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The treatment of large segmental bone defects and complex types of fractures caused by trauma, inflammation, or tumor resection is still a challenge in the field of orthopedics. Various natural or synthetic biological materials used in clinical applications cannot fully replicate the structure and performance of raw bone. This highlights how to endow materials with multiple functions and biological properties, which is a problem that needs to be solved in practical applications. Hydrogels with outstanding biocompatibility, for their casting into any shape, size, or form, are suitable for different forms of bone defects. Therefore, they have been used in regenerative medicine more widely. In this review, versatile hydrogels are compounded with nanoparticles of different dimensions, and many desirable features of these materials in bone regeneration are introduced, including drug delivery, cell factor vehicle, cell scaffolds, which have potential in bone regeneration applications. The combination of hydrogels and nanoparticles of different dimensions encourages better filling of bone defect areas and has higher adaptability. This is due to the minimally invasive properties of the material and ability to match irregular defects. These biological characteristics make composite hydrogels with different dimensional nanoparticles become one of the most attractive options for bone regeneration materials., (© 2021 Wiley-VCH GmbH.)

Diabetic foot ulcers (DFUs) are hard-healing chronic wounds and susceptible to bacterial infection. Conventional hydrogel dressings easily lose water at high temperature or freeze at low temperature, making them unsuitable for long-term use or in extreme environments. Herein, a temperature-tolerant (-20 to 60 °C) antibacterial hydrogel dressing is fabricated by the assembly of polyacrylamide, gelatin, and ε-polylysine. Owing to the water/glycerin (Gly) binary solvent system, the resultant hydrogel (G-PAGL) displayed good heat resistance and antifreezing properties. Within the wide temperature range (-20 to 60 °C), all the desirable features of the hydrogel, including superstretchability (>1400%), enduring water retention, adhesiveness, and persistent antibacterial property, are quite stable. Remarkably, the hydrogel wound dressing displayed lasting and broad antibacterial activity against Gram-positive and Gram-negative bacteria. Satisfactorily, the double-network (DN) G-PAGL hydrogel dressing could effectively promote the healing of DFUs by accelerating collagen deposition, promoting angiogenesis, and inhibiting bacterial breed. As far as we know, this is the first time that the extensive temperature-tolerant DN hydrogel with antibacterial ability is developed to use as DFU wound dressing. The G-PAGL hydrogel provides more choices for DFU wound dressings that could be used in extreme environments.

Rheumatoid arthritis (RA) is a severe inflammatory autoimmune disease, but its treatment has been very difficult. Recently, stem cell-based therapies have opened up possibilities for the treatment of RA. However, the hostile RA pathological conditions impede the survival and differentiation of transplanted cells, and it remains challenging to fabricate a suitable biomaterial for the improvement of stem cells survival, engraftment, and function. Here we construct an optimal scaffold for RA management through the integration of 3D printed porous metal scaffolds (3DPMS) and infliximab-based hydrogels. The presence of rigid 3DPMS is appropriate for repairing large-scale bone defects caused by RA, while the designed infliximab-based hydrogels are introduced because of their self-healable, anti-inflammatory, biocompatible, and biodegradable properties. We demonstrate that the bioengineered composite scaffolds support adipose-derived mesenchymal stem cells (ADSCs) proliferation, differentiation, and extracellular matrix production in vitro. The composite scaffolds, along with ADSCs, are then implanted into the critical-sized bone defect in the RA rabbit model. In vivo results prove that the bioengineered composite scaffolds are able to down-regulate inflammatory cytokines, rebuild damaged cartilage, as well as improve subchondral bone repair. To the best of the authors' knowledge, this is the first time that using the antirheumatic drug to construct hydrogels for stem cell-based therapies, and this inorganic-organic hybrid system has the potential to alter the landscape of RA study., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

