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Osteoarthritis (OA) is the most prevalent chronic joint disorder and is a major cause of disability among the elderly population. The degeneration and damage of articular cartilage associated with OA can result in a diminished range of motion in joints, subsequently impacting fundamental activities such as ambulation, standing, and grasping objects. In severe cases, it may culminate in disability. Traditional pharmacological treatments are often accompanied by various side effects, while invasive surgical procedures increase the risk of infection and thrombosis. Consequently, identifying alternative new methods for OA treatment remains a formidable challenge. With advancements in responsive hydrogel drug delivery platforms, an increasing number of strategies have emerged to enhance OA treatment protocols. Injectable response hydrogel drug delivery platforms show many advantages in treating OA, including improved biocompatibility, prolonged drug release duration, elevated drug loading capacity and enhanced sensitivity. This article reviews the recent progress of injectable responsive hydrogel drug delivery platform for OA treatment over the past few years. These innovative methodologies present new strategies and directions for future OA treatment while summarizing a series of challenges faced during the clinical transformation of injectable response hydrogel drug delivery platforms. Overall, injectable responsive hydrogel drug delivery platforms show great potential in treating OA, especially regarding improving drug retention time and stimulus-responsive release at the lesion sites. These innovative methods provide new hope for future OA treatment and point the way for clinical applications. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) constitutes a severe condition characterized by a sudden decrease in kidney function. Utilizing lineage-restricted stem/progenitor cells, directly reprogrammed from somatic cells, is a promising therapeutic option in personalized medicine for serious and incurable diseases such as AKI. The present study describes the therapeutic potential of induced nephron progenitor cell-sourced molecules (iNPC-SMs) as a cell-free strategy against cisplatin (CP)-induced nephrotoxicity, employing hyaluronic acid (HA) hydrogel-mediated local delivery to minimize systemic leakage and degradation. iNPC-SMs exhibited anti-apoptotic effects on HK-2 cells by inhibiting CP-induced ROS generation. Additionally, the localized biodistribution facilitated by hydrogel-mediated iNPC-SM delivery contributed to enhanced renal function, anti-inflammatory response, and renal regeneration in AKI mice. This study could serve as a 'proof of concept' for injectable hydrogel-mediated iNPC-SM delivery in AKI and as a model for further exploration of the development of cell-free regenerative medicine strategies. [ABSTRACT FROM AUTHOR]

Hydrogels have garnered significant interest in the biomedical field owing to their tissue-like properties and capability to incorporate various fillers. Among these, injectable hydrogels have been highlighted for their unique advantages, especially their minimally invasive administration mode for implantable use. These injectable hydrogels can be utilized in their pristine forms or as composites by integrating them with therapeutic filler materials. Given their primary application in implantable platforms, enzymatically crosslinked injectable hydrogels have been actively explored due to their excellent biocompatibility and easily controllable mechanical properties for the desired use. This review introduces the crosslinking mechanisms of such hydrogels, focusing on those mediated by horseradish peroxidase (HRP), transglutaminase (TG), and tyrosinase. Furthermore, several parameters and their relationships with the intrinsic properties of hydrogels are investigated. Subsequently, the representative biomedical applications of enzymatically crosslinked-injectable hydrogels are presented, including those for wound healing, preventing post-operative adhesion (POA), and hemostasis. Furthermore, hydrogel composites containing filler materials, such as therapeutic cells, proteins, and drugs, are analyzed. In conclusion, we examine the scientific challenges and directions for future developments in the field of enzymatically crosslinked-injectable hydrogels, focusing on material selection, intrinsic properties, and filler integration. [ABSTRACT FROM AUTHOR]

Conventional pulp capping materials have limited anti-inflammatory capacity. It is necessary to develop more effective pulp capping material for the treatment of inflamed pulps. Tannic acid (TA) is a natural, water-soluble polyphenol with antimicrobial and anti-inflammatory properties. This study aimed to investigate the effects of a tannin-containing hydroxypropyl chitin hydrogel (HPCH/TA hydrogel) as an innovative pulp capping material. The physicochemical properties of the composite hydrogels were characterized. The effects of HPCH/TA hydrogel as a pulp capping material were evaluated in vitro and in vivo. The underlying mechanism of the anti-inflammatory effects of HPCH/TA hydrogel was explored. The HPCH/TA hydrogel demonstrated favorable temperature sensitivity, injectability, and antibacterial properties. In vitro, the HPCH/TA hydrogel effectively promoted the proliferation of human dental pulp cells and inhibited interleukin-1β, interleukin-6, and tumor necrosis factor-α expression, possibly by suppressing the nuclear factor kappa-B pathway. In vivo, on the fourth day after capping, the HPCH/TA hydrogel group showed lower inflammatory scores compared to the control and iRoot BP Plus (commercial pulp capping material) group. By the sixth week, complete reparative dentin formation was observed in the HPCH/TA hydrogel group, with no difference in thickness compared to the iRoot BP Plus group. Collectively, the HPCH/TA hydrogel holds promise as a bioactive pulp capping material for promoting the repair of inflamed pulp in vital pulp therapy. [ABSTRACT FROM AUTHOR]

Irreversible fibrosis following myocardial infarction (MI) stiffens the infarcted myocardium, which remains challenging to restore. This study aimed to investigate whether the injectable RLP12 hydrogel, derived from recombinant resilin protein, could serve as a vehicle for stem cells to enhance the function of the infarcted myocardium. The RLP12 hydrogel was prepared and injected into the myocardium of rats with MI, and brown adipose-derived mesenchymal stem cells (BADSCs) were loaded. The survival and differentiation of BADSCs in vivo were investigated using immunofluorescence one week and four weeks after treatment, respectively. The heart function, MI area, collagen deposition, and microvessel density were further assessed four weeks after treatment through echocardiography, histology, immunohistochemistry, and immunofluorescence. The RLP12 hydrogel was prepared with a shear modulus of 10–15 kPa. Four weeks after transplantation, the RLP12 hydrogel significantly improved cardiac function by increasing microvessel density and reducing infarct area size and collagen deposition in MI rats. Furthermore, the distribution ratio of collagen III to I increased in both the centre and edge areas of the MI, indicating the improved compliance of the infarct heart. Moreover, the RLP12 hydrogel also promoted the survival and differentiation of BADSCs into cardiac troponin T- and α-smooth muscle-positive cells. The RLP12 hydrogel can be utilised as an injectable vehicle of BADSCs for treating MI and regulating collagen I and III expression profiles to improve the mechanical microenvironment of the infarct site, thereby restoring heart function. The study provides novel insights into the mechanical interactions between the hydrogel and the infarct microenvironment. [ABSTRACT FROM AUTHOR]

Wound infections caused by Staphylococcus aureus often result in localized suppurative lesions that severely impede the healing process, so it is urgent to develop a dress with efficient antimicrobial and pro-healing functions. In this study, the bifunctional injectable hydrogel lactoferrin (Lf)/NZ2114/lithium magnesium silicate hydrogel (LMSH) was first successfully prepared through the electrostatic interaction method. The physical, biological, and efficacy properties are systematically analyzed with good shear-thinning capacity and biocompatibility. More importantly, it inhibits infection and promotes wound healing in a mouse wound infection model after 14 d treatment, and the bactericidal rate and healing rate were over 99.92% and nearly 100%, respectively. Meanwhile, the massive reduction of inflammatory cells, restoration of tissue structure, and angiogenesis in mice showed the anti-inflammatory and pro-healing properties of the hydrogel. The healed wounds showed thickening with more hair follicles and glands, suggesting that the hydrogel Lf/NZ2114/LMSH (Three in One) could be a better dressing candidate for the treatment of S. aureus-induced wound infections. [ABSTRACT FROM AUTHOR]

