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      Freeform 3D printing of vascularized tissues: Challenges and strategies

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          Abstract

          In recent years, freeform three-dimensional (3D) printing has led to significant advances in the fabrication of artificial tissues with vascularized structures. This technique utilizes a supporting matrix that holds the extruded printing ink and ensures shape maintenance of the printed 3D constructs within the prescribed spatial precision. Since the printing nozzle can be translated omnidirectionally within the supporting matrix, freeform 3D printing is potentially applicable for the fabrication of complex 3D objects, incorporating curved, and irregular shaped vascular networks. To optimize freeform 3D printing quality and performance, the rheological properties of the printing ink and supporting matrix, and the material matching between them are of paramount importance. In this review, we shall compare conventional 3D printing and freeform 3D printing technologies for the fabrication of vascular constructs, and critically discuss their working principles and their advantages and disadvantages. We also provide the detailed material information of emerging printing inks and supporting matrices in recent freeform 3D printing studies. The accompanying challenges are further discussed, aiming to guide freeform 3D printing by the effective design and selection of the most appropriate materials/processes for the development of full-scale functional vascularized artificial tissues.

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          Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels

          Freeform reversible embedding of suspended hydrogels enables three-dimensional printing of soft extracellular matrix biopolymers in biomimetic structures.
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            Multivascular networks and functional intravascular topologies within biocompatible hydrogels

            Solid organs transport fluids through distinct vascular networks that are biophysically and biochemically entangled, creating complex three-dimensional (3D) transport regimes that have remained difficult to produce and study. We establish intravascular and multivascular design freedoms with photopolymerizable hydrogels by using food dye additives as biocompatible yet potent photoabsorbers for projection stereolithography. We demonstrate monolithic transparent hydrogels, produced in minutes, comprising efficient intravascular 3D fluid mixers and functional bicuspid valves. We further elaborate entangled vascular networks from space-filling mathematical topologies and explore the oxygenation and flow of human red blood cells during tidal ventilation and distension of a proximate airway. In addition, we deploy structured biodegradable hydrogel carriers in a rodent model of chronic liver injury to highlight the potential translational utility of this materials innovation.
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              3D Printing of Personalized Thick and Perfusable Cardiac Patches and Hearts

              Abstract Generation of thick vascularized tissues that fully match the patient still remains an unmet challenge in cardiac tissue engineering. Here, a simple approach to 3D‐print thick, vascularized, and perfusable cardiac patches that completely match the immunological, cellular, biochemical, and anatomical properties of the patient is reported. To this end, a biopsy of an omental tissue is taken from patients. While the cells are reprogrammed to become pluripotent stem cells, and differentiated to cardiomyocytes and endothelial cells, the extracellular matrix is processed into a personalized hydrogel. Following, the two cell types are separately combined with hydrogels to form bioinks for the parenchymal cardiac tissue and blood vessels. The ability to print functional vascularized patches according to the patient's anatomy is demonstrated. Blood vessel architecture is further improved by mathematical modeling of oxygen transfer. The structure and function of the patches are studied in vitro, and cardiac cell morphology is assessed after transplantation, revealing elongated cardiomyocytes with massive actinin striation. Finally, as a proof of concept, cellularized human hearts with a natural architecture are printed. These results demonstrate the potential of the approach for engineering personalized tissues and organs, or for drug screening in an appropriate anatomical structure and patient‐specific biochemical microenvironment.
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                Author and article information

                Journal
                J Tissue Eng
                J Tissue Eng
                TEJ
                sptej
                Journal of Tissue Engineering
                SAGE Publications (Sage UK: London, England )
                2041-7314
                29 November 2021
                Jan-Dec 2021
                : 12
                : 20417314211057236
                Affiliations
                [1 ]Department of Biomedical and Chemical Engineering (BMCE), The Catholic University of Korea, Bucheon, Republic of Korea
                [2 ]Department of Biotechnology, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, Republic of Korea
                [3 ]Department of Materials Science and Engineering, Chosun University, Gwangju, Republic of Korea
                [4 ]Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, Chungcheongnam-do, Republic of Korea
                [5 ]Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan, Chungcheongnam-do, Republic of Korea
                [6 ]Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungcheongnam-do, Republic of Korea
                [7 ]Cell & Matter Institute, Dankook University, Cheonan, Chungcheongnam-do, Republic of Korea
                [8 ]Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, Chungcheongnam-do, Republic of Korea
                Author notes
                [*]Hae-Won Kim, Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan, Chungcheongnam-do 31116, Republic of Korea. Email: kimhw@ 123456dku.edu
                [*]Hyun-Do Jung, Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea. Email: hdjung@ 123456catholic.ac.kr
                [*]

                The authors have equally contributed to this work.

                Author information
                https://orcid.org/0000-0001-6400-6100
                https://orcid.org/0000-0001-8632-7431
                Article
                10.1177_20417314211057236
                10.1177/20417314211057236
                8638074
                34868539
                3952c48b-d816-4ad0-9303-2fe85ad8e23a
                © The Author(s) 2021

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 21 August 2021
                : 17 October 2021
                Funding
                Funded by: the framework of international cooperation program managed by the National Research Foundation of Korea, ;
                Award ID: 2021K2A9A2A06037540
                Funded by: National Research Foundation of Korea (NRF), FundRef https://doi.org/10.13039/501100003725;
                Award ID: 2021R1A2C1091301
                Funded by: Korean Fund for Regenerative Medicine funded by Ministry of Science and ICT, and Ministry of Health and Welfare, ;
                Award ID: 2021M3E5E5096420
                Funded by: Catholic University of Korea, FundRef https://doi.org/10.13039/501100002648;
                Award ID: Research Fund, 2021
                Categories
                Review
                Custom metadata
                January-December 2021
                ts1

                Biomedical engineering
                additive manufacturing,freeform 3d printing,vascularized structures,artificial tissues,tissue engineering

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