Versatile Biodegradable Poly(acrylic acid)-Based Hydrogels Infiltrated in Porous Titanium Implants to Improve the Biofunctional Performance.

This research work proposes a synergistic approach to improve implants' performance through the use of porous Ti substrates to reduce the mismatch between Young's modulus of Ti (around 110 GPa) and the cortical bone (20-25 GPa), and the application of a biodegradable, acrylic acid-based polymeric coating to reduce bacterial adhesion and proliferation, and to enhance osseointegration. First, porous commercially pure Ti substrates with different porosities and pore size distributions were fabricated by using space-holder techniques to obtain substrates with improved tribomechanical behavior. On the other hand, a new diacrylate cross-linker containing a reduction-sensitive disulfide bond was synthesized to prepare biodegradable poly(acrylic acid)-based hydrogels with 1, 2, and 4% cross-linker. Finally, after the required characterization, both strategies were implemented, and the combination of 4% cross-linked poly(acrylic acid)-based hydrogel infiltrated in 30 vol % porosity, 100-200 µm average pore size, was revealed as an outstanding choice for enhancing implant performance.

Emerging Strategies to Improve the Design and Manufacturing of Biocompatible Therapeutic Materials.

Currently, the field of medicine is drastically advancing, mainly due to the progress in emerging areas such as nanomedicine, regenerative medicine, and personalized medicine. For example, the development of novel drug delivery systems in the form of nanoparticles is improving the liberation, absorption, distribution, metabolism, and excretion (LADME) properties of the derived formulations, with a consequent enhancement in the treatment efficacy, a reduction in the secondary effects, and an increase in compliance with the dosage guidelines. Additionally, the use of biocompatible scaffolds is translating into the possibility of regenerating biological tissues. Personalized medicine is also benefiting from the advantages offered by additive manufacturing. However, all these areas have in common the need to develop novel materials or composites that fulfill the requirements of each application. Therefore, the aim of this Special Issue was to identify novel materials/composites that have been developed with specific characteristics for the designed biomedical application.

Pathophysiology of Preeclampsia and L-Arginine/L-Citrulline Supplementation as a Potential Strategy to Improve Birth Outcomes.

In preeclampsia, the shallow invasion of cytotrophoblast cells to uterine spiral arteries, leading to a reduction in placental blood flow, is associated with an imbalance of proangiogenic/antiangiogenic factors to impaired nitric oxide (NO) production. Proangiogenic factors, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), require NO to induce angiogenesis through antioxidant regulation mechanisms. At the same time, there are increases in antiangiogenic factors in preeclampsia, such as soluble fms-like tyrosine kinase type 1 receptor (sFIt1) and toll-like receptor 9 (TLR9), which are mechanism derivates in the reduction of NO bioavailability and oxidative stress in placenta.Different strategies have been proposed to prevent or alleviate the detrimental effects of preeclampsia. However, the only intervention to avoid the severe consequences of the disease is the interruption of pregnancy. In this scenario, different approaches have been analysed to treat preeclamptic pregnant women safely. The supplementation with amino acids is one of them, especially those associated with NO synthesis. In this review, we discuss emerging concepts in the pathogenesis of preeclampsia to highlight L-arginine and L-citrulline supplementation as potential strategies to improve birth outcomes. Clinical and experimental data concerning L-arginine and L-citrulline supplementation have shown benefits in improving NO availability in the placenta and uterine-placental circulation, prolonging pregnancy in patients with gestational hypertension and decreasing maternal blood pressure.

Microbiota-Liver-Bile Salts Axis, a Novel Mechanism Involved in the Contrasting Effects of Sodium Selenite and Selenium-Nanoparticle Supplementation on Adipose Tissue Development in Adolescent Rats.

