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Traditional wound dressings have not been able to satisfy the needs of the regenerative medicine biomedical area. With the aim of improving tissue regeneration, nanofiber-based wound dressings fabricated by electrospinning (ES) processes have emerged as a powerful approach. Nowadays, nanofiber-based bioactive dressings are mainly developed with a combination of natural and synthetic polymers, such as polycaprolactone (PCL) and chitosan (CHI). Accordingly, herein, PCL/CHI nanofibers have been developed with varying PCL:CHI weight ratios (9:1, 8:2 and 7:3) or CHI viscosities (20, 100 and 600 mPa·s) using a novel alternating current ES (ACES) process. Such nanofibers were thoroughly characterized by determining physicochemical and nanomechanical properties, along with wettability, absorption capacity and hydrolytic plus enzymatic stability. Furthermore, PCL/CHI nanofiber biological safety was validated in terms of cytocompatibility and hemocompatibility (hemolysis < 2%), in addition to a notable antibacterial performance (bacterial reductions of 99.90% for S. aureus and 99.91% for P. aeruginosa ). Lastly, the enhanced wound healing activity of PCL/CHI nanofibers was confirmed thanks to their ability to remarkably promote cell proliferation, which make them ideal candidates for long-term applications such as wound dressings.

Among biomedical community, great efforts have been realized to develop antibacterial coatings that avoid implant-associated infections. To date, conventional mono-functional antibacterial strategies have not been effective enough for successful long-term implantations. Consequently, researchers have recently focused their attention on novel bifunctional or multifunctional antibacterial coatings, in which two or more antibacterial mechanisms interact synergistically. Thus, in this work different chitosan-based (CHI) hydrogel coatings were created on Ti6Al4V surface using genipin (Ti-CHIGP) and polyethylene glycol (Ti-CHIPEG) crosslinking agents. Hydrogel coatings demonstrated an exceptional in vivo biocompatibility plus a remarkable ability to promote cell proliferation and differentiation. Lastly, hydrogel coatings demonstrated an outstanding bacteria-repelling (17-28 % of S. aureus and 33-43 % of E. coli repelled) and contact killing (186-222 % of S. aureus and 72-83 % of E. coli damaged) ability. Such bifunctional antibacterial activity could be further improved by the controlled release of drugs resulting in powerful multifunctional antibacterial coatings., 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 © 2023 Elsevier B.V. All rights reserved.)

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.

Today, the treatment of implant-associated infections with conventional mono-functional antibacterial coatings has not been effective enough for a prosperous long-term implantation. Therefore, biomedical industry is making considerable efforts on the development of novel antibacterial coatings with a combination of more than one antibacterial strategies that interact synergistically to reinforce each other. Therefore, in this work hyaluronic acid-based (HA) hydrogel coatings were created on the surface Ti6Al4V biomaterial with 1,4-butanediol diglycidyl ether (Ti-HABDDE) and divinyl sulfone (Ti-HADVS) crosslinking agents. Hydrogel coatings displayed an extraordinary in vivo biocompatibility, a remarkable ability to promote cell proliferation, differentiation and mineralization, and capability to sustainedly release drugs. Finally, HA-based hydrogel coatings demonstrated an outstanding multifunctional antibacterial activity: bacteria-repelling (51-55 % of S. aureus and 27-40 % of E. coli), bacteria-killing (82-119 % of S. aureus and 83-87 % of E. coli) and bactericide release killing (drug-loaded hydrogel coatings, R > 2)., 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 © 2022 Elsevier Ltd. All rights reserved.)