As a kind of temperature-responsive hydrogel, polystyrene-co-poly(N-isopropylacrylamide)/poly(N-isopropylacrylamide) (PS-co-PNIPAM/PNIPAM) core-shell nanoparticles prepared by two-step copolymerization are widely studied and used because of their specific structures and properties. Unlike most reports about the steady stability of PS-co-PNIPAM/PNIPAM core-shell nanoparticle hydrogel emulsion, in this work, the PS-co-PNIPAM/PNIPAM core-shell nanoparticle hydrogel emulsion (symbolized as PS/PNIPAM hydrogel emulsion), which is prepared after the second step of synthesis and without washing out a large number of PNIPAM polymer segments, shows a reversible temperature-dependent sol-gel transition characteristic during the temperature range of 34-80 °C. The PS/PNIPAM hydrogel emulsion is a normal solution at room temperature, and it changes from a sol to a gel statue when the temperature approaches up to low critical solution temperature (LCST). As the temperature continues to increase, the gel (core-shell nanoparticles as the crosslinkers and the linear PNIPAM chain as the 3D gel network) of the PS/PNIPAM hydrogel emulsion gradually shrinks and drains linearly. Compared with most crosslinked hydrogels, the hydrogel here can be arbitrarily changed in shape according to use needs, which is convenient for use, transportation, and storage. Here a new route is provided for the preparation of a PS/PNIPAM core-shell hydrogel nanoparticle system, as well as a new supramolecular crosslinking sol-gel system for application in biomedical materials, sensors, biological separation, drug release, macromolecular adsorption, and purification., (© 2020 Wiley-VCH GmbH.)

In stomatology, the promotion of alveolar bone regeneration while preventing the reduction of ridge absorption remains a challenge. In this work, we designed and prepared bio-mimetic polysaccharide hydrogels that are multi-functional in terms of being injectable, promote self-healing, degradable, porous structure, et al. After introducing nano-hydroxyapatite particles, the composite scaffold of hydrogel/hydroxyapatite (GH) stent was obtained. When GH material was injected into the mandibular incisors of rats following tooth extraction, the new bone area was enhanced more than 50%, while the alveolar ridge was promoted in excess of 60% after 4 weeks. What's more, the wound soft tissue was healed within 1 week. Overall, our results indicate that this optimized GH stent has the potential to both maintain dimensional alveolar ridge, as well as to promote soft tissue healing. Moreover, using the hydroxyapatite-containing hydrogel platform has the potential to promote bone and soft tissue regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A type of dual-emission probe with highly recognizable luminescence-response to pH has been designed. For the prepared core-shell polymeric hydrogel nanoparticles probe (Eu(DBM) 3 Phen doped polystyrene (PS)-co-poly(N-isopropylacrylamide)(PNIPAM)/FITC), the red emission of inner encapsulated europium complexes Eu(DBM) 3 Phen is remained in the hydrophobic PS core and used as a stable reference signal. Comparingly, the green emission of outer electrostatic bonded fluorescent isothiocyanate (FITC) moieties on the hydrophilic PNIPAM shell is adjusted and acted linear and reversible luminescence-response to pH between 5.8 and 7.4 with an exact resolution of 0.1 units. As a remarkable and smart pH probe, the hydrogel nanoparticles show low biological toxicity and prolonged resistance to ions and photobleaching. Also, the probes have successfully discriminated the fluorescent imaging for cytoplasmic matrix based on different pH with minimum biologic background fluorescence. These dual-emission pH-sensitive hydrogel nanoparticles suggest potential applications in clinical medicine, such as cell imaging and disease diagnosis., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Purpose : Osteoporosis is more likely to cause serious complications after joint replacement, mainly due to physiological defects of endogenous osteogenic cells and the pathological osteoclast activity. It is a feasible solution to design a prosthetic surface interface that specifically addresses this troublesome situation. Methods : A novel "three-dimensional (3D) inorganic-organic supramolecular bioactive interface" was constructed consisting of stiff 3D printing porous metal scaffold and soft multifunctional, self-healable, injectable, and biodegradable supramolecular polysaccharide hydrogel. Apart from mimicking the bone extracellular matrix, the bioactive interface could also encapsulate bioactive substances, namely bone marrow mesenchymal stem cells (BMSCs) and bone morphogenetic protein-2 (BMP-2). A series of in vitro characterizations, such as topography and mechanical characterization, in vitro release of BMP-2, biocompatibility analysis, and osteogenic induction of BMSCs were carried out. After that, the in vivo osseointegration effect of the bioactive interface was investigated in detail using an osteoporotic model. Results : The administration of injectable supramolecular hydrogel into the inner pores of 3D printing porous metal scaffold could obviously change the morphology of BMSCs and facilitate its cell proliferation. Meanwhile, BMP-2 was capable of being sustained released from supramolecular hydrogel, and subsequently induced osteogenic differentiation of BMSCs and promoted the integration of the metal microspores-bone interface in vitro and in vivo . Moreover, the osteoporosis condition of bone around the bioactive interface was significantly ameliorated. Conclusion : This study demonstrates that the 3D inorganic-organic supramolecular bioactive interface can serve as a novel artificial prosthesis interface for various osteogenesis-deficient patients, such as osteoporosis and rheumatoid arthritis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Conductive hydrogels have recently gained impressive attention in biological medicine and intelligent electronics. Despite the multifunctions demonstrated by existing conductive hydrogels, it is still a challenge to introduce a hydrogel to adjust the distance between the peritumoral organs and the tumor, reducing the radiation damage to the peritumoral organs. Here, a hydrophobic associating hydrogel with multiple desirable features is fabricated based on diverse supramolecular assembly. The introduction of MXene and hydrolyzed keratin (HK) imparts the hydrogel with excellent conductivity, ultra‐stretchability (>2000%), and good self‐adhesion. Moreover, the hydrogel is utilized as an intelligent sensor intended for monitoring various human movements and physiological signals, demonstrating a wide strain window, the rapid response time (130 ms), and outstanding strain sensitivity (GF = 10.22). Inspired by balloon inflation, the hydrogel is designed to separate the tumor from the peritumoral organs in brachytherapy. It plays a role in reducing the radiation dose and damage to the peritumoral organs. The authors also simulate the attenuation process of the radiation signal according to the change of the hydrogel size and develop a smartphone application (app) to monitor the safety range of the different radiation risks, manifesting its great potential in soft intelligent sensors. [ABSTRACT FROM AUTHOR]

