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Traditional implanted drug delivery systems cannot easily change their release profile in real time to respond to physiological changes. Here we present a microfluidic aqueous two-phase system to generate microcapsules that can release drugs on demand as triggered by focused ultrasound (FUS). The biphasic microcapsules are made of hydrogels with an outer phase of mixed molecular weight (MW) poly(ethylene glycol) diacrylate that mitigates premature payload release and an inner phase of high MW dextran with payload that breaks down in response to FUS. Compound release from microcapsules could be triggered as desired; 0.4 μg of payload was released across 16 on-demand steps over days. We detected broadband acoustic signals amidst low heating, suggesting inertial cavitation as a key mechanism for payload release. Overall, FUS-responsive microcapsules are a biocompatible and wirelessly triggerable structure for on-demand drug delivery over days to weeks., (© 2022 Wiley-VCH GmbH.)

As a novel material that can be used at subzero temperatures, anti-freezing hydrogels have been attracting extensive attention. Inspired by the freeze-tolerance phenomenon in seawater, which is achieved by mixing salts into water, an ionic compound (CaCl 2 ) was used to gelatinize starch to form anti-freezing hydrogels. Native potato starch (NPS) anti-freezing hydrogels were formed at -10 °C, -18 °C, -30 °C, and - 50 °C with 6-9 kPa tensile strength and 100-230% elongation at break. The compressive stress of anti-freezing hydrogels at different environmental temperatures increased from 18.586 kPa to 36.551 kPa with the glass transform temperature of starch hydrogels dropped to -50 °C. The anti-freezing hydrogels showed excellent water retention ability, which could maintain a water content of 55% after 7 days at ambient temperature. The prototyping of anti-freezing starch hydrogels broadens the applications of starch in food, adhesives, medical materials, and intelligent materials., (Copyright © 2021 Elsevier B.V. All rights reserved.)

3D culture of cells in designer biomaterial matrices provides a biomimetic cellular microenvironment and can yield critical insights into cellular behaviours not available from conventional 2D cultures. Hydrogels with dynamic properties, achieved by incorporating either degradable structural components or reversible dynamic crosslinks, enable efficient cell adaptation of the matrix and support associated cellular functions. Herein we demonstrate that given similar equilibrium binding constants, hydrogels containing dynamic crosslinks with a large dissociation rate constant enable cell force-induced network reorganization, which results in rapid stellate spreading, assembly, mechanosensing, and differentiation of encapsulated stem cells when compared to similar hydrogels containing dynamic crosslinks with a low dissociation rate constant. Furthermore, the static and precise conjugation of cell adhesive ligands to the hydrogel subnetwork connected by such fast-dissociating crosslinks is also required for ultra-rapid stellate spreading (within 18 h post-encapsulation) and enhanced mechanosensing of stem cells in 3D. This work reveals the correlation between microscopic cell behaviours and the molecular level binding kinetics in hydrogel networks. Our findings provide valuable guidance to the design and evaluation of supramolecular biomaterials with cell-adaptable properties for studying cells in 3D cultures.

Hydrogels are polymer networks infiltrated with water. Many biological hydrogels in animal bodies such as muscles, heart valves, cartilages, and tendons possess extreme mechanical properties including being extremely tough, strong, resilient, adhesive, and fatigue-resistant. These mechanical properties are also critical for hydrogels' diverse applications ranging from drug delivery, tissue engineering, medical implants, wound dressings, and contact lenses to sensors, actuators, electronic devices, optical devices, batteries, water harvesters, and soft robots. Whereas numerous hydrogels have been developed over the last few decades, a set of general principles that can rationally guide the design of hydrogels using different materials and fabrication methods for various applications remain a central need in the field of soft materials. This review is aimed at synergistically reporting: (i) general design principles for hydrogels to achieve extreme mechanical and physical properties, (ii) implementation strategies for the design principles using unconventional polymer networks , and (iii) future directions for the orthogonal design of hydrogels to achieve multiple combined mechanical, physical, chemical, and biological properties. Because these design principles and implementation strategies are based on generic polymer networks, they are also applicable to other soft materials including elastomers and organogels. Overall, the review will not only provide comprehensive and systematic guidelines on the rational design of soft materials, but also provoke interdisciplinary discussions on a fundamental question: why does nature select soft materials with unconventional polymer networks to constitute the major parts of animal bodies?