Great efforts have been performed on the production of advanced biomaterials with the combination of self-healing and wound healing properties in implant/tissue engineering biomedical area. Inspired by this idea, chitosan (CHI) based hydrogels can be used to treat a less investigated class of harmful chronic wounds: ulcers or pressure ulcers. Thus, CHI was crosslinked with previously synthesized polyethylene glycol diacid (PEG-diacid) to obtain different CHI-PEG hydrogel formulations with high H-bonding tendency resulting in self-repair ability. Here presented results show biocompatible, antibacterial, anti-inflammatory, and self-healing CHI-PEG hydrogels with a promising future in the treatment of ulcerated wounds by a significant improvement in metabolic activity (94.51 ± 4.38 %), collagen and elastin quantities (2.12 ± 0.63 μg collagen and 4.97 ± 0.61 μg elastin per mg dermal tissue) and histological analysis. Furthermore, cefuroxime (CFX), tetracycline (TCN) and amoxicillin (AMX) antibiotics, and acetylsalicylic acid (ASA) anti-inflammatory agent were sustainedly released for enhancing antibacterial and anti-inflammatory activities of hydrogels., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Hyaluronic acid (HA) injectable biomaterials are currently applied in numerous biomedical areas, beyond their use as dermal fillers. However, bacterial infections and painful inflammations are associated with healthcare complications that can appear after injection, restricting their applicability. Fortunately, HA injectable hydrogels can also serve as drug delivery platforms for the controlled release of bioactive agents with a critical role in the control of certain diseases. Accordingly, herein, HA hydrogels were crosslinked with 1 4-butanediol diglycidyl ether (BDDE) loaded with cefuroxime (CFX), tetracycline (TCN), and amoxicillin (AMX) antibiotics and acetylsalicylic acid (ASA) anti-inflammatory agent in order to promote antibacterial and anti-inflammatory responses. The hydrogels were thoroughly characterized and a clear correlation between the crosslinking grade and the hydrogels' physicochemical properties was found after rheology, scanning electron microscopy (SEM), thermogravimetry (TGA), and differential scanning calorimetry (DSC) analyses. The biological safety of the hydrogels, expected due to the lack of BDDE residues observed in 1 H-NMR spectroscopy, was also corroborated by an exhaustive biocompatibility test. As expected, the in vitro antibacterial and anti-inflammatory activity of the drug-loaded HA-BDDE hydrogels was confirmed against Staphylococcus aureus by significantly decreasing the pro-inflammatory cytokine levels.

Chitosan (CHI) based hydrogels promote wound healing and relieve inflammations and chronic infections. However, in hardly healable ulcers with excessively painful inflammations, anti-inflammatory activity of hydrogels can be enhanced by the sustained release of non-steroidal anti-inflammatory drugs or combining them with antibiotics. Thus, CHI was crosslinked with genipin (GP) to obtain biocompatible hydrogels. Moreover, their antibacterial activity was confirmed against Staphylococcus aureus and Escherichia coli with an almost 100% bacteria reduction and a potential antibacterial efficacy (R > 2). Furthermore, hydrogels effective healing of ulcerated wounds was corroborated by a significant improvement in metabolic activity (95.58 ± 4.40%), collagen and elastin quantities (1.48 ± 0.07 μg collagen and 5.82 ± 0.73 μg elastin per mg dermal tissue) and histological analysis. Finally, the sustained release of acetylsalicylic acid (ASA), cefuroxime (CFX), tetracycline (TCN) and amoxicillin (AMX) were studied, as well as their anti-inflammatory activity. Results confirm the synergistic anti-inflammatory activity by the significant reduction in the amount of pro-inflammatory cytokines when ASA was combined with CFX (5.39 ± 0.81 ng·mL -1 TNF-α), TCN (4.70 ± 0.21 ng·mL -1 TNF-α and 49.06 ± 9.64 ng·mL -1 IL-8), and AMX (2.28 ± 0.36 ng·mL -1 TNF-α, 14.84 ± 5.57 ng·mL -1 IL-8, and total IL-6 removal)., (Copyright © 2021. Published by Elsevier B.V.)

Spontaneously formed hydrogels are attracting increasing interest as injectable or wound dressing materials because they do not require additional reactions or toxic crosslinking reagents. Highly valuable properties such as low viscosity before external application, adequate filmogenic capacity, rapid gelation and tissue adhesion are required in order to use them for those therapeutic applications. In addition, biocompatibility and biodegradability are also mandatory. Accordingly, biopolymers, such as hyaluronic acid (HA) and chitosan (CHI), that have shown great potential for wound healing applications are excellent candidates due to their unique physiochemical and biological properties, such as moisturizing and antimicrobial ability, respectively. In this study, both biopolymers were modified by covalent anchoring of catechol groups, and the obtained hydrogels were characterized by studying, in particular, their tissue adhesiveness and film forming capacity for potential skin wound healing applications. Tissue adhesiveness was related to o-quinone formation over time and monitored by visible spectroscopy. Consequently, an opposite effect was observed for both polysaccharides. As gelation advances for HA-CA, it becomes more adhesive, while competitive reactions of quinone in CHI-CA slow down tissue adhesiveness and induce a detriment of the filmogenic properties.

