Transdermal Delivery of Cannabidiol for the Management of Acute Inflammatory Pain: A Comprehensive Review of the Literature.

The emerging field of nanotechnology has paved the way for revolutionary advancements in drug delivery systems, with nanosystems emerging as a promising avenue for enhancing the therapeutic potential and the stability of various bioactive compounds. Among these, cannabidiol (CBD), the non-psychotropic compound of the Cannabis sativa plant, has gained attention for its therapeutic properties. Consequently, researchers have devoted significant efforts to unlock the full potential of CBD's clinical benefits, where various nanosystems and excipients have emerged to overcome challenges associated with its bioavailability, stability, and controlled release for its transdermal application. Therefore, this comprehensive review aims to explain CBD's role in managing acute inflammatory pain and offers an overview of the state of the art of existing delivery systems and excipients for CBD. To summarize this review, a summary of the cannabinoids and therapeutical targets of CBD will be discussed, followed by its conventional modes of administration. The transdermal route of administration and the current topical and transdermal delivery systems will also be reviewed. This review will conclude with an overview of in vivo techniques that allow the evaluation of the anti-inflammatory and analgesic potentials of these systems.

Protective role against hydrogen peroxide and fibroblast stimulation via Ce-doped TiO2 nanostructured materials.

BACKGROUND: Cerium oxide (CeO2) and Ce-doped nanostructured materials (NMs) are being seen as innovative therapeutic tools due to their exceptional antioxidant effects; nevertheless their bio-applications are still in their infancy. METHODS: TiO2, Ce-TiO2 and CeO2-TiO2 NMs were synthesized by a bottom-up microemulsion-mediated strategy and calcined during 7h at 650°C under air flux. The samples were compared to elucidate the physicochemical characteristics that determine cellular uptake, toxicity and the influence of redox balance between the Ce(3+)/Ce(4+) on the cytoprotective role against an exogenous ROS source: H2O2. Fibroblasts were selected as a cell model because of their participation in wound healing and fibrotic diseases. RESULTS: Ce-TiO2 NM obtained via sol-gel reaction chemistry of metallic organic precursors exerts a real cytoprotective effect against H2O2 over fibroblast proliferation, while CeO2 pre-formed nanoparticles incorporated to TiO2 crystalline matrix lead to a harmful CeO2-TiO2 material. TiO2 was processed by the same pathways as Ce-TiO2 and CeO2-TiO2 NM but did not elicit any adverse or protective influence compared to controls. CONCLUSIONS: It was found that the Ce atoms source and its concentration have a clear effect on material's physicochemical properties and its subsequent influence in the cellular response. It can induce a range of biological reactions that vary from cytotoxic to cytoprotective. GENERAL SIGNIFICANCE: Even though there are still some unresolved issues and challenges, the unique physical and chemical properties of Ce-based NMs are fascinating and versatile resources for different biomedical applications.

Human alveolar epithelial cell responses to core-shell superparamagnetic iron oxide nanoparticles (SPIONs).

Superparamagnetic iron oxide nanoparticles (SPIONs) have been prepared and coated with positively (-NH3(+)) and negatively (-COO(-)) charged shells. These NPs, as well as their "bare" precursor, which actually contain surface hydroxyl groups, have been characterized in vitro, and their influence on a human epithelial cell line has been assessed in terms of cell metabolic activity, cellular membrane lysis, mitochondrial activity, and reactive oxygen species production. Their physicochemical characterizations and protein-nanoparticle interactions have been determined using dynamic light scattering, high-resolution transmission electron microscopy, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) spectrometry, and Coomassie Blue fast staining. Cell-SPION interactions have been determined by PrestoBlue resazurin-based, Trypan Blue dye exclusion-based, and MTS cell proliferation assays as well as by reactive oxygen species determination. The results show that different surface characteristics cause different protein corona and cell responses. Some proteins (e.g., albumin) are adsorbed only on positively charged coatings and others (e.g., fibrinogen) only on negatively charged coating. No cell deaths occur, but cell proliferation is influenced by surface chemistry. Proliferation reduction is dose dependent and highest for bare SPIONs. Negatively charged SPIONs were the most biocompatible.

Nitric oxide delivery by core/shell superparamagnetic nanoparticle vehicles with enhanced biocompatibility.

