RESEARCH ◥ manner. Three-dimensional printing enables REVIEW SUMMARY architectural control of hydrogels at high pre- cision, with a potential to further integrate elements that enable change of hydrogel con- MATERIALS SCIENCE figurations along prescribed paths. OUTLOOK: We envision the continuation of Advances in engineering hydrogels innovation in new bioorthogonal chemistries for making hydrogels, enabling their fabri- Yu Shrike Zhang and Ali Khademhosseini* cation in the presence of ◥ ON OUR WEBSITE biological species with- out impairing cellular or Read the full article BACKGROUND: Hydrogels are formed through level and control over multiscale architecture. at http://dx.doi. biomolecule functions. We the cross-linking of hydrophilic polymer chains For example, formulations that combine per- org/10.1126/ also foresee opportunities within an aqueous microenvironment. The ge- manent polymer networks with reversibly bond- science.aaf3627 in the further development .................................................. lation can be achieved through a variety of mech- ing chains for energy dissipation show strong of more sophisticatedfab- anisms, spanning physical entanglement of toughness and stretchability. Similar strategies rication methods that allow better-controlled polymer chains, electrostatic interactions, and may also substantially enhance the bonding hydrogel architecture across multiple length covalent chemical cross-linking. The water-rich affinity of hydrogels at interfaces with solids scales. In addition, technologies that precisely nature of hydrogels makes them broadly appli- by covalently anchoring the polymer networks regulate the physicochemical properties of Downloaded from cable to many areas, including tissue engineering, of tough hydrogels onto solid surfaces. Shear- hydrogels in spatiotemporally controlled manners drug delivery, soft electronics, and actuators. Con- thinning hydrogels that feature reversible bonds are crucial in controlling their dynamics, such ventional hydrogels usually possess limited me- impart a fluidic nature upon application of as degradation and dynamic presentation of chanical strength and are prone to permanent shear forces and return back to their gel states biomolecules. We believe that the fabrication breakage. The lack of desired dynamic cues and once the forces are released. Self-healing hy- of hydrogels should be coupled with end ap- structural complexity within the hydrogels has drogels based on nanomaterial hybridization, plications in a feedback loop in order to achieve http://science.sciencemag.org/ further limited their functions. Broadened appli- electrostatic interactions, and slide-ring con- optimal designs through iterations. In the end, cations of hydrogels, however, require advanced figurations exhibit excellent abilities in spon- it is the combination of multiscale constituents engineering of parameters such as mechanics taneously healing themselves after damages. and complementary strategies that will enable and spatiotemporal presentation of active or bio- Additionally, harnessing techniques that can new applications of this important class of active moieties, as well as manipulation of multi- dynamically and precisely configure hydrogels materials.▪ scale shape, structure, and architecture. have resulted in flexibility to regulate their architecture, activity, and functionality. Dy- The list of author affiliations is available in the full article online. ADVANCES: Hydrogels with substantially im- namic modulations of polymer chain physics *Corresponding author. Email: [email protected] proved physicochemical properties have been and chemistry can lead to temporal altera- Cite this article as Y. S. Zhang, A. Khademhosseini, Science enabled by rational design at the molecular tion of hydrogel structures in a programmed 356, eaaf3627 (2017). DOI: 10.1126/science.aaf3627 on February 25, 2018 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. Zhang and Khademhosseini, Science 356, 500 (2017) 5 May 2017 1of1 RESEARCH ◥ (PNIPAAM), that gels above its LCST. The LCST/ REVIEW UCST of the thermo-responsive polymers may be tuned by their molecular weight, ratio of the co- polymers, and/or the balance of the hydrophobic/ MATERIALS SCIENCE hydrophilic segments (22, 23). Noncovalent molecular self-assembly is adop- ted as a common strategy, especially for protein- Advances in engineering hydrogels based hydrogels (24). Weak noncovalent bonding mechanisms—including hydrogen bonds, van der Yu Shrike Zhang1,2,3 and Ali Khademhosseini1,2,3,4,5* Waals forces, and hydrophobic interactions—cause macromolecules