Abstract
Fabrication of 3D scaffolds with patient-specific designs, high structural and component complexity, and rapid on-demand production at a low-cost by printing technique has attracted ever-increasing interests in tissue engineering. Cell-laden 3D bioprinting offers good prospects for future organ transplantation. Compared with nonbiological 3D printing, cell-laden 3D bioprinting involves more complex factors, including the choice of printing materials, the strategy of gelling, cell viability and technical challenges. Although cell-populated 3D bioprinting has so many complex factors, it has proven to be a useful and exciting tool with wide potential applications in regenerative medicine to generate a variety of transplantable tissues. In this review, we first overview the bioprinting materials, gelling strategies and some major applications of cell-laden 3D bioprinting, with main focus on the recent advances and current challenges of the field. Finally, we propose some future directions of the cell-populated 3D bioprinting in tissue engineering and regenerative medicine.
In this review, we first overview the bioprinting materials, gelling strategies and some major applications of cell-populated 3D bioprinting, with main focus on the recent advances and current challenges of the field. Finally, we propose some future directions of the cell-laden 3D bioprinting in tissue engineering and regenerative medicine.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Anonymous. Organ donation depends on trust. Lancet 387(10038), 2575 (2016).
- 2 . Bioprinting toward organ fabrication: challenges and future trends. IEEE Trans. Biomed. Eng. 60(3), 691–699 (2013).
- 3 . Tissue engineering. Science 260(5110), 920–926 (1993).
- 4 . Apparatus for production of three-dimensional objects by stereolithography. US 4575330 A (Google Patents) (1986).
- 5 Biofabrication: an overview of the approaches used for printing of living cells. Appl. Microbiol. Biotechnol. 97(10), 4243–4258 (2013).
- 6 . Three dimensional printers are opening up new worlds to research. Nature 487(7405), 22–23 (2012).
- 7 . Critical parameters influencing the quality of prototypes in fused deposition modelling. J. Mater. Process. Tech. 118(1–3), 385–388 (2001).
- 8 . Solid freeform fabrication of ceramics. Int. Mater. Rev. 48(6), 341–370 (2003).
- 9 . Digital light processing for high-brightness high-resolution applications. Proc. SPIE. 3013, 27–40 (1997).
- 10 A review of process development steps for new material systems in three dimensional printing (3DP). J. Manuf. Process. 10(2), 96–104 (2008).
- 11 . Laminated object manufacturing for rapid tooling and pattern making in foundry industry. Comput. Ind. 39(1), 47–53 (1999).
- 12 . Process capability study of polyjet printing for plastic components. J. Mech. Sci. Technol. 25(4), 1011–1015 (2011).
- 13 . 3D printing and neurosurgery-ready for prime time. World Neurosurg. 80(3–4), 233–235 (2013).
- 14 Bioresorbable airway splint created with a three-dimensional printer. N. Engl. J. Med. 368(21), 2043–2045 (2013).
- 15 3D printing based on imaging data: review of medical applications. Int. J. Comput. Assist. Radiol. Surg. 5(4), 335–341 (2010).
- 16 A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials. 33(26), 6020–6041 (2012).
- 17 Proliferation and enrichment of CD133+ glioblastoma cancer stem cells on 3D chitosan-alginate scaffolds. Biomaterials. 35(33), 9137–9143 (2014).
- 18 Microscale technologies for tissue engineering and biology. Proc. Natl Acad. Sci. USA 103(8), 2480–2487 (2006).
- 19 Rapid 3D printing of anatomically accurate and mechanically heterogeneous aortic valve hydrogel scaffolds. Biofabrication. 4(3), 035005 (2012).
- 20 In vivo biocompatibility and biodegradation of 3D-printed porous scaffolds based on a hydroxyl-functionalized poly(ε-caprolactone). Biomaterials 33(17), 4309–4318 (2012).
- 21 . Designing cell-compatible hydrogels for biomedical applications. Science 336(6085), 1124–1128 (2012).