We report the synthesis of Fe(3)O(4)/silica core/shell nanoparticles and their functionalization with S-nitrosothiols. These nanoparticles are of immense interest because of their nitric oxide (NO) release capabilities in human alveolar epithelial cells. Moreover, they act as large storage reservoirs of NO that can be targeted magnetically to the specific site with a sustainable release of NO for up to 50 h. Such nanoparticles provide an enhancement of the biocompatibility with released NO while allowing intracellular accumulation ascribed to their small size.

Quality, stability and radical scavenging activity of olive oils after Chétoui olives (Olea europaea L.) storage under modified atmospheres.

At the industrial scale, the major source of olive oil deterioration is the poor handling of the raw material during the time separating harvesting from processing. The objective of this work was to verify the effect of modified atmospheres and cold storage in relation to quality parameters of the extracted oils. Olives (cv Chétoui) intended for oil extraction, were stored for 21 days at two different temperatures (ambient temperature 14 ± 2 °C and 5 °C) and under two different modified atmospheres 21% O2 - 0% CO2 and 2% O2 - 5% CO2. Oils quality was ascertained with analytical parameters: free fatty acids, peroxide value, K232, K270 as suggested by European regulation. Oxidative stability, total phenols content, radical scavenging activity and fatty acids composition were carried out in order to measure the hydrolytic and oxidative degradation of oils. Olive oils quality parameters were significantly affected by treatments with especially a beneficial effect on primary oxidation indicators and free acidity. Most efficient treatments, with regard to oils phenolic content and involved parameters, were 21% O2 - 0% CO2 at ambient temperature (636.25 mg ca/kg) and 2% O2 - 5% CO2 under 5 °C (637.50 mg ca/kg). Those two treatments improved individually oil samples phenolic content of 25% but not at the same storage period.

Corrosion study of single crystal Ni-Mn-Ga alloy and Tb0.27Dy0.73Fe1.95 alloy for the design of new medical microdevices.

Once placed in a magnetic field, smart magnetic materials (SMM) change their shape, which could be use for the development of smaller minimally invasive surgery devices activated by magnetic field. However, the potential degradation and release of cytotoxic ions by SMM corrosion has to be determined. This paper evaluates the corrosion resistance of two SMM: a single crystal Ni-Mn-Ga alloy and Tb(0.27)Dy(0.73)Fe(1.95) alloy. Ni-Mn-Ga alloy displayed a corrosion potential (E (corr)) of -0.58 V/SCE and a corrosion current density (i (corr)) of 0.43 µA/cm(2). During the corrosion assay, Ni-Mn-Ga sample surface was partially protected; local pits were formed on 20% of the surface and nickel ions were mainly found in the electrolyte. Tb(0.27)Dy(0.73)Fe(1.95) alloy exhibited poor corrosion properties such as E (corr) of -0.87 V/SCE and i (corr) of 5.90 µA/cm(2). During the corrosion test, this alloy was continuously degraded, its surface was impaired by pits and cracks extensively and a high amount of iron ions was measured in the electrolyte. These alloys exhibited low corrosion parameters and a selective degradation in the electrolyte. They could only be used for medical applications if they are coated with high strain biocompatible materials or embedded in composites to prevent direct contact with physiological fluids.

Reduced stress shielding with limited micromotions using a carbon fibre composite biomimetic hip stem: a finite element model.

Total hip arthroplasty (THA) enjoys excellent rates of success in older patients, but younger patients are still at risk of aseptic loosening and bone resorption from stress shielding. One solution to the stress shielding problem is to use a hip stem with mechanical properties matching those of cortical bone. The objective of the present study was to investigate numerically the biomechanical performance of such a biomimetic hip stem based on a hydroxyapatite (HA)-coated carbon fibre composite. A finite element model (FEM) of the biomimetic stem was constructed. Contact elements were studied to model the bone-implant interface in a non-osseointegrated and osseointegrated state in the best way. Three static load cases representing slow walking, stair climbing, and gait in a healthy individual were considered. Stress shielding and bone-implant interface micromotions were evaluated and compared with the results of a similar FEM based on titanium alloy (Ti-6Al-4V). The composite stems allowed for reduced stress shielding when compared with a traditional Ti-6Al-4V stem. Micromotions were slightly higher with the composite stem, but remained below 40 microm on most of the HA-coated surface. It is concluded that a biomimetic composite stem might offer a better compromise between stress shielding and micromotions than the Ti-6Al-4V stem with the same external geometry.

