Hydrogels: The Next Generation Body Materials for Microfluidic Chips?

The integration of microfluidics with biomedical research is confronted with considerable limitations due to its body materials. With high content of water, hydrogels own superior biocompatibility and degradability. Can hydrogels become another material choice for the construction of microfluidic chips, particularly biofluidics? The present review aims to systematically establish the concept of hydrogel-based microfluidic chips (HMCs) and address three main concerns: i) why choosing hydrogels? ii) how to fabricate HMCs?, and iii) in which fields to apply HMCs? It is envisioned that hydrogels may be used increasingly as substitute for traditional materials and gradually act as the body material for microfluidic chips. The modifications of conventional process are highlighted to overcome issues arising from the incompatibility between the construction methods and hydrogel materials. Specifically targeting at the "soft and wet" hydrogels, an efficient flowchart of "i) high resolution template printing; ii) damage-free demolding; iii) twice-crosslinking bonding" is proposed. Accordingly, a broader microfluidic chip concept is proposed in terms of form and function. Potential biomedical applications of HMCs are discussed. This review also highlights the challenges arising from the material replacement, as well as the future directions of the proposed concept. Finally, the authors' viewpoints and perspectives for this emerging field are discussed.

[1]  Jianhua Qin,et al.  Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip , 2019, Advances in Materials.

[2]  Xu Hou,et al.  Design, Fabrication, Properties and Applications of Smart and Advanced Materials , 2016 .

[3]  A. Khademhosseini,et al.  Microfluidic fabrication of microengineered hydrogels and their application in tissue engineering. , 2012, Lab on a chip.

[4]  Dai Fukumura,et al.  Engineering vascularized tissue , 2005, Nature Biotechnology.

[5]  Jae Hong Park,et al.  Microporous cell‐laden hydrogels for engineered tissue constructs , 2010, Biotechnology and bioengineering.

[6]  Amanda C. Engler,et al.  Dual-Responsive Hydrogels for Direct-Write 3D Printing , 2015 .

[7]  D. Mooney,et al.  Hydrogels for tissue engineering. , 2001, Chemical Reviews.

[8]  Jianzhong Fu,et al.  Vessel-on-a-chip with Hydrogel-based Microfluidics. , 2018, Small.

[9]  Wenwen Chen,et al.  Engineering human islet organoids from iPSCs using an organ-on-chip platform. , 2019, Lab on a chip.

[10]  M. Djabourov,et al.  Influence of thermal treatments on the structure and stability of gelatin gels , 1983 .

[11]  Yuanjin Zhao,et al.  Microfluidic Electrospray Niacin Metal-Organic Frameworks Encapsulated Microcapsules for Wound Healing , 2019, Research.

[12]  D. Cho,et al.  Coaxial Cell Printing of Freestanding, Perfusable, and Functional In Vitro Vascular Models for Recapitulation of Native Vascular Endothelium Pathophysiology , 2018, Advanced healthcare materials.

[13]  P. Menasché,et al.  Use of the acyl azide method for cross-linking collagen-rich tissues such as pericardium. , 1990, Journal of biomedical materials research.

[14]  Richard M Crooks,et al.  Hydrogel-based microreactors as a functional component of microfluidic systems. , 2002, Analytical chemistry.

[15]  J. Wikswo,et al.  Effects of flow and diffusion on chemotaxis studies in a microfabricated gradient generator. , 2005, Lab on a chip.

[16]  Vernella Vickerman,et al.  Design, fabrication and implementation of a novel multi-parameter control microfluidic platform for three-dimensional cell culture and real-time imaging. , 2008, Lab on a chip.

[17]  M Cornelissen,et al.  Structural and rheological properties of methacrylamide modified gelatin hydrogels. , 2000, Biomacromolecules.

[18]  Ronan M. T. Fleming,et al.  Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices. , 2015, Biosensors & bioelectronics.

[19]  R. Kamm,et al.  In Vitro Model of Tumor Cell Extravasation , 2013, PloS one.

[20]  Matthias P Lutolf,et al.  Biomaterials meet microfluidics: building the next generation of artificial niches. , 2011, Current opinion in biotechnology.

[21]  Mark W. Tibbitt,et al.  Hydrogels as extracellular matrix mimics for 3D cell culture. , 2009, Biotechnology and bioengineering.

[22]  Duc-Huy T Nguyen,et al.  Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro , 2013, Proceedings of the National Academy of Sciences.

[23]  S. Nishikawa,et al.  Embryonic stem-cell culture as a tool for developmental cell biology , 2007, Nature Reviews Molecular Cell Biology.

[24]  Xin Zhao,et al.  Microfluidic Generation of Nanomaterials for Biomedical Applications. , 2020, Small.