- 22 . 3D bioprinting of tissues and organs. Nat. Biotechnol. 32(8), 773–785 (2014).
- 23 . Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 24(24), 4337–4351 (2003).
- 24 25th Anniversary article: engineering hydrogels for biofabrication. Adv. Mater. 25(36), 5011–5028 (2013).
- 25 . Evaluation of hydrogels for bio-printing applications. J. Biomed. Mater. Res. A. 101(1), 272–284 (2013).
- 26 3D bioprinting for engineering complex tissues. Biotechnol. Adv. 34(4), 422–434 (2016). •• Extensive review of bioprinting techniques, materials and tissues.
- 27 . 3D bioprinting: new directions in articular cartilage tissue engineering. ACS Biomater. Sci. Eng.
doi:10.1021/acsbiomaterials.6b00587 (2017) (Epub ahead of print). - 28 . Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials 20(1), 45–53 (1999).
- 29 . Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: part 1. Structure, gelation rate and mechanical properties. Biomaterials 22(6), 511–521 (2001).
- 30 . Alginate: properties and biomedical applications. Progr. Polym. Sci. 37(1), 106–126 (2012).
- 31 Enzymatically crosslinked alginate hydrogels with improved adhesion properties. Polym. Chem. 6(12), 2204–2213 (2015).
- 32 Increased mixing improves hydrogel homogeneity and quality of three-dimensional printed constructs. Tissue Eng. Part C Methods. 17(2), 239–248 (2011).
- 33 Collagen for bone tissue regeneration. Acta Biomater. 8(9), 3191–3200 (2012).
- 34 A comparative study on collagen type I and hyaluronic acid dependent cell behavior for osteochondral tissue bioprinting. Biofabrication 6(3), 035004 (2014).
- 35 . Antigenicity and immunogenicity of collagen. J. Biomed. Mater. Res. B. Appl. Biomater. 71B(2), 343–354 (2004).
- 36 Three-dimensional bioassembly tool for generating viable tissue-engineered constructs. Tissue Eng. 10(9–10), 1566–1576 (2004).
- 37 Generation of multi-scale vascular network system within 3D hydrogel using 3D bio-printing technology. Cell. Mol. Bioeng. 7(3), 460–472 (2014).
- 38 Bioprinted amniotic fluid-derived stem cells accelerate healing of large skin wounds. Stem Cells Transl. Med. 1(11), 792–802 (2012).
- 39 Functional and bioactive properties of collagen and gelatin from alternative sources: a review. Food Hydrocolloid 25(8), 1813–1827 (2011).
- 40 Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels. Biofabrication 6(2), 024105 (2014).
- 41 The 3D printing of gelatin methacrylamide cell-laden tissue-engineered constructs with high cell viability. Biomaterials 35(1), 49–62 (2014).
- 42 On-demand three-dimensional freeform fabrication of multi-layered hydrogel scaffold with fluidic channels. Biotechnol. Bioeng. 105(6), 1178–1186 (2010).
- 43 3D bioprinting of heterogeneous aortic valve conduits with alginate/gelatin hydrogels. J. Biomed. Mater. Res. Part A 101(5), 1255–1264 (2013).
- 44 BMSCs-laden gelatin/sodium alginate/carboxymethyl chitosan hydrogel for 3D bioprinting. RSC Adv. 6(110), 108423–108430 (2016).
- 45 Laser printing of three-dimensional multicellular arrays for studies of cell–cell and cell–environment interactions. Tissue Eng. Part C Methods 17(10), 973–982 (2011).
- 46 . The structure and biological features of fibrinogen and fibrin. Ann. NY Acad. Sci. 936, 11–30 (2001).
- 47 . Gelation of soluble fibrin in plasma by ethanol. Scand. J. Haematol. 3(5), 342–346 (1966).