Conductive hydrogels as flexible electronic devices, not only have unique attractions but also meet the basic need of mechanical flexibility and intelligent sensing. How to endow anisotropy and a wide application temperature range for traditional homogeneous conductive hydrogels and flexible sensors is still a challenge. Herein, a directional freezing method is used to prepare anisotropic MXene conductive hydrogels that are inspired by ordered structures of muscles. Due to the anisotropy of MXene conductive hydrogels, the mechanical properties and electrical conductivity are enhanced in specific directions. The hydrogels have a wide temperature resistance range of −36 to 25 °C through solvent substitution. Thus, the muscle‐inspired MXene conductive hydrogels with anisotropy and low‐temperature resistance can be used as wearable flexible sensors. The sensing signals are further displayed on the mobile phone as images through wireless technology, and images will change with the collected signals to achieve motion detection. Multiple flexible sensors are also assembled into a 3D sensor array for detecting the magnitude and spatial distribution of forces or strains. The MXene conductive hydrogels with ordered orientation and anisotropy are promising for flexible sensors, which have broad application prospects in human–machine interface compatibility and medical monitoring. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFU) remain a very considerable health care burden, and their treatment is difficult. Hydrogel‐based wound dressings are appealing to provide an optimal environment for wound repair. However, the currently available hydrogel dressings still need surgical or mechanical debridement from the wound, causing reinjury of the newly formed tissues, wound infection, delayed healing time, and personal suffering. Additionally, to meet people's increasing demand, hydrogel wound dressings with improved performance and multifunctionality are urgently required. Here, a new multifunctional supramolecular hydrogel for on‐demand dissolvable diabetic foot wound dressings is designed and constructed. Based on multihydrogen bonds between hydrophilic polymers, the resultant supramolecular hydrogels present controlled and excellent properties, such as good transparency, antibacterial ability, conductive, and self‐healing properties. Thus, the supramolecular hydrogels improve the new tissue formation and provide a significant therapeutic effect on DFU by inducing angiogenesis, enhancing collagen deposition, preventing bacterial infection, and controlling wound infection. Remarkably, the resultant hydrogels also exhibit stimuli‐responsive ability, which renders its capability to be dissolved on‐demand, allowing for a facile DFU dressing removal. This multifunctional supramolecular hydrogel may provide a novel concept in the design of on‐demand dissolvable wound dressings. [ABSTRACT FROM AUTHOR]