[25]  Jungmok You,et al.  Microfluidic fabrication of bioactive microgels for rapid formation and enhanced differentiation of stem cell spheroids. , 2016, Acta biomaterialia.

[26]  Hongkai Wu,et al.  Gradient‐Regulated Hydrogel for Interface Tissue Engineering: Steering Simultaneous Osteo/Chondrogenesis of Stem Cells on a Chip , 2013, Advanced healthcare materials.

[27]  Zhiyuan Zhong,et al.  Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering. , 2014, Biomaterials.

[28]  F. Sonntag,et al.  A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. , 2015, Lab on a chip.

[29]  Albert J. Keung,et al.  Progress and prospects for stem cell engineering. , 2011, Annual review of chemical and biomolecular engineering.

[30]  Luke M. Geever,et al.  Thermal behavior and mechanical properties of physically crosslinked PVA/Gelatin hydrogels. , 2010, Journal of the mechanical behavior of biomedical materials.

[31]  Li Lin,et al.  Rheological study on 3D printability of alginate hydrogel and effect of graphene oxide , 2016 .

[32]  Ruey-Jen Yang,et al.  A glass microfluidic chip adhesive bonding method at room temperature , 2006 .

[33]  Jianzhong Fu,et al.  Rapid Customization of 3D Integrated Microfluidic Chips via Modular Structure-Based Design. , 2017, ACS biomaterials science & engineering.

[34]  J. Feijen,et al.  Crosslinking of dermal sheep collagen using hexamethylene diisocyanate , 1995 .

[35]  Kytai Truong Nguyen,et al.  Photopolymerizable hydrogels for tissue engineering applications. , 2002, Biomaterials.

[36]  D. Beebe,et al.  Responsive biomimetic hydrogel valve for microfluidics , 2001 .

[37]  Jianzhong Fu,et al.  Micro/nanofabrication of brittle hydrogels using 3D printed soft ultrafine fiber molds for damage-free demolding , 2019, Biofabrication.

[38]  Christopher S. Chen,et al.  Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. , 2004, Developmental cell.

[39]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

[40]  P. Mali,et al.  Facile Engineering of Long‐Term Culturable Ex Vivo Vascularized Tissues Using Biologically Derived Matrices , 2018, Advanced healthcare materials.

[41]  D. Huh,et al.  Organs-on-chips at the frontiers of drug discovery , 2015, Nature Reviews Drug Discovery.

[42]  Jianzhong Fu,et al.  Electro-Assisted Bioprinting of Low-Concentration GelMA Microdroplets. , 2019, Small.

[43]  Jianzhong Fu,et al.  Construction of multi-scale vascular chips and modelling of the interaction between tumours and blood vessels , 2020 .

[44]  P. Tresco,et al.  Technology of mammalian cell encapsulation. , 2000, Advanced drug delivery reviews.

[45]  T. Chandy,et al.  Chitosan--as a biomaterial. , 1990, Biomaterials, artificial cells, and artificial organs.

[46]  R. Kamm,et al.  Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels , 2012, Nature Protocols.

[47]  S. Bhatia,et al.  Fabrication of 3D hepatic tissues by additive photopatterning of cellular hydrogels , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  Chaenyung Cha,et al.  25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine , 2014, Advanced materials.

[49]  Gwo-Bin Lee,et al.  A fast prototyping process for fabrication of microfluidic systems on soda-lime glass , 2001 .

[50]  A. Khademhosseini,et al.  Microscale technologies for tissue engineering and biology. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Feng Xu,et al.  The assembly of cell-encapsulating microscale hydrogels using acoustic waves. , 2011, Biomaterials.

[52]  Yuanjin Zhao,et al.  NK Cell-Encapsulated Porous Microspheres via Microfluidic Electrospray for Tumor Immunotherapy. , 2019, ACS applied materials & interfaces.

[53]  Weihua Huang,et al.  Engineering interconnected 3D vascular networks in hydrogels using molded sodium alginate lattice as the sacrificial template. , 2014, Lab on a chip.

[54]  J. Kopeček,et al.  Hydrogels as smart biomaterials , 2007 .

[55]  Rossana E. Madrid,et al.  Microfluidics and hydrogel: A powerful combination , 2019 .

[56]  D J Beebe,et al.  Gelatin based microfluidic devices for cell culture. , 2006, Lab on a chip.

[57]  D. Beebe,et al.  Physics and applications of microfluidics in biology. , 2002, Annual review of biomedical engineering.

[58]  Ying Zheng,et al.  In vitro microvessels for the study of angiogenesis and thrombosis , 2012, Proceedings of the National Academy of Sciences.

[59]  Duc-Huy T Nguyen,et al.  Fluid shear stress threshold regulates angiogenic sprouting , 2014, Proceedings of the National Academy of Sciences.

