Autonomous Ultrafast Self‐Healing Hydrogels by pH‐Responsive Functional Nanofiber Gelators as Cell Matrices

The synthesis of hybrid hydrogels by pH‐controlled structural transition with exceptional rheological properties as cellular matrix is reported. “Depsi” peptide sequences are grafted onto a polypeptide backbone that undergo a pH‐induced intramolecular O–N–acyl migration at physiological conditions affording peptide nanofibers (PNFs) as supramolecular gelators. The polypeptide–PNF hydrogels are mechanically remarkably robust. They reveal exciting thixotropic behavior with immediate in situ recovery after exposure to various high strains over long periods and self‐repair of defects by instantaneous reassembly. High cytocompatibility, convenient functionalization by coassembly, and controlled enzymatic degradation but stability in 2D and 3D cell culture as demonstrated by the encapsulation of primary human umbilical vein endothelial cells and neuronal cells open many attractive opportunities for 3D tissue engineering and other biomedical applications.     

Amino Acids and Peptide‐Based Supramolecular Hydrogels for Three‐Dimensional Cell Culture

Supramolecular hydrogels assembled from amino acids and peptide‐derived hydrogelators have shown great potential as biomimetic three‐dimensional (3D) extracellular matrices because of their merits over conventional polymeric hydrogels, such as non‐covalent or physical interactions, controllable self‐assembly, and biocompatibility. These merits enable hydrogels to be made not only by using external stimuli, but also under physiological conditions by rationally designing gelator structures, as well as in situ encapsulation of cells into hydrogels for 3D culture. This review will assess current progress in the preparation of amino acids and peptide‐based hydrogels under various kinds of external stimuli, and in situ encapsulation of cells into the hydrogels, with a focus on understanding the associations between their structures, properties, and functions during cell culture, and the remaining challenges in this field. The amino acids and peptide‐based hydrogelators with rationally designed structures have promising applications in the fields of regenerative medicine, tissue engineering, and pre‐clinical evaluation.     

Near‐Infrared Light‐Sensitive Polyvinyl Alcohol Hydrogel Photoresist for Spatiotemporal Control of Cell‐Instructive 3D Microenvironments

Advanced hydrogel systems that allow precise control of cells and their 3D microenvironments are needed in tissue engineering, disease modeling, and drug screening. Multiphoton lithography (MPL) allows true 3D microfabrication of complex objects, but its biological application requires a cell‐compatible hydrogel resist that is sufficiently photosensitive, cell‐degradable, and permissive to support 3D cell growth. Here, an extremely photosensitive cell‐responsive hydrogel composed of peptide‐crosslinked polyvinyl alcohol (PVA) is designed to expand the biological applications of MPL. PVA hydrogels are formed rapidly by ultraviolet light within 1 min in the presence of cells, providing fully synthetic matrices that are instructive for cell‐matrix remodeling, multicellular morphogenesis, and protease‐mediated cell invasion. By focusing a multiphoton laser into a cell‐laden PVA hydrogel, cell‐instructive extracellular cues are site‐specifically attached to the PVA matrix. Cell invasion is thus precisely guided in 3D with micrometer‐scale spatial resolution. This robust hydrogel enables, for the first time, ultrafast MPL of cell‐responsive synthetic matrices at writing speeds up to 50 mm s^?1. This approach should enable facile photochemical construction and manipulation of 3D cellular microenvironments with unprecedented flexibility and precision.     

Poly(vinyl alcohol) as versatile biomaterial for potential biomedical applications

In this paper, we present some new case examples where the chemical versatility of poly (vinyl alcohol) (PVA) can be used for potential biomedical applications. PVA, the polymeric material used for designing new nanostructured devices, is water soluble, biocompatible and has excellent physical properties. We point out the possibility of obtaining wall-to-wall chemical hydrogels as well as microgels without diminishing the biocompatibility available in the starting PVA material. Injectability is another important factor to take into account in controlled drug delivery for gene therapy. In this respect, in this paper, established and more innovative methods are prospected in order to obtain particles with dimensions suitable for these applications.     