- 48 . Epsilon-aminocaproic acid is a useful fibrin degradation inhibitor for cartilage tissue engineering. Tissue Eng. Part A. 15(8), 2309–2313 (2009).
- 49 . Hyaluronic acid based scaffolds for tissue engineering – a review. Carbohyd. Polym. 92(2), 1262–1279 (2013).
- 50 Hyaluronic acid and dextran-based semi-IPN hydrogels as biomaterials for bioprinting. Biomacromolecules 12(5), 1831–1838 (2011).
- 51 . Pluronic (R) block copolymers as novel polymer therapeutics for drug and gene delivery. J. Control. Rel. 82(2–3), 189–212 (2002).
- 52 Thermodynamic studies on the gel sol transition of some pluronic polyols. Int. J. Pharm. 22(2–3), 207–218 (1984).
- 53 . Omnidirectional printing of 3D microvascular networks. Adv. Mater. 23(24), H178–H183 (2011).
- 54 Nanostructured pluronic hydrogels as bioinks for 3D bioprinting. Biofabrication 7(3), 035006 (2015).
- 55 . PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm. Res. 26(3), 631–643 (2009).
- 56 Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: Synthetic ECM analogs for tissue engineering. Biomaterials 22(22), 3045–3051 (2001).
- 57 Direct human cartilage repair using three-dimensional bioprinting technology. Tissue Eng. Part A. 18(11–12), 1304–1312 (2012).
- 58 Inkjet-bioprinted acrylated peptides and PEG hydrogel with human mesenchymal stem cells promote robust bone and cartilage formation with minimal printhead clogging. Biotechnol. J. 10(10), 1568–1577 (2015).
- 59 . The expanding world of tissue engineering: the building blocks and new applications of tissue engineered constructs. IEEE Rev. Biomed. Eng. 6, 47–62 (2013).
- 60 . Molecular complexity and dynamics of cell–matrix adhesions. J. Cell Sci. 114(20), 3583–3590 (2001).
- 61 Natural and genetically engineered proteins for tissue engineering. Prog. Polymer Sci. 37(1), 1–17 (2012).
- 62 Cell-based therapeutics from an economic perspective: primed for a commercial success or a research sinkhole? Regen. Med. 3(6), 925–937 (2008).
- 63 . Current research on the blends of natural and synthetic polymers as new biomaterials: review. Prog. Polymer Sci. 36(9), 1254–1276 (2011).
- 64 . Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2. Biomaterials 31(30), 7836–7845 (2010).
- 65 . A strategy for the covalent functionalization of resorbable polymers with heparin and osteoinductive growth factor. Biomacromolecules 9(3), 901–905 (2008).
- 66 Probing cellular mechanobiology in three-dimensional culture with collagen–agarose matrices. Biomaterials 31(7), 1875–1884 (2010).
- 67 A tailored three-dimensionally printable agarose-collagen blend allows encapsulation, spreading, and attachment of human umbilical artery smooth muscle cells. Biofabrication 8(2), 025011 (2016).
- 68 . Nanostructuring PEG–fibrinogen hydrogels to control cellular morphogenesis. Biomaterials 32(31), 7839–7846 (2011).
- 69 Elucidating the role of matrix stiffness in 3D cell migration and remodeling. Biophys. J. 110(2), 284–293 (2011).
- 70 Cells (MC3T3-E1)-laden alginate scaffolds fabricated by a modified solid-freeform fabrication process supplemented with an aerosol spraying. Biomacromolecules 13(9), 2997–3003 (2012).
- 71 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv. Mater. 26(19), 3124–3130 (2014).
- 72 Microscale strategies for generating cell-encapsulating hydrogels. Polymers 4(3), 1554–1579 (2012).
- 73 Preparation and characterization of a novel thermosensitive nanoparticle for drug delivery in combined hyperthermia and chemotherapy. J. Mater. Chem. B. 1(46), 6442–6448 (2013).
- 74 A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat. Biotechnol. 34(3), 312–319 (2016). • Example of fabricating stable, human-scale tissue constructs of any shape.