Antimicrobial Properties of the Ag, Cu Nanoparticle System.

Microbes, including bacteria and fungi, easily form stable biofilms on many surfaces. Such biofilms have high resistance to antibiotics, and cause nosocomial and postoperative infections. The antimicrobial and antiviral behaviors of Ag and Cu nanoparticles (NPs) are well known, and possible mechanisms for their actions, such as released ions, reactive oxygen species (ROS), contact killing, the immunostimulatory effect, and others have been proposed. Ag and Cu NPs, and their derivative NPs, have different antimicrobial capacities and cytotoxicities. Factors, such as size, shape and surface treatment, influence their antimicrobial activities. The biomedical application of antimicrobial Ag and Cu NPs involves coating onto substrates, including textiles, polymers, ceramics, and metals. Because Ag and Cu are immiscible, synthetic AgCu nanoalloys have different microstructures, which impact their antimicrobial effects. When mixed, the combination of Ag and Cu NPs act synergistically, offering substantially enhanced antimicrobial behavior. However, when alloyed in Ag-Cu NPs, the antimicrobial behavior is even more enhanced. The reason for this enhancement is unclear. Here, we discuss these results and the possible behavior mechanisms that underlie them.

Chemico-physical modifications induced by plasma and ozone sterilizations on shape memory polyurethane foams.

Thermally activated shape memory polyurethane foams are promising materials for minimally invasive surgical procedures. Understanding their physical and chemical properties, in vitro response and effects of sterilization is mandatory when evaluating their potential as biomaterials. In this work, we report on the characterization of two Cold Hibernated Elastic Memory (CHEM) foams before and after two novel low-temperature sterilization techniques (plasma and ozone). Foams have different transition temperatures (T(trans)), as determined by Tandelta peaks in DMA tests, that depend on their chemical composition: both foams possess excellent shape recovery ability (Recovery Rate up to 99%) in conventional shape recovery tests. Plasma sterilization (Sterrad sterilization system) resulted in a slight increase of open porosity, but no effects on bulk chemical and thermo-mechanical properties were observed. Ozone sterilization had a stronger effect on foams morphology, both in terms of an evident rupture of pore walls and surface oxidation. These modifications affected both thermomechanical and shape recovery behavior. Furthermore, plasma sterilized foams cytocompatibility was investigated with L929 fibroblast cell line in vitro, showing a good adhesion and proliferation, as confirmed by SEM observation and Alamar blue assay. The obtained results contribute to define the role of shape memory foams as biomaterials and open novel questions on the role of sterilization technique effects on cellular solids.

The effect of six knotting methods on the biomechanical properties of three large diameter absorbable suture materials.

OBJECTIVE: To evaluate the effect of 6 different knotting methods on the mechanical properties of 3 large absorbable suture materials used in large animal surgery. STUDY DESIGN: In vitro mechanical study. Sample Population- Knotted suture loops (n=15 per group). METHODS: Suture loops were created between two low-friction pulleys with either 2 polydioxanone, 2 polyglactin 910 or 3 polyglactin 910. Strands were tied using 1 of 6 knotting technique: square knot, surgeon knot, clamped surgeon's knot, sliding half-hitch knot (HH), Delimar knot and self-locking knot (SLK). A single cycle to failure test was performed on each suture loop with a distraction rate of 100 mm/min. Failure modes were evaluated and breaking strength, elongation to failure and stiffness were compared. RESULTS: All loops except two HH failed at the knot by acute breaking. The double-stranded SLK was both stronger and stiffer than all other knots for each suture material. Clamping the first throw of the surgeon knot decreased load to failure significantly (143.11 +/- 8.64 N) compared with not clamping (159.21 +/- 6.14 N) for polydioxanone. Stiffness and elongation to failure were respectively lower and increased for 2 polydioxanone compared with both polyglactin 910 materials for all knotting techniques. CONCLUSIONS: Knotting techniques do influence structural properties of suture loops. The double strand loop conferred stiffer and stronger properties to the SLK CLINICAL RELEVANCE: Clamping the first throw of polydioxanone should be avoided when tying a suture under tension even using large diameter suture materials. Using a SLK might be considered as a useful alternative when excessive tension is present.

Physicochemical Characterization of Polyvinyl Pyrrolidone: A Tale of Two Polyvinyl Pyrrolidones.