The treatment adherence of narcotics-addicted individuals with reduced incidences of relapse can be enhanced by a sustained drug release formulation of antinarcotics. So far, different drug formulations have been reported with sustained drug release periods of 28 and 35 days. To further enhance this duration, different formulations of injectable hydrogels (IHs) have been developed by combining low molecular weight (LMW) and high molecular weight (HMW) chitosan (CS) with guar gum (GG) and crosslinking them by sodium bi phosphate dibasic. The structural, morphological, and physicochemical properties of LMW-CS IH, and HMW-CS IH were evaluated using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), and rheological, swelling, and biodegradation analysis. The HMW-CS IH showed high crosslinking, increased thermal stability, high mechanical strength, elevated swelling, and low biodegradation. The antinarcotic drugs naltrexone (NTX) and disulfiram (DSF) were loaded separately into the HMW-CS IH and LMW-CS IH. The release of NTX and DSF was investigated in phosphate buffer saline (PBS) and ethanol (0.3%, 0.4%, and 0.5%) over a 56-day period using an UV spectrophotometer. The drug release data were tested in zero-order, first-order, and Korsemeyer–Peppas mathematical models. In PBS, all prepared formulations followed non-Fickian drug release, while in ethanol, only NTX HMW-CS IH followed non-Fickian release in all three different concentrations of ethanol. [ABSTRACT FROM AUTHOR]

Endogenous stimuli-responsive injectable hydrogels hold significant promise for practical applications due to their spatio-temporal controllable drug delivery. Herein, we report a facile strategy to construct a series of in situ formation polypeptide hydrogels with thermal responsiveness and enzyme-triggered dynamic self-assembly. The thermo-responsive hydrogels are from the diblock random copolymer mPEG-b-P(Glu-co-Tyr). The L-glutamic acid (Glu) segments with different γ-alkyl groups, including methyl, ethyl, and n-butyl, offer specific secondary structure, facilitating the formation of hydrogel. The L-tyrosine (Tyr) residues not only provide hydrogen-bond interactions and thus adjust the sol–gel transition temperatures, but also endow polypeptide enzyme-responsive properties. The PTyr segments could be phosphorylated, and the phosphotyrosine copolymers were amphiphilies, which could readily self-assemble into spherical aggregates and transform into sheet-like structures upon dephosphorylation by alkaline phosphatase (ALP). P(MGlu-co-Tyr/P) and P(MGlu-co-Tyr) copolymers showed good compatibility with both MC3T3-E1 and Hela cells, with cell viability above 80% at concentrations up to 1000 μg/mL. The prepared injectable polypeptide hydrogel and its enzyme-triggered self-assemblies show particular potential for biomedical applications. [ABSTRACT FROM AUTHOR]

Photoinduced metal-free ATRP has been successfully applied to fabricate thermo-responsive cellulose graft copolymer (PNIPAM-g-Cell) using 2-bromoisobuturyl bromide-modified cellulose as the macroinitiator. The polymerization of N-isopropylacrylamide (NIPAM) from cellulose was efficiently activated and deactivated with UV irradiation in the presence of an organic-based photo-redox catalyst. Both FTIR and 13C NMR analysis confirmed the structural similarity between the obtained PNIPAM-g-Cell and that synthesized via traditional ATRP methods. When the concentration of the PNIPAM-g-Cell is over 5% in water, it forms an injectable thermos-responsive hydrogel composed of micelles at 37 °C. Since organic photocatalysis is a metal-free ATRP, it overcomes the challenge of transition-metal catalysts remaining in polymer products, making this cellulose-based graft copolymer suitable for biomedical applications. In vitro release studies demonstrated that the hydrogel can continuously release DOX for up to 10 days, and its cytotoxicity indicates that it is highly biocompatible. Based on these findings, this cellulose-based injectable, thermo-responsive drug-loaded hydrogel is suitable for intelligent drug delivery systems. [ABSTRACT FROM AUTHOR]

The tissue engineering field is currently advancing towards minimally invasive procedures to reconstruct soft tissue defects. In this regard, injectable hydrogels are viewed as excellent scaffold candidates to support and promote the growth of encapsulated cells. Cross-linked gelatin methacryloyl (GelMA) gels have received substantial attention due to their extracellular matrix-mimicking properties. In particular, GelMA microgels were recently identified as interesting scaffold materials since the pores in between the microgel particles allow good cell movement and nutrient diffusion. The current work reports on a novel microgel preparation procedure in which a bulk GelMA hydrogel is ground into powder particles. These particles can be easily transformed into a microgel by swelling them in a suitable solvent. The rheological properties of the microgel are independent of the particle size and remain stable at body temperature, with only a minor reversible reduction in elastic modulus correlated to the unfolding of physical cross-links at elevated temperatures. Salts reduce the elastic modulus of the microgel network due to a deswelling of the particles, in addition to triple helix denaturation. The microgels are suited for clinical use, as proven by their excellent cytocompatibility. The latter is confirmed by the superior proliferation of encapsulated adipose tissue-derived stem cells in the microgel compared to the bulk hydrogel. Moreover, microgels made from the smallest particles are easily injected through a 20G needle, allowing a minimally invasive delivery. Hence, the current work reveals that powdered cross-linked GelMA is an excellent candidate to serve as an injectable hydrogel for adipose tissue engineering. [ABSTRACT FROM AUTHOR]

Utilizing the immune system as a strategy for disease prevention and treatment is promising, especially with dendritic cells (DCs) playing a central role in adaptive immune responses. The unique properties of DCs drive interest in developing materials for cell-based therapy and immune modulation. Injectable systems require syringe-compatible scaffolds, while hydrogels, like alginate, known for their programmability and biocompatibility, offer a versatile platform for immune medicine enhancement through easy preparation and room-temperature cross-linking. In this study, we synthesized alginate balls loaded with DCs or cytosine–phosphorothioate–guanine deoxyribonucleotide (CpG DNA) microparticles, aiming for long-term immune cell culture with potential immune stimulation effects. Encapsulated DCs exhibited proliferation within the alginate balls for up to 7 days, and CpG MPs were uniformly dispersed, which can facilitate uptake by DCs. This was supported by the result that DCs effectively phagocytosed CpG microparticles in a 2D environment. After the uptake of CpG MPs, the alginate balls with CpG-MP-uptaken DCs were synthesized successfully. The injectable properties of the alginate balls were easily modulated by adjusting the syringe needle gauges. This innovative strategy holds substantial promise for advancing medical treatments, offering effective and comfortable solutions for controlled immune modulation. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severe neurological injury caused by traffic accidents, trauma, or falls, which leads to significant loss of sensory, motor, and autonomous functions and seriously affects the patient's life quality. Although considerable progress has been made in mitigating secondary injury and promoting the regeneration/repair of SCI, the therapeutic effects need to be improved due to drug availability. Given their good biocompatibility, biodegradability, and low immunogenicity, injectable hydrogels can be used as delivery systems to achieve controlled release of drugs and other substances (cells and proteins, etc.), offering new hope for SCI repair. In this article, we summarized the types of injectable hydrogels, analyzed their application as delivery systems in SCI, and further discussed the mechanisms of hydrogels in the treatment of SCI, such as anti-inflammatory, antioxidant, anti-apoptosis, and pro-neurogenesis. Moreover, we highlighted the potential benefits of hydrogels in the treatment of SCI in combination with therapies, including the recent advances and achievements of these promising tools. Our review may offer new strategies for the development of SCI treatments based on injectable hydrogels as delivery systems. [ABSTRACT FROM AUTHOR]

