Therapeutic neovascularization promoted by injectable hydrogels

Abstract

The aim of therapeutic neovascularization is to repair ischemic tissues via formation of new blood vessels by delivery of angiogenic growth factors, stem cells or expansion of pre-existing cells. For efficient neovascularization, controlled release of growth factors is particularly necessary since bolus injection of molecules generally lead to a poor outcome due to inadequate retention within the injured site. In this regard, injectable hydrogels, made of natural, synthetic or hybrid biomaterials, have become a promising solution for efficient delivery of angiogenic factors or stem and progenitor cells for in situ tissue repair, regeneration and neovascularization. This review article will broadly discuss the state-of-the-art in the development of injectable hydrogels from natural and synthetic precursors, and their applications in ischemic tissue repair and wound healing. We will cover a wide range of in vitro and in vivo studies in testing the functionalities of the engineered injectable hydrogels in promoting tissue repair and neovascularization. We will also discuss some of the injectable hydrogels that exhibit self-healing properties by promoting neovascularization without the presence of angiogenic factors.

Keywords: Angiogenic factors; Cell-therapy; Injectable hydrogels; Neovascularization; Tissue regeneration.

Graphical abstract

Fig. 1

(i-iv) Chemical structure of natural polymers being used as injectable hydrogel scaffold. (v) Representative H&E stained histological images of the vascularization for the different groups of injected chitosan hydrogel using rat model on day 4, 8, and 14 post-injection. (vi) Quantification of capillary number for different injection groups on Day 4, 8 and 14. (Adapted with permission from Elsevier [Biomaterials] copyright (2004)[35]. (vii) Representative H&E stained histological images of skin and subcutaneous tissue after 14 days of surgery with different groups of implantation. (vii) Neovascularization index after day 14 of the surgery. (Adapted with permission from Elsevier [Biomaterials] copyright (2005) [51].

Fig. 2

(i-ii) Chemical structures of synthetic polymers being used as injectable hydrogel scaffold. (iv) Angiogenic effects due to the release of bFGF from pH-responsive p (NIPAAm-co-PAA-co-BA) hydrogel. Representative images of the histological sections of the tissues with rat endothelial cell antigen-1 (RECA-1) staining (a-d) and smooth muscle α-actin (α-SMA) staining (f-i). Quantification of capillary density by RECA-1 (v) and arteriolar density by α-SMA (vi) staining. (Adapted with permission from Elsevier [Biomaterials] copyright (2011)[89]. (vii) Schematic representation of proposed mechanism of wound healing using nanofibrous SLanc hydrogels (A-D). (Adapted with permission from ACS Publications [ACS Nano] copyright (2015) [101].