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      Advances in engineering hydrogels

      1 , 2 , 3 , 1 , 2 , 3 , 4 , 5
      Science
      American Association for the Advancement of Science (AAAS)

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          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. [Related article:]eaaf3627

          Abstract

          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.

          Abstract

          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.

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          Most cited references141

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          Matrix elasticity directs stem cell lineage specification.

          Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.
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            3D bioprinting of tissues and organs.

            Additive manufacturing, otherwise known as three-dimensional (3D) printing, is driving major innovations in many areas, such as engineering, manufacturing, art, education and medicine. Recent advances have enabled 3D printing of biocompatible materials, cells and supporting components into complex 3D functional living tissues. 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. Addressing these complexities requires the integration of technologies from the fields of engineering, biomaterials science, cell biology, physics and medicine. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. Other applications include developing high-throughput 3D-bioprinted tissue models for research, drug discovery and toxicology.
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              Highly stretchable and tough hydrogels.

              Hydrogels are used as scaffolds for tissue engineering, vehicles for drug delivery, actuators for optics and fluidics, and model extracellular matrices for biological studies. The scope of hydrogel applications, however, is often severely limited by their mechanical behaviour. Most hydrogels do not exhibit high stretchability; for example, an alginate hydrogel ruptures when stretched to about 1.2 times its original length. Some synthetic elastic hydrogels have achieved stretches in the range 10-20, but these values are markedly reduced in samples containing notches. Most hydrogels are brittle, with fracture energies of about 10 J m(-2) (ref. 8), as compared with ∼1,000 J m(-2) for cartilage and ∼10,000 J m(-2) for natural rubbers. Intense efforts are devoted to synthesizing hydrogels with improved mechanical properties; certain synthetic gels have reached fracture energies of 100-1,000 J m(-2) (refs 11, 14, 17). Here we report the synthesis of hydrogels from polymers forming ionically and covalently crosslinked networks. Although such gels contain ∼90% water, they can be stretched beyond 20 times their initial length, and have fracture energies of ∼9,000 J m(-2). Even for samples containing notches, a stretch of 17 is demonstrated. We attribute the gels' toughness to the synergy of two mechanisms: crack bridging by the network of covalent crosslinks, and hysteresis by unzipping the network of ionic crosslinks. Furthermore, the network of covalent crosslinks preserves the memory of the initial state, so that much of the large deformation is removed on unloading. The unzipped ionic crosslinks cause internal damage, which heals by re-zipping. These gels may serve as model systems to explore mechanisms of deformation and energy dissipation, and expand the scope of hydrogel applications.
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                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                May 05 2017
                May 05 2017
                : 356
                : 6337
                Affiliations
                [1 ]Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
                [2 ]Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [3 ]Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
                [4 ]Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
                [5 ]Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia.
                Article
                10.1126/science.aaf3627
                5841082
                28473537
                65733590-1f10-41dd-b985-25d9390537a9
                © 2017

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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