The current treatment for periodontitis is aimed at resolving gingival inflammation, whilst complete periodontal tissue regeneration is not predictable, and it represents a therapeutic challenge. Injectable biomaterials hold tremendous potential in dental tissue regeneration. This study aimed to investigate the ability of an injectable thermosensitive β-tricalcium phosphate (β-TCP) and chitosan-based hydrogel to carry cells and promote periodontal tissue regeneration. In this study, different concentrations of β-TCP-loaded chitosan hydrogels were prepared (0%, 2%, 4%, or 6% β-TCP, 10% β-glycerol phosphate, and 1.5% chitosan). The characteristics of the hydrogels were tested using rheology, a scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), degradation, and biological analyses. The new biomaterial showed a sol–gel transformation ability at body temperature and exhibited excellent chemical and physical characteristics, whilst the existence of β-TCP enhanced the structure and the properties of the hydrogels. The SEM confirmed the three-dimensional networks of the hydrogels, and the typical rheological properties of strong gel were observed. The EDX and XRD validated the successful incorporation of β-TCP, and similar patterns between different groups were found in terms of the FTIR spectra. The stable structure of the hydrogels under 100 °C was confirmed via DSC. Biological tests such as Alamar Blue assay and Live/Dead staining confirmed the remarkable biocompatibility of the hydrogels with pre-osteoblast MC3T3-E1 and human gingival fibroblast (HGF) cells for 14 days, and the results were validated with confocal imaging. This preliminary study shows great promise for the application of the β-TCP-loaded thermosensitive chitosan hydrogels as a scaffold in periodontal bone and soft tissue repair. [ABSTRACT FROM AUTHOR]

Injectable hydrogels offer numerous advantages in various areas, which include tissue engineering and drug delivery because of their unique properties such as tunability, excellent carrier properties, and biocompatibility. These hydrogels can be administered with minimal invasiveness. In this study, we synthesized an injectable hydrogel by rehydrating lyophilized mixtures of guar adamantane (Guar-ADI) and poly-β-cyclodextrin (p-βCD) in a solution of phosphate-buffered saline (PBS) maintained at pH 7.4. The hydrogel was formed via host-guest interaction between modified guar (Guar-ADI), obtained by reacting guar gum with 1-adamantyl isocyanate (ADI) and p-βCD. Comprehensive characterization of all synthesized materials, including the hydrogel, was performed using nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and rheology. The in vitro drug release study demonstrated the hydrogel's efficacy in controlled drug delivery, exemplified by the release of bovine serum albumin (BSA) and anastrozole, both of which followed first-order kinetics. Furthermore, the hydrogel displayed excellent biocompatibility and served as an ideal scaffold for promoting the growth of mouse osteoblastic MC3T3 cells as evidenced by the in vitro biocompatibility study. [ABSTRACT FROM AUTHOR]

The application of hydrogels in bone repair is limited due to their low mechanical strength. Simulating bone extracellular matrix, methylacrylylated gelatin (GelMA)/methylacrylylated hyaluronic acid (HAMA)/nano-hydroxyapatite(nHap) composite hydrogels were prepared by combining the double network strategy and composite of nHap in this study. The precursor solutions of the composite hydrogels were injectable due to their shear thinning property. The compressive elastic modulus of the composite hydrogel was significantly enhanced, the fracture strength of the composite hydrogel nearly reached 1 MPa, and the composite hydrogel retained its high water content at above 88%. The composite hydrogels possess good compatibility with BMSCS and have the potential to be used as injectable hydrogels for bone defect treatment. [ABSTRACT FROM AUTHOR]

To prevent local tumor recurrence caused by possible residual cancer cells after surgery, avoid toxicity of systemic chemotherapy and protect the fragile immune system of postsurgical patients, an increasing amount of attention has been paid to local anti–cancer drug delivery systems. In this paper, golden buckwheat was first applied to prevent post–operative tumor recurrence, which is a Chinese herb and possesses anti–tumor activity. Golden buckwheat extract–loaded gellan gum injectable hydrogels were fabricated via Ca2+ crosslinking for localized chemotherapy. Blank and/or drug–loaded hydrogels were characterized via FT–IR, TG, SEM, density functional theory, drug release and rheology studies to explore the interaction among gellan gum, Ca2+ and golden buckwheat extract (GBE). Blank hydrogels were non–toxic to NIH3T3 cells. Of significance, GBE and GBE–loaded hydrogel inhibited the proliferation of tumor cells (up to 90% inhibition rate in HepG2 cells). In vitro hemolysis assay showed that blank hydrogel and GBE–loaded hydrogel had good blood compatibility. When GBE–loaded hydrogel was applied to the incompletely resected tumor of mice bearing B16 tumor xenografts, it showed inhibition of tumor growth in vivo and induced the apoptosis of tumor cells. Taken together, gellan gum injectable hydrogel containing GBE is a potential local anticancer drug delivery system for the prevention of postsurgical tumor recurrence. [ABSTRACT FROM AUTHOR]

Periodontal diseases significantly impact about half of the global population, and their treatment often encompasses relieving symptoms as well as regenerating the destroyed tissues. Revolutionary research in the management of periodontal disease includes biomaterials, a boon to re-generative dentistry owing to their excellent biological properties: non-toxicity, anti-inflammatory, biocompatibility, biodegradability, and adhesion. This study aimed to fabricate an injectable fucoidan containing chitosan hydrogel and prove its effectiveness in periodontal bone regeneration. The injectable hydrogel was prepared using the sol-gel method and was subjected to various physical, chemical, and biological characterizations to understand its efficacy in formation of new bone. The effectiveness of the developed hydrogel was assessed in periodontal bony defects to study the soft and hard tissue changes. A total of 40 periodontitis patients with bony defects were recruited and randomized into two groups to receive fucoidan-chitosan hydrogel and concentrated growth factor, respectively. Customized acrylic stents were used to guide the hydrogel placement into the defect site. Post-surgical changes in clinical parameters were assessed at 3, 6, and 9 months to appreciate the soft and hard tissue changes using repeated measures analysis of variance and Bonferroni's post hoc test. Significance was kept at 5%. The porosity, water uptake of the prepared hydrogel showed good efficacy, with particle size of the fucoidan containing chitosan hydrogel of 6.000 nm. The MG-63 osteoblasts cell line revealed biocompatibility, biodegradability and showed slow and sustained drug release, increased cell proliferation, and enhanced alkaline phosphatase secretion. Mineralization assay was greatest in the fucoidan containing chitosan hydrogel. Clinically, it exhibited significantly lower probing depth values and a higher mean improvement in clinical attachment level as compared to the concentrated growth factor (CGF) group at the end of 3 and 6 months (p < 0.05). The mean of the defect fills in the fucoidan containing chitosan group was 1.20 at the end of 9 months (p < 0.001) as compared with defect fills observed in the CGF group. The presence of fucoidan in the hydrogel significantly contributed to bone regeneration in humans, thus strengthening its potential in tissue engineering. Fucoidan-chitosan will be a promising biomaterial for bone tissue regeneration. [ABSTRACT FROM AUTHOR]