Composite Microgels Created by Complexation between Polyvinyl Alcohol and Graphene Oxide in Compressed Double‐Emulsion Drops

Microgels, microparticles made of hydrogels, show fast diffusion kinetics and high reconfigurability while maintaining the advantages of hydrogels, being useful for various applications. Here, presented is a new microfluidic strategy for producing polymer‐graphene oxide (GO) composite microgels without chemical cues or a temperature swing for gelation. As a main component of microgels, polymers that are able to form hydrogen bonds, such as polyvinyl alcohol (PVA), are used. In the mixture of PVA and GO, GO is tethered by PVA through hydrogen bonding. When the mixture is rapidly concentrated in the core of double‐emulsion drops by osmotic‐pressure‐driven water pumping, PVA‐tethered GO sheets form a nematic phase with a planar alignment. In addition, the GO sheets are linked by additional hydrogen bonds, leading to a sol–gel transition. Therefore, the PVA–GO composite remains undissolved when it is directly exposed to water by oil‐shell rupture. These composite microgels can be also produced using poly(ethylene oxide) or poly(acrylic acid), instead of PVA. In addition, the microgels can be functionalized by incorporating other polymers in the presence of the hydrogel‐forming polymers. It is shown that the multicomponent microgels made from a mixture of polyacrylamide, PVA, and GO show an excellent adsorption capacity for impurities.     

Inside Front Cover: Rigid,Self‐Assembled Hydrogel Composed of a Modified Aromatic Dipeptide (Adv. Mater. 11/2006)

Formation of a self‐assembled hydrogel with remarkable mechanical rigidity using a very simple building block, 9‐fluorenylmethoxycarbonyl‐diphenylalanine peptide, is reported by Gazit and co‐workers on p. 1365. The hydrogel forms under mild conditions in aqueous solution, using a much shorter peptide than previously reported, and has physical properties exceeding those of hydrogels formed by much longer polypeptides, as previously reported for diphenylalanine nanotubes. The rigidity is likely facilitated by the aromatic nature of the peptide building block. The hydrogel is stable under extreme conditions, and can be shaped in accordance to the vessel it is assembled in, making it useful for a variety of applications.     

Evaluation of poly(vinyl alcohol) hydrogels as a component of hybrid artificial tissues

Hydrogels are three-dimensional polymeric networks very similar to biological tissues. Many synthetic polymers can be used in preparing hydrogels. Among them poly(vinyl alcohol) (PVA), physically crosslinked by repeated freeze-thawing cycles of polymer aqueous solutions, is widely employed to make hydrogels for biomedical applications. To increase the similarity between hydrogels and natural tissues and to obtain polymeric hybrid tissues, we attempted to incorporate 3T3 cells, from a mouse fibroblast cell line, into PVA hydrogels obtained by one freeze-thawing cycle using as a solvent complete culture medium. Hydrogels were also made using eight freeze-thawing cycles from PVA solutions prepared using as a solvent either complete culture medium or water. Cell adhesion experiments were performed by seeding 3T3 and human umbilical vein endothelial cells (HUVEC) on to the hydrogel surface. The effect of the solvent and of the different number of freeze-thawing cycles on the mechanical characteristics of the PVA hydrogels were investigated by dynamic-mechanical techniques. A scanning force microscope analysis of the hydrogel surface viscoelastic properties was also carried out. Our results show that PVA is not cytotoxic. Although PVA hydrogel surface characteristics do not seem to favour the adhesion of substrate-dependent cells, encouraging results were obtained with the 3T3 cells incorporation. DMA analysis indicates that the networks prepared by eight freeze-thawing cycles possess a mechanical consistency comparable, even slightly better, than the ones prepared by only one freeze-thawing cycle and used for the cell incorporation studies.     

Topographical heterogeneity in transparent PVA hydrogels studied by AFM

Physically crosslinked poly (vinyl alcohol) (PVA) hydrogels have a wide range of biomedical applications. Transparent and stable PVA hydrogels synthesized by freeze-thawing method are potential candidates to be used as tissue engineering scaffolds provided they exhibit suitable topographical roughness and surface energy. The effect of processing parameters i.e., polymer concentration and number of freeze-thaw cycles on the resulting topography of the freeze-thawed transparent hydrogels has been studied and quantified using non-contact mode of an atomic force microscope (AFM) and image analysis. Simultaneously captured phase contrast images have revealed significant information about morphological changes in the topographical features and crystallinity of the hydrogels. Topographical roughness was found to decrease as a function of number of freeze-thaw cycles.     

