Advances in engineering hydrogels

Wet, soft, squishy, and tunable Hydrogels are highly cross-linked polymer networks that are heavily swollen with water. Hydrogels have been used as dynamic, tunable, degradable materials for growing cells and tissues. Zhang and Khademhosseini review the advances in making hydrogels with improved mechanical strength and greater flexibility for use in a wide range of applications. Science, this issue p. eaaf3627 BACKGROUND Hydrogels are formed through the cross-linking of hydrophilic polymer chains within an aqueous microenvironment. The gelation can be achieved through a variety of mechanisms, spanning physical entanglement of polymer chains, electrostatic interactions, and covalent chemical cross-linking. The water-rich nature of hydrogels makes them broadly applicable to many areas, including tissue engineering, drug delivery, soft electronics, and actuators. Conventional hydrogels usually possess limited mechanical strength and are prone to permanent breakage. The lack of desired dynamic cues and structural complexity within the hydrogels has further limited their functions. Broadened applications of hydrogels, however, require advanced engineering of parameters such as mechanics and spatiotemporal presentation of active or bioactive moieties, as well as manipulation of multiscale shape, structure, and architecture. ADVANCES Hydrogels with substantially improved physicochemical properties have been enabled by rational design at the molecular level and control over multiscale architecture. For example, formulations that combine permanent polymer networks with reversibly bonding chains for energy dissipation show strong toughness and stretchability. Similar strategies may also substantially enhance the bonding affinity of hydrogels at interfaces with solids by covalently anchoring the polymer networks of tough hydrogels onto solid surfaces. Shear-thinning hydrogels that feature reversible bonds impart a fluidic nature upon application of shear forces and return back to their gel states once the forces are released. Self-healing hydrogels based on nanomaterial hybridization, electrostatic interactions, and slide-ring configurations exhibit excellent abilities in spontaneously healing themselves after damages. Additionally, harnessing techniques that can dynamically and precisely configure hydrogels have resulted in flexibility to regulate their architecture, activity, and functionality. Dynamic modulations of polymer chain physics and chemistry can lead to temporal alteration of hydrogel structures in a programmed manner. Three-dimensional printing enables architectural control of hydrogels at high precision, with a potential to further integrate elements that enable change of hydrogel configurations along prescribed paths. OUTLOOK We envision the continuation of innovation in new bioorthogonal chemistries for making hydrogels, enabling their fabrication in the presence of biological species without impairing cellular or biomolecule functions. We also foresee opportunities in the further development of more sophisticated fabrication methods that allow better-controlled hydrogel architecture across multiple length scales. In addition, technologies that precisely regulate the physicochemical properties of hydrogels in spatiotemporally controlled manners are crucial in controlling their dynamics, such as degradation and dynamic presentation of biomolecules. We believe that the fabrication of hydrogels should be coupled with end applications in a feedback loop in order to achieve optimal designs through iterations. In the end, it is the combination of multiscale constituents and complementary strategies that will enable new applications of this important class of materials. Engineering functional hydrogels with enhanced physicochemical properties. Advances have been made to improve the mechanical properties of hydrogels as well as to make them shear-thinning, self-healing, and responsive. In addition, technologies have been developed to manipulate the shape, structure, and architecture of hydrogels with enhanced control and spatial precision. Hydrogels are formed from hydrophilic polymer chains surrounded by a water-rich environment. They have widespread applications in various fields such as biomedicine, soft electronics, sensors, and actuators. Conventional hydrogels usually possess limited mechanical strength and are prone to permanent breakage. Further, the lack of dynamic cues and structural complexity within the hydrogels has limited their functions. Recent developments include engineering hydrogels that possess improved physicochemical properties, ranging from designs of innovative chemistries and compositions to integration of dynamic modulation and sophisticated architectures. We review major advances in designing and engineering hydrogels and strategies targeting precise manipulation of their properties across multiple scales.

[1]  Bing Xu,et al.  Supramolecular hydrogels based on biofunctional nanofibers of self-assembled small molecules , 2007 .

[2]  Y. S. Zhang,et al.  An injectable shear-thinning biomaterial for endovascular embolization , 2016, Science Translational Medicine.

[3]  Tiefeng Li,et al.  Supramolecular Lego Assembly Towards Three‐Dimensional Multi‐Responsive Hydrogels , 2014, Advanced materials.

[4]  Ali Khademhosseini,et al.  Surface‐directed assembly of cell‐laden microgels , 2010, Biotechnology and Bioengineering.

[5]  Joseph H. Gorman,et al.  Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition , 2014, Nature materials.

