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Automated micro-fabrication of a vascular graft mimicking the structure of human coronary arteries based on layer deposition, nanofibers and dipping-spinning technologies

      Design strategies and fabrication of vascular grafts has been converging from synthetics toward tissue engineered grafts, especially for replacement of small diameter blood vessels. Synthetic grafts with diameter smaller than 6 mm present recurring thrombus induction due to blood–graft interface contact activation, and mechanical mismatching with natural blood vessels. Tissue engineered small diameter blood vessels (SDBV) are intended to recapitulate the native structure and function of blood vessels. We have developed an automated microfabrication technology for the standardized fabrication of cellularized multilayer cylindrical constructs with control and native-liked mechanical behavior. The biofabrication technique combines the deposition of cell-laden ECM layers by a new dipping-spinning methodology, and the intercalated deposition of reinforcing nanofibers by an adapted solution blow spinning device. The versatility of this automated technique allowed us to reassemble the nature inspired pattern of different concentric cell types, and the structural configuration of nanofibers in specific angles and arrangements, similar to collagen and elastin fibers in native vessels. This approach was tested using a collagen-based hydrogel for encapsulation and distribution of MSCs and HUVECs, and polycaprolactone as long-term biodegradable and oriented nanofibers for mechanical reinforcement. Configuration designs of SDBV were adjusted to obtain a middle and outer layer capable to resemble stress-strain curve of the media and adventitia layer of human coronary arteries. Combination of both layers in one construct allowed the production of a vascular graft with the typical J-shape mechanical response and compliance (4 %C) of a human coronary artery. The cellular component was successfully included in absence of significant cytotoxic effect which was assessed by proliferation assays. Additionally, encapsulated cells showed a homogenous distribution with well-defined concentric patterns across the multilayer vessel grafts. This study demonstrated the wide versatility and scalability of the automated system to easily and rapidly fabricate complex cellularized multilayer vascular grafts with important potential application in bypass surgery, that will be first tested in a preclinical surgical model.
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