Adolescence is a period during which body composition changes deeply. Selenium (Se) is an excellent antioxidant trace element related to cell growth and endocrine function. In adolescent rats, low Se supplementation affects adipocyte development differently depending on its form of administration (selenite or Se nanoparticles (SeNPs). Despite this effect being related to oxidative, insulin-signaling and autophagy processes, the whole mechanism is not elucidated. The microbiota-liver-bile salts secretion axis is related to lipid homeostasis and adipose tissue development. Therefore, the colonic microbiota and total bile salts homeostasis were explored in four experimental groups of male adolescent rats: control, low-sodium selenite supplementation, low SeNP supplementation and moderate SeNPs supplementation. SeNPs were obtained by reducing Se tetrachloride in the presence of ascorbic acid. Supplementation was received orally through water intake; low-Se rats received twice more Se than control animals and moderate-Se rats tenfold more. Supplementation with low doses of Se clearly affected anaerobic colonic microbiota profile and bile salts homeostasis. However, these effects were different depending on the Se administration form. Selenite supplementation primarily affected liver by decreasing farnesoid X receptor hepatic function, leading to the accumulation of hepatic bile salts together to increase in the ratio Firmicutes/Bacteroidetes and glucagon-like peptide-1 (GLP-1) secretion. In contrast, low SeNP levels mainly affected microbiota, moving them towards a more prominent Gram-negative profile in which the relative abundance of Akkermansia and Muribaculaceae was clearly enhanced and the Firmicutes/Bacteroidetes ratio decreased. This bacterial profile is directly related to lower adipose tissue mass. Moreover, low SeNP administration did not modify bile salts pool in serum circulation. In addition, specific gut microbiota was regulated upon administration of low levels of Se in the forms of selenite or SeNPs, which are properly discussed. On its side, moderate-SeNPs administration led to great dysbiosis and enhanced the abundance of pathogenic bacteria, being considered toxic. These results strongly correlate with the deep change in adipose mass previously found in these animals, indicating that the microbiota-liver-bile salts axis is also mechanistically involved in these changes.

Effects of polyphenolic maqui (Aristotelia chilensis) extract on the inhibition of NLRP3 inflammasome and activation of mast cells in a mouse model of Crohn's disease-like colitis.

Introduction: Crohn's disease (CD) involves activation of mast cells (MC) and NF-кB in parallel with the PPAR-α/NLRP3 inflammasome/IL-1ß pathway in the inflamed colon. Whether polyphenols from maqui (Aristotelia chilensis) represent a natural alternative treatment for CD is unclear. Therefore, we used an animal model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD-like colitis to investigate protective effects of maqui extract through monitoring NLRP3 inflammasome and MC activation in colon tissue. Methods: Maqui extract was administered via orogastric route to mice after (post-Treatment group) or prior (pre-Treatment group) to TNBS-induction. Colon pathology was characterized by histoarchitectural imaging, disease activity index (DAI), and assessing NF-кB, p-NF-кB, PPAR-α/NLRP3 expression and IL-1ß levels. Results: Compared to mice treated with TNBS alone administration of anthocyanin-rich maqui extract improved the DAI, colon histoarchitecture and reduced both colon wet-weight and transmural inflammation. Induction with TNBS significantly increased colonic NLPR3 inflammasome activation, while co-treatment with maqui extract (either post- or pre-Treatment) significantly downregulated NLRP3, ASC and caspase-1 levels, which manifested as reduced colonic IL-1ß levels. Supplemented maqui extract marginally diminished NF-кB activity in epithelial cells but reached statistical significance in immune cells (as judged by decreased NF-кB phosphorylation). PPAR-α signaling was largely unaffected by Maqui whereas MC infiltration into the colon mucosa and submucosa decreased and their level of degranulation was suppressed. Conclusion: These outcomes show the post- and pre- Treatment effect of a polyphenolic extract rich in anthocyanins from maqui the acute phase of TNBS- induced CD-like colitis is linked to suppression of the NLRP3 inflammasome and reduced MC responses. These data indicate that maqui extract represents a potential nutraceutical for the treatment of inflammatory bowel disease (IBD).

Antimicrobial and Antibiofilm Effect of 4,4'-Dihydroxy-azobenzene against Clinically Resistant Staphylococci.