- 75 Development of liver decellularized extracellular matrix bioink for three-dimensional cell printing-based liver tissue engineering. Biomacromolecules. 18(4), 1229–1237 (2017).
- 76 3D bioprinting of BMSC-laden methacrylamide gelatin scaffolds with CBD-BMP2-collagen microfibers. Biofabrication 7(4), 044104 (2015).
- 77 Three-dimensional printed trileaflet valve conduits using biological hydrogels and human valve interstitial cells. Acta Biomater. 10(5), 1836–1846 (2014).
- 78 3D printed stem-cell-laden, microchanneled hydrogel patch for the enhanced release of cell-secreting factors and treatment of myocardial infarctions. ACS Biomater. Sci. Eng. 3(9), 1980–1987 (2017).
- 79 Laser assisted bioprinting of engineered tissue with high cell density and microscale organization. Biomaterials 31(28), 7250–7256 (2010).
- 80 A generalizable strategy for the 3D bioprinting of hydrogels from nonviscous photo-crosslinkable inks. Adv. Mater. 29(8), 1604983 (2017).
- 81 Optimizing photo-encapsulation viability of heart valve cell types in 3D printable composite hydrogels. Ann. Biomed. Eng. 45(2), 360–377 (2017). • Systematically test variables associated with photo-cross-linking hydrogels for their effects on encapsulated cells during laser-assisted 3D bioprinting.
- 82 . Bystander effects in UV-induced genomic instability: antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation. J. Carcinog. 4, 11 (2005).
- 83 Development and characterization of a new bioink for additive tissue manufacturing. J. Mater. Chem. B. 2(16), 2282–2289 (2014).
- 84 Overcoming oxygen inhibition in UV-curing of acrylate coatings by carbon dioxide inerting, part I. Prog. Org. Coat. 48(1), 92–100 (2003).
- 85 . Kinetic approach of oxygen inhibition in ultraviolet- and laser-induced polymerizations. Macromolecules 18(6), 1241–1242 (1985).
- 86 New visible-light photoinitiating system for improved print fidelity in gelatin-based bioinks. ACS Biomater. Sci. Eng. 2(10), 1752–1762 (2016). • Extends laser-assisted gelling method from UV light to visible light.
- 87 3D bioprinted glioma stem cells for brain tumor model and applications of drug susceptibility. Biofabrication 8(4), 045005 (2016).
- 88 . Inkjet bioprinting of 3D silk fibroin cellular constructs using sacrificial alginate. ACS Biomater. Sci. Eng. 3(8), 1519–1526 (2017).
- 89 Bioprintable, cell-laden silk fibroin-gelatin hydrogel supporting multilineage differentiation of stem cells for fabrication of three-dimensional tissue constructs. Acta Biomater. 11, 233–246 (2015).
- 90 Biomatrices and biomaterials for future developments of bioprinting and biofabrication. Biofabrication 2(1), 014110 (2010).
- 91 . Investigation of the material properties of alginate for the development of hydrogel repair of dura mater. J. Mech. Behav. Biomed. Mater. 4(1), 16–33 (2011).
- 92 Bioprinting of a mechanically enhanced three-dimensional dual cell-laden construct for osteochondral tissue engineering using a multi-head tissue/organ building system. J. Micromech. Microeng. 22(8), 085014 (2012).
- 93 Cardiac tissue engineering using tissue printing technology and human cardiac progenitor cells. Biomaterials 33(6), 1782–1790 (2012).
- 94 . Alginate hydrogels as biomaterials. Macromol. Biosci. 6(8), 623–633 (2006).
- 95 Cell-laden 3D bioprinting hydrogel matrix depending on different compositions for soft tissue engineering: characterization and evaluation. Mater. Sci. Eng. C. 71, 678–684 (2017).
- 96 . Investigation of cell viability and morphology in 3D bio-printed alginate constructs with tunable stiffness. J. Biomed. Mater. Res. Part A. 105(4), 1009–1018 (2017).
