Inspired by Nature: Hydrogels as Versatile Tools for Vascular Engineering

Abstract

Diseases related to vascular malfunction, hyper-vascularization, or lack of vascularization are among the leading causes of morbidity and mortality. Engineered, vascularized tissues as well as angiogenic growth factor-releasing hydrogels could replace defective tissues. Further, treatments and testing of novel vascular therapeutics will benefit significantly from models that allow for the study of vascularized tissues under physiological relevant conditions. Inspired by fibrin, the provisional matrix during wound healing, naturally derived and synthetic hydrogel scaffolds have been developed for vascular engineering. Today, engineers and biologists use commercially available hydrogels to pre-vascularize tissues, to control the delivery of angiogenic growth factors, and to establish vascular diseases models. For clinical translation, pre-vascularized tissue constructs must be sufficiently large and stable to substitute function-relevant tissue defects and integrate with host vascular perfusion. Moreover, the continuous integration of knowhow from basic vascular biology with innovative, tailorable materials and advanced manufacturing technologies is key to achieving near-physiological tissue models and new treatments to control vascularization. For transplantation, engineered tissues must comprise hierarchically organized vascular trees of different caliber and function. The development of novel vascularization-promoting or -inhibiting therapeutics will benefit from physiologically relevant vessel models. In addition, tissue models representing treatment-relevant vascular tissue functions will increase the capacity to screen for therapeutic compounds and will significantly reduce the need for animals for their validation.

Assessing the ability of human endothelial cells derived from induced‐pluripotent stem cells to form functional microvasculature in vivo

“…Fibrin was selected as the material for implantation because it is a naturally occurring biopolymer that promotes wound healing and neovascularization (Christman et al, 2004) and is Food and Drug Administration cleared for some uses in humans (Ceccarelli & Putnam, 2014). In addition, fibrin was selected for these studies due to its track record of supporting neovascularization in vivo (Blache & Ehrbar, 2018;Ceccarelli & Putnam, 2014;Christman et al, 2004). and to match our prior in vitro study in which we evaluated the potential of iPSC-ECs relative to HUVECs (Bezenah et al, 2018).…”

Bioprinting of high cell‐density constructs leads to controlled lumen formation with self‐assembly of endothelial cells

“…For prospective in vivo applications, artificial, randomly selfassembled EC networks in hydrogels have been successfully produced within implants and showed host angiogenesis and anastomosis in previously published studies (Alajati et al, 2008;Blache & Ehrbar, 2018;Cheng et al, 2011;Koob et al, 2011). One limitation of these approaches was the lack of spatial control, to orientate such a neovascular network within the implant.…”

In vitro 3D Systems to Model Tumor Angiogenesis and Interactions With Stromal Cells

“…These PEG hydrogels support capillary network formation in vitro. Indeed, in several studies, co-culture of EC and mesenchymal cells leads to formation of capillaries displaying lumens, BM deposition (laminin and collagen IV), and perivascular localization of mesenchymal cells (Blache et al, 2016;Blache and Ehrbar, 2017). These vessels recapitulate many features of angiogenesis in vitro and are similar to those formed in natural hydrogels.…”

“…Collagen hydrogels provide bioactive microenvironments supporting cellular processes, such as cell adhesion sites, proteolytic-degradable sites, and ECM crosslinking (Laib et al, 2009). Several in vitro studies have demonstrated that collagen hydrogels support capillary network formation using 3D vasculogenesis or EC spheroid assays (Heiss et al, 2015;Blache and Ehrbar, 2017). Collagen I also supports invasion and growth of numerous tumor cell lines (Jeong et al, 2016).…”

“…Collagen I, the major protein of the interstitial ECM ( Blache and Ehrbar, 2017 ), is a biocompatible and biodegradable material that possesses the intrinsic capacity to self-assemble into hydrogels under physiological conditions ( Sorushanova et al, 2019 ). Collagen gels can also be produced using multiple cross-linking methods resulting in fibrous architectures similar to those of native ECM.…”