Injectable hydrogels can be applied to treat damaged meniscus in minimally invasive conditions. Generally, injectable hydrogels can be prepared from various polymers such as polycaprolactone (PCL) and poly (N-isopropylacrylamide) (PNIPAAm). Poly (ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer-diacrylate (PEO-PPO-PEO-DA) is an interesting polymer due to its biodegradability and can be prepared as water-insoluble injectable hydrogel after curing with UV light at low intensity. However, mechanical and cell adhesion properties are not optimal for these hydrogels. For the improved mechanical performance of the injectable hydrogel, cellulose nanofiber (CNF) extracted from cassava pulp was used as a reinforcing filler in this study. In addition, gelatin methacrylate (GelMA), the denatured form of collagen was used to enhance cell adhesion. PEO-PPO-PEO-DA/CNF/GelMA injectable hydrogels were prepared with 2-hydroxy-1-(4-(hydroxy ethoxy) phenyl)-2-methyl-1-propanone as a photoinitiator and then cured with UV light, 365 nm at 6 mW/cm2. Physicochemical characteristics of the hydrogels and hydrogels with CNF were studied in detail including morphology characterization, pore size diameter, porosity, mechanical properties, water uptake, and swelling. In addition, cell viability was also studied. CNF-reinforced injectable hydrogels were successfully prepared after curing with UV light within 10 min with a thickness of 2 mm. CNF significantly improved the mechanical characteristics of injectable hydrogels. The incorporation of GelMA into the injectable hydrogels improved the viability of human cartilage stem/progenitor cells. At optimum formulation, 12%PEO-PPO-PEO-DA/0.5%CNF/3%GelMA injectable hydrogels significantly promoted cell viability (>80%) and also showed good physicochemical properties, which met tissue engineering requirements. In summary, this work shows that these novel injectable hydrogels have the potential for meniscus tissue engineering. [ABSTRACT FROM AUTHOR]

Granular polymer hydrogels based on dynamic covalent bonds are attracting a great deal of interest for the design of injectable biomaterials. Such materials generally exhibit shear-thinning behavior and properties of self-healing/recovery after the extrusion that can be modulated through the interactions between gel microparticles. Herein, bulk macro-hydrogels based on thiolated-hyaluronic acid were produced by disulphide bond formation using oxygen as oxidant at physiological conditions and gelation kinetics were monitored. Three different thiol substitution degrees (SD%: 65%, 30% and 10%) were selected for hydrogel formation and fully characterized as to their stability in physiological medium and morphology. Then, extrusion fragmentation technique was applied to obtain hyaluronic acid microgels with dynamic disulphide bonds that were subsequently sterilized by autoclaving. The resulting granular hyaluronic hydrogels were able to form stable filaments when extruded through a syringe. Rheological characterization and cytotoxicity tests allowed to assess the potential of these materials as injectable biomaterials. The application of extrusion fragmentation for the formation of granular hyaluronic hydrogels and the understanding of the relation between the autoclaving processes and the resulting particle size and rheological properties should expand the development of injectable materials for biomedical applications. [ABSTRACT FROM AUTHOR]

Conductive hydrogels are promising materials in bioelectronics that ensure a tissue-like soft modulus and re-enact the electrophysiological function of damaged tissues. However, recent approaches to fabricating conductive hydrogels have proved difficult: fixing of the conductive hydrogels on the target tissues hydrogels requires the aids from other medical glues because of their weak tissue-adhesiveness. In this study, an intrinsically conductive and tissue-adhesive granular hydrogel consisting of a PEDOT:PSS conducting polymer and an adhesive catechol-conjugated alginate polymer was fabricated via an electrohydrodynamic spraying method. Because alginate-based polymers can be crosslinked by calcium ions, alginate-catechol polymers mixed with PEDOT:PSS granular hydrogels (ACP) were easily fabricated. The fabricated ACP exhibited not only adhesive and shear-thinning properties but also conductivity similar to that of muscle tissue. Additionally, the granular structure makes the hydrogel injectable through a syringe, enabling on-tissue printing. This multifunctional granular hydrogel can be applied to soft and flexible electronics to connect humans and machines. [ABSTRACT FROM AUTHOR]

Silk fibroin is regarded as a promising biomaterial in various areas, including bone tissue regeneration. Herein, Laponite® (LAP), which can promote osteogenic differentiation, was introduced into regenerated silk fibroin (RSF) to prepare an RSF/LAP hybrid hydrogel. This thixotropic hydrogel is injectable during the operation process, which is favorable for repairing bone defects. Our previous work demonstrated that the RSF/LAP hydrogel greatly promoted the osteogenic differentiation of osteoblasts in vitro. In the present study, the RSF/LAP hydrogel was found to have excellent biocompatibility and significantly improved new bone formation in a standard rat calvarial defect model in vivo. Additionally, the underlying biological mechanism of the RSF/LAP hydrogel in promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was extensively explored. The results indicate that the RSF/LAP hydrogels provide suitable conditions for the adhesion and proliferation of BMSCs, showing good biocompatibility in vitro. With the increase in LAP content, the alkaline phosphatase (ALP) activity and mRNA and protein expression of the osteogenic markers of BMSCs improved significantly. Protein kinase B (AKT) pathway activation was found to be responsible for the inherent osteogenic properties of the RSF/LAP hybrid hydrogel. Therefore, the results shown in this study firmly suggest such an injectable RSF/LAP hydrogel with good biocompatibility (both in vitro and in vivo) would have good application prospects in the field of bone regeneration. [ABSTRACT FROM AUTHOR]

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments. [ABSTRACT FROM AUTHOR]

Background: Diabetic wound (DW) is the most devastating complication resulting in significant mortality and morbidity in diabetic patients. The objective of the current study was to formulate Epidermal Growth Factor loaded Chitosan nanoparticle impregnated with thermos-responsive injectable hydrogel with protease inhibitor. EGF, shown in all stages of wound healing from inflammation to proliferation and remodelling, combined with Doxycycline, a well-known anti-inflammatory and anti-bacterial drug, could be a better strategy in diabetic wound healing. However, EGF's low stability makes it difficult to use. Methodology: The nanoparticles were prepared using the ionic gelation method. The prepared nanoparticles were evaluated for particle size, zeta potential, entrapment efficiency, and SEM studies. Further, the optimized nanoparticle batch was loaded into hydrogel with a protease inhibitor. The hydrogel was evaluated for morphology, protease degradation, in vitro drug release, anti-bacterial activity, cell migration, in vitro cell biocompatibility, and in vivo wound healing studies. Results and Conclusion: The particle size analysis of nanoparticles revealed the size (203 ± 1.236 nm), Zeta potential (+28.5 ± 1.0 mV), and entrapment efficiency of 83.430 ± 1.8%, respectively. The hydrogel showed good porous morphology, injectability, thermo-responsive, biocompatibility, and controlled drug release. In vitro anti-bacterial studies revealed the potential anti-bacterial activity of doxycycline against various microbes. In vivo data indicated that combining EGF and DOX considerably reduced inflammation time-dependent than single-agent treatment. Furthermore, histological studies corroborated these findings. After topical application of hydrogel, histopathology studies revealed significant collagen synthesis and a fully regenerated epithelial layer and advancement in all three stages (proliferation, remodelling, and maturation), which are required to improve the diabetic wound healing process by any dressing. These findings demonstrated that hydrogel promoted cutaneous wound healing in STZ-induced rats by suppressing inflammation at the wound site. Furthermore, histological studies corroborated these findings. After topical application of hydrogel, histopathology studies revealed significant collagen synthesis, a fully regenerated epithelial layer, and advancement in all three stages (proliferation, remodelling, and maturation), which are required to improve the diabetic wound healing process by any dressing. These findings demonstrated that hydrogel promoted cutaneous wound healing in STZ-induced rats by suppressing inflammation at the wound site. [ABSTRACT FROM AUTHOR]

