University of Alabama at Birmingham School of Medicine
Ge Gao1, Jun Hee Lee2, Jinah Jang3, Dong Han Lee4, Jeong-Sik Kong5, Byoung Soo Kim1, Yeong-Jin Choi6, Woong Bi Jang4, Young Joon Hong7,*, Sang-Mo Kwon8,* andDong-Woo Cho1,*
1Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea
2Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
3Department of Creative IT Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea
4Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea
5School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Republic of Korea
6Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea
7Heart Center of Chonnam National University Hospital, Gwangju, Republic of Korea
8Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan, Republic of Korea
G.G., J.H.L., and J.J. contributed equally to this work.
Endothelial progenitor cells (EPCs) are a promising cell source for the treatment of several ischemic diseases for their potentials in neovascularization. However, the application of EPCs in cell-based therapy has shown low therapeutic efficacy due to hostile tissue conditions after ischemia. In this study, a bio-blood-vessel (BBV) is developed, which is produced using a novel hybrid bioink (a mixture of vascular-tissue-derived decellularized extracellular matrix (VdECM) and alginate) and a versatile 3D coaxial cell printing method for delivering EPC and proangiogenic drugs (atorvastatin) to the ischemic injury sites. The hybrid bioink not only provides a favorable environment to promote the proliferation, differentiation, and neovascularization of EPCs but also enables a direct fabrication of tubular BBV. By controlling the printing parameters, the printing method allows to construct BBVs in desired dimensions, carrying both EPCs and atorvastatin-loaded poly(lactic-co-glycolic) acid microspheres. The therapeutic efficacy of cell/drug-laden BBVs is evaluated in an ischemia model at nude mouse hind limb, which exhibits enhanced survival and differentiation of EPCs, increased rate of neovascularization, and remarkable salvage of ischemic limbs. These outcomes suggest that the 3D-printed ECM-mediated cell/drug implantation can be a new therapeutic approach for the treatment of various ischemic diseases.
Keywords : 3D coaxial cell printing; atorvastatin; decellularized extracellular matrix (dECM); endothelial progenitor cells; vascular tissue engineering