Tough,Transparent, and Slippery PVA Hydrogel Led by Syneresis

Slippery and transparent polyvinyl alcohol (PVA) hydrogels with mechanical robustness exhibit broad applications in artificial biological soft tissues, flexible wearable electronics, and implantable biomedical devices. Most of the current PVA hydrogels, however, are unable to integrate these features, which compromises its performance in biological and engineering applications. To achieve such purpose, herein, a novel tactic is proposed, salting-out-after-syneresis of PVA, to realize a mechanically robust and highly transparent slippery PVA hydrogel. The syneresis of PVA sol is first conducted to form highly dense and transparent PVA polymer networks, then the salting-out effect tunes the aggregation of the polymer chains to rapidly induce the phase separation and crystallization. The resultant hydrogels show the transparency up to 98% in the visible region, the tribological coefficient down to 0.0081, and the excellent mechanical properties with strength, modulus, and toughness of 26.72 ± 1.05, 6.66 ± 0.29 MPa, and 55.21 ± 1.62 MJ m⁻³, respectively. To reveal the potentials, PVA contact lens that combine remarkable lubrication, anti-protein adhesion, biocompatibility, and drug-loading functions are demonstrated. This strategy provides a simple and new avenue for developing the mechanically robust, transparent, and hydrated hydrogels, showing the potential in biomedicine and wearable devices.     

Development of a novel porous cryo-foam for potential wound healing applications

This body of work describes the development of a porous hydrogel for wound healing applications. In the present study poly (vinyl alcohol) (PVA) and poly (acrylic acid) (PAA) based hydrogels were prepared, and their properties were examined. Varying concentrations of the polymers and distilled water were used to prepare the hydrogels. The use of a high shear mixer, for foaming the PVA and PVA/PAA gels, and how this physical change can affect the structure and porosity of the hydrogel in question, represents a key feature of this work. The mechanical and thermal properties were determined by parallel plate rheometry and modulated differential scanning calorimetry (MDSC) respectively. The results indicated that the hydrogels containing low concentration of PVA and high volume of H₂O are significantly weaker than those synthesised with higher concentrations of PVA. The thermal analysis shows distinct endotherms and provides evidence of crystallisation. The chemical structure of the hydrogels was confirmed by means of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR).     

纳米细菌纤维素/聚乙烯醇复合水凝胶在模拟体液中的疲劳行为

聚乙烯醇(PVA)复合水凝胶作为半月板及软骨等长期承重植入体,在生理环境中的疲劳行为关系到植入体的持久性和稳定性。采用弥散增强的方法将纳米细菌纤维素(BC)均匀分散在PVA水凝胶基体中,制备了纳米BC/PVA复合水凝胶。在模拟体液(SBF)环境中,采用压缩疲劳过程分析、疲劳前后刚度变化分析及疲劳前后尺寸稳定性分析3种方法,测试和评价了复合水凝胶的抗疲劳性能和力学稳定性。结果表明:纳米BC/PVA复合水凝胶在模拟人体环境中具有良好的抗疲劳性能,能够满足体内植入物的抗疲劳性能需求;纳米BC的加入可以有效提升复合水凝胶的力学稳定性和抗疲劳性能,但随着纳米BC含量的进一步升高,复合水凝胶的抗疲劳性能有所减弱,当PVA与纳米BC质量比为30∶1时,纳米BC/PVA复合水凝胶疲劳前期与后期最大位移变化量最小(0.002mm),疲劳前后刚度变化最小(5.41%),且疲劳前后尺寸稳定性最强,变形量仅为0.427mm,抗疲劳性能达到最佳。     

物理交联聚乙烯醇/明胶复合水凝胶透明性的溶剂敏感性

以二甲基亚砜(DMSO)水溶液为分散介质,采用冷冻-解冻法制备了聚乙烯醇/明胶复合水凝胶,并研究了其透明性的溶剂敏感性。研究发现,将水凝胶交替置于去离子水和不同浓度的DMSO水溶液中,其透光率呈周期性变化;随DM-SO浓度的升高,其透光率的响应速率加快。通过X射线衍射(XRD)研究了聚乙烯醇/明胶复合水凝胶和纯聚乙烯醇水凝胶的聚集态结构。结果表明,两种水凝胶在不同溶剂中结构差异很大,并具有可逆转变性。随复合水凝胶中水含量的增加,其结晶度减小。该复合水凝胶的溶剂敏感性可能与其内部的结晶形态在不同溶剂中的转变或溶剂诱导相分离有关。     