to fold into scaffolds possessing Hydrogels are formed from hydrophilic polymer chains surrounded by a water-rich well-defined structures and functionality. A nota- environment. They have widespread applications in various fields such as biomedicine, soft ble example is the hierarchical self-assembly of electronics, sensors, and actuators. Conventional hydrogels usually possess limited collagen, the most abundant protein in the human mechanical strength and are prone to permanent breakage. Further, the lack of dynamic body (Fig. 1B). The assembly procedure relies on cues and structural complexity within the hydrogels has limited their functions. Recent the regular arrangement of the amino acids in developments include engineering hydrogels that possess improved physicochemical collagen molecules that are rich in proline or hy- properties, ranging from designs of innovative chemistries and compositions to integration droxyproline (25). These molecules facilitate the of dynamic modulation and sophisticated architectures. We review major advances in formation of the triple helix termed tropocollagen. designing and engineering hydrogels and strategies targeting precise manipulation of their Subsequent stabilization upon further packing of properties across multiple scales. the tropocollagen subunits into fibrils/fibers even- Downloaded from tually forms a collagen hydrogel (24–26). Inspired by this mechanism, biomimetic supramolecular ydrogels, a class of three-dimensional (3D) veloped not only to achieve dynamic modula- formulations have been designed that can follow networks formed by hydrophilic polymer tion of the hydrogels that can evolve their shapes similar hierarchical self-assembly processes, such chains embedded in a water-rich environ- along predefined paths, but also to control the as collagen-mimetic peptides (26)andthosebased ment, possess broadly tunable physical and spatial heterogeneity that will determine local- on peptide-amphiphiles and hydrogelators (27, 28). H http://science.sciencemag.org/ chemical properties (1–3). A variety of nat- ized cellular behaviors, tissue integration, and de- Spontaneous physical gelation may alternatively urally derived and synthetic polymers can be pro- vice functions. depend on chelation or electrostatic interactions. cessed into hydrogels, from those formed through Alginate, a polysaccharide composed of a-L-guluronic physical entanglement to ones stabilized via co- Hydrogel formation acid (G) and b-D-mannuronic acid (M) residues valent cross-linking. Hydrogels may be further Hydrogels are formed by cross-linking polymer derived mainly from brown algae, is a prominent tuned toward the integration of chemically and chains dispersed in an aqueous medium through example of hydrogel formation based on chelation biologically active recognition moieties such as a myriad of mechanisms, including physical en- (29). The G-blocks in alginate rapidly gel in pres- stimuli-responsive molecules and growth factors tanglement, ionic interactions, and chemical cross- ence of certain species of divalent cations such as that enhance their functionality. The versatility linking (Fig. 1). Majority of the physical gelation Ca2+ or Ba2+ in an “egg-box” form, in which pairs of of the hydrogel system has endowed it with wide- methods depend on the intrinsic properties of the helical chains pack and surround ions that are 30 spread applications in various fields, including polymers. This dependence limits the ability to locked in between (Fig. 1C) ( ). The sophisticated on February 25, 2018 biomedicine (1–3), soft electronics (4, 5), sensors fine-tune the attributes of hydrogels, but gela- structures of natural macromolecules often ren- (6–8), and actuators (9–14). As an example, when tion is easy to achieve without the need for modi- der them varying degrees of electrostatic charges a hydrogel is created with proper stiffness and fying the polymer chains and is usually easy to along the backbone. Although many natural poly- bioactive moieties, it modulates the behavior of reverse when necessary. Conversely, chemical ap- mers are negatively charged at neutral pH be- the embedded cells (15, 16). In addition, chemically proaches can be used to allow for more control- cause of the presence of carboxyl groups (such as active moieties and light-guiding properties allow lable, precise management of the cross-linking hyaluronic acid and alginate), some may also pre- hydrogels to sense substances of interest and per- procedure, potentially in a spatially and dynam- sent positive charges when amine groups dominate form on-demand actuation