[6]  Ritu Raman,et al.  Optogenetic skeletal muscle-powered adaptive biological machines , 2016, Proceedings of the National Academy of Sciences.

[7]  Wei Zhu,et al.  4D printing smart biomedical scaffolds with novel soybean oil epoxidized acrylate , 2016, Scientific Reports.

[8]  Y. S. Zhang,et al.  Reduced Graphene Oxide-GelMA Hybrid Hydrogels as Scaffolds for Cardiac Tissue Engineering. , 2016, Small.

[9]  A. Khademhosseini,et al.  Bioactive Silicate Nanoplatelets for Osteogenic Differentiation of Human Mesenchymal Stem Cells , 2013, Advanced materials.

[10]  Ali Khademhosseini,et al.  Advancing Tissue Engineering: A Tale of Nano-, Micro-, and Macroscale Integration. , 2016, Small.

[11]  Faisal A. Aldaye,et al.  Organization of Intracellular Reactions with Rationally Designed RNA Assemblies , 2011, Science.

[12]  Shoji Takeuchi,et al.  Long-term in vivo glucose monitoring using fluorescent hydrogel fibers , 2011, Proceedings of the National Academy of Sciences.

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

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

[15]  Xiaodan Gu,et al.  Intrinsically stretchable and healable semiconducting polymer for organic transistors , 2016, Nature.

[16]  J. Hubbell,et al.  Development of growth factor fusion proteins for cell‐triggered drug delivery , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  Y. Li,et al.  Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting , 2016, Proceedings of the National Academy of Sciences.

[18]  Hye Rin Kwag,et al.  Self-Folding Thermo-Magnetically Responsive Soft Microgrippers , 2015, ACS applied materials & interfaces.

[19]  A. Khademhosseini,et al.  Microfluidic Bioprinting of Heterogeneous 3D Tissue Constructs Using Low‐Viscosity Bioink , 2016, Advanced materials.

[20]  Shoji Takeuchi,et al.  Cell Origami: Self-Folding of Three-Dimensional Cell-Laden Microstructures Driven by Cell Traction Force , 2012, PloS one.

[21]  Gulden Camci-Unal,et al.  Elastomeric Recombinant Protein-based Biomaterials. , 2013, Biochemical engineering journal.

[22]  Mark W. Tibbitt,et al.  Dynamic Microenvironments: The Fourth Dimension , 2012, Science Translational Medicine.

[23]  Leonid Ionov,et al.  Hydrogel-based actuators: possibilities and limitations , 2014 .

[24]  Ali Khademhosseini,et al.  Functionalization, preparation and use of cell-laden gelatin methacryloyl–based hydrogels as modular tissue culture platforms , 2016, Nature Protocols.

[25]  Elisabetta A. Matsumoto,et al.  Biomimetic 4 D printing , 2016 .

[26]  C. Werner,et al.  Biohybrid networks of selectively desulfated glycosaminoglycans for tunable growth factor delivery. , 2014, Biomacromolecules.

[27]  S. Stupp,et al.  Self-Assembly and Mineralization of Peptide-Amphiphile Nanofibers , 2001, Science.

[28]  Xuanhe Zhao,et al.  Stretchable Hydrogel Electronics and Devices , 2016, Advanced materials.

[29]  R. Hayward,et al.  Designing Responsive Buckled Surfaces by Halftone Gel Lithography , 2012, Science.

[30]  N. Seeman Nucleic acid junctions and lattices. , 1982, Journal of theoretical biology.

[31]  P. R. van Weeren,et al.  Gelatin-methacrylamide hydrogels as potential biomaterials for fabrication of tissue-engineered cartilage constructs. , 2013, Macromolecular bioscience.

[32]  Ali Khademhosseini,et al.  Engineered cell-laden human protein-based elastomer. , 2013, Biomaterials.

[33]  Ali Khademhosseini,et al.  Nanocomposite hydrogels for biomedical applications. , 2014, Biotechnology and bioengineering.

[34]  byBrooke LaBranche,et al.  3 D bioprinting of tissues and organs , 2017 .

[35]  J. Greener,et al.  Three-dimensional shape transformations of hydrogel sheets induced by small-scale modulation of internal stresses , 2013, Nature Communications.

[36]  Panče Naumov,et al.  Photogated humidity-driven motility , 2015, Nature Communications.

[37]  Jeong-Woo Choi,et al.  Phototactic guidance of a tissue-engineered soft-robotic ray , 2016, Science.

[38]  V. Khutoryanskiy,et al.  Biomedical applications of hydrogels: A review of patents and commercial products , 2015 .

[39]  Feihe Huang,et al.  Self-healing supramolecular gels formed by crown ether based host-guest interactions. , 2012, Angewandte Chemie.