Of several samples of polyvinyl pyrrolidone (PVP) used to coat and stabilize freshly manufactured aqueous dispersions of silver nanoparticles, one batch gave anomalous results: the dispersion maintained continued stability, even on extensive dilution. Our efforts to understand this desirable feature concluded that the generally used spectral method of PVP purity verification, Fourier transform infrared (FTIR) spectroscopy, was incapable of answering our inquiry. This led to the employment of several other methods, including X-ray photoelectron and nuclear magnetic resonance spectroscopies, which ultimately revealed several possible reasons for the dilution stability, including incomplete PVP hydrolysis during manufacture and the presence of hydroperoxide contaminants. It led, as well, to explanations for the shortcomings of FTIR spectroscopy as a verification method for PVP purity.

Biocompatibility of novel polymer-apatite nanocomposite fibers.

On the basis of the bioactivity of hydroxyapatite (HA) and the excellent mechanical and biocompatible performance of polyethylene terephthalate (PET), composite microfibers made of nanograde HA with PET was designed and fabricated to mimic the structure of biological bone, which exhibits a composite of nanograde apatite crystals and natural polymer. The PET/HA nanocomposite was molded into fibers so that the bulk structures' mechanical properties can be custom tailored by changing the final 3D orientation of the fibbers. This study focused on the in vitro biocompatibility evaluation of the PET/HA composite fibers as potential bone fixation biomaterial for total hip replacement prosthesis surfaces. The MTT assay was performed with the extracts of the composite fibers in order to evaluate the short-term effects of the degradation products. The cell morphology of L929 mouse fibroblast cell line was analyzed after direct contact with the fiber scaffolds for different time periods, and the cell viability was also analyzed by the Alamar Blue assay. The release of the inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), from RAW 264.7 macrophages in the presence of fiber extracts and fibers was used as a measure of the inflammatory response. The ability of the fiber matrices to support L929 attachment, spreading, and growth in vitro, combined with the compatible degradation extracts and low inflammation potential of the fibers and extracts, suggests potential use of these fibers as load-baring bone fixation biomaterial structures.

Evaluating the Sporicidal Activity of Disinfectants against Clostridium difficile and Bacillus amyloliquefaciens Spores by Using the Improved Methods Based on ASTM E2197-11.

Spore-forming pathogenic bacteria, such as Clostridium difficile, are associated with nosocomial infection, leading to the increased use of sporicidal disinfectants, which impacts socioeconomic costs. However, C. difficile can be prevented using microorganisms such as Bacillus amyloliquefaciens, a prophylactic agent that has been proven to be effective against it in recent tests or it can be controlled by sporicidal disinfectants. These disinfectants against spores should be evaluated according to a known and recommended standard. Unfortunately, some newly manufactured disinfectants like Bioxy products have not yet been tested. ASTM E2197-11 is a standard test that uses stainless steel disks (1 cm in diameter) as carriers, and the performance of the test formulation is calculated by comparing the number of viable test organisms to that on the control carriers. Surface tests are preferable for evaluating disinfectants with sporicidal effects on hard surfaces. This study applies improved methods, based on the ASTM E2197-11 standard, for evaluating and comparing the sporicidal efficacies of several disinfectants against spores of C. difficile and B. amyloliquefaciens, which are used as the test organisms. With the improved method, all spores were recovered through vortexing and membrane filtration. The results show that chlorine-based products are effective in 5 min and Bioxy products at 5% w/v are effective in 10 min. Although Bioxy products may take longer to prove their effectiveness, their non-harmful effects to hospital surfaces and people have been well established in the literature.

Design of a biomimetic polymer-composite hip prosthesis.

A new biomimetic composite hip prosthesis (stem) was designed to obtain properties similar to those of the contiguous bone, in particular stiffness, to allow normal loading of the surrounding femoral bone. This normal loading would reduce excessive stress shielding, known to result in bone loss, and micromotions at the bone-implant interface, leading to aseptic prosthetic loosening. The design proposed is based on a hollow substructure made of hydroxyapatite-coated, continuous carbon fiber (CF) reinforced polyamide 12 (PA12) composite with an internal soft polymer-based core. Different composite configurations were studied to match the properties of host tissue. Nonlinear three-dimensional analysis of the hip prosthesis was carried out using a three-dimensional finite element bone model based on the composite femur. The performance of composite-based hip and titanium alloy-based (Ti-6Al-4V) stems embedded into femoral bone was compared. The effect of core stiffness and ply configuration was also analyzed. Results show that stresses in composite stem are lower than those in Ti stem, and that the femoral bone implanted with composite structure sustains more load than the one implanted with Ti stem. Micromotions in the composite stem are significantly smaller than those in Ti stem over the entire bone-implant surface because of the favorable interfacial stress distribution.

