Building vascular networks

Abstract

Only a few engineered tissues-skin, cartilage, bladder-have achieved clinical success, and biomaterials designed to replace more complex organs are still far from commercial availability. This gap exists in part because biomaterials lack a vascular network to transfer the oxygen and nutrients necessary for survival and integration after transplantation. Thus, generation of a functional vasculature is essential to the clinical success of engineered tissue constructs and remains a key challenge for regenerative medicine. In this Perspective, we discuss recent advances in vascularization of biomaterials through the use of biochemical modification, exogenous cells, or microengineering technology.

Fig. 1. Vasculogenesis and angiogenesis

Two distinct mechanisms of blood vessel formation. Vasculogenesis gives rise to the primitive vascular plexus during embryogenesis. Stimulated by tumors and hypoxic conditions, angiogenesis remodels and expands the vascular network.

Fig. 2. Cue gardens

Biochemical cues can be integrated in hydrogels to induce vascularization. (A) Biomimetic hydrogels with platelet-derived growth factor (PDGF), immobilized RGDs, and poly(ethylene glycol) (PEG)-ephrinA1 (top panel) showed more robust response than hydrogels with PDGF only (lower panel) when implanted into the mouse cornea micropocket. [Reprinted from (18) with permission from the American Chemical Society] (B) Microcomputed tomography (micro-CT) image of a porous poly(L/DL-Lactide) (PLDL) copolymer filled with growth factor–treated, RGD-alginate hydrogel several weeks after implantation in a rat 8-mm segmental defect model; formation of vascular network is shown (32). [Reprinted from (32) with permission from Elsevier] (C) Formation of endothelial colony–forming cell (ECFC)—lined lumens within a gelatin methacrylate (GelMA) hydrogel that contains both ECFCs (DsRed) and mesenchymal stem cells (MSCs) (7 days after seeding the hydrogel with cells). ECFC-lined lumens were surrounded by MSC-derived pericyte cells that expressed α-smooth muscle actin (α-SMA) (yellow arrow). [Reprinted from (31) with permission from Wiley-VCH Verlag] (D) ECFC- and MSC-containing GelMA hydrogel implants were retrieved from the subcutaneous tissue of the dorsum of 6-week old nude mice 7 days after implantation; functional vascular network formation in vivo is shown. Top panel, image of hematoxylin and eosin (H&E)–stained GelMA explants. Numerous blood vessels containing murine red blood cells are shown (yellow arrowheads). The dark purple spots indicate nuclei of cells, and shades of light purple in the background indicate GelMA hydrogel. The inset shows the macroscopic view of the GelMA explant; middle panel, immunohistochemistry shows human cluster of differentiation 31 (CD31)–positive engineered microvessels; bottom panel, single human CD31–positive microvessel at higher magnification carrying murine erythrocytes (star). [Reproduced from (31) with permission from Wiley-VCH Verlag] (E) A microfluidic hydrogel containing microvascular-like structures fabricated using self-assembled monolayer (SAM)–based cell transfer. Left panel, double-layer construct generated using 3T3 cells (red) encircling a human umbilical–vein endothelial cell (HUVEC) (green) monolayer; middle panel, confocal cross-sectional image of the vascular construct; right panel, merged confocal image of the construct. Inset shows the entire channel section. [Reproduced from (34) with permission from Elsevier]