The spread of antibiotic resistance among human and animal pathogens is one of the more significant public health concerns. Moreover, the restrictions on the use of particular antibiotics can limit the options for the treatment of infections in veterinary clinical practice. In this context, searching for alternative antimicrobial substances is crucial nowadays. In this study, 4,4'-dihydroxy-azobenzene (DHAB) was tested for its potential in vitro as an antimicrobial agent against two relevant human and animal pathogens, namely Staphylococcus aureus and Staphylococcus pseudintermedius. The values of minimal inhibitory concentration (MIC) were 64 and 32 mg/L respectively, and they comparable to other azo compounds of probed antimicrobial activity. In addition, the minimal bactericidal concentrations (MCB) were 256 and 64 mg/L. The mechanism by which DHAB produces toxicity in staphylococci has been investigated. DHAB caused membrane damage as revealed by the increase in thiobarbituric acid reactive substances (TBARS) such as malondialdehyde. Furthermore, differential induction of the enzymes peroxidases and superoxide dismutase in S. aureus and S. pseudintermedius suggested their prevalent role in ROS-scavenging due to the oxidative burst induced by this compound in either species. In addition, this substance was able to inhibit the formation of biofilms by both bacteria as observed by colorimetric tests and scanning electron microscopy. In order to assess the relevance of DHAB against clinical strains of MRSA, 10 clinical isolates resistant to either methicillin or daptomycin were assayed; 80% of them gave values of CMI and CMB similar to those of the control S. aureus strain. Finally, cutaneous plasters containing a composite formed by an agar base supplemented with DHAB were designed. These plasters were able to inhibit in vitro the growth of S. aureus and S. pseudintermedius, particularly the later, and this suggests that this substance could be a promising candidate as an alternative to antibiotics in the treatment of animal skin infections, as it has been proven that the toxicity of this substance is very low particularly at a dermal level.

Different Effects of Low Selenite and Selenium-Nanoparticle Supplementation on Adipose Tissue Function and Insulin Secretion in Adolescent Male Rats.

Adolescence is a period of intense growth and endocrine changes, and obesity and insulin-resistance processes during this period have lately been rising. Selenium (Se) homeostasis is related to lipid metabolism depending on the form and dose of Se. This study tests the actions of low-dose selenite and Se nanoparticles (SeNPs) on white (WAT) and brown adipose tissue (BAT) deposition, insulin secretion, and GPx1, IRS-1 and FOXO3a expression in the WAT of adolescent rats as regards oxidative stress, adipocyte length and adipokine secretion. Four groups of male adolescent rats were treated: control (C), low selenite supplementation (S), low SeNP supplementation (NS) and moderate SeNP supplementation (NSS). Supplementation was received orally through water intake; NS and NSS rats received two- and tenfold more Se than C animals, respectively. SeNPs were obtained by reducing Se tetrachloride in the presence of ascorbic acid. For the first time in vivo, it was demonstrated that low selenite supplementation contributed to increased adipogenesis via the insulin signaling pathway and LCN2 modulation, while low SeNP administration prevented fat depots in WAT via the decrease in insulin signaling and FOXO3a autophagy in WAT, lowering inflammation. These effects were independent of GPx1 expression or activity in WAT. These findings provide data for dietary approaches to prevent obesity and/or anorexia during adolescence. These findings may be relevant to future studies looking at a nutritional approach aimed at pre-venting obesity and/or anorexia in adolescence.

Novel Utilization of Therapeutic Coatings Based on Infiltrated Encapsulated Rose Bengal Microspheres in Porous Titanium for Implant Applications.

Despite the increasing progress achieved in the last 20 years in both the fabrication of porous dental implants and the development of new biopolymers for targeting drug therapy, there are important issues such as bone resorption, poor osseointegration, and bacterial infections that remain as critical challenges to avoid clinical failure problems. In this work, we present a novel microtechnology based on polycaprolactone microspheres that can adhere to porous titanium implant models obtained by the spacer holder technique to allow a custom biomechanical and biofunctional balance. For this purpose, a double emulsion solvent evaporation technique was successfully employed for the fabrication of the microparticles properly loaded with the antibacterial therapeutic agent, rose bengal. The resulting microspheres were infiltrated into porous titanium substrate and sintered at 60 °C for 1 h, obtaining a convenient prophylactic network. In fact, the sintered polymeric microparticles were demonstrated to be key to controlling the drug dissolution rate and favoring the early healing process as consequence of a better wettability of the porous titanium substrate to promote calcium phosphate nucleation. Thus, this joint technology proposes a suitable prophylactic tool to prevent both early-stage infection and late-stage osseointegration problems.