Osteoporosis is one of the most prevalent age-related diseases worldwide and is characterized by a systemic deterioration of bone strength (bone mineral density and bone quality) with a resulting increase in fragility fractures. Due to the complex osteoporotic pathological environment, it is a huge challenge to induce bone regeneration under osteoporosis conditions. In this study, we successfully nanoengineer a bioinspired mineralized hydrogel from the supramolecular assembly of nano-hydroxyapatite, sodium carbonate, and polyacrylic acid, termed as CHAp-PAA. The resultant nanocomposite hydrogels can maintain their initial morphology and mechanical properties under physiological conditions, while exhibiting good primary stability, biocompatibility, bioactivity, and osteoconductivity. We demonstrate that this optimized hydrogel scaffold has shown superior performance for bone marrow stem cells (BMSCs) proliferation, differentiation, and extracellular matrix production in vitro. Remarkably, the mineralized CHAp-PAA hydrogels could be used as scaffolds for the critical-sized bone defect (6.0 mm diameter and 10.0 mm depth) in the osteoporotic rabbit model. Without the delivery of additional therapeutic agents or stem cells, these CHAp-PAA hydrogel scaffolds can improve bone ingrowth and accelerate new bone formation even in complex osteoporotic pathological environments. Therefore, this work presents a type of bioinspired multifunctional mineral hydrogel that offers an alternative strategy to manage osteoporosis. • We successfully nanoengineer a bioinspired mineralized hydrogel from supramolecular assembly of nano-hydroxyapatite, sodium carbonate, and polyacrylic acid, termed as CHAp-PAA. The resultant nanocomposite hydrogels can maintain their initial morphology and mechanical properties under physiological conditions, while exhibiting good primary stability, biocompatibility, bioactivity, and osteoconductivity. • We demonstrate that this optimized hydrogel scaffold has shown superior performance for bone marrow stem cells (BMSCs) proliferation, differentiation, and extracellular matrix production in vitro. • Remarkably, the mineralized CHAp-PAA hydrogels could be used as scaffold for the critical-sized bone defect (6.0 mm diameter and 10.0 mm depth) in osteoporotic rabbit model. Without delivery of additional therapeutic agents or stem cells, these CHAp-PAA hydrogel scaffolds can improve bone ingrowth and accelerate new bone formation even in complex osteoporotic pathological environment. Image, graphical abstract [ABSTRACT FROM AUTHOR]

A diabetic foot ulcer (DFUs) is a state of prolonged chronic inflammation, which can result in amputation. Different from normal skin wounds, various commercially available dressings have not sufficiently improved the healing of DFUs. In this study, a novel self-healing hydrogel was prepared by in situ crosslinking of N -carboxyethyl chitosan (N -chitosan) and adipic acid dihydrazide (ADH) with hyaluronic acid-aldehyde (HA-ALD), to provide a moist and inflammatory relief environment to promote stem cell proliferation or secretion of growth factors, thus accelerating wound healing. The results demonstrated that this injectable and self-healing hydrogel has excellent swelling properties, stability, and mechanical properties. This biocompatible hydrogel stimulated secretion of growth factors from bone marrow mesenchymal stem cells (BM-MSCs) and regulated the inflammatory environment by inhibiting the expression of M1 macrophages and promoting the expression of M2 macrophages, resulting in granulation tissue formation, collagen deposition, nucleated cell proliferation, neovascularization, and enhanced diabetic wound healing. This study showed that N -chitosan/HA-ALD hydrogel could be used as a multifunctional injectable wound dressing to regulate chronic inflammation and provide an optimal environment for BM-MSCs to promote diabetic wound healing. [ABSTRACT FROM AUTHOR]