[40]  Harry M. T. Choi,et al.  Programming DNA Tube Circumferences , 2008, Science.

[41]  Kristi S. Anseth,et al.  Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments , 2009 .

[42]  A. Studart,et al.  Multimaterial magnetically assisted 3D printing of composite materials , 2015, Nature Communications.

[43]  Marcel A. Heinrich,et al.  Rapid Continuous Multimaterial Extrusion Bioprinting , 2017, Advanced materials.

[44]  M. Ward,et al.  Thermoresponsive Polymers for Biomedical Applications , 2011 .

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

[46]  Choon Chiang Foo,et al.  Stretchable, Transparent, Ionic Conductors , 2013, Science.

[47]  Mario Miscuglio,et al.  Highly Elastic and Conductive Human‐Based Protein Hybrid Hydrogels , 2016, Advanced materials.

[48]  Zhigang Suo,et al.  Hybrid Hydrogels with Extremely High Stiffness and Toughness. , 2014, ACS macro letters.

[49]  Cheng-Chih Hsu,et al.  Rapid self-healing hydrogels , 2012, Proceedings of the National Academy of Sciences.

[50]  Horst Fischer,et al.  Controlling Shear Stress in 3D Bioprinting is a Key Factor to Balance Printing Resolution and Stem Cell Integrity , 2016, Advanced healthcare materials.

[51]  Xuanhe Zhao,et al.  Skin-inspired hydrogel–elastomer hybrids with robust interfaces and functional microstructures , 2016, Nature Communications.

[52]  James J. Yoo,et al.  A 3D bioprinting system to produce human-scale tissue constructs with structural integrity , 2016, Nature Biotechnology.

[53]  A. Laschewsky,et al.  Tailoring of stimuli-responsive water soluble acrylamide and methacrylamide polymers , 2001 .

[54]  Z. Suo,et al.  Highly stretchable and tough hydrogels , 2012, Nature.

[55]  Jos Malda,et al.  Reinforcement of hydrogels using three-dimensionally printed microfibres , 2015, Nature Communications.

[56]  Akira Harada,et al.  Redox-responsive self-healing materials formed from host–guest polymers , 2011, Nature communications.

[57]  Anna V. Taubenberger,et al.  3D extracellular matrix interactions modulate tumour cell growth, invasion and angiogenesis in engineered tumour microenvironments. , 2016, Acta biomaterialia.

[58]  David A Tirrell,et al.  A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels. , 2015, Nature materials.

[59]  Y. S. Zhang,et al.  Hydrophobic Hydrogels: Toward Construction of Floating (Bio)microdevices , 2016 .

[60]  D J Mooney,et al.  Alginate hydrogels as synthetic extracellular matrix materials. , 1999, Biomaterials.

[61]  Elisabetta A. Matsumoto,et al.  Biomimetic 4D printing. , 2016, Nature materials.

[62]  P. Yin,et al.  Complex shapes self-assembled from single-stranded DNA tiles , 2012, Nature.

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

[64]  Manish K Jaiswal,et al.  Bioactive nanoengineered hydrogels for bone tissue engineering: a growth-factor-free approach. , 2015, ACS nano.

[65]  M. Djabourov,et al.  Gelation of aqueous gelatin solutions. II. Rheology of the sol-gel transition , 1988 .

[66]  Megan L. McCain,et al.  A tissue-engineered jellyfish with biomimetic propulsion , 2012, Nature Biotechnology.

[67]  Pengrui Wang,et al.  Automation Highlights from the Literature , 2016, Journal of laboratory automation.

[68]  Wim E Hennink,et al.  25th Anniversary Article: Engineering Hydrogels for Biofabrication , 2013, Advanced materials.

[69]  Jason A Burdick,et al.  Moving from static to dynamic complexity in hydrogel design , 2012, Nature Communications.

[70]  Toru Takehisa,et al.  Nanocomposite Hydrogels: A Unique Organic–Inorganic Network Structure with Extraordinary Mechanical, Optical, and Swelling/De‐swelling Properties , 2002 .

[71]  M. Djabourov,et al.  Gelation of aqueous gelatin solutions. I. Structural investigation , 1988 .

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

[73]  A. Khademhosseini,et al.  Shear-Thinning Nanocomposite Hydrogels for the Treatment of Hemorrhage , 2014, ACS nano.

[74]  Malav S. Desai,et al.  Light-controlled graphene-elastin composite hydrogel actuators. , 2013, Nano letters.

[75]  Thomas J Ober,et al.  Microfluidic Printheads for Multimaterial 3D Printing of Viscoelastic Inks , 2015, Advanced materials.