Influence of Femtosecond Laser Modification on Biomechanical and Biofunctional Behavior of Porous Titanium Substrates.

Bone resorption and inadequate osseointegration are considered the main problems of titanium implants. In this investigation, the texture and surface roughness of porous titanium samples obtained by the space holder technique were modified with a femtosecond Yb-doped fiber laser. Different percentages of porosity (30, 40, 50, and 60 vol.%) and particle range size (100-200 and 355-500 µm) were compared with fully-dense samples obtained by conventional powder metallurgy. After femtosecond laser treatment the formation of a rough surface with micro-columns and micro-holes occurred for all the studied substrates. The surface was covered by ripples over the micro-metric structures. This work evaluates both the influence of the macro-pores inherent to the spacer particles, as well as the micro-columns and the texture generated with the laser, on the wettability of the surface, the cell behavior (adhesion and proliferation of osteoblasts), micro-hardness (instrumented micro-indentation test, P-h curves) and scratch resistance. The titanium sample with 30 vol.% and a pore range size of 100-200 µm was the best candidate for the replacement of small damaged cortical bone tissues, based on its better biomechanical (stiffness and yield strength) and biofunctional balance (bone in-growth and in vitro osseointegration).

Antimicrobial Properties of Amino-Acid-Derived N-Heterocyclic Carbene Silver Complexes.

Complexes {Ag[NHCMes,R]}n (R = H, 2a; Me, 2b and 2b'; iPr, 2c; iBu, 2d), were prepared by treatment of imidazolium precursor compounds [ImMes,R] (2-(3-mesityl-1H-imidazol-3-ium-1-yl)acetate, 1a, (S)-2-alkyl(3-mesityl-1H-imidazol-3-ium-1-yl)acetate, 1b-d, and (R)-2-methyl(3-mesityl-1H-imidazol-3-ium-1-yl)acetate, 1b', with Ag2O under appropriate conditions. They were characterised by analytical, spectroscopic (IR, 1H, and 13C NMR and polarimetry), and X-ray methods (2a). In the solid state, 2a is a one-dimensional coordination polymer, in which the silver(I) cation is bonded to the carbene ligand and to the carboxylate group of a symmetry-related Ag[NHCMes,H] moiety. The coordination environment of the silver centre is well described by the DFT study of the dimeric model {Ag[NHCMes,H]}2. The antimicrobial properties of these complexes were evaluated versus Gram-negative bacteria E. coli and P. aeruginosa. From the observed MIC and MBC values (minimal inhibitory concentration and minimal bactericidal concentration, respectively), complex 2b' showed the best antimicrobial properties (eutomer), which were significantly better than those of its enantiomeric derivative 2b (distomer). Additionally, analysis of MIC and MBC values of 2a-d reveal a clear structure-antimicrobial effect relationship. Antimicrobial activity decreases when the steric properties of the R alkyl group in {Ag[NHCMes,R]}n increase.

Homochiral imidazolium-based dicarboxylate silver(I) compounds: synthesis, characterisation and antimicrobial properties.

Complexes [Ag(LR)], 2 (LR = 2,2'-(imidazolium-1,3-diyl)di(2-alkylacetate)), were prepared by treatment of compounds HLR, 1, with Ag2O. They were characterised by analytical, spectroscopic (IR, 1H and 13C NMR and polarimetry) and X-ray methods (2c, 2c' and 2e). In the solid state, these compounds are novel one-dimensional or two-dimensional coordination polymers in which silver(I) cations are connected via the chiral [LR]- anion with unprecedented coordination modes. The antimicrobial properties of these complexes were evaluated. 2a and 2b' showed the best antimicrobial properties (minimal inhibitory concentrations and minimal bactericidal concentration) for Pseudomonas aeruginosa and Escherichia coli pathogens. Eutomers 2b' and 2c' showed slightly better antimicrobial properties than their respective enantiomers 2b and 2c.