Hydrogels have been used as scaffolds for biomineralization in tissue engineering and regenerative medicine for the repair and treatment of many tissue types. In the present work, we studied an amino acid-based material that is attached to protecting groups and self-assembles into biocompatible and stable nanostructures that are suitable for tissue engineering applications. Specifically, the doubly protected aspartic residue (Asp) with fluorenyl methoxycarbonyl (Fmoc) protecting groups have been shown to lead to the formation of well-ordered fibrous structures. Many amino acids and small peptides which are modified with protecting groups display relatively fast self-assembly and exhibit remarkable physicochemical properties leading to three-dimensional (3D) networks, the trapping of solvent molecules, and forming hydrogels. In this study, the self-assembling fibrous structures are targeted toward calcium binding and act as nucleation points for the binding of the available phosphate groups. The cell viability, proliferation, and osteogenic differentiation of pre-osteoblastic cells cultured on the formed hydrogel under various conditions demonstrate that hydrogel formation in CaCl2 and CaCl2-Na2HPO4 solutions lead to calcium ion binding onto the hydrogels and enrichment with phosphate groups, respectively, rendering these mechanically stable hydrogels osteoinductive scaffolds for bone tissue engineering. [ABSTRACT FROM AUTHOR]

Traditional hydrogels have drawbacks such as surgical implantation, large wound surfaces, and uncontrollable drug release during tumor treatment. In this paper, targeted nanomedicine has been combined with injectable hydrogel for photothermal–chemotherapy combination therapy. First, targeted nanomedicine (ICG—MTX) was fabricated by combining near-infrared (NIR) photothermal reagents (ICG) and chemotherapy drugs (MTX). The ICG—MTX was then mixed with the hydrogel precursor and radical initiator to obtain an injectable hydrogel precursor solution. Under the irradiation of NIR light, the precursor solution could release alkyl radicals, which promote the transition of the precursor solution from a liquid to a colloidal state. As a result, the nanomedicine could effectively remain at the site of the tumor and continue to be released from the hydrogel. Due to the targeted nature of MTX, the released ICG—MTX could target tumor cells and improve the accuracy of photothermal–chemo combination therapy. The results indicated that the injectable nanomedicine–hydrogel system has a favorable therapeutic effect on tumors. [ABSTRACT FROM AUTHOR]

For the delivery of anticancer drugs, an injectable in situ hydrogel with thermal responsiveness and prolonged drug release capabilities shows considerable potential. Here, we present a series of thermosensitive in situ hydrogels that serve as drug delivery systems for the treatment of liver cancer. These hydrogels were created by utilizing the polydimethylsiloxane (PDMS) oligomer, polyethylene glycol (PEG) and polypropylene glycol (PPG)'s chemical cross-linking capabilities. Doxorubicin (DOX) was encapsulated in a hydrogel with a hydrophobic core and hydrophilic shell to enhance DOX solubility. Studies into the behavior of in situ produced hydrogels at the microscopic and macroscopic levels revealed that the copolymer solution exhibits a progressive shift from sol to gel as the temperature rises. The hydrogels' chemical composition, thermal properties, rheological characteristics, gelation period, and DOX release behavior were all reported. Subcutaneous injection in mice was used to confirm the injectability. Through the in vitro release of DOX in a PBS solution that mimics the tumor microenvironment, the hydrogel's sustained drug release behavior was confirmed. Additionally, using human hepatocellular hepatoma, the anticancer efficacy of thermogel (DEP-2@DOX) was assessed (HepG2). The carrier polymer material DEP-2 was tested for cytotoxicity using HepG2 cells and its excellent cytocompatibility was confirmed. In conclusion, these thermally responsive injectable hydrogels are prominent potential candidates as drug delivery vehicles for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Polysaccharides-based injectable hydrogels are a unique group of biodegradable and biocompatible materials that have shown great potential in the different biomedical fields. The biomolecules or cells can be simply blended with the hydrogel precursors with a high loading capacity by homogenous mixing. The different physical and chemical crosslinking approaches for preparing polysaccharide-based injectable hydrogels are reviewed. Additionally, the review highlights the recent work using polysaccharides-based injectable hydrogels as stimuli-responsive delivery vehicles for the controlled release of different therapeutic agents and viscoelastic matrix for cell encapsulation. Moreover, the application of polysaccharides-based injectable hydrogel in regenerative medicine as tissue scaffold and wound healing dressing is covered. [ABSTRACT FROM AUTHOR]

Previously, 5% w/v hyaluronic acid-tyramine (HA-TA) and dextran-tyramine (Dex-TA) enzymatically cross-linked hybrid hydrogels were demonstrated to provide a mechanically stable environment, maintain cell viability, and promote cartilaginous-specific matrix deposition in vitro. In this study, 5% w/v hybrid hydrogels were combined with human mesenchymal stem cells (hMSCs), bovine chondrocytes (bCHs), or a combination of both in a 4:1 ratio and subcutaneously implanted in the backs of male and female nude rats to assess the performance of cell-laden hydrogels in tissue formation. Subcutaneous implantation of these biomaterials showed signs of integration of the gels within the host tissue. Histological analysis showed residual fibrotic capsules four weeks after implantation. However, enhanced tissue invasion and some giant cell infiltration were observed in the HA-TA/Dex-TA hydrogels laden with either hMSCs or bCHs but not with the co-culture. Moreover, hMSC-bCH co-cultures showed beneficial interaction with the hydrogels, for instance, in enhanced cell proliferation and matrix deposition. In addition, we provide evidence that host gender has an impact on the performance of bCHs encapsulated in HA-TA/Dex-TA hydrogels. This study revealed that hydrogels laden with different types of cells result in distinct host responses. It can be concluded that 5% w/v hydrogels with a higher concentration of Dex-TA (≥50%) laden with bCH-hMSC co-cultures are adequate for injectable applications and in situ cell delivery in cartilage regeneration approaches. [ABSTRACT FROM AUTHOR]

The irregular shape and depth of wounds could be the major hurdles in wound healing for the common three-dimensional foam, sheet, or film treatment design. The injectable hydrogel is a splendid alternate technique to enhance healing efficiency post-implantation via injectable or 3D-bioprinting technologies. The authentic combination of natural and synthetic polymers could potentially enhance the injectability and biocompatibility properties. Thus, the purpose of this study was to characterise a hybrid gelatin–PVA hydrogel crosslinked with genipin (GNP; natural crosslinker). In brief, gelatin (GE) and PVA were prepared in various concentrations (w/v): GE, GPVA3 (3% PVA), and GPVA5 (5% PVA), followed by a 0.1% (w/v) genipin (GNP) crosslink, to achieve polymerisation in three minutes. The physicochemical and biocompatibility properties were further evaluated. GPVA3_GNP and GPVA5_GNP with GNP demonstrated excellent physicochemical properties compared to GE_GNP and non-crosslinked hydrogels. GPVA5_GNP significantly displayed the optimum swelling ratio (621.1 ± 93.18%) and excellent hydrophilicity (38.51 ± 2.58°). In addition, GPVA5_GNP showed an optimum biodegradation rate (0.02 ± 0.005 mg/h) and the highest mechanical strength with the highest compression modulus (2.14 ± 0.06 MPa). In addition, the surface and cross-sectional view for scanning electron microscopy (SEM) displayed that all of the GPVA hydrogels have optimum average pore sizes (100–199 μm) with interconnected pores. There were no substantial changes in chemical analysis, including FTIR, XRD, and EDX, after PVA and GNP intervention. Furthermore, GPVA hydrogels influenced the cell biocompatibility, which successfully indicated >85% of cell viability. In conclusion, gelatin–PVA hydrogels crosslinked with GNP were proven to have excellent physicochemical, mechanical, and biocompatibility properties, as required for potential bioinks for chronic wound healing. [ABSTRACT FROM AUTHOR]

