Glycerylphytate crosslinker as a potential osteoinductor of chitosan-based systems for guided bone regeneration

Chitosan-based membranes are promising systems for guided bone regeneration. In this work, we used glycerylphytate as ionic crosslinker and osteinductor compound for the fabrication of chitosan membranes as supports for human mesenchymal stem cells. Three different glycerylphytate-crosslinked membranes were developed by changing the crosslinker concentration, from 2.5–10 wt-%, respect to chitosan. Physico-chemical characterization in terms of composition, morphology, and thermal behavior was further analyzed. Swelling degree, crosslinking density, and crosslinker release showed a glycerylphytate content-dependent behavior. Glycerylphytate suggested to improve osteointegration ability of chitosan surfaces by the formation of apatite-like aggregates after incubation in body simulated fluid. Stem cells cultured on the membranes increased their viability over time, and the incorporation of glycerylphytate improved osteogenic and osteoinductivity potential of chitosan by increasing calcium deposition and alkaline phosphatase (ALP) activity on cultured stem cells. These results demonstrated a potential application of glycerylphytate-crosslinked chitosan systems for promising bone tissue regeneration.

Injectable hydrogel-based drug delivery system for cartilage regeneration

Osteoarthrosis is a chronic degenerative disease of slow progression that constitutes a severe clinical and public health problem. The current clinical treatments available are incapable to reverse disease progression so that nowadays there is a demand of developing alternative systems to avoid or delay the application of surgical procedures. In this work, injectable hydrogel drug delivery systems loaded with naproxen or dexamethasone are formulated based on a ready to use simple two components system. Hydrogels consist of gelatin and hyaluronic acid forming a semi-interpenetrating network structure (semi-IPN). This study mainly focuses on the physicochemical characterization of hydrogels, the in vitro analysis and in vivo performance after injection in New Zealand rabbit knees with an OA model. Results indicate that there is a close relationship between the drug release and the hydrogel degradation. All hydrogels are cytocompatible and support good cell viability of human chondrocytes and osteoblast. The in vivo results reveal that both hydrogels promote cartilage regeneration after their injection in osteoarthrosis knees. The extracellular matrix reflects presence of proteoglycans for the naproxen loaded hydrogel group, and collagen type II expression in both loaded groups, more evident for that containing dexamethasone.

García-Fernández, L. et al. Injectable hydrogel-based drug delivery system for cartilage regeneration. Materials Science and Engineering: C 110, 110702 (2020). Cite

A Comparative Study on HCN Polymers Synthesized by Polymerization of NH4CN or Diaminomaleonitrile in Aqueous Media: New Perspectives for Prebiotic Chemistry and Materials Science

HCN polymers are a group of complex and heterogeneous substances that are widely known in the fields of astrobiology and prebiotic chemistry. In addition, they have recently received considerable attention as potential functional material coatings. However, the real nature and pathways of formation of HCN polymers remain open questions. It is well established that the tuning of macromolecular structures determines the properties and practical applications of a polymeric material. Herein, different synthetic conditions were explored for the production of HCN polymers from NH4CN or diaminomaleonitrile in aqueous media with different concentrations of the starting reactants and several reaction times. By using a systematic methodology, both series of polymers were shown to exhibit similar, but not identical, spectroscopic and thermal fingerprints, which resulted in a clear differentiation of their morphological and electrochemical properties. New macrostructures are proposed for HCN polymers, and promising insights are discussed for prebiotic chemistry and materials science on the basis of the experimental results.

Ruiz‐Bermejo, M., de la Fuente, J. L., Carretero‐González, J., García‐Fernández, L. & Aguilar, M. R. A Comparative Study on HCN Polymers Synthesized by Polymerization of NH4CN or Diaminomaleonitrile in Aqueous Media: New Perspectives for Prebiotic Chemistry and Materials Science. Chemistry – A European Journal 25, 11437–11455 (2019). Cite

Anti-inflammatory Surface Coatings Based on Polyelectrolyte Multilayers of Heparin and Polycationic Nanoparticles of Naproxen- Bearing Polymeric Drugs