[76]  Kristi S. Anseth,et al.  Photodegradable Hydrogels for Dynamic Tuning of Physical and Chemical Properties , 2009, Science.

[77]  Amir Hosein Sakhaei,et al.  Multimaterial 4D Printing with Tailorable Shape Memory Polymers , 2016, Scientific Reports.

[78]  A. Khademhosseini,et al.  A Highly Elastic and Rapidly Crosslinkable Elastin‐Like Polypeptide‐Based Hydrogel for Biomedical Applications , 2015, Advanced functional materials.

[79]  D. Seliktar Designing Cell-Compatible Hydrogels for Biomedical Applications , 2012, Science.

[80]  Z. Suo,et al.  Stiff, strong, and tough hydrogels with good chemical stability. , 2014, Journal of materials chemistry. B.

[81]  Joon Hyung Park,et al.  Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels , 2015, Science Advances.

[82]  Allan S Hoffman,et al.  Hydrogels for biomedical applications. , 2002, Advanced drug delivery reviews.

[83]  Jiaxi Cui,et al.  Multivalent H-bonds for self-healing hydrogels. , 2012, Chemical communications.

[84]  Kristi S. Anseth,et al.  Mechanical memory and dosing influence stem cell fate , 2014, Nature materials.

[85]  Anthony Atala,et al.  3D bioprinting of tissues and organs , 2014, Nature Biotechnology.

[86]  Ali Khademhosseini,et al.  From cardiac tissue engineering to heart-on-a-chip: beating challenges , 2015, Biomedical materials.

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

[88]  Seok Hyun Yun,et al.  Light-guiding hydrogels for cell-based sensing and optogenetic synthesis in vivo , 2013, Nature Photonics.

[89]  Xuanhe Zhao,et al.  Tough Bonding of Hydrogels to Diverse Nonporous Surfaces , 2015, Nature materials.

[90]  K. Shull,et al.  Ionically Cross-Linked Triblock Copolymer Hydrogels with High Strength , 2010 .

[91]  John R. Tumbleston,et al.  Continuous liquid interface production of 3D objects , 2015, Science.

[92]  A. Khademhosseini,et al.  Injectable Graphene Oxide/Hydrogel-Based Angiogenic Gene Delivery System for Vasculogenesis and Cardiac Repair , 2014, ACS nano.

[93]  David J. Mooney,et al.  Harnessing Traction-Mediated Manipulation of the Cell-Matrix Interface to Control Stem Cell Fate , 2010, Nature materials.

[94]  A. Khademhosseini,et al.  DNA directed self-assembly of shape-controlled hydrogels , 2013, Nature Communications.

[95]  Skylar Tibbits,et al.  4D Printing: Multi‐Material Shape Change , 2014 .

[96]  Sanlin S. Robinson,et al.  Highly stretchable electroluminescent skin for optical signaling and tactile sensing , 2016, Science.

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

[98]  Ritu Raman,et al.  Three-dimensionally printed biological machines powered by skeletal muscle , 2014, Proceedings of the National Academy of Sciences.

[99]  F. Crick,et al.  The Structure of Collagen , 1954, Nature.

[100]  Tapomoy Bhattacharjee,et al.  Writing in the granular gel medium , 2015, Science Advances.

[101]  Stephen Z. D. Cheng,et al.  Three-dimensional actuators transformed from the programmed two-dimensional structures via bending, twisting and folding mechanisms , 2011 .

[102]  Xuanhe Zhao,et al.  Strong, Tough, Stretchable, and Self‐Adhesive Hydrogels from Intrinsically Unstructured Proteins , 2017, Advanced materials.

[103]  Matt A. King,et al.  Three-Dimensional Structures Self-Assembled from DNA Bricks , 2012 .

[104]  Tejal A Desai,et al.  Programmed synthesis of three-dimensional tissues , 2015, Nature Methods.

[105]  Adam W Feinberg,et al.  Biological Soft Robotics. , 2015, Annual review of biomedical engineering.

[106]  Kristi S. Anseth,et al.  Cytocompatible Click-based Hydrogels with Dynamically-Tunable Properties Through Orthogonal Photoconjugation and Photocleavage Reactions , 2011, Nature chemistry.

[107]  S. Sen,et al.  Matrix Elasticity Directs Stem Cell Lineage Specification , 2006, Cell.

[108]  Mark W. Tibbitt,et al.  Self-Assembled Hydrogels Utilising Polymer-Nanoparticle Interactions , 2015, Nature Communications.

[109]  Luca Gasperini,et al.  Natural polymers for the microencapsulation of cells , 2014, Journal of The Royal Society Interface.