[60]  A. Khademhosseini,et al.  Hydrogel bioprinted microchannel networks for vascularization of tissue engineering constructs. , 2014, Lab on a chip.

[61]  A. Sanati‐Nezhad,et al.  Geomaterial‐Functionalized Microfluidic Devices Using a Universal Surface Modification Approach , 2019, Advanced Materials Interfaces.

[62]  Gang Zhao,et al.  All-Aqueous-Phase Microfluidics for Cell Encapsulation. , 2019, ACS applied materials & interfaces.

[63]  Vivek Gupta,et al.  Microfluidics‐based 3D cell culture models: Utility in novel drug discovery and delivery research , 2016, Bioengineering & translational medicine.

[64]  Sebastian J Maerkl,et al.  Integration column: Microfluidic high-throughput screening. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[65]  Dae Kun Hwang,et al.  Microfluidic-based synthesis of non-spherical magnetic hydrogel microparticles. , 2008, Lab on a chip.

[66]  L. Fu,et al.  Microfluidic Mixing: A Review , 2011, International journal of molecular sciences.

[67]  S. Yoo,et al.  On‐demand three‐dimensional freeform fabrication of multi‐layered hydrogel scaffold with fluidic channels , 2010, Biotechnology and bioengineering.

[68]  Jennifer L. West,et al.  Three-dimensional micropatterning of bioactive hydrogels via two-photon laser scanning photolithography for guided 3D cell migration. , 2008, Biomaterials.

[69]  J. Lewis,et al.  Omnidirectional Printing of 3D Microvascular Networks , 2011, Advanced materials.

[70]  Ali Khademhosseini,et al.  Micromolding of shape-controlled, harvestable cell-laden hydrogels. , 2006, Biomaterials.

[71]  Stephanie J Bryant,et al.  Controlling the spatial distribution of ECM components in degradable PEG hydrogels for tissue engineering cartilage. , 2003, Journal of biomedical materials research. Part A.

[72]  Ali Khademhosseini,et al.  Mechanically robust and bioadhesive collagen and photocrosslinkable hyaluronic acid semi-interpenetrating networks. , 2009, Tissue engineering. Part A.

[73]  P. Devreotes,et al.  Chemotaxis: signalling the way forward , 2004, Nature Reviews Molecular Cell Biology.

[74]  Peng Zhao,et al.  3D printed Lego®-like modular microfluidic devices based on capillary driving , 2018, Biofabrication.

[75]  Y. S. Zhang,et al.  Bioprinted thrombosis-on-a-chip. , 2016, Lab on a chip.

[76]  A. Khademhosseini,et al.  Cell-laden microengineered gelatin methacrylate hydrogels. , 2010, Biomaterials.

[77]  D. Muller,et al.  Hanying Li in Agarose Hydrogels Visualizing the 3 D Internal Structure of Calcite Single Crystals Grown , 2010 .

[78]  Dursun Saraydın,et al.  Swelling equilibria and dye adsorption studies of chemically crosslinked superabsorbent acrylamide/maleic acid hydrogels , 2002 .

[79]  Hanry Yu,et al.  Towards a human-on-chip: culturing multiple cell types on a chip with compartmentalized microenvironments. , 2009, Lab on a chip.

[80]  Joe Tien,et al.  Formation of perfused, functional microvascular tubes in vitro. , 2006, Microvascular research.

[81]  Frédéric Reymond,et al.  Polymer microfluidic chips for electrochemical and biochemical analyses , 2002, Electrophoresis.

[82]  M. Ansari,et al.  Biomaterials for repair and regeneration of the cartilage tissue , 2018, Bio-Design and Manufacturing.

[83]  A. Khademhosseini,et al.  Building Vascular Networks , 2012, Science Translational Medicine.

[84]  David J Beebe,et al.  Characterization of a membrane-based gradient generator for use in cell-signaling studies. , 2006, Lab on a chip.

[85]  François Gallaire,et al.  Microchannel deformations due to solvent-induced PDMS swelling. , 2010, Lab on a chip.

[86]  K. Cheung,et al.  Alginate-based microfluidic system for tumor spheroid formation and anticancer agent screening , 2010, Biomedical microdevices.

[87]  Shannon E Bakarich,et al.  Extrusion printing of ionic-covalent entanglement hydrogels with high toughness. , 2013, Journal of materials chemistry. B.

[88]  Robin H. Liu,et al.  Functional hydrogel structures for autonomous flow control inside microfluidic channels , 2000, Nature.

[89]  Wei Zhu,et al.  Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture. , 2017, Biomaterials.

[90]  Mingming Wu,et al.  Cooperative Roles of SDF-1α and EGF Gradients on Tumor Cell Migration Revealed by a Robust 3D Microfluidic Model , 2013, PloS one.

