Integration of Self‐Assembled Microvascular Networks with Microfabricated PEG‐Based Hydrogels

Abstract

Despite tremendous efforts, tissue engineered constructs are restricted to thin, simple tissues sustained only by diffusion. The most significant barrier in tissue engineering is insufficient vascularization to deliver nutrients and metabolites during development in vitro and to facilitate rapid vascular integration in vivo. Tissue engineered constructs can be greatly improved by developing perfusable microvascular networks in vitro in order to provide transport that mimics native vascular organization and function. Here a microfluidic hydrogel is integrated with a self-assembling pro-vasculogenic co-culture in a strategy to perfuse microvascular networks in vitro. This approach allows for control over microvascular network self-assembly and employs an anastomotic interface for integration of self-assembled micro-vascular networks with fabricated microchannels. As a result, transport within the system shifts from simple diffusion to vessel supported convective transport and extra-vessel diffusion, thus improving overall mass transport properties. This work impacts the development of perfusable prevascularized tissues in vitro and ultimately tissue engineering applications in vivo.

Harnessing developmental processes for vascular engineering and regeneration

“…Various kinds of engineered materials can mimic the ECM in order to support vascular differentiation, morphogenesis and tube formation, with the aim of recapitulating the in vivo microenvironment of vascular formation. The engineered ECM-like scaffold provides a structural framework and is capable of presenting various physiologically relevant signals, including cell-adhesion sites and proteolytically degradable sites (Cuchiara et al, 2012;Hanjaya-Putra et al, 2012;Kusuma et al, 2013;Turturro et al, 2013). In this section, we discuss the application of fundamental theories of vascular development either to create engineered vasculatures in vitro, or to promote neovascularization in situ.…”

“…They then applied the hydrogel to a microfluidic system in order to mimic native vascular organization and function (Moon et al, 2010). PEG-based hydrogels tailored with RGD-and MMP-sensitive peptides have been widely used for supporting vascular network formation (Moon et al, 2009(Moon et al, , 2010Cuchiara et al, 2012;Turturro et al, 2013). The authors first encapsulated HUVECs and mesenchymal progenitors (10T1/2 cells) that exhibited a perivascular cell morphology within PEG hydrogels containing both RGD peptides and MMP-sensitive sites (Cuchiara et al, 2012).…”

“…PEG-based hydrogels tailored with RGD-and MMP-sensitive peptides have been widely used for supporting vascular network formation (Moon et al, 2009(Moon et al, , 2010Cuchiara et al, 2012;Turturro et al, 2013). The authors first encapsulated HUVECs and mesenchymal progenitors (10T1/2 cells) that exhibited a perivascular cell morphology within PEG hydrogels containing both RGD peptides and MMP-sensitive sites (Cuchiara et al, 2012). They found that the hydrogel supported rapid vascular morphogenesis of the HUVEC and 10T1/2 cells, and that the synthetic matrix was soon replaced with newly formed basement membrane proteins, such as laminin and collagen type IV.…”

“…MSCs have been shown to differentiate into SMCs and perivascular cells in the presence of transforming growth factor β (TGFβ) (Hirschi et al, 1998;Kinner et al, 2002) as in the in vivo vascular developmental process. Co-culture of mesenchymal stem cells or progenitor cells with ECs or EPCs (Cuchiara et al, 2012) All cell sources are human unless specified otherwise. ECFC, endothelial colony-forming cell; ESC, embryonic stem cell; HA, hyaluronic acid; HUMECs, human microvascular endothelial cells; HUVEC, human umbilical vein endothelial cell; iPSC, induced pluripotent stem cells; MSC, mesenchymal stem cell; PEG, polyethylene glycol.…”

“…The current state-of-the-art technology in engineering and cellular therapies allow an unprecedented level of control over the patient specificity of vascular therapeutics (Sun et al, 2011;Chen et al, 2012;Cuchiara et al, 2012;Kusuma et al, 2013). Tailor-made biomaterials and patient-specific stem cells are only part of the promise held by regenerative medicine, but whereas advanced engineering approaches can provide effective therapies and implantable vasculatures, obstacles Box 1.…”