Latest Trends in Surface Modification for Dental Implantology: Innovative Developments and Analytical Applications.

An increase in the world population and its life expectancy, as well as the ongoing concern about our physical appearance, have elevated the relevance of dental implantology in recent decades. Engineering strategies to improve the survival rate of dental implants have been widely investigated, focusing on implant material composition, geometry (usually guided to reduce stiffness), and interface surrounding tissues. Although efforts to develop different implant surface modifications are being applied in commercial dental prostheses today, the inclusion of surface coatings has gained special interest, as they can be tailored to efficiently enhance osseointegration, as well as to reduce bacterial-related infection, minimizing peri-implantitis appearance and its associated risks. The use of biomaterials to replace teeth has highlighted the need for the development of reliable analytical methods to assess the therapeutic benefits of implants. This literature review considers the state-of-the-art strategies for surface modification or coating and analytical methodologies for increasing the survival rate for teeth restoration.

Native Chilean Berries Preservation and In Vitro Studies of a Polyphenol Highly Antioxidant Extract from Maqui as a Potential Agent against Inflammatory Diseases.

The best conservation method for native Chilean berries has been investigated in combination with an implemented large-scale extract of maqui berry, rich in total polyphenols and anthocyanin to be tested in intestinal epithelial and immune cells. The methanolic extract was obtained from lyophilized and analyzed maqui berries using Folin-Ciocalteu to quantify the total polyphenol content, as well as 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC) to measure the antioxidant capacity. Determination of maqui's anthocyanins profile was performed by ultra-high-performance liquid chromatography (UHPLC-MS/MS). Viability, cytotoxicity, and percent oxidation in epithelial colon cells (HT-29) and macrophages cells (RAW 264.7) were evaluated. In conclusion, preservation studies confirmed that the maqui properties and composition in fresh or frozen conditions are preserved and a more efficient and convenient extraction methodology was achieved. In vitro studies of epithelial cells have shown that this extract has a powerful antioxidant strength exhibiting a dose-dependent behavior. When lipopolysaccharide (LPS)-macrophages were activated, noncytotoxic effects were observed, and a relationship between oxidative stress and inflammation response was demonstrated. The maqui extract along with 5-aminosalicylic acid (5-ASA) have a synergistic effect. All of the compiled data pointed out to the use of this extract as a potential nutraceutical agent with physiological benefits for the treatment of inflammatory bowel disease (IBD).

Erratum: Guillermo M., et al. Environmental Impact of Nanoparticles' Application as an Emerging Technology: A Review. Materials 2021, 14, 166.

The authors wish to make the following corrections to this paper [...].

Author Correction: Design of highly stabilized nanocomposite inks based on biodegradable polymer-matrix and gold nanoparticles for Inkjet Printing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects.

The complexity of some diseases-as well as the inherent toxicity of certain drugs-has led to an increasing interest in the development and optimization of drug-delivery systems. Polymeric nanoparticles stand out as a key tool to improve drug bioavailability or specific delivery at the site of action. The versatility of polymers makes them potentially ideal for fulfilling the requirements of each particular drug-delivery system. In this review, a summary of the state-of-the-art panorama of polymeric nanoparticles as drug-delivery systems has been conducted, focusing mainly on those applications in which the corresponding disease involves an important morbidity, a considerable reduction in the life quality of patients-or even a high mortality. A revision of the use of polymeric nanoparticles for ocular drug delivery, for cancer diagnosis and treatment, as well as nutraceutical delivery, was carried out, and a short discussion about future prospects of these systems is included.

Polyphenolic Maqui Extract as a Potential Nutraceutical to Treat TNBS-Induced Crohn's Disease by the Regulation of Antioxidant and Anti-Inflammatory Pathways.