[91]  Patrick S Doyle,et al.  Permeation-driven flow in poly(dimethylsiloxane) microfluidic devices. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Yong He,et al.  3D Printed Paper-Based Microfluidic Analytical Devices , 2016, Micromachines.

[93]  Ali Khademhosseini,et al.  Development of functional biomaterials with micro‐ and nanoscale technologies for tissue engineering and drug delivery applications , 2014, Journal of tissue engineering and regenerative medicine.

[94]  Jason P. Gleghorn,et al.  Microfluidic scaffolds for tissue engineering. , 2007, Nature materials.

[95]  J. Lewis,et al.  Chaotic mixing in three-dimensional microvascular networks fabricated by direct-write assembly , 2003, Nature materials.

[96]  N. Peppas,et al.  Crosslinked poly(vinyl alcohol) hydrogels as swollen elastic networks , 1977 .

[97]  M. Menger,et al.  Vascularization in Tissue Engineering: Angiogenesis versus Inosculation , 2012, European Surgical Research.

[98]  S. Tay,et al.  Microfluidic cell culture. , 2014, Current opinion in biotechnology.

[99]  Mingqiang Li,et al.  Cell-laden microfluidic microgels for tissue regeneration. , 2016, Lab on a chip.

[100]  John A Rogers,et al.  A photocurable poly(dimethylsiloxane) chemistry designed for soft lithographic molding and printing in the nanometer regime. , 2003, Journal of the American Chemical Society.

[101]  Liang Ma,et al.  Coaxial nozzle-assisted 3D bioprinting with built-in microchannels for nutrients delivery. , 2015, Biomaterials.

[102]  P. Vlachos,et al.  Three-dimensional microfluidic collagen hydrogels for investigating flow-mediated tumor-endothelial signaling and vascular organization. , 2014, Tissue engineering. Part C, Methods.

[103]  H. Craighead,et al.  Fabrication of an artificial 3-dimensional vascular network using sacrificial sugar structures , 2009 .

[104]  S. Bryant,et al.  Cell encapsulation in biodegradable hydrogels for tissue engineering applications. , 2008, Tissue engineering. Part B, Reviews.

[105]  Ali Khademhosseini,et al.  SAM-based cell transfer to photopatterned hydrogels for microengineering vascular-like structures. , 2011, Biomaterials.

[106]  D. Beebe,et al.  Fundamentals of microfluidic cell culture in controlled microenvironments. , 2010, Chemical Society reviews.

[107]  Mark A. Skylar-Scott,et al.  Three-dimensional bioprinting of thick vascularized tissues , 2016, Proceedings of the National Academy of Sciences.

[108]  Milica Radisic,et al.  Medium perfusion enables engineering of compact and contractile cardiac tissue. , 2004, American journal of physiology. Heart and circulatory physiology.

[109]  Dong-Woo Cho,et al.  One-step fabrication of an organ-on-a-chip with spatial heterogeneity using a 3D bioprinting technology. , 2016, Lab on a chip.

[110]  J. Gennisson,et al.  Sol-gel transition in agar-gelatin mixtures studied with transient elastography , 2006, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[111]  M. E. van der Rest,et al.  Collagen family of proteins , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[112]  T. Kurokawa,et al.  Double‐Network Hydrogels with Extremely High Mechanical Strength , 2003 .

[113]  A. Orekhov,et al.  Effects of shear stress on endothelial cells: go with the flow , 2017, Acta physiologica.

[114]  Jie Hao,et al.  Three-dimensional bio-printing , 2015, Science China Life Sciences.

[115]  C. Highley,et al.  Complex 3D‐Printed Microchannels within Cell‐Degradable Hydrogels , 2018, Advanced Functional Materials.

[116]  Christopher S. Chen,et al.  Manipulation of cell-cell adhesion using bowtie-shaped microwells. , 2007, Methods in molecular biology.

[117]  L. Suggs,et al.  Dynamic phototuning of 3D hydrogel stiffness , 2015, Proceedings of the National Academy of Sciences.

[118]  Roger D Kamm,et al.  Microfluidic devices for studying heterotypic cell-cell interactions and tissue specimen cultures under controlled microenvironments. , 2011, Biomicrofluidics.

[119]  A. Lee,et al.  Alternating droplet generation and controlled dynamic droplet fusion in microfluidic device for CdS nanoparticle synthesis. , 2006, Lab on a chip.

[120]  C. Colton,et al.  Oxygen supply to encapsulated therapeutic cells. , 2014, Advanced drug delivery reviews.

[121]  S. Quake,et al.  Microfluidics: Fluid physics at the nanoliter scale , 2005 .

[122]  Kenneth M. Yamada,et al.  Cell migration in 3D matrix. , 2005, Current opinion in cell biology.

[123]  A. Khademhosseini,et al.  Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. , 2015, Biomaterials.