Immune response to biomaterials can produce chronic inflammation and fibrosis leading to implant failure, which is related to the surface properties of the biomaterials. This work describes the preparation and characterization of polyelectrolyte multilayer (PEM) coatings that combine the anti-inflammatory activity of heparin as polyanion with the potential release of Naproxen, a nonsteroidal anti-inflammatory drug from polymeric nanoparticles (NP) with cationic surface charge. The polyelectrolyte multilayers were characterized by physical methods to estimate multilayer growth, thickness, zeta potential, and topography. It was found that multilayers with NP had negative zeta potentials and
expressed a viscoelastic behavior, while studies of topography showed that nanoparticles formed continuous surface coatings. THP-1-derived macrophages were used to study short-term antiinflammatory activity (time scale 48 h), showing that PEM that contained heparin reduced cell adhesion and IL1-β secretion, when compared to those with polystyrenesulfonate, used as alternative polyanion in multilayer formation. On the other hand, the presence of NP in PEM was related to a reduced foreign body giant cell formation after 15 days, when compared to PEM that contained chitosan as alternative polycation, which suggests a long-term anti-inflammatory effect of Naproxen-containing nanoparticles. It was also shown that macrophages were able to take up NP from multilayers, which indicates a release of Naproxen by digestion of NP in the lysosomal compartment. These findings indicate that surface coatings composed of heparin and Naproxen-based NP on implants such as biosensors have the potential to attenuate foreign body reaction after implantation, which may improve the long-term functionality of implants.

Tissue Engineering therapies based on folic acid and other vitamin B derivatives. Functional mechanisms and current applications in Regenerative Medicine.

B-vitamins are a group of soluble vitamins which are cofactors of some of the enzymes involved in the metabolic pathways of carbohydrates, fats and proteins. These compounds participate in a number of functions as cardiovascular, brain or nervous systems. Folic acid is described as an accessible and multifunctional niche component that can be used safely, even combined with other compounds, which gives it high versatility. Also, due to its non-toxicity and great stability, folic acid has attracted much attention from researchers in the biomedical and bioengineering area, with an increasing number of works directed at using folic acid and its derivatives in tissue engineering therapies as well as regenerative medicine. Thus, this review provides an updated discussion about the most relevant advances achieved during the last five years, where folic acid and other vitamins B have been used as key bioactive compounds for enhancing the effectiveness of biomaterials’ performance and biological functions for the regeneration of tissues and organs.

Fernández-Villa, D., Jiménez Gómez-Lavín, M., Abradelo, C., San Román, J. & Rojo, L. Tissue Engineering Therapies Based on Folic Acid and Other Vitamin B Derivatives. Functional Mechanisms and Current Applications in Regenerative Medicine. Int J Mol Sci 19, (2018). Cite

Bibliographic review on the state of the art of strontium and zinc based regenerative therapies. Recent developments and clinical applications

This review brings up to date the state of the art of strontium and zinc based regenerative therapies, both having a promoting effect on tissue formation and a role inhibiting resorption in musculoskeletal disorders.


A single coating with antibacterial properties for prevention of medical device-associated infections

Human bacterial pathogens found on medical implants are one of the main causes of morbidity and mortality, making the development of novel coatings the primary strategy in the prevention of medical device-associated infections. Here, we describe organic-inorganic hybrid coatings for metallic bone implants, based on sol-gel materials of proven osteogenic capacity. The coatings were doped with two bactericides: octenidine dihydrochloride (OCT) and chlorhexidine diacetate (CHX). These bactericides, known for their efficiency, are widely used in the prevention and elimination of bacterial infections. The coatings have good chemical and mechanical properties, making them suitable for use on medical devices. They also demonstrate strong antibacterial capacity, dependent on the concentration of the bactericide. They are not toxic to human osteoblasts. Our results suggest this system as a tool for coating medical devices to prevent bacterial infections.

García-Arnáez, I. et al. A single coating with antibacterial properties for prevention of medical device-associated infections. European Polymer Journal 113, 289–296 (2019). Cite

Nanoparticles of 4,7-dichloro-2-quinolinemethylacrylate-based copolymers and their potential cytotoxic activity on human breast carcinoma cells

In this article, an improved synthesis strategy of the potent anticancer compound 4,7-dichloro-2-quinolinemethanol (QM) and its acrylate ester 4,7-dichloro-2-quinolinemethylacrylate (AQM) are described. AQM is copolymerized using free-radical polymerization with N-vinyl-2-pyrrolidone (VP) and the copolymers obtained from different molar ratios of monomers are subjected to nanoprecipitation to produce suspensions of nanoparticles (NPs) in phosphate buffered saline (PBS). The smallest and stable NPs are

prepared with the AQM-VP copolymers 45:55 and 40:60 (118.9 and 128.7 nm in diameter, respectively) at 1 mg mL−1, and along with AQM and QM, are evaluated for their cytotoxic activity on MDA-MB-453 breast carcinoma cells using MTT bioassay. AQM and QM are highly cytotoxic (IC50: 19 and 41 μM, respectively); however, the NPs are not cytotoxic in the range of the assayed concentrations. These results contribute to the search for new polymeric NPs with potential application as QM delivery systems for the treatment of cancer or other diseases treatable with QM.