- 97 Well-ordered biphasic calcium phosphate-alginate scaffolds fabricated by multi-channel 3D plotting under mild conditions. J. Mater. Chem. B. 1(33), 4088–4098 (2013).
- 98 Engineering alginate as bioink for bioprinting. Acta. Biomater. 10(10), 4323–4331 (2014).
- 99 Engineering a morphogenetically active hydrogel for bioprinting of bioartificial tissue derived from human osteoblast-like SaOS-2 cells. Biomaterials 35(31), 8810–8819 (2014).
- 100 Stability of hydrogels used in cell encapsulation: an in vitro comparison of alginate and agarose. Biotechnol. Bioeng. 50(4), 374–381 (1996).
- 101 Synthesis of poly(ethylene glycol)-based hydrogels via amine-michael type addition with tunable stiffness and postgelation chemical functionality. Chem. Mater. 26(12), 3624–3630 (2014).
- 102 Shear-thinning supramolecular hydrogels with secondary autonomous covalent crosslinking to modulate viscoelastic properties in vivo. Adv. Funct. Mater. 25(4), 636–644 (2015).
- 103 . Injectable oxidized hyaluronic acid/adipic acid dihydrazide hydrogel for nucleus pulposus regeneration. Acta. Biomater. 6(8), 3044–3055 (2010).
- 104 A multimaterial bioink method for 3D printing tunable, cell-compatible hydrogels. Adv Mater. 27(9), 1607–1614 (2015).
- 105 Bioprinting for cancer research. Trends Biotechnol. 33(9), 504–513 (2015).
- 106 3D bioprinting for drug discovery and development in pharmaceutics. Acta Biomater. 57, 26–46 (2017).
- 107 . Printing technologies for medical applications. Trends. Mol. Med. 22(3), 254–255 (2016).
- 108 . 3D bioprinting: a new insight into the therapeutic strategy of neural tissue regeneration. Organogenesis 11(4), 153–158 (2015).
- 109 3D bioprinting for vascularized tissue fabrication. Ann. Biomed. Eng. 45(1), 132–147 (2017).
- 110 3D bioprinting technologies for hard tissue and organ engineering. Mater. 9(10), 802–824 (2016).
- 111 . Three-dimensional bioprinting emerging technology in cardiovascular medicine. Circulation 135(14), 1281–1283 (2017).
- 112 3D bioprinting for tissue and organ fabrication. Ann. Biomed. Eng. 45(1), 148–163 (2017).
- 113 Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11(9), 768–774 (2012).
- 114 Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl Acad. Sci. USA 113(12), 3179–3184 (2016). •• Opens new avenues for fabricating and investigating human tissues for both ex vivo and in vivo applications.
- 115 Direct 3D bioprinting of perfusable vascular constructs using a blend bioink. Biomaterials 106, 58–68 (2016).
- 116 3D bioprinting of vessel-like structures with multilevel fluidic channels. ACS Biomater. Sci. Eng. 3(3), 399–408 (2017).
- 117 A novel method for fabricating engineered structures with branched micro-channel using hollow hydrogel fibers. Biomicrofluidics 10(6), 064106 (2016).
- 118 . Bioprinting for vascular and vascularized tissue biofabrication. Acta Biomater. 51, 1–20 (2017).
- 119 . Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions. Expert Opin. Biol. Ther. 15(8), 1–18 (2015).
- 120 Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction. Biomaterials 61, 339–348 (2015).
- 121 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. Biomaterials 112, 264–274 (2017).
- 122 Functional 3D neural mini-tissues from printed gel-based bioink and human neural stem cells. Adv. Healthcare Mater. 5(12), 1429–1438 (2016).
- 123 Human skin 3D bioprinting using scaffold-free approach. Adv. Healthcare Mater. 6(4), 1601101 (2017).
