Alternating Current Electrospinning of Polycaprolactone/Chitosan Nanofibers for Wound Healing Applications.

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.

Multifunctional antibacterial chitosan-based hydrogel coatings on Ti6Al4V biomaterial for biomedical implant applications.

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.

Hyaluronic acid-based hydrogel coatings on Ti6Al4V implantable biomaterial with multifunctional antibacterial activity.

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).

Self-healing, antibacterial and anti-inflammatory chitosan-PEG hydrogels for ulcerated skin wound healing and drug delivery.

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.

Drug Delivery from Hyaluronic Acid-BDDE Injectable Hydrogels for Antibacterial and Anti-Inflammatory Applications.

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 1H-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.

Wound healing and antibacterial chitosan-genipin hydrogels with controlled drug delivery for synergistic anti-inflammatory activity.

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).

Biocompatible hyaluronic acid-divinyl sulfone injectable hydrogels for sustained drug release with enhanced antibacterial properties against Staphylococcus aureus.

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.

Injectable Hydrogels: From Laboratory to Industrialization.

The transfer of some innovative technologies from the laboratory to industrial scale is many times not taken into account in the design and development of some functional materials such as hydrogels to be applied in the biomedical field. There is a lack of knowledge in the scientific field where many aspects of scaling to an industrial process are ignored, and products cannot reach the market. Injectable hydrogels are a good example that we have used in our research to show the different steps needed to follow to get a product in the market based on them. From synthesis and process validation to characterization techniques used and assays performed to ensure the safety and efficacy of the product, following regulation, several well-defined protocols must be adopted. Therefore, this paper summarized all these aspects due to the lack of knowledge that exists about the industrialization of injectable products with the great importance that it entails, and it is intended to serve as a guide on this area to non-initiated scientists. More concretely, in this work, the characteristics and requirements for the development of injectable hydrogels from the laboratory to industrial scale is presented in terms of (i) synthesis techniques employed to obtain injectable hydrogels with tunable desired properties, (ii) the most common characterization techniques to characterize hydrogels, and (iii) the necessary safety and efficacy assays and protocols to industrialize and commercialize injectable hydrogels from the regulatory point of view. Finally, this review also mentioned and explained a real example of the development of a natural hyaluronic acid hydrogel that reached the market as an injectable product.

Bioactive Coatings on Titanium: A Review on Hydroxylation, Self-Assembled Monolayers (SAMs) and Surface Modification Strategies.

Titanium (Ti) and its alloys have been demonstrated over the last decades to play an important role as inert materials in the field of orthopedic and dental implants. Nevertheless, with the widespread use of Ti, implant-associated rejection issues have arisen. To overcome these problems, antibacterial properties, fast and adequate osseointegration and long-term stability are essential features. Indeed, surface modification is currently presented as a versatile strategy for developing Ti coatings with all these challenging requirements and achieve a successful performance of the implant. Numerous approaches have been investigated to obtain stable and well-organized Ti coatings that promote the tailoring of surface chemical functionalization regardless of the geometry and shape of the implant. However, among all the approaches available in the literature to functionalize the Ti surface, a promising strategy is the combination of surface pre-activation treatments typically followed by the development of intermediate anchoring layers (self-assembled monolayers, SAMs) that serve as the supporting linkage of a final active layer. Therefore, this paper aims to review the latest approaches in the biomedical area to obtain bioactive coatings onto Ti surfaces with a special focus on (i) the most employed methods for Ti surface hydroxylation, (ii) SAMs-mediated active coatings development, and (iii) the latest advances in active agent immobilization and polymeric coatings for controlled release on Ti surfaces.