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Bioprinting of 3D pre-vascularized stem cell delivery platform for the treatment of ischemic cardiac diseases

Jinah Jang1, Hun-Jun Park2, Soo Jin Na2, Seok-Won Kim1, Heejin Kim2, Ju Young Park3, Hyeon Ji Kim1, Moon Nyeo Park1, Seung Hyun Choi4, 5, 6, Sun Hwa Park7, 8, Sung Won Kim7, 8, Sang-Mo Kwon4, 5, 6, Pom-Joon Kim2 and Dong-Woo Cho1
  • 1 POSTECH, Dept. of Mechanical Engineering, Korea
  • 2 The Catholic University of Korea, Division of Cardiovascular Medicine, Korea
  • 3 POSTECH, Division of Integrative Biosciences and Biotechnology, Korea
  • 4 Pusan National University, Medical Research Institute,School of Medicine, Korea
  • 5 Pusan National University, Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, School of Medicine, Korea
  • 6 Pusan National University, Convergence Stem Cell Research Center, Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Korea
  • 7 The Catholic University of Korea, Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Korea
  • 8 The Catholic University of Korea, Department of Biomedical Science, College of Medicine, Korea

Introduction: Stem cell therapy emerges as a new therapeutic method for the treatment of ischemic heart diseases. Towards the enhancement of therapeutic efficiency, a functionalized patch type cell delivery platform can be a potential alternative to achieve high retention, survival, engraftment, and differentiation of cells. Although there have been many successful results, fabricating an organized vascular plexus within the 3D structure remains a key barrier to enhancement of cell survival and function. 3D bioprinting is considered as a promising approach to generate 3D engineered tissues by emulating the cellular organization of the native tissue with high repeatability. Here, we developed a 3D pre-vascularized patch type stem cell delivery platform by patterning vascular cells and cardiac progenitor cells.

Materials and Methods: Two 3D patches were fabricated using heart tissue-derived decellularized extracellular matrix (hdECM) and fibrin bioink. The fabricated bioink patches (hdECM and fibrin bioink) were implanted into the rat myocardiac infarction (MI) model for verifying the therapeutic efficacy of bioink. Human c-kit+ cardiac tissue derived cardiac progenitor cells (CPCs) and human turbinate tissue derived mesenchymal stem cells (MSCs) were prepared by following protocol described in elsewhere. To print the patch for stem cell delivery, we used three different bioinks’ formulation as follow: 1) CPCs-laden hdECM bioink (Bioink I), 2) MSCs-laden hdECM bioink with 10 μg/ml VEGF (Bioink II) for vessel formation and 3) the mixture of CPCs and MSCs-laden hdECM bioink with 10 μg/ml VEGF (Bioink III). We printed the cell deliverable patch spatially alternating Bioink I and Bioink II (patterned patch) using lab-built multi-head bioprinter. The mixed patch was fabricated using Bioink III. The printed patches were implanted either in the mice subcutaneous site to investigate the vascularization capability or transplanted the printed patch into rat MI model to verify the therapeutic effect of the patch.

Results and Discussion: hdECM bioink enhanced angiogenesis and promoted fetal reprogramming through the endogenous paracrine signaling of epicardium compared to fibrin bioink. In addition, the patterned patch shortened the time for inosculation with the host circulatory system and promoted strong vasculogenesis which is distinct from the capillary formation made by the mixed patch. After 8 weeks of transplantation of the patch to the infarct tissue, the major cardiac functions were significantly enhanced in the group of patterned patch (ejection fraction 8.12±1.1 %, fractional shortening 6.24±2.46 % compared to baseline). It is because the patterned patch may provide a suitable environment which contributes to prolonged therapeutic efficacy and viability of delivered cells. Moreover, partial re-muscularization was progressed in both the implanted patch and the infarct region. The larger number of cells were migrated from the patterned patch to the infarct and differentiated into the endothelium compared to the mixed patch.

Conclusion: A major advantage of the developed platform technology is the spatial patterning of each cell to promote rapid vascularization in the 3D structure and prolonged survival of delivered cells in vivo. This 3D pre-vascularized stem cell delivery platform may open new avenues for delivering cells with high retention capability and regenerating ischemic tissue area.

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2010-0018294).; This study was supported by Research Fund of Seoul St.Mary’s Hospital, The Catholic University of Korea.

Keywords: Extracellular Matrix, Tissue Regeneration, Bioprinting, MYOCARDIAL TISSUE

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: New Frontier Oral

Topic: Biomaterials in printing

Citation: Jang J, Park H, Na S, Kim S, Kim H, Park J, Kim H, Park M, Choi S, Park S, Kim S, Kwon S, Kim P and Cho D (2016). Bioprinting of 3D pre-vascularized stem cell delivery platform for the treatment of ischemic cardiac diseases. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02507

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.