3D Printing Patches for Cardiac Regeneration

Cardiovascular diseases represent the major cause of morbidity and mortality worldwide. Chronic heart failure usually starts with the narrowing of the coronary artery, leading to progressive cardiomyocyte loss and, as a consequence, a deficiency of the cardiac muscle. Therefore, effective therapies to regenerate the myocardium could help millions of patients every year. Current treatment techniques are focused on slowing down the disease’s progression by limiting secondary damages instead of providing patients ways to repair the organ. Thus, patients with end-stage heart failure frequently need heart transplantation; however, there is a severe problem of shortage of organ donation and also a recurrent issue related to the risk of rejection. Several experimental strategies to repair and revascularize the injured heart using tissue engineering are in progress. These interventions can lead to better approaches to treat or prevent heart failure, despite the challenges that remain to find an accurate strategy [1,2,3].


The heart is one of the least regenerative organs in the body; after birth, the human heart becomes very limited in replacing cardiomyocytes. The regenerative response of the heart is deficient when compared to other tissues, such as liver, skeletal muscle, lung, bone, and skin [3]. Mimicking the hierarchical property of the native myocardium and replicating the complex nature of a large cardiac construct with a continuous contraction and relaxation dynamic is a big challenge for the tissue engineering field. Cardiac tissues are composed of ECM proteins and different cells aligned in a special order to maintain their spontaneous contraction to pump blood. Therefore, it is essential to develop a tissue engineering technique based on scaffolds able to mimic the natural heart ECM to hold the cardiomyocytes and promote their regeneration [4].

Figure 1: Graphical representation of challenges in cardiac tissue engineering [4].


A general strategy for cardiac tissue engineering is to create stable cardiac tissue through 3D printing using bioinks for implantation therapy [5,6]. Manufacturing an accurate 3D construct is a complex process that involves sequential stages, including diagnostic image acquisition, digital modeling, and the printing process [7]. A 3D bioprinted cardiac patch can act as an alternative treatment, providing a support matrix that allows stem cell adhesion and proliferation in a damaged heart and also can improve the regeneration of cardiac tissue, promoting angiogenesis in the infarcted tissues and reducing the scar tissue formation [5,6].


Ong et al. (2017) developed a biomaterial-free technique to deliver stem cells using 3D bioprinted cardiac patches. Cardiac patches were created from spheroids, composed of stem cell-derived cardiomyocytes, fibroblasts, and endothelial cells using a 3D bioprinter. Cardiac patches were analyzed through several in vitro assays, and the in vivo implantation indicated vascularization of 3D bioprinted cardiac patches with engraftment into native rat myocardium. In the first step of the patch fabrication, the 3D bioprinter identified the locations and then transferred and loaded cardiospheres individually onto a needle array in exact spatial coordinates, according to a pre-specified 3D design. The printed tissue model exhibited spontaneous beating, electrical integration of the cardiospheres, ventricular myocyte-like cellular electrophysiological properties, and also in vivo engraftment and vascularization [8].


Figure 2: In vivo implantation of 3D bioprinted cardiac patches. (A) Transplantation of 3D bioprinted cardiac patches onto the anterior surface of the rat heart. (B) Explanted heart (cross-section). (C) Explanted heart (anterior aspect) [8].


The use of hydrogels as biomaterials associated with cells to obtain bioinks for 3D bioprinting is an interesting approach for engineering personalized tissues and organs, as demonstrated by Noor et al. (2019). In this study, cells were collected via biopsy of fatty tissue from the patient and then reprogrammed to become pluripotent stem cells, while the acellular material of the tissue was processed to originate an extracellular matrix-based hydrogel. The cells were differentiated into cardiomyocytes and endothelial cells and combined with the hydrogel to form bioinks. These materials were used to print patient-specific and immune-compatible vascularized engineered cardiac patches and a heart prototype [9]. These outcomes demonstrate the viability of 3D bioprinting cardiac patches as a tool for cardiac regeneration.




REFERENCES


1- Gaetani, R., Feyen, D. A. M., Verhage, V., Slaats, R., Messina, E., Christman, K. L., … Sluijter, J. P. G. (2015). Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction. Biomaterials, 61, 339–348.

2- Jang, J., Park, H.-J., Kim, S.-W., Kim, H., Park, J. Y., Na, S. J., … Cho, D.-W. (2017). 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. Biomaterials, 112, 264–274.

3- Laflamme, M. A., & Murry, C. E. (2011). Heart regeneration. Nature, 473(7347), 326–335.

4- Qasim M, Haq F, Kang MH, Kim JH. (2019) 3D printing approaches for cardiac tissue engineering and role of immune modulation in tissue regeneration. Int J Nanomedicine. 14:1311-1333. Published 2019 Feb 20.

5- Gaebel, R., Ma, N., Liu, J., Guan, J., Koch, L., Klopsch, C., … Steinhoff, G. (2011). Patterning human stem cells and endothelial cells with laser printing for cardiac regeneration. Biomaterials, 32(35), 9218–9230.

6- Yeung E, Fukunishi T, Bai Y, et al. (2019). Cardiac regeneration using human-induced pluripotent stem cell-derived biomaterial-free 3D-bioprinted cardiac patch in vivo. J Tissue Eng Regen Med. 13(11):2031-2039.

7- Gardin C, Ferroni L, Latremouille C, Chachques JC, Mitrečić D, Zavan B. (2020). Recent Applications of Three Dimensional Printing in Cardiovascular Medicine. Cells. 9(3):742. Published 2020 Mar 17.

8- Ong, C.S., Fukunishi, T., Zhang, H. et al. (2017) Biomaterial-Free Three-Dimensional Bioprinting of Cardiac Tissue using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes. Sci Rep 7, 4566.

9- Noor, Nadav; Shapira, Assaf; Edri, Reuven; Gal, Idan; Wertheim, Lior; Dvir, Tal (2019). 3D Printing of Personalized Thick and Perfusable Cardiac Patches and Hearts. Advanced Science, 1900344.

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