[124]  Frantisek Svec,et al.  Injection molded microfluidic chips featuring integrated interconnects. , 2006, Lab on a chip.

[125]  T. Kurokawa,et al.  A novel double-network hydrogel induces spontaneous articular cartilage regeneration in vivo in a large osteochondral defect. , 2009, Macromolecular bioscience.

[126]  Alicia C B Allen,et al.  Multilayer microfluidic PEGDA hydrogels. , 2010, Biomaterials.

[127]  Y. S. Zhang,et al.  Three-dimensional bioprinting of gelatin methacryloyl (GelMA) , 2018, Bio-Design and Manufacturing.

[128]  Joe Tien,et al.  Fabrication of microfluidic hydrogels using molded gelatin as a sacrificial element. , 2007, Lab on a chip.

[129]  A. Khademhosseini,et al.  A cell-laden microfluidic hydrogel. , 2007, Lab on a chip.

[130]  Yaxiong Liu,et al.  Fabrication of circular microfluidic network in enzymatically-crosslinked gelatin hydrogel. , 2016, Materials science & engineering. C, Materials for biological applications.

[131]  Rapid and cost-effective fabrication of selectively permeable calcium-alginate microfluidic device using "modified" embedded template method. , 2012, Biomicrofluidics.

[132]  G. Whitesides,et al.  Micropatterned agarose gels for stamping arrays of proteins and gradients of proteins , 2004, Proteomics.

[133]  R. Hill,et al.  Effects of bacterial communities on biofuel-producing microalgae: stimulation, inhibition and harvesting , 2016, Critical reviews in biotechnology.

[134]  Luoran Shang,et al.  Bioinspired living structural color hydrogels , 2018, Science Robotics.

[135]  Justine J. Roberts,et al.  Degradation Improves Tissue Formation in (Un)Loaded Chondrocyte-laden Hydrogels , 2011, Clinical orthopaedics and related research.

[136]  Xingyu Jiang,et al.  Modular microfluidics for gradient generation. , 2008, Lab on a chip.

[137]  J. Lewis,et al.  3D Bioprinting of Vascularized, Heterogeneous Cell‐Laden Tissue Constructs , 2014, Advanced materials.

[138]  J. Hubbell,et al.  Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering , 2005, Nature Biotechnology.

[139]  Ying Luo,et al.  A photolabile hydrogel for guided three-dimensional cell growth and migration , 2004, Nature materials.

[140]  Alexander K. Nguyen,et al.  Hydrogel-based microfluidics for vascular tissue engineering , 2016 .

[141]  V. Weaver,et al.  Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis. , 2016, Cold Spring Harbor symposia on quantitative biology.

[142]  G. Whitesides,et al.  Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). , 1998, Analytical chemistry.

[143]  D. Mooney,et al.  Hydrogels for tissue engineering: scaffold design variables and applications. , 2003, Biomaterials.

[144]  G. Whitesides,et al.  Fabrication of microfluidic systems in poly(dimethylsiloxane) , 2000, Electrophoresis.

[145]  Roger D Kamm,et al.  In vitro 3D collective sprouting angiogenesis under orchestrated ANG-1 and VEGF gradients. , 2011, Lab on a chip.

[146]  Brendon M. Baker,et al.  Rapid casting of patterned vascular networks for perfusable engineered 3D tissues , 2012, Nature materials.

[147]  H. Sheardown,et al.  Glucose permeable poly (dimethyl siloxane) poly (N-isopropyl acrylamide) interpenetrating networks as ophthalmic biomaterials. , 2005, Biomaterials.

[148]  C. Parent,et al.  A cell's sense of direction. , 1999, Science.

[149]  J. Berg,et al.  Studies on surface wettability of poly(dimethyl) siloxane (PDMS) and glass under oxygen-plasma treatment and correlation with bond strength , 2005, Journal of Microelectromechanical Systems.

[150]  Curtis W. Frank,et al.  A microfluidic actuator based on thermoresponsive hydrogels , 2003 .

[151]  L. Griffith,et al.  Capturing complex 3D tissue physiology in vitro , 2006, Nature Reviews Molecular Cell Biology.

[152]  Mingming Wu,et al.  A hydrogel-based microfluidic device for the studies of directed cell migration. , 2007, Lab on a chip.

[153]  G M Whitesides,et al.  Patterning cells and their environments using multiple laminar fluid flows in capillary networks. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[154]  B. Rodriguez,et al.  Liquid-phase 3D bioprinting of gelatin alginate hydrogels: influence of printing parameters on hydrogel line width and layer height , 2019, Bio-Design and Manufacturing.

[155]  Jason P. Gleghorn,et al.  A microfluidic biomaterial. , 2005, Journal of the American Chemical Society.

[156]  M. Mosesson Fibrinogen and fibrin structure and functions , 2005, Journal of thrombosis and haemostasis : JTH.

