Integrating Engineered Macro Vessels with Self-assembled Capillaries in 3D Implantable Tissue for Promoting Vascular Integration In-vivo

Abstract

<jats:title>Abstract</jats:title><jats:p>Fabrication of a functional hierarchical vascular network remains an unmet need for cultivation and transplantation of 3D engineered tissues. In this work, an effective approach was developed to fabricate a functional, perfusable and biocompatible, multi-scale vascular network (MSVT) within thick, implantable engineered tissues. Using a templating technique, macro-vessels were patterned in a 3D biodegradable polymeric scaffold seeded with endothelial and support cells within a collagen gel. The lumen of the macro-vessel was lined with endothelial cells, which further sprouted and anastomosed with the surrounding self-assembled capillaries. Anastomoses between the two-scaled vascular systems displayed tightly bonded cell junctions, as indicated by vascular endothelial cadherin expression. Moreover, MSVT functionality and patency were demonstrated by dextran passage through the interconnected hierarchical vasculature. Additionally, physiological flow conditions were applied with home-designed flow bioreactors, to achieve a MSVT with a natural endothelium structure. Finally, implantation of a multi-scale-vascularized graft in a mouse model resulted in a clear beneficial effect, as reflected by extensive host vessel penetration into the graft and an increase in blood perfusion via the engineered vessels as compared to control microscale-vascularized graft. Designing and fabricating such multi-scale vascular architectures within 3D engineered tissues is essential, both for in-vitro models and for therapeutic translation research.</jats:p>

3D Bioprinting of Engineered Tissue Flaps with Hierarchical Vessel Networks (VesselNet) for Direct Host‐To‐Implant Perfusion

“…We speculate that this happens due to the hydrogel compaction and subsequent endothelium seeding, which lined the compacted gel covering the fenestrations, and the endothelium ECs sprouted into the gel. Many works have presented very similar occurrences in microfluidic devices, [ 80,81 ] gel channels, [ 61,82 ] or perforated scaffolds, [ 83 ] but, to our knowledge, this is the first time this phenomenon was observed in a system built using 3D printing technologies. Additionally, we successfully perfused the gel's vascular network by injecting a fluorescent microsphere solution into the scaffold lumen (Figure 4C), furtherly evidencing the communication between endothelium and microvasculature.…”

Engineering Tissue‐Specific, Multiscale Microvasculature with a Capillary Network for Prevascularized Tissue

“…[47] After isolation, the viability of the hepatocytes was confirmed to be >85% via the trypan blue exclusion test. All animal studies were conducted according to protocols approved by the Institutional Animal Care and Use Committee at Ulsan National Institute of Science and Technology (IACUC protocol number: UNIST-IACUC- [19][20][21][22][23].…”

“…[7,[12][13][14][15][16]20] In addition, the multiscale architecture can significantly improve the integration with the host vasculature in vivo. [21] However, because the introduced technologies could produce only capillary networks with random architectures, it was not possible to fabricate biomimetic vasculatures. Metabolically active tissues contain microvasculatures composed of capillaries, which possess tissue-specific patterns and directly interact with parenchymal cells.…”

Cell delivery systems: Toward the next generation of cell therapies for type 1 diabetes

“…Representative CDS used in pre‐clinical studies. A: Novo Nordisk Electrospun nanofibrous encapsulation device; B: Procyon oxygenation cell delivery device; 45 C: Technion vascular bed platform 47 . Pictures used with the permission of Novo Nordisk…”

“…To improve the results, the same group reports the use of a moulding technique to create macro scale vessels with an inner diameter of 600 μm that run through the platform resulting in dual scale vessel supporting constructs (Figure 4C). 47 It is reasonable to assume human islets will behave similarly to mouse islets, although there are no reports of such experiments. Moreover, the multi‐cell vascular bed will not result in immuno‐isolation of the islets if allografted.…”