Various immunotherapeutic agents that can elicit antitumor immune responses have recently been developed with the potential for improved efficacy in treating cancer. However, insufficient delivery efficiency at the tumor site, along with severe side effects after systemic administration of these anticancer agents, have hindered their therapeutic application in cancer immunotherapy. Hydrogels that can be directly injected into tumor sites have been developed to help modulate or elicit antitumor responses. Based on the biocompatibility, degradability, and controllable mechanochemical properties of these injectable hydrogels, various types of immunotherapeutic agents, such as hydrophobic anticancer drugs, cytokines, antigens, and adjuvants, have been easily and effectively encapsulated, resulting in the successful elicitation of antitumor immune responses and the retention of long-term immunotherapeutic efficacy following administration. This review summarizes recent advances in combination immunotherapy involving injectable hydrogel-based chemoimmunotherapy, photoimmunotherapy, and radioimmunotherapy. Finally, we briefly discuss the current limitations and future perspectives on injectable hydrogels for the effective combination immunotherapy of tumors. [ABSTRACT FROM AUTHOR]

This study develops a multi-functional hydrogel with a dual injection system based on the adhesive and self-healing properties of the byssus excretion found in mussels. Through precisely controlling the composite cross-linking hydrophobic association (HA) structure composed of A and B solutions, a high-strength, temperature-sensitive injectable hydrogel can be obtained, and it has good self-healing properties. The main composition of A solution contains the surfactant SDS, which can form amphiphilic micelles, the strength increasing component stearyl methacrylate (C18), and NIPAAm, which provides thermo-sensitivity. Solution B contains dopamine acrylate (DAA), which has self-healing properties, and ferric chloride (FeCl3), which is a connecting agent. The rheological behavior shows that when the temperature is increased from 25 °C to 32 °C, the gel can be completed in seven minutes to form a composite hydrogel of NIPAAm-DAA-HA. When NMR identification was conducted on composite DAA, it was found that when comparing DAA and dopamine hydrochloride there were new peaks with specific characteristics, which confirm that this study successfully prepared DAA; swelling tests found that swelling could surpass a rate of 100%, and a higher ratio of crosslinking agent decreased the amount of moisture absorbed; the results of the compression test showed that the addition of hydrophobic micelles C18 effectively enhanced the mechanical properties of hydrogel, allowing it to withstand increased external stress; the adhesiveness results show that an increase in the catechol-Fe3+ concentration of the NIPAAm-DAA-HA hydrogel results in an increased adhesiveness of 0.0081 kg/cm2 on pig skin; the self-healing tests show that after taking damage, NIPAAm-DAA-HA hydrogel can be reactivated with catechol-Fe3+ and self-heal at a rate of up to 70% after 24 h; antibacterial tests show that hydrogel has good bacterial resistance to against E. coli, staphylococcus epidermidis, and bacillus cereus; through in vitro transdermal absorption, it can be seen that the release ability of drugs within the hydrogel can reach up to 8.87 μg/cm2. The NIPAAm-DAA-HA hydrogel prepared by this study performed excellently in both adhesion and self-healing tests. The thermo-sensitive and antibacterial properties can be applied to the treatment of deep wounds and address some of the flaws of traditional wound dressings. [ABSTRACT FROM AUTHOR]

Flexible and soft bioelectronics used on skin tissue have attracted attention for the monitoring of human health. In addition to typical metal-based rigid electronics, soft polymeric materials, particularly conductive hydrogels, have been actively developed to fabricate biocompatible electrical circuits with a mechanical modulus similar to biological tissues. Although such conductive hydrogels can be wearable or implantable in vivo without any tissue damage, there are still challenges to directly writing complex circuits on the skin due to its low tissue adhesion and heterogeneous mechanical properties. Herein, we report cellulose-based conductive hydrogel inks exhibiting strong tissue adhesion and injectability for further on-skin direct printing. The hydrogels consisting of carboxymethyl cellulose, tannic acid, and metal ions (e.g., HAuCl4) were crosslinked via multiple hydrogen bonds between the cellulose backbone and tannic acid and metal-phenol coordinate network. Owing to this reversible non-covalent crosslinking, the hydrogels showed self-healing properties and reversible conductivity under cyclic strain from 0 to 400%, as well as printability on the skin tissue. In particular, the on-skin electronic circuit printed using the hydrogel ink maintained a continuous electrical flow under skin deformation, such as bending and twisting, and at high relative humidity of 90%. These printable and conductive hydrogels are promising for implementing structurally complicated bioelectronics and wearable textiles. [ABSTRACT FROM AUTHOR]

Although osteoarthritis (OA) is a chronic inflammatory degenerative disease affecting millions of people worldwide, the current therapies are limited to palliative care and do not eliminate the necessity of surgical intervention in the most severe cases. Several dietary and nutraceutical factors, such as hydroxytyrosol (Hyt), have demonstrated beneficial effects in the prevention or treatment of OA both in vitro and in animal models. However, the therapeutic application of Hyt is limited due to its poor bioavailability following oral administration. In the present study, a localized drug delivery platform containing a combination of Hyt-loading chitosan nanoparticles (Hyt-NPs) and in situ forming hydrogel have been developed to obtain the benefits of both hydrogels and nanoparticles. This thermosensitive formulation, based on Pluronic F-127 (F-127), hyaluronic acid (HA) and Hyt-NPs (called Hyt@tgel) presents the unique ability to be injected in a minimally invasive way into a target region as a freely flowing solution at room temperature forming a gel at body temperature. The Hyt@tgel system showed reduced oxidative and inflammatory effects in the chondrocyte cellular model as well as a reduction in senescent cells after induction with H2O2. In addition, Hyt@tgel influenced chondrocytes gene expression under pathological state maintaining their metabolic activity and limiting the expression of critical OA-related genes in human chondrocytes treated with stressors promoting OA-like features. Hence, it can be concluded that the formulated hydrogel injection could be proposed for the efficient and sustained Hyt delivery for OA treatment. The next step would be the extraction of "added-value" bioactive polyphenols from by-products of the olive industry, in order to develop a green delivery system able not only to enhance the human wellbeing but also to promote a sustainable environment. [ABSTRACT FROM AUTHOR]

During wound healing, bacterial infection is one of the main limiting factors for the desired efficiency. Wound dressing-mediated antibiotics therapies could overcome this problem to a great extent due to sustained drug release and controllable dose. Here, we designed a kind of alginate injectable hydrogel loaded with minocycline (SA@MC) as a dressing for staphylococcus aureus-infected wound healing. SA@MC hydrogel possessed good injectability and can be injected by syringes. MC participated in the gel formation, causing the microstructure change based on the morphology characterization. The element mapping and FT-IR spectra further confirmed the successful loading of MC in SA hydrogel. Interestingly, MC was released more efficiently in a weakly alkaline condition (pH 7–8) than in a weakly acidic condition (pH 4–6) from SA@MC injectable hydrogel, which means that there is an accelerated release to respond to the weakly alkaline wound microenvironment. Meanwhile, SA@MC injectable hydrogel had high biocompatibility and excellent antibacterial activity due to the sustained release of MC. Further, in vivo experiment results demonstrated that SA@MC injectable hydrogel promoted staphylococcus aureus-infected wound healing efficiently. In summary, the injectable composite hydrogel can serve as an ideal dressing to prevent bacterial infection and promote wound healing. [ABSTRACT FROM AUTHOR]

In pain relief, lidocaine has gained more attention as a local anesthetic. However, there are several side effects that limit the use of local anesthetics. Therefore, it is hypothesized that a hydrogel system with facile design can be used for prolonged release of lidocaine. In this study, we developed a formulation comprises of sodium alginate (SA) and graphene oxide (GO) to prolong the release of lidocaine. The gelation was induced by physically crosslinking the alginate with Ca2+ ions. The formation of blank SA and GO-reinforced SA hydrogels was investigated with different concentration of Ca2+ ions. The controlled release of lidocaine hydrochloride (LH) on both hydrogel systems was studied in PBS solution. The GO-reinforced SA hydrogels exhibited more sustained release than SA hydrogels without GO. In vitro biocompatibility test in L929 fibroblast cells confirmed the non-toxic property of hydrogels. Furthermore, to prove the in-situ gelation and biodegradability of hydrogels the hydrogels were injected on mice model and confirmed the stable gel formation. The hydrogels implanted onto the subcutaneous tissue of hydrogels retained over one week. These results indicate that LH-loaded GO-reinforced SA hydrogel can be a potential biomaterial for controlled release of local anesthetics. [ABSTRACT FROM AUTHOR]

