Fabrication of Thermoresponsive Hydrogel Scaffolds with Engineered Microscale Vasculatures

Abstract

Precise fabrication of microscale vasculatures (MSVs) has long been an unresolved challenge in tissue engineering. Currently, light-assisted printing is the most common approach. However, this approach is often associated with an intricate fabrication process, high cost, and a requirement for specific photoresponsive materials. Here, thermoresponsive hydrogels are employed to induce volume shrinkage at 37 °C, which allows for MSV engineering without complex protocols. The thermoresponsive hydrogel consists of thermosensitive poly(N-isopropylacrylamide) and biocompatible gelatin methacrylate (GelMA). In cell culture, the thermoresponsive hydrogel exhibits an apparent volume shrinkage and effectively triggers the creation of MSVs with smaller size. The results show that a higher concentration of GelMA blocks the shrinkage, and the thermoresponsive hydrogel demonstrates different behaviors in water and air at 37 °C. The MSVs can be effectively fabricated using the sacrificial alginate fibers, and the minimum MSV diameter achieved is 50 µm. Human umbilical vein endothelial cells form endothelial monolayers in the MSVs. Osteosarcoma cells maintain high viability in the thermoresponsive hydrogel, and the in vivo experiment shows that the MSVs provide a site for the perfusion of host vessels. This technique may help in the development of a facile method for fabricating MSVs and demonstrates strong potential for clinical application in tissue regeneration.

Bioprinting Technologies and Bioinks for Vascular Model Establishment

“…In this regard, the sacrificial material is shaped into the core of the desired vascular network structure and then dissolved away by physical removal, such as adjusting the pH and temperature, or chemical reaction. Several materials, such as gelatin, sugar glass, agarose, alginate, pluronic and polyvinyl alcohol, have been used as sacrificial inks, to build complex vascular networks within the 3D printed structures [68,[140][141][142][143][144][145][146][147][148][149][150].…”

Application Status of Sacrificial Biomaterials in 3D Bioprinting

“…When sodium alginate solutions are exposed to divalent calcium ions, Ca 2+ can replace the Na + in sodium alginate to form calcium alginate gels. Some calcium chelating agents, such as sodium citrate and ethylenediaminetetraacetic acid (EDTA), can capture Ca 2+ in the calcium alginate gels and mildly liquefy the solidified alginate structures, which provides the chemical basis of sodium alginate as a sacrificial biomaterial for 3D bioprinting [ 123 , 124 , 125 ] ( Figure 7 a). As a chemical sacrificial biomaterial, alginate is particularly effective in preparing protein-based microfibers for cell proliferation [ 126 ].…”

Biomaterials to promote vascularization in tissue engineering organs and ischemic fibrotic diseases

“…The thermosensitive hydrogel poly‐ N ‐isopropylacrylamide (PNIPAM) and GelMA were used to achieve the Fabrication of small‐sized microscale vasculatures by sacrificial template method and shrinkage effect of thermally responsive hydrogel scaffolds. At 37°C, the thermosensitive volume shrinkage of PNIPAM was utilized to efficiently induce the fabrication of smaller‐sized microscale vasculatures 97 (Figure 6).…”

“…(C) Vascular patterning (coating patterned networks of microfluidic channels with endothelial cells [ECs]). Copyright permission from Li et al 97 (D) Self‐assembly (stimulates the microvascular network to self‐organize through angiogenesis and achieve stable anastomosis with adjacent microfluidic channels). Copyright permission from Barrs et al 98 …”

“…By modifying alginate with RGD (an integrin-binding peptide for cell adhesion), and a VEGF mimetic peptide with a matrix metalloproteinase cleavable linkage 97 (D) Self-assembly (stimulates the microvascular network to self-organize through angiogenesis and achieve stable anastomosis with adjacent microfluidic channels). Copyright permission from Barrs et al 98 (MMPQK).…”