Solvent‐Assisted Micromolding of Biohybrid Hydrogels to Maintain Human Hematopoietic Stem and Progenitor Cells Ex Vivo

Array‐format cell‐culture carriers providing tunable matrix cues are instrumental in current cell biology and bioengineering. A new solvent‐assisted demolding approach for the fabrication of microcavity arrays with very small feature sizes down to single‐cell level (3 µm) of very soft biohybrid glycosaminoglycan–poly(ethylene glycol) hydrogels (down to a shear modulus of 1 kPa) is reported. It is further shown that independent additional options of localized conjugation of adhesion ligand peptides, presentation of growth factors through complexation to gel‐based glycosaminoglycans, and secondary gel deposition for 3D cell embedding enable a versatile customization of the hydrogel microcavity arrays for cell culture studies. As a proof of concept, cell‐instructive hydrogel compartment arrays are used to analyze the response of human hematopoietic stem and progenitor cells to defined biomolecular and spatial cues.     

Adaptable Hydrogel Networks with Reversible Linkages for Tissue Engineering

Adaptable hydrogels have recently emerged as a promising platform for three‐dimensional (3D) cell encapsulation and culture. In conventional, covalently crosslinked hydrogels, degradation is typically required to allow complex cellular functions to occur, leading to bulk material degradation. In contrast, adaptable hydrogels are formed by reversible crosslinks. Through breaking and re‐formation of the reversible linkages, adaptable hydrogels can be locally modified to permit complex cellular functions while maintaining their long‐term integrity. In addition, these adaptable materials can have biomimetic viscoelastic properties that make them well suited for several biotechnology and medical applications. In this review, an overview of adaptable‐hydrogel design considerations and linkage selections is presented, with a focus on various cell‐compatible crosslinking mechanisms that can be exploited to form adaptable hydrogels for tissue engineering.     

Self‐Healing Zwitterionic Microgels as a Versatile Platform for Malleable Cell Constructs and Injectable Therapies

Injectable and malleable hydrogels that combine excellent biocompatibility, physiological stability, and ease of use are highly desirable for biomedical applications. Here, a simple and scalable strategy is reported to make injectable and malleable zwitterionic polycarboxybetaine hydrogels, which are superhydrophilic, nonimmunogenic, and completely devoid of nonspecific interactions. When zwitterionic microgels are reconstructed, the combination of covalent crosslinking inside each microgel and supramolecular interactions between them gives the resulting zwitterionic injectable pellet (ZIP) constructs supportive moduli and tunable viscoelasticity. ZIP constructs can be lyophilized to a sterile powder that fully recovers its strength and elasticity upon rehydration, simplifying storage and formulation. The lyophilized powder can be reconstituted with any aqueous suspension of cells or therapeutics, and rapidly and spontaneously self‐heals into a homogeneous composite construct. This versatile and highly biocompatible platform material shows great promise for many applications, including as an injectable cell culture scaffold that promotes multipotent stem cell expansion and provides oxidative stress protection.     

25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine

Hydrogels are hydrophilic polymer‐based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three‐dimensional (3D) matrices for tissue engineering, drug‐delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light‐sensitive, composite, and shape‐memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life.     

Controlling Mechanical Properties of Cell‐Laden Hydrogels by Covalent Incorporation of Graphene Oxide

Graphene‐based materials are useful reinforcing agents to modify the mechanical properties of hydrogels. Here, an approach is presented to covalently incorporate graphene oxide (GO) into hydrogels via radical copolymerization to enhance the dispersion and conjugation of GO sheets within the hydrogels. GO is chemically modified to present surface‐grafted methacrylate groups (MeGO). In comparison to GO, higher concentrations of MeGO can be stably dispersed in a pre‐gel solution containing methacrylated gelatin (GelMA) without aggregation or significant increase in viscosity. In addition, the resulting MeGO‐GelMA hydrogels demonstrate a significant increase in fracture strength with increasing MeGO concentration. Interestingly, the rigidity of the hydrogels is not significantly affected by the covalently incorporated GO. Therefore, this approach can be used to enhance the structural integrity and resistance to fracture of the hydrogels without inadvertently affecting their rigidity, which is known to affect the behavior of encapsulated cells. The biocompatibility of MeGO‐GelMA hydrogels is confirmed by measuring the viability and proliferation of the encapsulated fibroblasts. Overall, this study highlights the advantage of covalently incorporating GO into a hydrogel system, and improves the quality of cell‐laden hydrogels.     

