Abstract
Vascularization and efficient perfusion are long-standing challenges in cardiac tissue engineering. Here we report engineered perfusable microvascular constructs, wherein human embryonic stem cell-derived endothelial cells (hESC-ECs) are seeded both into patterned microchannels and the surrounding collagen matrix. In vitro, the hESC-ECs lining the luminal walls readily sprout and anastomose with de novo-formed endothelial tubes in the matrix under flow. When implanted on infarcted rat hearts, the perfusable microvessel grafts integrate with coronary vasculature to a greater degree than non-perfusable self-assembled constructs at 5 days post-implantation. Optical microangiography imaging reveal that perfusable grafts have 6-fold greater vascular density, 2.5-fold higher vascular velocities and >20-fold higher volumetric perfusion rates. Implantation of perfusable grafts containing additional hESC-derived cardiomyocytes show higher cardiomyocyte and vascular density. Thus, pre-patterned vascular networks enhance vascular remodeling and accelerate coronary perfusion, potentially supporting cardiac tissues after implantation. These findings should facilitate the next generation of cardiac tissue engineering design.
Highlights
Vascularization and efficient perfusion are long-standing challenges in cardiac tissue engineering
We recently demonstrated an application of optical coherence tomography (OCT)-based optical microangiography (OMAG)[20,21,22,23,24] to obtain high-resolution coronary angiograms on ex vivo Langendorffperfused and fixed rat hearts[25]
We previously demonstrated that these differentiated endothelial cells (ECs) undergo tubulogenesis when embedded in soft collagen gels and extensive angiogenesis when lined in a three-dimensional (3D) engineered μV platform[16]
Summary
Vascularization and efficient perfusion are long-standing challenges in cardiac tissue engineering. Heart failure is the leading cause of death worldwide, and no available treatment options outside of whole heart transplantation address the problem of cellular deficiency[5,6] Despite this burgeoning clinical need, the therapeutic application of engineered cardiac tissues has not been achieved, partially due to the lack of comprehensive tissue perfusion in vitro and effective integration with host vessels in vivo[4]. The presence of these vessels improves cardiomyocyte maturation and tissue function, the formed network architecture does not provide efficient perfusion, preventing large-scale construct fabrication and culture When implanted, these grafts partially integrate with host vasculature but do not establish effective perfusion in a timely fashion[10]. This imaging technique allows for simultaneous image acquisition of high-resolution structural information as well as velocimetry data of the coronary vasculature in both graft and host
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