Doubly charged pH-responsive core/shell hydrogel nanoparticles with green fluorescence were prepared and were shown to be viable bioprobes for active targeting tumor tissue and imaging of cancer cells. Via emulsionfree copolymerization hydrogel nanoparticles as VANPs were prepared, the core of which was polystyrene (Ps) and the shell was comprised of strongly positive electrolyte (ar-vinylbenzyl)trimethylammonium (VBTAC) with weak negative electrolyte acrylic acid (AA). Through conventional amidation, the shell was conjugated with cell-specific folic acid (FA), denoted as VANPs-FA. Then, negatively charged sulfonated 9,10-distyrylanthracene derivatives (SDSA) based on aggregation induced emission (AIE), was binding tightly to positively charged VBTAC of VANPs-FA shell. The prepared double charged fluorescent core/shell hydrogel nanoparticles abbreviated as VANPs-FS, showed excitation/emission wavelengths at ~420/528 nm. Dynamic light scattering (DLS) measurements were performed to determine the size and surficial zeta potential of VANPs-FS. Under proper ratio of VBTAC to AA, the VANPs-FS was stable (~ 64.63 nm, −20.2 mV) at high pH (> 7), started to aggregate (~ 683.0 nm, −3.2 mV) at pH around 6, and can redispers at low pH (< 5). The MTT analysis proved that VANPs-FS had good biocompatibility and low cytotoxicity. The targeting effectiveness of VANPs-FS was confirmed by confocal laser scanning microscopy (CLSM). [ABSTRACT FROM AUTHOR]

Recently, artificial intelligence research has driven the development of stretchable and flexible electronic systems. Conductive hydrogels are a class of soft electronic materials that have emerging applications in wearable and implantable biomedical devices. However, current conductive hydrogels possess fundamental limitations in terms of their antibacterial performance and a mechanical mismatch with human tissues, which severely limits their applications in biological interfaces. Here, inspired by animal skin, a conductive hydrogel is fabricated from a supramolecular assembly of polydopamine decorated silver nanoparticles (PDA@Ag NPs), polyaniline, and polyvinyl alcohol, namely PDA@Ag NPs/CPHs. The resultant hydrogel has many desirable features, such as tunable mechanical and electrochemical properties, eye‐catching processability, good self‐healing ability as well as repeatable adhesiveness. Remarkably, PDA@Ag NPs/CPHs exhibit broad antibacterial activity against Gram‐negative and Gram‐positive bacteria. The potential application of this versatile hydrogel is demonstrated by monitoring large‐scale movements of the human body in real time. In addition, PDA@Ag NPs/CPHs have a significant therapeutic effect on diabetic foot wounds by promoting angiogenesis, accelerating collagen deposition, inhibiting bacterial growth, and controlling wound infection. To the best of the authors' knowledge, this is the first time that conductive hydrogels with antibacterial ability are developed for use as epidermal sensors and diabetic foot wound dressing. [ABSTRACT FROM AUTHOR]

[Display omitted] • Reversible dynamic bonds give hydrogels injectable and self-healing properties. • Insulin released from the hydrogel in a pH-responsive mode. • Bioactive dressings improve healing and peripheral neuropathy of diabetic wounds. The healing of diabetic foot ulcers (DFUs) is a major challenge for clinical treatment because of the hyperglycemic and acidic microenvironment in the wound area. In this study, a self-healing, injectable, and pH-responsive hydrogel was synthesized by N-carboxyethyl chitosan (N-chitosan), hyaluronic acid–aldehyde (HA-ALD), adipic acid dihydrazide (ADH) through the formation of the reversible dynamic bonds, acylhydrazone and imine bonds. The presence of the acylhydrazone bond characterizes the hydrogel pH-responsive property. In this study, the insulin glargine was successfully incorporated into the hydrogel, allowing its sustained and pH-responsive releasing from the hydrogel for up to 14 days. The hydrogel presented good compatibility and pore structure, and the insulin released from the hydrogel maintained its original bioactivity. Full thickness wounds were established on the feet of diabetic rats to evaluate the therapeutic effect of the dressing. The results revealed that the bioactive insulin-loaded hydrogel dressing shortened the inflammatory phase, enhanced granulation tissue formation, promoted collagen deposition, accelerated re-epithelialization and neovascularization, and postponed or even improved peripheral neuropathy, thus, significantly accelerated DFUs healing. Our findings showed that the insulin-loaded hydrogels had promising potential as a multifunctional bioactive wound dressing for enhancing DFUs healing. [ABSTRACT FROM AUTHOR]