Automated and Enclosed Three-Dimensional Biofabrication System for Mesenchymal Stem Cell Culture to Enhance Diabetic Wound Healing

Yanmei Chen; Yang Xu; Jiawei Cai; Marianne Lauwers; Liwei Xiang; Yali Zheng; Hua Chu; Xianglong Chen; Dai Fei Elmer Ker; Cheng Zhang; Dan Michelle Wang; Zhiyong Zhang

doi:10.34133/bmr.0205

Automated and Enclosed Three-Dimensional Biofabrication System for Mesenchymal Stem Cell Culture to Enhance Diabetic Wound Healing

Biomater Res. 2025 May 26:29:0205. doi: 10.34133/bmr.0205. eCollection 2025.

Authors

Yanmei Chen¹, Yang Xu^{2

3}, Jiawei Cai¹, Marianne Lauwers⁴, Liwei Xiang¹, Yali Zheng¹, Hua Chu¹, Xianglong Chen¹, Dai Fei Elmer Ker⁵, Cheng Zhang¹, Dan Michelle Wang^{2

3

4

6}, Zhiyong Zhang¹

Affiliations

¹ Translational Research Centre of Regenerative Medicine and 3D Printing, Department of Orthopaedic Surgery, Guangzhou Key Laboratory of Spine Disease Prevention and Treatment, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
² School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
³ Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴ Centre for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China.
⁵ Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China.
⁶ Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.

Abstract

The industrialization of mesenchymal stem cells for regenerative medicine faces substantial challenges, particularly in large-scale production. Conventional 2-dimensional (2D) culture systems demonstrate limitations in meeting clinical requirements, such as inadequate cell yield, and poor cell-cell and cell-matrix interactions. These challenges can potentially be addressed by employing a 3D culture platform, which offers higher cell yields and enhanced efficacy. Moreover, it is essential to conduct a systematic and rigorous evaluation of cells produced in 3D culture systems to ensure their successful clinical translation. In this study, we cultured human umbilical cord mesenchymal stem cells (hUCMSCs) using an automated, scalable, and enclosed 3D microcarrier-bioreactor system, and comprehensively investigated their biological characteristics and potential therapeutic effects for diabetic wound repair. Our findings revealed that hUCMSCs harvested from this 3D microcarrier-bioreactor system are genetically stable and maintain the trilineage differentiation potential. Compared to hUCMSCs expanded under 2D conditions, those cultured in 3D exhibited reduced senescence and enhanced capabilities in migration, angiogenesis, and anti-inflammatory responses across different passages in vitro. RNA-sequencing analysis showed higher expression levels of genes related to angiogenesis and anti-inflammatory pathways in hUCMSCs cultured in 3D compared to those in 2D, which was further validated using quantitative real-time polymerase chain reaction and Western blot analysis. Additionally, 3D-cultured hUCMSCs demonstrated superior therapeutic effects for diabetic wound repair in mice, potentially due to their enhanced angiogenetic and anti-inflammatory effects. Collectively, our finding showcases the high quality of hUCMSCs cultured using an automated and enclosed 3D microcarrier-bioreactor system and their promising potential for diabetic wound repair.