. A key aspect of many non-healing wounds is the reduced presence of vessel growth through the process of angiogenesis. This review surveys the creation of new treatments for healing cutaneous wounds through therapeutic angiogenesis. In particular, we discuss the challenges and advancement that have been made in delivering biologic, pharmaceutical and cell-based therapies as enhancers of wound vascularity and healing.

Keywords: Angiogenesis; Cell-based therapies; Chronic wounds; Diabetic ulcers; Growth factor therapy; Neovascularization; Non-healing wounds; Stem cell therapy; Wound healing.

Figure 1.

Summary diagram of the cellular and molecular components of wound healing and wound angiogenesis (created using BioRender and Adobe Illustrator).

Figure 2.

Wound angiogenesis enhancement by syndecan-4 proteoliposomes. (A) von-Willebrand Factor (vWF) staining in the wound bed. Bar = 250 um. (B) Quantification of the small and (C) large vessels in the wound bed. (D) PECAM-1 fluorescence immunostaining for (red), αSMA (green) and nuclei (blue). Bar = 50 um. (E) Quantification of PECAM-1⁺/β-SMA⁺ vessels in the wound beds. *p < 0.05 versus control group. ^†p < 0.05 versus control and S4PL groups (p < 0.05). Used with permission from [71].

Figure 3.

(A) Expression of miR-92a in healthy and diabetic mice, and in acute and chronic human wounds. (B) Percent wound closure over time in full thickness excisional wound model. (C) Photographs of wound area over time for each treatment group. (D) Distance between epithelial tips as a measure of re-epithelialization. (E) Amount of granulated tissue, measured as an area. (F) Distance between the ends of the panniculus carnosus. (G). Representative images of hematoxylin and eosin staining, indicating granulation tissue (gt), epithelium (e), and ends of the panniculus carnosus (arrow heads). Used with permission from [328].

Figure 4.

Effects of simvastatin on vascularity and lymphangiogenesis in full-thickness excision skin wound of db/db mice. (A) Neovascularization 14 days post-wounding at the wound margin of simvastatin-treated or vehicle-treated db/db mice. (B) Quantification of percent of vascularity. (C) Lymphangiogenesis 14 days post-wounding at the wound margin of simvastatin-treated or vehicle-treated db/db mice. (D) Quantification of percent of lymphatic vascularity. Green corresponds to LYVE-1-positive, newly formed lymphatic vessels. Blue fluorescence indicates DAPI-labeled nuclei. Scale bar =100 μm. Used with permission from [246].

Figure 5.

Deferoxamine-treated diabetic ulcers exhibit increased neovascularization and improved dermal thickness. (A) Immunohistochemical staining for newly formed capillaries via endothelial cell marker PECAM-1 (red). Scale bar = 10 μm. (B) Quantification of PECAM-1⁺ pixels per high-power field (HPF). (C) Picrosirius red staining used to assess dermal thickness of completely healed diabetic mice ulcers. Scale bar = 10 μm. (D) Quantification of picrosirius red-positive pixels per HPF. Used with permission [271].

Figure 6.

Anti-scar effects of astragaloside IV on rat full-thickness skin excision wounds 30 days after wounding. (A) Masson’s trichrome staining of granulation tissue to assess collagen synthesis and blood vessels formation. Collagen and blood vessels identified by red and green arrows, respectively. (B) Effect on angiogenesis assessed by presence of blood vessels in granulation tissue indicated by black arrows. (C) Sirius red staining to evaluate collagen composition in healed tissue. Type I collagen indicated by white arrow, and type III collagen indicated by pink arrows. Blank control refers to the no treatment group. Used with permission from [272].

Figure 7.

The angiogenic potential of hiPSC-derived and hESC-derived ECs (red) and vSMCs (green) to HUVEC/vSMC controls in a co-culture tube formation assay were compared. Equal numbers of cells across each group were cultured on Matrigel and allowed to form tubules overnight. Multiple EC to vSMC ratios were tested across all groups including 100:0, 60:40 and 40:60. (A) Fluorescent microscopy images of the tube formation assay. (B) Quantification of the tube area for the cells in the tube formation assay. *p < 0.05 versus 100:0 HUVEC group. Scale bar = 100 μm. Used with permission [313].