Enzymatically Cross-Linked Silk Fibroin-Based Hierarchical Scaffolds for Osteochondral Regeneration

Osteochondral (OC) regeneration faces several limitations in orthopedic surgery, owing to the complexity of the OC tissue that simultaneously entails the restoration of articular cartilage and subchondral bone diseases.

In this study, novel biofunctional hierarchical scaffolds composed of a horseradish peroxidase (HRP)-cross-linked silk fibroin (SF) cartilage-like layer (HRP-SF layer) fully integrated into a HRP-SF/ZnSr-doped β-tricalcium phosphate (β-TCP) subchondral bone-like layer (HRP-SF/dTCP layer) were proposed as a promising strategy for OC tissue regeneration. For comparative purposes, a similar bilayered structure produced with no ion incorporation (HRP-SF/TCP layer) was used. A homogeneous porosity distribution was achieved throughout the scaffolds, as shown by micro-computed tomography analysis. The ion-doped bilayered scaffolds presented a wet compressive modulus (226.56 ± 60.34 kPa) and dynamic mechanical properties (ranging from 403.56 ± 111.62 to 593.56 ± 206.90 kPa) superior to that of the control bilayered scaffolds (189.18 ± 90.80 kPa and ranging from 262.72 ± 59.92 to 347.68 ± 93.37 kPa, respectively). Apatite crystal formation, after immersion in simulated body fluid (SBF), was observed in the subchondral bone-like layers for the scaffolds incorporating TCP powders. Human osteoblasts (hOBs) and human articular chondrocytes (hACs) were co-cultured onto the bilayered structures and monocultured in the respective cartilage and subchondral bone half of the partitioned scaffolds. Both cell types showed good adhesion and proliferation in the scaffold compartments, as well as adequate integration of the interface regions. Osteoblasts produced a mineralized extracellular matrix (ECM) in the subchondral bone-like layers, and chondrocytes showed GAG deposition. The gene expression profile was different in the distinct zones of the bilayered constructs, and the intermediate regions showed pre-hypertrophic chondrocyte gene expression, especially on the BdTCP constructs. Immunofluorescence analysis supported these observations. This study showed that the proposed bilayered scaffolds allowed a specific stimulation of the chondrogenic and osteogenic cells in the co-culture system together with the formation of an osteochondral-like tissue interface. Hence, the structural adaptability, suitable mechanical properties, and biological performance of the hierarchical scaffolds make these constructs a desired strategy for OC defect regeneration.

Ribeiro, V. P. et al. Enzymatically Cross-Linked Silk Fibroin-Based Hierarchical Scaffolds for Osteochondral Regeneration. ACS Appl. Mater. Interfaces (2019) doi:10.1021/acsami.8b21259. Cite


α-Tocopheryl Succinate-Based Polymeric Nanoparticles for the Treatment of Head and Neck Squamous Cell Carcinoma

The aim of this work is to study, in an in vitro head and neck squamous cell carcinomas model the anti-angiogenic and anti-migratory properties of self-assembled polymeric nanoparticles (NPs) with demonstrated selective anticancer activity. The NPs are based on α-tocopheryl succinate (α-TOS) encapsulated in the hydrophobic core of the NPs. We analyzed the effect of the newly synthetized α-TOS-loaded NPs in proliferating endothelial cells and hypopharynx carcinoma squamous cells and measured markers of angiogenesis, apoptosis and reactive oxygen species (ROS). α-TOS-loaded NPs suppressed angiogenesis by inducing accumulation of ROS and inducing apoptosis of proliferating endothelial cells. These NPs also decrease the number and quality of capillary-like tubes in an in vitro three-dimensional (3D) experiment, decrease the production of the pro-angiogenic vascular endothelial growth factor and down-regulate the expression of its receptor. The anti-migratory efficacy of α-TOS is corroborated in hypopharynx carcinoma cells by decreasing the secretion of matrix metalloproteases 2 and 9 (MMP-2 and MMP-9) and inhibiting cell migration. These results confirm that α-TOS-based NPs not only present anticancer properties, but also antiangiogenic properties, therefore making them promising candidates for multi-active combinatorial anticancer therapy.

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