Featured Application: The developed thermoresponsive injectable hydrogels might be used as cell-delivery systems, 3D matrices for cell culture study, drug screening platforms, and for regenerative medicine applications. The three-dimensional complexity of the native extracellular matrix (ECM) suggests switching from 2D to 3D culture systems for providing the cells with an architecture more similar to the physiological environment. Reproducing the three-dimensionality in vitro can guarantee beneficial effects in terms of cell growth, adhesion, proliferation, and/or their differentiation. Hydrogels have the same tailorable physico-chemical and biological characteristics as ECM materials. In this study, we propose a thermoresponsive chitosan-based hydrogel that gels thanks to the addition of organic and inorganic salt solutions (beta-glycerolphosphate and sodium hydrogen carbonate) and is suitable for cell encapsulation allowing obtaining 3D culture systems. Physico-chemical analyses showed that the hydrogel formulations jellify at physiological conditions (37 °C, pH 7.4), are stable in vitro up to three weeks, have high swelling ratios and mechanical stiffness suitable for cellular encapsulation. Moreover, preliminary biological tests underlined the pronounced biocompatibility of the system. Therefore, these chitosan-based hydrogels are proposed as valid biomaterials for cell encapsulation. [ABSTRACT FROM AUTHOR]

Oxidized sodium alginate is a handily modifiable polysaccharide owing to the pendant aldehyde groups which can form dynamic covalent bonds with amines, acylhydrazines, etc., providing oxidized sodium alginate-based hydrogels with stimuli-responsive properties. However, due to the stiffness and, in particular, the hydrophobicity of sodium alginate dialdehyde at low pH, the mechanical performance and pH stimuli responsiveness of oxidized sodium alginate-based hydrogels are still strictly limited. Herein, we report a new strategy to build an injectable, dual responsive, and self-healing hydrogel based on oxidized sodium alginate and hydrazide-modified poly(ethyleneglycol) (PEG). The hydrazide-modified PEG, referred to as PEG-DTP, acts as a macromolecule crosslinker. We found that the presence of PEG-DTP reduces the hydrophobicity of oxidized sodium alginate at low pH so effectively that even a pH-induced reversible sol-gel transitions can be realized. Meanwhile, the disulfide bonds in PEG-DTP endows the hydrogel with the other reversible sol-gel transitions by redox stimuli. In particular, due to the softness of PEG-DTP chains, mechanical performance was also enhanced significantly. Our results indicate we can easily integrate multi-stimuli responsiveness, injectability, and self-healing behavior together into an oxidized sodium alginate-based hydrogel merely by mixing an oxidized sodium alginate solution with PEG-DTP solution in certain proportions. [ABSTRACT FROM AUTHOR]

Novel thermo-responsive ABA-type triblock copolymers (poly(NAAMen-b-NAGMe240-b- NAAMen), n = 18-72) composed of naturally occurring amino acid--based vinyl polymer blocks such as poly(N-acryloyl-L-alanine methyl ester (poly(NAAMe)) as the A segment and poly(Nacryloyl- glycine methylester)(poly(NAGMe)) as the B segment have been synthesized by the atom transfer radical polymerization (ATRP). Their thermal behaviors were analyzed in dilute aqueous solutions by turbidimetry. The turbidity curves provided two-step LCST transitions, and a flower-like micelle formation was confirmed at the temperature region between the first and second LCST transitions by dynamic light scattering, AFM and TEM. At higher copolymer concentrations, hydrogels were obtained at temperatures above the first LCST due to network formation induced with the flower-like micelles as cross-linker. The hydrogels were found to be switched to a sol state when cooled below the first LCST. These hydrogels also exhibited self-healable and injectable capabilities, which were evaluated by rheological measurements. [ABSTRACT FROM AUTHOR]

Toward the next generation of nerve guidance conduits (NGCs), novel biomaterials and functionalization concepts are required to address clinical demands in peripheral nerve regeneration (PNR). As a biological polymer with bioactive motifs, gelatinous peptides are promising building blocks. In combination with an anhydride-containing oligomer, a dual-component hydrogel system (cGEL) was established. First, hollow cGEL tubes were fabricated by a continuous dosing and templating process. Conduits were characterized concerning their mechanical strength, in vitro and in vivo degradation and biocompatibility. Second, cGEL was reformulated as injectable shear thinning filler for established NGCs, here tyrosine-derived polycarbonate-based braided conduits. Thereby, the formulation contained the small molecule LM11A-31. The biofunctionalized cGEL filler was assessed regarding building block integration, mechanical properties, in vitro cytotoxicity, and growth permissive effects on human adipose tissue-derived stem cells. A positive in vitro evaluation motivated further application of the filler material in a sciatic nerve defect. Compared to the empty conduit and pristine cGEL, the functionalization performed superior, though the autologous nerve graft remains the gold standard. In conclusion, LM11A-31 functionalized cGEL filler with extracellular matrix (ECM)-like characteristics and specific biochemical cues holds great potential to support PNR. [ABSTRACT FROM AUTHOR]

We have developed a "self-healing" polyglycerol sebacate-polyethylene glycol methyl ether methacrylate (PGS-PEGMEMA)/ -Cyclodextrin ( CD) hydrogel which could be sheared into a liquid during injection and has the potential to quickly "heal" itself back into gel post-injection. This hydrogel was shown to be biocompatible and biodegradable and therefore appropriate for use in vivo. Furthermore, the storage and loss moduli of the hydrogels could be tuned (by varying the concentration of αCD) between a fraction of a kPa to a few 100 kPa, a range that coincides with the moduli of cells and human soft tissues. This property would allow for this hydrogel to be used in vivo with maximal mechanical compatibility with human soft tissues. In vitro experiments showed that the hydrogel demonstrated a linear mass erosion profile and a biphasic drug (doxorubicin) release profile: Phase I was primarily driven by diffusion and Phase II was driven by hydrogel erosion. The diffusion mechanism was modeled with the First Order equation and the erosion mechanism with the Hopfenberg equation. This established fitting model could be used to predict releases with other drugs and estimate the composition of the hydrogel required to achieve a desired release rate. [ABSTRACT FROM AUTHOR]

Injectable hydrogels are gaining popularity as tissue engineering constructs because of their ease of handling and minimal invasive delivery. Making hydrogels from natural polymers helps to overcome biocompatibility issues. Here, we have developed an Amorphous Chitin (ACh)-Agarose (Agr) composite hydrogel using a simpletechnique. Rheological studies, such as viscoelastic behavior (elastic modulus, viscous modulus, yield stress, and consistency), inversion test, and injectability test, were carried out for different ACh-Agr concentrations. The composite gel, having a concentration of 1.5% ACh and 0.25% Agr, showed good elastic modulus (17.3 kPa), yield stress (3.8 kPa), no flow under gravity, injectability, and temperature stability within the physiological range. Based on these studies, the optimum concentration for injectability was found to be 1.5% ACh and 0.25% Agr. This optimized concentration was used for further studies and characterized using FT-IR and SEM. FT-IR studies confirmed the presence of ACh and Agr in the composite gel. SEM results showed that the lyophilized composite gel had good porosity and mesh like networks. The cytocompatibility of the composite gel was studied using human mesenchymal stem cells (hMSCs). The composite gels showed good cell viability.These results indicated that this injectable composite gel can be used for biomedical applications. [ABSTRACT FROM AUTHOR]

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments.

