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RESEARCH ARTICLE

Thermo-sensitive Sacrificial Microsphere-based Bioink

for Centimeter-scale Tissue with Angiogenesis

Mingjun Xie 1,2,3† , Yuan Sun 1,2,3† , Ji Wang *, Zhenliang Fu , Lei Pan , Zichen Chen ,
2,3
1
2,3
1
Jianzhong Fu , Yong He 2,3,4,5 *
2,3
1 Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People’s
Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China
2 State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University,
Hangzhou 310027, Zhejiang, China
3 Key Laboratory of Materials Processing and Mold, Zhengzhou University, Zhengzhou 450002, Henan, China
4 Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province, College of Mechanical Engineering, Zhejiang
University, Hangzhou 310027, Zhejiang, China
5 Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
† These authors contributed equally to this work

Abstract: Centimeter-scale tissue with angiogenesis has become more and more significant in organ regeneration and
drug screening. However, traditional bioink has obvious limitations such as balance of nutrient supporting, printability, and
vascularization. Here, with “secondary bioprinting” of printed microspheres, an innovative bioink system was proposed,
in which the thermo-crosslinked sacrificial gelatin microspheres encapsulating human umbilical vein endothelial cells
(HUVECs) printed by electrospraying serve as auxiliary component while gelatin methacryloyl precursor solution mixed with
subject cells serve as subject component. Benefiting from the reversible thermo-crosslinking feature, gelatin microspheres
would experience solid-liquid conversion during 37°C culturing and form controllable porous nutrient network for promoting
the nutrient/oxygen delivery in large-scale tissue and accelerate the functionalization of the encapsulated cells. Meanwhile,
the encapsulated HUVECs would be released and attach to the pore boundary, which would further form three-dimensional
vessel network inside the tissue with suitable inducing conditions. As an example, vascularized breast tumor tissue over 1 cm
was successfully built and the HUVECs showed obvious sprout inside, which indicate the great potential of this bioink system
in various biomedical applications.
Keywords: Bioprinting; Angiogenesis; Microsphere; Large-scale tissue; Gelatin methacryloyl; Thermo-sensitive material

*Correspondence to: Ji Wang, Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial
People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China; jiwang1004@zju.edu.cn; Yong
He, State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou 310027,
Zhejiang, China; yongqin@zju.edu.cn
Received: February 24, 2022; Accepted: April 18, 2022; Published Online: August 4, 2022
(This article belongs to the Special Issue: 3D Bioprinting with Photocurable Bioink)

Citation: Xie M, Sun Y, Wang J, et al., 2022. Thermo-sensitive Sacrificial Microsphere-based Bioink for Centimeter-scale
Tissue with Angiogenesis. Int J Bioprint, 8(4):599. http://doi.org/10.18063/ijb.v8i4.599

1. Introduction also of great application value, such as drug screening
In addition to various published microsphere functional based on large-scale tissues, and repair of large defects
[3]
units (micro tissues), in practical studies, centimeter- at the centimeter level . However, the development of
scale tissues based on hydrogel materials constructed bioprinting of biologically active centimeter-scale large
by three-dimensional (3D) bioprinting technology [1,2] are tissues has been impeded, mainly due to two reasons:

© 2022 Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution and
reproduction in any medium, provided the original work is cited.
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