[110]  P. Dubruel,et al.  The 3D printing of gelatin methacrylamide cell-laden tissue-engineered constructs with high cell viability. , 2014, Biomaterials.

[111]  Kevin E. Shopsowitz,et al.  Scalable Manufacture of Built‐to‐Order Nanomedicine: Spray‐Assisted Layer‐by‐Layer Functionalization of PRINT Nanoparticles , 2013, Advanced materials.

[112]  Cindi M Morshead,et al.  Spatially controlled simultaneous patterning of multiple growth factors in three-dimensional hydrogels. , 2011, Nature materials.

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

[114]  A. Metters,et al.  Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Wei Sun,et al.  Multi‐nozzle deposition for construction of 3D biopolymer tissue scaffolds , 2005 .

[116]  Ramesh Raskar,et al.  Active Printed Materials for Complex Self-Evolving Deformations , 2014, Scientific Reports.

[117]  S. Pérez,et al.  Molecular basis of C(2+)-induced gelation in alginates and pectins: the egg-box model revisited. , 2001, Biomacromolecules.

[118]  C. Highley,et al.  Direct 3D Printing of Shear‐Thinning Hydrogels into Self‐Healing Hydrogels , 2015, Advanced materials.

[119]  A. Khademhosseini,et al.  Carbon-nanotube-embedded hydrogel sheets for engineering cardiac constructs and bioactuators. , 2013, ACS nano.

[120]  Cecilia Laschi,et al.  Soft robotics: a bioinspired evolution in robotics. , 2013, Trends in biotechnology.

[121]  Kristi S. Anseth,et al.  Bioorthogonal Click Chemistry: An Indispensable Tool to Create Multifaceted Cell Culture Scaffolds , 2012, ACS macro letters.

[122]  J. Fallas,et al.  Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. , 2011, Nature chemistry.

[123]  Ali Khademhosseini,et al.  4D bioprinting: the next-generation technology for biofabrication enabled by stimuli-responsive materials , 2016, Biofabrication.

[124]  T. Sakai,et al.  “Nonswellable” Hydrogel Without Mechanical Hysteresis , 2014, Science.

[125]  Xuanhe Zhao,et al.  Multi-scale multi-mechanism design of tough hydrogels: building dissipation into stretchy networks. , 2014, Soft matter.

[126]  C. van Nostrum,et al.  Novel crosslinking methods to design hydrogels. , 2002, Advanced drug delivery reviews.

[127]  Shuguang Zhang Fabrication of novel biomaterials through molecular self-assembly , 2003, Nature Biotechnology.

[128]  K. Ito,et al.  Extremely stretchable thermosensitive hydrogels by introducing slide-ring polyrotaxane cross-linkers and ionic groups into the polymer network , 2014, Nature Communications.

[129]  Jian Ping Gong,et al.  Physical hydrogels composed of polyampholytes demonstrate high toughness and viscoelasticity. , 2013, Nature materials.

[130]  Thomas J Ober,et al.  Active mixing of complex fluids at the microscale , 2015, Proceedings of the National Academy of Sciences.

[131]  Jean-François Lutz,et al.  Point by point comparison of two thermosensitive polymers exhibiting a similar LCST: is the age of poly(NIPAM) over? , 2006, Journal of the American Chemical Society.

[132]  David J. Mooney,et al.  Active scaffolds for on-demand drug and cell delivery , 2010, Proceedings of the National Academy of Sciences.

[133]  C. Werner,et al.  TGFβ functionalized starPEG-heparin hydrogels modulate human dermal fibroblast growth and differentiation. , 2015, Acta biomaterialia.

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

[135]  A. Khademhosseini,et al.  Aligned Carbon Nanotube–Based Flexible Gel Substrates for Engineering Biohybrid Tissue Actuators , 2015, Advanced functional materials.

[136]  Marco Rasponi,et al.  Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. , 2016, Biomaterials.

[137]  D. Arifin,et al.  MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted cell viability , 2012, Nature materials.

[138]  Wesley R. Legant,et al.  Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels , 2013, Nature materials.

[139]  Ali Khademhosseini,et al.  Make better, safer biomaterials , 2016, Nature.

[140]  J. Schneider,et al.  Evolution‐Based Design of an Injectable Hydrogel , 2012 .

[141]  O. Muratoglu,et al.  Poly(vinyl alcohol)-acrylamide hydrogels as load-bearing cartilage substitute. , 2009, Biomaterials.

[142]  Guy Riddihough,et al.  Structure of collagen , 1998, Nature Structural Biology.

[143]  H. Hansma,et al.  Building Programmable Jigsaw Puzzles with RNA , 2004, Science.