[157]  A. Khademhosseini,et al.  Hydrogels in Regenerative Medicine , 2009, Advanced materials.

[158]  Vittorio Cristini,et al.  Monodispersed microfluidic droplet generation by shear focusing microfluidic device , 2006 .

[159]  Matthew B Hoy 3D Printing: Making Things at the Library , 2013, Medical reference services quarterly.

[160]  D. Ingber,et al.  From 3D cell culture to organs-on-chips. , 2011, Trends in cell biology.

[161]  H. Kasai,et al.  Implementation of tetra-poly(ethylene glycol) hydrogel with high mechanical strength into microfluidic device technology. , 2013, Biomicrofluidics.

[162]  Matthias W Laschke,et al.  Prevascularization in tissue engineering: Current concepts and future directions. , 2016, Biotechnology advances.

[163]  C. S. Chen,et al.  Geometric control of cell life and death. , 1997, Science.

[164]  A. Khademhosseini,et al.  Hydrogels in Biology and Medicine: From Molecular Principles to Bionanotechnology , 2006 .

[165]  Zhongze Gu,et al.  Bio-inspired self-healing structural color hydrogel , 2017, Proceedings of the National Academy of Sciences.

[166]  Roman Stocker,et al.  Bacterial chemotaxis in linear and nonlinear steady microfluidic gradients. , 2010, Nano letters.

[167]  F. Omenetto,et al.  Bio‐microfluidics: Biomaterials and Biomimetic Designs , 2010, Advanced materials.

[168]  Tomitake Tsukihara,et al.  Spatiotemporal protein crystal growth studies using microfluidic silicon devices , 1999 .

[169]  T. Johnson,et al.  Rapid microfluidic mixing. , 2002, Analytical chemistry.

[170]  T. Boland,et al.  Human microvasculature fabrication using thermal inkjet printing technology. , 2009, Biomaterials.

[171]  J. Qin,et al.  Stimulation of chondrocytes and chondroinduced mesenchymal stem cells by osteoinduced mesenchymal stem cells under a fluid flow stimulus on an integrated microfluidic device , 2017, Molecular medicine reports.

[172]  S. Yoo,et al.  Creating perfused functional vascular channels using 3D bio-printing technology. , 2014, Biomaterials.

[173]  Shaochen Chen,et al.  Light-assisted direct-write of 3D functional biomaterials. , 2014, Lab on a chip.

[174]  Bahareh Behkam,et al.  A PEG-DA microfluidic device for chemotaxis studies , 2013 .

[175]  O. Wichterle,et al.  Hydrophilic Gels for Biological Use , 1960, Nature.

[176]  Xu Li,et al.  Flow control concepts for thread-based microfluidic devices. , 2011, Biomicrofluidics.

[177]  Robert Langer,et al.  Micromolding of photocrosslinkable hyaluronic acid for cell encapsulation and entrapment. , 2006, Journal of biomedical materials research. Part A.

[178]  Donald E Ingber,et al.  Microengineered physiological biomimicry: organs-on-chips. , 2012, Lab on a chip.

[179]  Michael S Detamore,et al.  Hierarchically designed agarose and poly(ethylene glycol) interpenetrating network hydrogels for cartilage tissue engineering. , 2010, Tissue engineering. Part C, Methods.

[180]  F. Mizutani,et al.  Use of Polydimethylsiloxane for Constructing Amperometric Glucose-Sensing Enzyme Electrode with Low Interference Level , 2001 .

[181]  Masayoshi Esashi,et al.  Silicon carbide micro-reaction-sintering using micromachined silicon molds , 2001 .

[182]  Tae Jin Kim,et al.  A rapid and simple fabrication method for 3-dimensional circular microfluidic channel using metal wire removal process , 2010 .

[183]  Albert Folch,et al.  Measurement of cell migration in response to an evolving radial chemokine gradient triggered by a microvalve. , 2006, Lab on a chip.

[184]  M. Dadsetan,et al.  Effect of hydrogel porosity on marrow stromal cell phenotypic expression. , 2008, Biomaterials.

[185]  Xin Zhao,et al.  Human-on-Leaf-Chip: A Biomimetic Vascular System Integrated with Chamber-Specific Organs. , 2020, Small.

[186]  R. Kamm,et al.  Microfluidic models of vascular functions. , 2012, Annual review of biomedical engineering.

[187]  Tadashi Sasagawa,et al.  Pre-vascularization of in vitro three-dimensional tissues created by cell sheet engineering. , 2010, Biomaterials.

[188]  Celeste M Nelson,et al.  Cell‐cell signaling by direct contact increases cell proliferation via a PI3K‐dependent signal , 2002, FEBS letters.

[189]  J. West Protein-patterned hydrogels: Customized cell microenvironments. , 2011, Nature materials.

