Abstract
Tissue-engineered blood vessels (TEBV) can serve as vascular grafts and may also play an important role in the development of organs-on-a-chip. Most TEBV construction involves scaffolding with biomaterials such as collagen gel or electrospun fibrous mesh. Hypothesizing that a scaffold-free TEBV may be advantageous, we constructed a tubular structure (1 mm i.d.) from aligned human mesenchymal cell sheets (hMSC) as the wall and human endothelial progenitor cell (hEPC) coating as the lumen. The burst pressure of the scaffold-free TEBV was above 200 mmHg after three weeks of sequential culture in a rotating wall bioreactor and perfusion at 6.8 dynes/cm2. The interwoven organization of the cell layers and extensive extracellular matrix (ECM) formation of the hMSC-based TEBV resembled that of native blood vessels. The TEBV exhibited flow-mediated vasodilation, vasoconstriction after exposure to 1 μM phenylephrine and released nitric oxide in a manner similar to that of porcine femoral vein. HL-60 cells attached to the TEBV lumen after TNF-α activation to suggest a functional endothelium. This study demonstrates the potential of a hEPC endothelialized hMSC-based TEBV for drug screening.
Highlights
One essential and often neglected tissue component of an in vitro microphysiological system for drug screening is the blood vessel[9]
We have previously shown that the hypoxic environment helps sustain human mesenchymal cell sheets (hMSC) viability and multipotency and facilitates the formation of a uniform and confluent hMSC cell sheet[22]
The uniform alignment could be seen in microscopic images of hMSCs grown on nanopatterned PDMS (Fig. 2B,C)
Summary
One essential and often neglected tissue component of an in vitro microphysiological system for drug screening is the blood vessel[9]. The vast majority of tissue-engineered blood vessel (TEBV) development has relied on the use of scaffolds such as synthetic polymers and hydrogels. Human mesenchymal stem cells (hMSCs) are an attractive cell source for the medial layer of TEBVs based on their unique antithrombogenic properties, immune response modulation abilities, and multipotency for differentiation into vascular phenotypes[18]. They are more readily available and proliferative for cell sheet formation compared with SMCs19. We fabricated a small-diameter (1 mm i.d.) TEBV comprising hMSCs in the wall and human cord blood derived endothelial progenitor cells (hEPCs) on the luminal surface without any synthetic or exogenous materials. The mechanical strength was evaluated through burst pressure analysis
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