Reliable functions of bioelectronic devices require conformal, stable and conductive interfaces with biological tissues. Integrating bioelectronic devices with tissues usually relies on physical attachment or surgical suturing; however, these methods face challenges such as non-conformal contact, unstable fixation, tissue damage, and/or scar formation. Here, we report an electrical bioadhesive (e-bioadhesive) interface, based on a thin layer of a graphene nanocomposite, that can provide rapid (adhesion formation within 5 s), robust (interfacial toughness >400 J m -2 ) and on-demand detachable integration of bioelectronic devices on diverse wet dynamic tissues. The electrical conductivity (>2.6 S m -1 ) of the e-bioadhesive interface further allows bidirectional bioelectronic communications. We demonstrate biocompatibility, applicability, mechanical and electrical stability, and recording and stimulation functionalities of the e-bioadhesive interface based on ex vivo porcine and in vivo rat models. These findings offer a promising strategy to improve tissue-device integration and enhance the performance of biointegrated electronic devices.

Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have potential advantages over sutures and staples for wound closure, hemostasis, and integration of implantable devices onto wet tissues. However, existing bioadhesives display several limitations including slow adhesion formation, weak bonding, low biocompatibility, poor mechanical match with tissues, and/or lack of triggerable benign detachment. Here, we report a bioadhesive that can form instant tough adhesion on various wet dynamic tissues and can be benignly detached from the adhered tissues on demand with a biocompatible triggering solution. The adhesion of the bioadhesive relies on the removal of interfacial water from the tissue surface, followed by physical and covalent cross-linking with the tissue surface. The triggerable detachment of the bioadhesive results from the cleavage of bioadhesive's cross-links with the tissue surface by the triggering solution. After it is adhered to wet tissues, the bioadhesive becomes a tough hydrogel with mechanical compliance and stretchability comparable with those of soft tissues. We validate in vivo biocompatibility of the bioadhesive and the triggering solution in a rat model and demonstrate potential applications of the bioadhesive with triggerable benign detachment in ex vivo porcine models., Competing Interests: Competing interest statement: X.C., H.Y., and X.Z. are inventors on a patent application (US No. 63/034,644) that covers the instant tough bioadhesive with triggerable benign detachment.

A physical, noninvasive, and reversible means of controlling the nanoscale presentation of bioactive ligands is highly desirable for regulating and investigating the time-dependent responses of cells, including stem cells. Herein we report a magnetically actuated dynamic cell culture platform consisting of a soft hydrogel substrate conjugated with RGD-bearing magnetic nanoparticle (RGD-MNP). The downward/upward magnetic attraction conceals/promotes the presentation of the RGD-MNP in/on the soft hydrogel matrix, thereby inhibiting/enhancing the cell adhesion and mechanosensing-dependent differentiation. Meanwhile, the lateral magnetic attraction promotes the unidirectional migration of cells in the opposite direction on the hydrogel. Furthermore, cyclic switching between the "Exposed" and "Hidden" conditions induces the repeated cycles of differentiation/dedifferentiation of hMSCs which significantly enhances the differentiation potential of hMSCs. Our design approach capitalizes on the bulk biomaterial matrix as the macroscopic caging structure to enable dynamic regulation of cell-matrix interactions reversibly, which is hard to achieve by using conventional cell culture systems.

Hydrogels have been widely used as the carrier material of therapeutic cell and drugs for articular cartilage repair. We previously demonstrated a unique host-guest macromer (HGM) approach to prepare mechanically resilient, self-healing and injectable supramolecular gelatin hydrogels free of chemical crosslinking. In this work, we show that compared with conventional hydrogels our supramolecular gelatin hydrogels mediate more sustained release of small molecular (kartogenin) and proteinaceous (TGF-β1) chondrogenic agents, leading to enhanced chondrogenesis of the encapsulated human bone marrow-derived mesenchymal stem cells (hBMSCs) in vitro and in vivo. More importantly, the supramolecular nature of our hydrogels allows injection of the pre-fabricated hydrogels containing the encapsulated hBMSCs and chondrogenic agents, and our data show that the injection process has little negative impact on the viability and chondrogenesis of the encapsulated cells and subsequent neocartilage development. Furthermore, the stem cell-laden supramolecular hydrogels administered via injection through a needle effectively promote the regeneration of both hyaline cartilage and subchondral bone in the rat osteochondral defect model. These results demonstrate that our supramolecular HGM hydrogels are promising delivery biomaterials of therapeutic agents and cells for cartilage repair via minimally invasive procedures. This unique capability of injecting cell-laden hydrogels to target sites will greatly facilitate stem cell therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Folded single chain polymeric nano-objects are the molecular level soft material with ultra-small size. Here, we report an easy and scalable method for preparing single-chain nanogels (SCNGs) with improved efficiency. We further investigate the impact of the dynamic molecular conformational change of SCNGs on cellular interactions from molecular to bulk scale. First, the supramolecular unfoldable SCNGs efficiently deliver siRNAs into stem cells as a molecular drug carrier in a conformation-dependent manner. Furthermore, the conformation changes of SCNGs enable dynamic and precise manipulation of ligand tether structure on 2D biomaterial interfaces to regulate the ligand-receptor ligation and mechanosensing of cells. Lastly, the dynamic SCNGs as the building blocks provide effective energy dissipation to bulk biomaterials such as hydrogels, thereby protecting the encapsulated stem cells from deleterious mechanical shocks in 3D matrix. Such a bottom-up molecular tailoring strategy will inspire further applications of single-chain nano-objects in the biomedical area.