- 124 3D Bioprinting of developmentally inspired templates for whole bone organ engineering. Adv. Healthcare Mater. 5(18), 2353–2362 (2016). •• Describes a novel biofabrication strategy for engineering whole-bone organs.
- 125 Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting. Proc. Natl Acad. Sci. USA 113(8), 2206–2211 (2016). •• Demonstrates great potential to serve as a patient-specific platform for pathophysiological studies, early drug screening and clinical translation.
- 126 . In situ elasticity modulation with dynamic substrates to direct cell phenotype. Biomaterials 31(1), 1–8 (2010).
- 127 . State-of-the-art review of 3D bioprinting for cardiovascular tissue engineering. Ann. Biomed. Eng. 45(1), 1–15 (2016).
- 128 . Bioprinting a cardiac valve. Biotechnol. Adv. 33(8), 1503–1521 (2015).
- 129 Biofabrication and testing of a fully cellular nerve graft. Biofabrication 5(4), 045007 (2013).
- 130 3D printing of layered brain-like structures using peptide modified gellan gum substrates. Biomaterials 67, 264–273 (2015).
- 131 Tissue engineered skin substitutes created by laser-assisted bioprinting form skin-like structures in the dorsal skin fold chamber in mice. PLoS ONE 8(3), e57741 (2013).
- 132 Skin tissue generation by laser cell printing. Biotechnol. Bioeng. 109(7), 1855–1863 (2012).
- 133 3D bioprinting of functional human skin: production and in vivo analysis. Biofabrication 9(1), 015006 (2017).
- 134 3D bioprinted extracellular matrix mimics facilitate directed differentiation of epithelial progenitors for sweat gland regeneration. Acta. Biomater. 32, 170–177 (2016). •• Example of functional bioprinted organ model with demonstrable applicability.
- 135 . Bioprinting scale-up tissue and organ constructs for transplantation. Trends Biotechnol. 33(7), 395–400 (2015).
- 136 A synthetic thermosensitive hydrogel for cartilage bioprinting and its biofunctionalization with polysaccharides. Biomacromolecules 17(6), 2137–2147 (2016).
- 137 Hybrid printing of mechanically and biologically improved constructs for cartilage tissue engineering applications. Biofabrication 5(1), 015001 (2013).
- 138 3D-bioprinting of polylactic acid (PLA) nanofiber-alginate hydrogel bioink containing human adipose-derived stem cells. ACS Biomater. Sci. Eng. 2(10), 1732–1742 (2016).
- 139 3D bioprinting of spatially heterogeneous collagen constructs for cartilage tissue engineering. ACS Biomater. Sci. Eng. 2(10), 1800–1805 (2016).
- 140 Biofabrication of tissue constructs by 3D bioprinting of cell-laden microcarriers. Biofabrication 6(3), 035020 (2014).
- 141 . Active mixing of complex fluids at the microscale. Proc. Natl Acad. Sci. USA 112(40), 12293–12298 (2015).
- 142 Three-dimensional bioprinting of multilayered constructs containing human mesenchymal stromal cells for osteochondral tissue regeneration in the rabbit knee joint. Biofabrication 8(1), 014102 (2016).
- 143 . Advances in three-dimensional bioprinting for hard tissue engineering. Tissue Eng. Regen. Med. 13(6), 622–635 (2016).
- 144 Development of a 3D cell printed construct considering angiogenesis for liver tissue engineering. Biofabrication 8(1), 015007 (2016).
- 145 3D printing of composite tissue with complex shape applied to ear regeneration. Biofabrication 6(2), 024103 (2014).
- 146 A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat. Commun. 8, 15261 (2017).
- 147 . Single cell epitaxy by acoustic picolitre droplets. Lab on A Chip 7(9), 1139–1145 (2007).
- 148 Rapid generation of multiplexed cell cocultures using acoustic droplet ejection followed by aqueous two-phase exclusion patterning. Tissue Eng. Part C Methods 18(9), 647–657 (2012).