Revista nº 809

Ruiz-de-Almirón Ingeniería tisular del miocardio · 44 · Actualidad Médica · Número 809 · Enero/Abril 2020 Páginas 39 a 47 in vitro . The bioengineered cardiac tissue was transplanted into another pig and observed to beat spontaneously after reperfusion with blood, but waiting for immunogenicity, steri- lity and scalability responses (47). Neovascularization and Lymphangiogenesis After a myocardial injury, the vascularization plays a crucial rol to allow tissue engineering constructs to survive and grow. It is essential to overcome the challenging of neovascularization in TE, which aim is similar as much in ischemic disease and in pe- ripheral vascular disease. Therefore, results in therse areas are important for the clinical aplicaction of angiogenesis in tissue engineerring. Angiogenesis is te formation of new vessels from pre-existing vessels and vasculogenesis is the formation of vessels fron endothelial progenitor cells. This two strategies have been approached by reserchers to overcome the inadequate vascula- rization (48,49). The mechanisms of neovascularization are not yet well defined, but it has been proposed that the epicardium is reactived after the injury and secretes classical angiogenic factors (VEGF, CXCL12, C-X-C motif chemokine 12, or SDF-1), fibroblast growth factor, and retinoic acid. These factors would promote the epithelial-to-mesenchymal transition of epicardium-derived cells that invade the underlying myocardium, giving rise to pericytes, smooth muscle cells and fibroblasts (25). On the one hand, strategies for improving local circula- tion could be induce angiogenesis by manipulating pro-angio- genic growth factors. Other alternatives have been proposed such as combining endothelial cells with tissue-specific cells on a scaffold before transplantation to improve the prevascu- larize of the graft or target site before implantation. On the other hand, hypoxia may have certain advantages. Under hy- poxic conditions carries out its function and regulates gene expression of VEGF and stromal cell-derived factor (SCDF-1). SCDF-1 binds to the receptor CXCR4 acting as a chemokine and attracts stem cells, including circulating endothelial progenitor cells, to areas of hypoxia (48). As far as the lymphatic system, it is important for tissue fluid homeostasis and trafficking of inmune cells. It has been described above that inflamation can activates regenerative pathways and in rodent it has been observed that an induction of lymphangiogenesis with with VEGF-C (vascular endothelial growth factor C) improves healing, reduces fibrosis, and pre- serves myocardial function after myocardial infarction (25). 3D Bioprinting Construction of a vascular organ like heart is still being a challenge, as well as the synchronization of synthesized tissue constructs with native tissue and execution of spontaneous contraction. Recently, once of the most important technolo- gical advances is 3D bioprinting. This strategy provides an al- ternative to develop a heterogeneous 3D scaffold with strong mechanical strength and with all required characteristics of an ideal scaffold for cardiac tissue engineering. There are two main categories of 3D printing processes: scaffold-based printing and scaffold-free printing. First one, preprinting of scaffold and then cell layers printing or simultaneous printing of biomaterials and cells. Second one, bioink consists of indi- vidual cells or tissue spheroids are used for direct printing on substrate (50). Noor et al. have demonstrated an approach for engineering personalized tissues and organs using non supplemented materials as bioinks for 3D bioprinting (Figure 4). They reported on the potential of 3D bioprinting to engi- neer vascularized cardiac patches that fully match the anato- mical structure, the biochemical and cellular components of any individual. Furthemore, cellularized hearts with a natural architecture were engineered, demonstrating the potential for organ replacement or for drug screening in an appropriate anatomical structure. However, it is necessary to perform fur- ther in vitro studies and in vivo implantation experiments in animal models (51), and to consider the heterogeneity of the polymeric materials selected as bioinks, but also the influence the cell material dynamisms in the printing process because the shear stress caused during the bioprinting also affects cell viabili- ty and integrity (8). Another emerging technology with promising advances is organs-on-a-chip (OOAC), which are miniature tissues and organs grown in vitro that enable modeling of human physio- logy and disease. OOAC offer a promising approach to emulate human patho/physiology in vitro , drug development, disease modeling, and precision medicine (52). Microfluidics devices like organ-on-a-chip and lab-on-a-chip could be a potential te- chnique to observe a real-time effect of biochemical, mechanical, and electrical stimulations on new heart tissue constructs to im- prove tissue functions (50). Figure 3. Cell-sheet onto a vascular bed . (A) Endothelial cells (ECs) cocultured cardiac cell sheets are stacked. Then overlaid on a vascular bed in vitro and after appropriate perfusion using a bioreactor, the cocultured ECs formed new blood vessels and connected with the blood vessels that originated from the vascular bed. (B) Vascular bed created from porcine small intestine. Histological analysis with Azan trichrome staining revealed the adequate resection of the mucosa and the preservation of the extracellular matrix and small vessels (before vessels perfusion) without damage to the tissue. (C) Hematoxylin-eosin staining confirmed that the tissue had not been damaged by mucosal resection and cell nuclei were present throughout the remaining tissue (before perfusion culture). (B) and (C) reproduced from Inui et al 47 with permission. Copyright © 2019, The Japanese Society for Regenerative Medicine. https://creativecommons.org/ licenses/by-nc-nd/4.0/ Figure 4. Personalized 3D bioprinting. It is extracted an omentum tissue from the patient. Cells are separated from the matrix, reprogrammed to become pluripotent and differenciated to cardiomyocytes and endothelial cells. The matrix is processed into a personalized hydrogel. Then, cells and personalized hydrogel are encapsulated to generate bioinks in order to printed them to engineer vascularized patches and complex cellularized structures (51).