[190]  A. Kasko,et al.  Shape-Changing Photodegradable Hydrogels for Dynamic 3D Cell Culture. , 2016, ACS applied materials & interfaces.

[191]  Thomas Laurell,et al.  Microfluidic enzyme immunoassay using silicon microchip with immobilized antibodies and chemiluminescence detection. , 2002, Analytical chemistry.

[192]  Jeffrey S. Moore,et al.  Rapid 3D Extrusion of Synthetic Tumor Microenvironments , 2015, Advanced materials.

[193]  Roger D. Kamm,et al.  Microfluidic Platforms for Studies of Angiogenesis, Cell Migration, and Cell–Cell Interactions , 2010, Annals of Biomedical Engineering.

[194]  Xu Hou,et al.  Inner Surface Design of Functional Microchannels for Microscale Flow Control. , 2019, Small.

[195]  A. Khademhosseini,et al.  Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs , 2008, Proceedings of the National Academy of Sciences.

[196]  N. Jeon,et al.  Biological applications of microfluidic gradient devices. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[197]  Gabriel Popescu,et al.  High‐Resolution Projection Microstereolithography for Patterning of Neovasculature , 2016, Advanced healthcare materials.

[198]  S. Li,et al.  Protein release from physically crosslinked hydrogels of the PLA/PEO/PLA triblock copolymer-type. , 2001, Biomaterials.

[199]  M. Lutolf,et al.  Hydrogel microfluidics for the patterning of pluripotent stem cells , 2014, Scientific Reports.

[200]  Yan Yan Shery Huang,et al.  Bioprinting of three-dimensional culture models and organ-on-a-chip systems , 2017 .

[201]  Noo Li Jeon,et al.  Diffusion limits of an in vitro thick prevascularized tissue. , 2005, Tissue engineering.

[202]  R. Xiao,et al.  Bio‐Origami Hydrogel Scaffolds Composed of Photocrosslinked PEG Bilayers , 2013, Advanced healthcare materials.

[203]  Yu-Hsin Lin,et al.  Physically crosslinked alginate/N,O-carboxymethyl chitosan hydrogels with calcium for oral delivery of protein drugs. , 2005, Biomaterials.

[204]  Smart hydrogels containing adenylate kinase: translating substrate recognition into macroscopic motion. , 2008, Journal of the American Chemical Society.

[205]  M. A. Lauffer,et al.  Diffusion measurements in agar gel. , 1962, Biochemistry.

[206]  Hans-Günther Machens,et al.  Hydrogels for Engineering of Perfusable Vascular Networks , 2015, International journal of molecular sciences.

[207]  Po Ki Yuen,et al.  Perfusion-based microfluidic device for three-dimensional dynamic primary human hepatocyte cell culture in the absence of biological or synthetic matrices or coagulants. , 2010, Lab on a chip.

[208]  Wei Sun,et al.  Microfluidic hydrogels for tissue engineering , 2011, Biofabrication.

[209]  Shuichi Takayama,et al.  Regulating microenvironmental stimuli for stem cells and cancer cells using microsystems. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[210]  R. Kamm,et al.  Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function , 2012, Proceedings of the National Academy of Sciences.

[211]  M. Shuler,et al.  A three-channel microfluidic device for generating static linear gradients and its application to the quantitative analysis of bacterial chemotaxis. , 2006, Lab on a chip.

[212]  Liliang Ouyang,et al.  A Generalizable Strategy for the 3D Bioprinting of Hydrogels from Nonviscous Photo‐crosslinkable Inks , 2017, Advanced materials.

[213]  Ali Khademhosseini,et al.  Coaxial extrusion bioprinting of 3D microfibrous constructs with cell-favorable gelatin methacryloyl microenvironments , 2018, Biofabrication.

[214]  Gwo-Bin Lee,et al.  Microfluidic cell culture systems for drug research. , 2010, Lab on a chip.

[215]  C. Luo,et al.  Gel integration for microfluidic applications. , 2016, Lab on a chip.

[216]  Deqing Mei,et al.  Projection-Based 3D Printing of Cell Patterning Scaffolds with Multiscale Channels. , 2018, ACS applied materials & interfaces.

[217]  Paolo A Netti,et al.  Induction of directional sprouting angiogenesis by matrix gradients. , 2007, Journal of biomedical materials research. Part A.

[218]  Jianzhong Fu,et al.  3D Bioprinting of Vessel-like Structures with Multilevel Fluidic Channels. , 2017, ACS biomaterials science & engineering.

[219]  Ali Khademhosseini,et al.  Sequential assembly of cell‐laden hydrogel constructs to engineer vascular‐like microchannels , 2011, Biotechnology and bioengineering.