Hyaluronic acid (HA) hydrogels display a wide variety of biomedical applications ranging from tissue engineering to drug vehiculization and controlled release. To date, most of the commercially available hyaluronic acid hydrogel formulations are produced under conditions that are not compatible with physiological ones. This review compiles the currently used approaches for the development of hyaluronic acid hydrogels under physiological/mild conditions. These methods include dynamic covalent processes such as boronic ester and Schiff-base formation and click chemistry mediated reactions such as thiol chemistry processes, azide-alkyne, or Diels Alder cycloaddition. Thermoreversible gelation of HA hydrogels at physiological temperature is also discussed. Finally, the most outstanding biomedical applications are indicated for each of the HA hydrogel generation approaches.

Hyaluronic acid (HA) solutions were crosslinked with divinyl sulfone (DVS) and subsequently loaded with antibiotic molecules to obtain biocompatible and antibacterial injectable hydrogels. The crosslinking degree of the hydrogels was modulated by varying the reaction time and the HA:DVS weight ratio. Synthesized HA-DVS hydrogels were characterized by their rheological properties, pore size, swelling capacity and hydrolytic and thermal degradation. Biocompatibility was assessed by measuring pH, osmolality and by in vitro cytotoxic assay. Acetyl salicylic (AAS) loaded hydrogels display anti-inflammatory properties in vitro, whereas cefuroxime (CFX), tetracycline (TCN) and amoxicillin (AMX) loaded hydrogels show in vitro antibacterial activity against Staphylococcus aureus. The combine use of antibiotics and AAS produces a synergic effect that reduces the S. aureus population up to a log10 reduction (R) of 5.55. Overall results show that antibiotic/AAS loaded HA-DVS hydrogels could be effectively used to combat S. aureus infections and to increase the antibacterial activity of antibiotics commonly used against S. aureus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Stable hyaluronic acid nanogels were obtained following the water-in-oil microemulsion method by covalent crosslinking with three biocompatible crosslinking agents: Divinyl sulfone, 1,4-butanediol diglycidyl ether (BDDE), and poly(ethylene glycol) bis(amine). All nanoparticles showed a pH-sensitive swelling behavior, according to the pKa value of hyaluronic acid, as a consequence of the ionization of the carboxylic moieties, as it was corroborated by zeta potential measurements. QELS studies were carried out to study the influence of the chemical structure of the crosslinking agents on the particle size of the obtained nanogels. In addition, the effect of the molecular weight of the biopolymer and the degree of crosslinking on the nanogels dimensions was also evaluated for BDDE crosslinked nanoparticles, which showed the highest pH-responsive response., Competing Interests: The authors declare no conflict of interest.

Purpose: The use of the Schirmer strips (SS) as a tool in the characterisation of dry eye disease, depends upon the quantitative assessment of tear production and constituents. The aim of this study was to ascertain the extent to which the properties of commercially available SS can vary and the way in which this baseline information may relate to their comparability in clinical use., Methods: Five SS were analysed: Clement Clarke®, TearFlo®, Bio Schirmer®, Omni Schirmer® and JingMing®. Various aspects of their physical appearance and physicochemical behaviour were measured, including size, weight, and thickness together with surface morphology (assessed by SEM) and aqueous uptake and release behaviour (including the influence of each strip on protein retention and eluent osmolarity)., Results: All physical parameters varied between the strips studied for example the Clement Clark was the largest, thickest, and heaviest strip assessed in this study. SEM images showed that each of the SS had unique surface morphologies. Statistically significant differences among the strips were found for uptake (p=0.001) and release volume (p=0.014). Clement Clarke absorbed the highest volume over a fixed time period (23.8±1.6μl) and Omni the lowest (19.3±0.5μl). Clement Clarke showing the highest eluent osmolarity value (5.0±0.0mOsm/L) and TearFlo the lowest (2.8±0.4mOsm/L)., Conclusion: The five strips investigated in this study indicate that there is no standardisation of commercial strips, despite the fact that the need for standardisation was recognised over fifty years ago. This study provides useful baseline information relating to SS comparability in clinical use., (Copyright © 2017 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)