Nutraceuticals include a wide variety of bioactive compounds, such as polyphenols, which have been highlighted for their remarkable health benefits. Specially, maqui berries have shown great antioxidant activity and anti-inflammatory effects on some inflammatory diseases. The objectives of the present study were to explore the therapeutic effects of maqui berries on acute-phase inflammation in Crohn's disease. Balb/c mice were exposed to 2,4,6-trinitrobenzene sulfonic acid (TNBS) via intracolonic administration. Polyphenolic maqui extract (Ach) was administered orally daily for 4 days after TNBS induction (Curative Group), and for 7 days prior to the TNBS induction until sacrifice (Preventive Group). Our results showed that both preventive and curative Ach administration inhibited body weight loss and colon shortening, and attenuated the macroscopic and microscopic damage signs, as well as significantly reducing transmural inflammation and boosting the recovery of the mucosal architecture and its muco-secretory function. Additionally, Ach promotes macrophage polarization to the M2 phenotype and was capable of down-regulating significantly the expression of inflammatory proteins COX-2 and iNOS, and at the same time it regulates the antioxidant Nrf-2/HO-1 pathway. In conclusion, this is the first study in which it is demonstrated that the properties of Ach as could be used as a preventive and curative treatment in Crohn's disease.

Biofunctional and Tribomechanical Behavior of Porous Titanium Substrates Coated with a Bioactive Glass Bilayer (45S5-1393).

The porous substrates of commercially pure titanium have been coated with a novel bilayer of bioactive glasses (BGs), 45S5 and 1393, to improve the osseointegration and solve the stress-shielding phenomenon of titanium partial implants. The porosity of the substrates and the scratch resistance and bioactivity of the coating have been evaluated. Results are discussed in terms of stiffness and yield strength of the substrates, as well as the chemical composition, thickness, and design of the bioglass coating (monolithic vs bilayer). The role of the pores was a crucial issue in the anchoring of the coating, both in porosity percentage (30 and 60 vol %) and in pore range size (100-200 and 355-500 µm). The study was focused on the adhesion and infiltration of a 1393 bioglass layer (in contact with a porous titanium substrate), in combination with the biofunctionality of the 45S5 bioglass layer (surrounded by the host bone tissue), as 1393 bioglass enhances the adherence, while 45S5 bioglass promotes higher bioactivity. This bioactivity of the raw powder was initially estimated by nuclear magnetic resonance, through the evaluation of the chemical environments, and confirmed by the formation of hydroxyapatite when immersed in a simulated body fluid. The results revealed that the substrate with 30 vol % of porosity and a range of 355-500 µm pore size, coated with this novel BG bilayer, presented the best combination in terms of mechanical and biofunctional properties.

Environmental Impact of Nanoparticles' Application as an Emerging Technology: A Review.

The unique properties that nanoparticles exhibit, due to their small size, are the principal reason for their numerous applications, but at the same time, this might be a massive menace to the environment. The number of studies that assess the possible ecotoxicity of nanomaterials has been increasing over the last decade to determine if, despite the positive aspects, they should be considered a potential health risk. To evaluate their potential toxicity, models are used in all types of organisms, from unicellular bacteria to complex animal species. In order to better understand the environmental consequences of nanotechnology, this literature review aims to describe and classify nanoparticles, evaluating their life cycle, their environmental releasing capacity and the type of impact, particularly on living beings, highlighting the need to develop more severe and detailed legislation. Due to their diversity, nanoparticles will be discussed in generic terms focusing on the impact of a great variety of them, highlighting the most interesting ones for the industry.

Design of highly stabilized nanocomposite inks based on biodegradable polymer-matrix and gold nanoparticles for Inkjet Printing.

Nowadays there is a worldwide growing interest in the Inkjet Printing technology owing to its potentially high levels of geometrical complexity, personalization and resolution. There is also social concern about usage, disposal and accumulation of plastic materials. In this work, it is shown that sugar-based biodegradable polyurethane polymers exhibit outstanding properties as polymer-matrix for gold nanoparticles composites. These materials could reach exceptional stabilization levels, and demonstrated potential as novel robust inks for Inkjet based Printing. Furthermore, a physical comparison among different polymers is discussed based on stability and printability experiments to search for the best ink candidate. The University of Seville logo was printed by employing those inks, and the presence of gold was confirmed by ToF-SIMS. This approach has the potential to open new routes and applications for fabrication of enhanced biomedical nanometallic-sensors using stabilized AuNP.