Traumatic injury of the oral cavity is atypical and often accompanied by uncontrolled bleeding and inflammation. Injectable hydrogels have been considered to be promising candidates for the treatment of oral injuries because of their simple formulation, minimally invasive application technique, and site-specific delivery. Fibrinogen-based hydrogels have been widely explored as effective materials for wound healing in tissue engineering due to their uniqueness. Recently, an injectable foam has taken the spotlight. However, the fibrin component of this biomaterial is relatively stiff. To address these challenges, we created keratin-conjugated fibrinogen (KRT-FIB). This study aimed to develop a novel keratin biomaterial and assess cell–biomaterial interactions. Consequently, a novel injectable KRT-FIB hydrogel was optimized through rheological measurements, and its injection performance, swelling behavior, and surface morphology were investigated. We observed an excellent cell viability, proliferation, and migration/cell–cell interaction, indicating that the novel KRT-FIB-injectable hydrogel is a promising platform for oral tissue regeneration with a high clinical applicability. [ABSTRACT FROM AUTHOR]

Injectable hydrogels, which are formed in situ by changing the external stimuli, have the unique characteristics of easy handling and minimal invasiveness, thus providing the advantage of bypass surgical operation and improving patient compliance. Using external temperature stimuli to realize the sol-to-gel transition when preparing injectable hydrogel is essential since the temperature is stable in vivo and controllable during ex vivo, although the hydrogels obtained possibly have low mechanical strength and stability. In this work, we designed an in situ fast-forming injectable cellulose/albumin-based hydrogel (HPC-g-AA/BSA hydrogels) that responded to body temperature and which was a well-stabilized hydrogen-bonding network, effectively solving the problem of poor mechanical properties. The application of localized delivery of chemotherapeutic drugs of HPC-g-AA/BSA hydrogels was evaluated. In vitro and in vivo results show that HPC-g-AA/BSA hydrogels exhibited higher antitumor efficacy of reducing tumor size and seem ideal for localized antitumor therapy. [ABSTRACT FROM AUTHOR]

The irregular deep chronic wound is a grand challenge to be healed due to multiple factors including slow angiogenesis that causing regenerated tissue failure. The narrow gap of deep wounds could hinder and slow down normal wound healing. Thus, the current study aimed to develop a polymerised genipin-crosslinked gelatin (gelipin) hydrogel (GNP_GH) as a potential biodegradable filler for the abovementioned limitations. Briefly, GNP_GH bioscaffolds have been developed successfully within three-minute polymerisation at room temperature (22–24 °C). The physicochemical and biocompatibility of GNP_GH bioscaffolds were respectively evaluated. Amongst GNP_GH groups, the 0.1%GNP_GH10% displayed the highest injectability (97.3 ± 0.6%). Meanwhile, the 0.5%GNP_GH15% degraded within more than two weeks with optimum swelling capacity (108.83 ± 15.7%) and higher mechanical strength (22.6 ± 3.9 kPa) than non-crosslinked gelatin hydrogel 15% (NC_GH15%). Furthermore, 0.1%GNP_GH15% offered higher porosity (>80%) and lower wettability (48.7 ± 0.3) than NC_GH15%. Surface and cross-section SEM photographs displayed an interconnected porous structure for all GNP_GH groups. The EDX spectra and maps represented no major changes after GNP modification. Moreover, no toxicity effect of GNP_GH against dermal fibroblasts was shown during the biocompatibility test. In conclusion, the abovementioned findings indicated that gelipin has excellent physicochemical properties and acceptable biocompatibility as an acellular rapid treatment for future use in irregular deep cutaneous wounds. [ABSTRACT FROM AUTHOR]

The review is focused on the hydrogel systems dedicated to the intravaginal delivery of antibacterial, antifungal and anti-Trichomonas vaginalis activity drugs for the treatment of gynaecological infections. The strategies for the enhancement of the hydrophobic drug solubility in the hydrogel matrix based on the formation of bigel systems and the introduction of nano- and microparticles as a drug reservoir are presented. Hydrogel carriers of natural and synthetic pharmacological substances, drug-free systems displaying antimicrobial activity thanks to the hydrogel building elements and systems combining the antimicrobial activity of both drug and polymer building components are distinguished. The design of hydrogels facilitating their administration and proper distribution in the vaginal mucosa and the vagina based on thermoresponsive systems capable of gelling at vaginal conditions and already-cross-linked injectable systems after reaching the yield stress are discussed. In addition, the mechanisms of hydrogel bioadhesion that regulate the retention time in the vagina are indicated. Finally, the prospects for the further development of hydrogel-based drug carriers in gynaecological therapies are highlighted. [ABSTRACT FROM AUTHOR]

Facile method for the preparation of β–cyclodextrin–functionalized hydrogels based on guanosine quartet assembly was described. A series of seven hydrogels were prepared by linking β–cyclodextrin molecules with guanosine moieties in different ratios through benzene–1,4–diboronic acid linker in the presence of potassium hydroxide. The potassium ions acted as a reticulation agent by forming guanosine quartets, leading to the formation of self–sustained transparent hydrogels. The ratios of the β–cyclodextrin and guanosine components have a significant effect on the internal structuration of the components and, correspondingly, on the mechanical properties of the final gels, offering a tunablity of the system by varying the components ratio. The insights into the hydrogels' structuration were achieved by circular dichroism, scanning electron microscopy, atomic force microscopy, and X–ray diffraction. Rheological measurements revealed self–healing and thixotropic properties of all the investigated samples, which, in combination with available cyclodextrin cavities for active components loading, make them remarkable candidates for specific applications in biomedical and pharmaceutical fields. Moreover, all the prepared samples displayed selective antimicrobial properties against S. aureus in planktonic and biofilm phase, the activity also depending on the guanosine and cyclodextrin ratio within the hydrogel structure. [ABSTRACT FROM AUTHOR]

Biomaterials are widely used for effectively controlling bleeding in oral/dental surgical procedures. Here, gelatin methacryloyl (GelMA) was synthesized by grafting methacrylic anhydride on gelatin backbone, and phenyl isothiocyanate-modified gelatin (Gel-Phe) was synthesized by conjugating different gelatin/phenyl isothiocyanate molar ratios (G/P ratios) (i.e., 1:1, 1:5, 1:10, 1:15, 1:25, 1:50, 1:100, and 1:150) with gelatin polymer chains. Afterward, we combined GelMA and Gel-Phe as an injectable and photo-crosslinkable bioadhesive. This hybrid material system combines photo-crosslinking chemistry and supramolecular interactions for the design of bioadhesives exhibiting a highly porous structure, injectability, and regulable mechanical properties. By simply regulating the G/P ratio (1:1–1:15) and UV exposure times (15–60 s), it was possible to modulate the injectability and mechanical properties of the GelMA/Gel-Phe bioadhesive. Moreover, we demonstrated that the GelMA/Gel-Phe bioadhesive showed low cytotoxicity, a highly porous network, and the phenyl-isothiourea and amine residues on Gel-Phe and GelMA polymers with synergized hemostatic properties towards fast blood absorption and rapid clotting effect. An in vitro porcine skin bleeding and an in vitro dental bleeding model confirmed that the bioadhesive could be directly extruded into the bleeding site, rapidly photo-crosslinked, and reduced blood clotting time by 45%. Moreover, the in situ crosslinked bioadhesive could be easily removed from the bleeding site after clotting, avoiding secondary wound injury. Overall, this injectable GelMA/Gel-Phe bioadhesive stands as a promising hemostatic material in oral/dental surgical procedures. [ABSTRACT FROM AUTHOR]