Resembling soft tissues, stretchable hydrogels are promising biomaterials for many biomedical applications due to their excellent mechanical robustness. However, conventional stretchable hydrogels with a synthetic polymer matrix are usually bioinert. The lack of cell and tissue adhesiveness of such hydrogels limits their applications. An easy but reliable postgelation functionalization method is desirable. Herein, we report the fabrication of stretchable supramolecular hydrogels cross-linked by multivalent host-guest interactions. Such hydrogels containing thiourea ( TU) functionalities can be bioactivated with a catechol-modified peptide (Cat-RGD) via thiourea-catechol ( TU-Cat) coupling reaction. This postgelation bioactivation of the otherwise bioinert hydrogels not only conjugates bioactive ligands for cell attachment but also introduces and preserves the catechol structures for tissue adhesion. This straightforward fabrication and one-stone-two-bird bioactivation of the stretchable hydrogels may find broad applications in developing advanced soft biomaterials for tissue repair, wound dressing, and lesion sealing.

Biomimetic hydrogels with hierarchical network structures are promising biomaterials for tissue engineering due to their unique mechanical properties. One successful biomimetic strategy for facile construction of high-performance hydrogels is to incorporate reversible crosslinks as sacrificial bonds into chemical polymer networks. By mimicking the unfolding-refolding functions of the skeletal muscle protein titin, the reversible crosslinks can reinforce the otherwise weak and brittle hydrogels. However, the contribution of multivalent reversible crosslinks to the overall hydrogel mechanical properties has rarely been investigated. Herein we present the biomimetic hydrogels with multivalent host-guest interactions as reversible crosslinks, which provide not only energy storage capacity, but also elevated energy dissipation capacity to the dually crosslinked networks, therefore leading to the improved hydrogel ductility and tensile strength. Our results also reveal the manner of multivalent host-guest crosslinks contributing to the hydrogel mechanical properties, including gelation rate, energy storage and dissipation, tensile hysteresis, and fast spontaneous recovery.