Microfluidic Templating of Spatially Inhomogeneous Protein Microgels

3D scaffolds in the form of hydrogels and microgels have allowed for more native cell‐culture systems to be developed relative to flat substrates. Native biological tissues are, however, usually spatially inhomogeneous and anisotropic, but regulating the spatial density of hydrogels at the microscale to mimic this inhomogeneity has been challenging to achieve. Moreover, the development of biocompatible synthesis approaches for protein‐based microgels remains challenging, and typical gelation conditions include UV light, extreme pH, extreme temperature, or organic solvents, factors which can compromise the viability of cells. This study addresses these challenges by demonstrating an approach to fabricate protein microgels with controllable radial density through microfluidic mixing and physical and enzymatic crosslinking of gelatin precursor molecules. Microgels with a higher density in their cores and microgels with a higher density in their shells are demonstrated. The microgels have robust stability at 37 °C and different dissolution rates through enzymolysis, which can be further used for gradient scaffolds for 3D cell culture, enabling controlled degradability, and the release of biomolecules. The design principles of the microgels could also be exploited to generate other soft materials for applications ranging from novel protein‐only micro reactors to soft robots.     

Multicolor Photo‐Crosslinkable AIEgens toward Compact Nanodots for Subcellular Imaging and STED Nanoscopy

Aggregation induced emission (AIE) has attracted considerable interest for the development of fluorescence probes. However, controlling the bioconjugation and cellular labeling of AIE dots is a challenging problem. Here, this study reports a general approach for preparing small and bioconjugated AIE dots for specific labeling of cellular targets. The strategy is based on the synthesis of oxetane‐substituted AIEgens to generate compact and ultrastable AIE dots via photo‐crosslinking. A small amount of polymer enriched with oxetane groups is cocondensed with most of the AIEgens to functionalize the nanodot surface for subsequent streptavidin bioconjugation. Due to their small sizes, good stability, and surface functionalization, the cell‐surface markers and subcellular structures are specifically labeled by the AIE dot bioconjugates. Remarkably, stimulated emission depletion imaging with AIE dots is achieved for the first time, and the spatial resolution is significantly enhanced to ≈95 nm. This study provides a general approach for small functional molecules for preparing small sized and ultrastable nanodots.     

Sustainable,Insoluble, and Photonic Cellulose Nanocrystal Patches for Calcium Ion Sensing in Sweat

Self-assembly of cellulose nanocrystals (CNCs) is invaluable for the development of sustainable optics and photonics. However, the functional failure of CNC-derived materials in humid or liquid environments inevitably impairs their development in biomedicine, membrane separation, environmental monitoring, and wearable devices. Here, a facile and robust method to fabricate insoluble hydrogels in a self-assembled CNC–polyvinyl alcohol (PVA) system is reported. Due to the reconstruction of inter- or intra-molecular hydrogen bond interactions, thermal dehydration makes an optimized CNC/PVA photonic film form a stable hydrogel network in an aqueous solution rather than dissolve. Notably, the resulting hydrogel exhibits superb mechanical performance (stress up to 3.3 Mpa and tough up to 0.73 MJ m⁻³) and reversible conversion between dry and wet states, enabling it convenient for specific functionalization. Sodium alginate (SA) can be adsorbed into the CNC photonic structure by swelling dry CNC/PVA film in a SA solution. The prepared hydrogel showcases the comprehensive properties of freezing resistance (−20°C), strong adhesion, satisfactory biocompatibility, and highly sensitive and selective Ca²⁺ sensing. The material could act as a portable wearable patch on the skin for the continuous analysis of calcium trends during different physical exercises, facilitating their development in precision nutrition and health monitoring.