[220]  Wentao Su,et al.  A Biomimetic Human Gut‐on‐a‐Chip for Modeling Drug Metabolism in Intestine , 2018, Artificial organs.

[221]  Y. S. Zhang,et al.  Interplay between materials and microfluidics. , 2017, Nature reviews. Materials.

[222]  D. Beebe,et al.  Protocol for the fabrication of enzymatically crosslinked gelatin microchannels for microfluidic cell culture , 2007, Nature Protocols.

[223]  Hyunmin Yi,et al.  Biofabrication with chitosan. , 2005, Biomacromolecules.

[224]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[225]  Zhao-Lun Fang,et al.  Bonding of glass microfluidic chips at room temperatures. , 2004, Analytical chemistry.

[226]  D. Lin,et al.  Cross-linking characteristics of biological tissues fixed with monofunctional or multifunctional epoxy compounds. , 1996, Biomaterials.

[227]  John J. Vericella,et al.  High‐Throughput Printing via Microvascular Multinozzle Arrays , 2013, Advanced materials.

[228]  David Beebe,et al.  Engineers are from PDMS-land, Biologists are from Polystyrenia. , 2012, Lab on a chip.

[229]  Jens Anders Branebjerg,et al.  Microfluidics-a review , 1993 .

[230]  P. Carmeliet,et al.  Angiogenesis Revisited: An Overlooked Role of Endothelial Cell Metabolism in Vessel Sprouting , 2015, Microcirculation.

[231]  Sarit B. Bhaduri,et al.  Drop-on-demand printing of cells and materials for designer tissue constructs , 2007 .

[232]  Ali Khademhosseini,et al.  Direct 3D bioprinting of perfusable vascular constructs using a blend bioink. , 2016, Biomaterials.

[233]  M. Yamada,et al.  Facile fabrication processes for hydrogel-based microfluidic devices made of natural biopolymers. , 2014, Biomicrofluidics.

[234]  B Lepioufle,et al.  Study of osteoblastic cells in a microfluidic environment. , 2006, Biomaterials.

[235]  D. Beebe,et al.  Biological implications of polydimethylsiloxane-based microfluidic cell culture. , 2009, Lab on a chip.

[236]  Yong He,et al.  From Microfluidic Paper-Based Analytical Devices to Paper-Based Biofluidics with Integrated Continuous Perfusion. , 2017, ACS biomaterials science & engineering.

[237]  Ashutosh Kumar Singh,et al.  Solid freeform fabrication of designer scaffolds of hyaluronic acid for nerve tissue engineering , 2011, Biomedical microdevices.

[238]  P. Chu,et al.  Vascular lumen simulation and highly-sensitive nitric oxide detection using three-dimensional gelatin chip coupled to TiC/C nanowire arrays microelectrode. , 2012, Lab on a chip.

[239]  Robert Langer,et al.  A 3D Interconnected Microchannel Network Formed in Gelatin by Sacrificial Shellac Microfibers , 2012, Advanced materials.

[240]  Luke P. Lee,et al.  Continuous perfusion microfluidic cell culture array for high-throughput cell-based assays. , 2005, Biotechnology and bioengineering.

[241]  David L. Kaplan,et al.  Microfabricated Porous Silk Scaffolds for Vascularizing Engineered Tissues , 2013 .

[242]  Hanseup Kim,et al.  Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). , 2012, Lab on a chip.

[243]  Li Wang,et al.  Paper supported long-term 3D liver co-culture model for the assessment of hepatotoxic drugs. , 2018, Toxicology research.

[244]  Xavier Intes,et al.  The integration of 3-D cell printing and mesoscopic fluorescence molecular tomography of vascular constructs within thick hydrogel scaffolds. , 2012, Biomaterials.

[245]  Hon Fai Chan,et al.  3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures , 2015, Advanced materials.

[246]  Nupura S. Bhise,et al.  Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels , 2014, Biofabrication.

[247]  G. Whitesides,et al.  Soft lithographic methods for nano-fabrication , 1997 .

[248]  G. Vunjak‐Novakovic,et al.  Engineered microenvironments for controlled stem cell differentiation. , 2009, Tissue engineering. Part A.

[249]  L. Bian,et al.  Influence of decreasing nutrient path length on the development of engineered cartilage. , 2009, Osteoarthritis and cartilage.

[250]  P. Renaud,et al.  Microfluidic patterning of alginate hydrogels , 2007, Biointerphases.

[251]  Joel Voldman,et al.  Fluid shear stress primes mouse embryonic stem cells for differentiation in a self‐renewing environment via heparan sulfate proteoglycans transduction , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[252]  Ali Khademhosseini,et al.  Fabrication of gradient hydrogels using a microfluidics/photopolymerization process. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[253]  D. Pochan,et al.  Rheological properties of peptide-based hydrogels for biomedical and other applications. , 2010, Chemical Society reviews.