Stem cells reside in a three-dimensional (3D) niche microenvironment, which provides specific cues, including cell-matrix interactions and soluble factors, that are essential to the differentiation of stem cells in vivo. Herein we demonstrate a general approach to the synthetic reconstruction of 3D biomimetic niche environment of stem cells by the multiscale combination of macroscopic porous hydrogels and a nanoscale upconversion nanoparticles (UCNP)-based nanocomplex. The porous biopolymeric hydrogels emulate the spongy bone microstructure and provide 3D environment conducive to the differentiation of seeded stem cells. The UCNP-based nanocomplex (Pur-UCNP-peptide-FITC), which is stably encapsulated in the porous hydrogels, emulates the repertoire of inductive factors in bone matrix by maintaining localized long-term delivery of inductive small molecules. The nanocomplex also generates biomarker-specific reporting emissions that correlate with the extent and stage of differentiation of the stem cells in synthetic niche, thereby allowing long-term tracking of stem cell fate in a non-contact, non-destructive, and potentially high-throughput manner in living cultures. To the best of our knowledge, this is first demonstration of synthetic niche reconstruction. The modular nature of this synthetic niche platform allows various parameters to be easily tuned to accommodate a variety of fundamental studies of dynamic cellular events under controlled settings., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Repeated administrations of insulin injection on daily basis evoke pain and numerous complications with adverse effects on the diabetic patients' life quality. Moreover, wearing insulin pump is also associated with several problems of diabetic ketoacidosis, catheter site infection, contact dermatitis and high cost., Method: We have developed an in situ gel system, consisting of insulin-loaded liposomes dispersed within a thermoreversible gel (Pluronic® F127 gel), which increases the duration of insulin action for the treatment of diabetes. Vesicular phospholipid gel technique was used to encapsulate the insulin into liposomes., Results: The resulting liposomal gel formulation had a longer drug-release period in vitro than a free insulin solution or liposomes and Pluronic® F127 gel individually. Furthermore, the addition of liposomes to the Pluronic® F127 gel improved the stability of the encapsulated insulin at a physiological temperature. In vivo study was performed to investigate the bioactivity and absorption of insulin released from the liposomal gel and other formulations. The liposomal gel released insulin into the bloodstream continuously for up to 7 days and significantly enhanced drug bioavailability compared to insulin released from liposomes or Pluronic® F127 gel individually. Blood glucose levels were reduced for up to 4 days. Histology data demonstrated excellent biocompatibility of the Pluronic® F127 gel-based delivery systems, with no observable inflammatory response in rat subcutaneous tissues., Conclusion: Obtained results show that the insulin-loaded liposomes dispersed within Pluronic® F127 gel can be used as a long-acting drug delivery system, and replacement for conventional insulin therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The engineering of catechol-based hydrogels to bind to wet biological tissues with high adhesion energy remains a challenge. Herein, fast quinone-nucleophile coupling and dynamic boronate ester bond were used to enhance the interfacial adhesion and bulk cohesion of our dual-crosslinked hydrogels, respectively, for fabricating mussel-mimetic tough adhesives.

A novel core-shell hydrogel bead was fabricated for effective removal of methylene blue dye from aqueous solutions. The core, made of sodium alginate-g-polyacrylamide and attapulgite nanofibers, was cross-linked by Calcium ions (Ca2+). The shell, composed of a chitosan/activated carbon mixture, was then coated onto the core. Fourier transform infrared spectroscopy confirmed the grafting polymerization of acrylamide onto sodium alginate. Scanning electron microscopy images showed the core-shell structure. The core exhibited a high water uptake ratio, facilitating the diffusion of methylene blue into the core. During the diffusion process, the methylene blue was first adsorbed by the shell and then further adsorbed by the core. Adsorption tests showed that the coreshell structure had a larger adsorption capacity than the core alone. The shell effectively enhanced the adsorption capacity to methylene blue compared to the single core. Methylene blue was adsorbed by activated carbon and chitosan in the shell, and the residual methylene blue diffused into the core and was further adsorbed. [ABSTRACT FROM AUTHOR]

Herein, we have fabricated starch–borax double cross-linked network (DC) hydrogels with tough and self-healing properties using a one-pot method. The addition of borax significantly increased the storage modulus and loss modulus of these starch–borax DC hydrogels. The maximum compression stress (~288 kPa) of starch–borax DC hydrogels containing 5% borax was about ten times greater than that of a pure-starch hydrogel. The texture profile analysis values of the DC hydrogels—including hardness, springiness, cohesiveness, and adhesiveness—increased compared to pure-starch hydrogels. In addition, starch–borax DC hydrogels exhibited excellent self-healing and shape-recovery properties. These DC hydrogels, with a variety of excellent properties, have potential applications in agricultural, biomedical, and industrial fields. [ABSTRACT FROM AUTHOR]

Artemisia sphaerocephala Krasch. polysaccharide (ASKP) contained two fractions of 60P and 60S with different molecular weight. It was found the potential performance of interface adsorption and gelation activities for the high molecular weight of 60P in comparison with low molecular weight of 60S. The emulsion stability and droplets filling in gel network was highly dependent on the medium chain triglyceride (MCT) concentrations. The emulsion gels fabricated through a complexation of 60P and gelatin or collagen peptides exhibited significantly improved emulsifying activity and gel strength at higher concentration of MCT. Gelatin or collagen peptide could be adsorbed on the droplets interface and interact with 60P in gel matrix, thus presenting an active filling. However, 60P based emulsion gel complexed with pullulan contributed to a lower strength than hydrogel, which was probably due to the existence of spaces between droplets and gel matrix, weakening the stability of gel network, considered as an inactive filling. • 60P fraction exhibited potential interface adsorption and gelation activities. • The complexed emulsion gel exhibited improved emulsifying activity and gel strength. • Protein on droplets interface can interact with 60P in gel matrix as active filling. [ABSTRACT FROM AUTHOR]

[Display omitted] • The complexed hydrogel exhibited a significantly enhanced gel strength. • Pullulan or gelatin was entangled with ASKP by hydrogen bond or electrostatic force. • The molecules interaction contributed to a semi-interpenetrating dense network. Artemisia sphaerocephala Krasch. polysaccharide (ASKP) was found to be crosslinked with ferric ions to form hydrogels in the previous study. In this work, it was demonstrated that ASKP-Fe3+ hydrogel complexed with pullulan or gelatin contributed to a significantly enhanced gel strength at 1.5% ASKP, 60 mM Fe2+, pH 4.0, and the mixing ratio of 9: 1. The complexed hydrogels presented a dense semi-interpenetrating network along with the delay of gelation time and the increase of water retention. ASKP based complexes exhibited good compatibility, probably because pullulan and gelatin could be entangled with ASKP chain under hydrogen bonding and electrostatic interaction, respectively. The interaction between ASKP and pullulan or gelatin contributed to the formation of complexed hydrogels with dense network and significantly enhanced gel strength. It is inferred that ASKP would have great potential to be a new gelling material as well as for the ferric ions delivery. [ABSTRACT FROM AUTHOR]

Artemisia sphaerocephala Krasch. polysaccharide (ASKP) has attracted growing attention in the field of food and medical engineering due to its biological activity and colloidal property. In this study, the binding between ASKP and ferric ions was found and the binding mechanism was explored. The results showed that ASKP could form a hydrogel with three-dimensional network structure in the presence of ferric ions. Ferric ions could specifically bind with the carboxyl and hydroxyl groups of the high molecular weight fraction of 60P with the binding stoichiometry of [M3+]/[repeating unit] = 2.5. The possible mechanism of the formation of ASKP-Fe3+ complex was proposed as two binding modes of monodentate and bridging binding. ASKP-Fe3+ complex exhibited higher thermal stability than ASKP revealed with DSC thermograms. The study indicated that ASKP would be a novel gelation biopolymer and the ASKP-Fe3+ complex hydrogel could be exploited as a new iron fortifier. • The binding between ASKP and ferric ions was found. • The thermodynamic parameters of the binding between ASKP and ferric ions were calculated. • The possible mechanism of ASKP-Fe3+ hydrogel formation was proposed as monodentate and bridging binding. • ASKP-Fe3+ complex exhibited higher thermal stability than ASKP. [ABSTRACT FROM AUTHOR]

Hydrogels are important bionic materials that can be used in a wide variety of biomedical applications. Artemisia sphaerocephala Krasch polysaccharide (ASKP) has been demonstrated to be crosslinked by ferric ions to form three-dimensional network. Here, a semi-interpenetrating network (semi-IPN) hydrogel based on ASKP and cellulose nanocrystals (CNC) crosslinked by ferric ions was fabricated and the effect of specific rod-like CNC was evaluated. It was found that the network of ASKP-Fe3+ hydrogel incorporated by CNC became denser along with the decreased pore diameter and the thickened pore wall. ASKP/CNC-Fe3+ hydrogel displayed an enhanced gel strength and water holding capacity. The dominant interaction of ASKP and CNC was hydrogen bonds proved by FTIR and QCM-D. Additionally, the elasticity of the semi-IPN hydrogel significantly increased along with the decrease of platform height in MSD curves based on particles tracking. These results may be caused by the fact that the rod-shaped CNC can be entangled with ASKP and prone to induce the orderly extension of ASKP chains, resulting in more hydroxyl and carboxyl groups exposed to be crosslinked with ferric ions. What's more, the stiff CNC located on the pore wall of ASKP-Fe3+ hydrogel can also strengthen the rigidity of network. Thus, this study suggests a new strategy to improve the properties of ASKP based hydrogel, and can be developed as a carrier to deliver iron ions. [Display omitted] • The ASKP-Fe3+ based semi-IPN hydrogel was fabricated by incorporation of rod-like CNC. • The rod-like CNC induced the extension of ASKP chain and filled in the gap of ASKP-Fe3+ network. • The gel properties were improved by interpenetrating of CNC in ASKP-Fe3+ network. [ABSTRACT FROM AUTHOR]