The effect of varying Al2O3 percentage in hydroxyapatite/Al2O3 composite materials: morphological, chemical and cytotoxic evaluation.

Hydroxyapatite (HA) and HA-alumina (HA/Al2O3) composites, with Al2O3 contents of 5, 10, 20, and 30%, were synthesized using a wet precipitation method and sintered at 900 and 1300 degrees C. We investigated the effect of sintering temperature and relative concentration of HA and Al2O3 on the chemical composition, surface morphology, and cytotoxicity of the composite powders. The XRD results show that in the 1300 degrees C composites, HA partially decomposed into CaO which combined with Al2O3 to form different calcium aluminates. For the 900 degrees C composites the CaO phase was not detected, though a Ca/P ratio larger than 1.67 measured by XPS suggests that CaO was present in trace amounts. SEM-EDX analysis indicated that the HA microstructure was affected by the sintering temperature, and this HA is present on the surface of Al2O3 particles. The cytotoxicity of the composites was assessed indirectly using the MTT assay. The short-term effect of leachables was quantified by exposing a L929 mouse fibroblast cell line to the degradation products released by the composites after immersion in the cell culture medium. Degradation products were less toxic to L-929 at lower extract concentrations (10, 50%) than at 100% concentration. Cell viability was also influenced by leachable size.

Combustion synthesis of porous biomaterials.

This article discusses the unique material manufacturing process of self-propagating high temperature synthesis (SHS) as applied to the making of porous biomaterials. Porous materials have long been considered as the first step toward in-vivo bone tissue engineering and the creation of patient life-time implants. The authors have approached this challenge by utilizing combustion synthesis, to create novel materials such as NiTi + TiC as well as porous forms of materials that are commonly accepted for biomedical applications such as tricalcium phosphate and hydroxyapatite. In the SHS product, physico-chemical properties are controlled by, but not limited to, reactant stoichiometry; green density; particle size of the reactant mix; use or presence of a gasifying agent; heating rate of the reactants and gravity. By balancing these parameters, the energy of the reaction is controlled to create the desired product stoichiometry, porosity, and mechanical properties. SHS provides a means to rapidly manufacture materials, saving time and production costs as well as enabling the synthesis of custom devices through the use of individual molds. Mold materials can range from graphite to paper or paper machete. Combustion synthesis offers a method for the rapid manufacture of affordable, individual biomedical devices that will reduce patient recovery time.

Retroperitoneal masses: magnetic resonance imaging findings with pathologic correlation.

Primary retroperitoneal masses are a rare but diverse group of benign and malignant processes. Magnetic resonance (MR) imaging is playing an increasing role in evaluating retroperitoneal soft-tissue masses. Since the MR imaging features of most retroperitoneal soft-tissue masses are nonspecific, prediction of a specific histologic diagnosis remains a challenge for the radiologist. However, there are certain specific MR imaging appearances that are helpful. Dynamic enhancement patterns can reflect the vascularity of masses, differentiating benign from malignant soft-tissue masses. This article pictorially illustrates the MR imaging features of various common and uncommon retroperitoneal masses.

Accelerated fatigue behavior and mechano-physical characterizations of in vitro physiological simulation of nitinol stents.

In this study, we have provided an experimental evaluation of the fatigue behavior of the nitinol (NiTi) endovascular device (peripheral stent). The accelerated fatigue tests were performed using arterial conditions, which mimicked actual physiological conditions. Natural, rubber latex-tubing materials were used to simulate human arteries. The equipment design and the test parameters used allowed for the simulation of a compliant artery and the application of circumferential forces to the device.The stent compliance values were good indicators for tracking the time evolution of fatigue behavior. Moreover, the analyses of changes on the surface morphology and on the chemical composition were used to establish a relationship between surface characteristics and peripheral stent response during 400 million cycles, which is equivalent to 10 yrs of human life. In order to determine the influence of the accelerated fatigue, an evaluation of both mechanical and surface characteristics was carried out before and after testing using the following tests and methods, respectively: radial hoop testing (RH), scanning electron microscope analysis (SEM), auger electron spectroscopy (AES), atomic absorption spectroscopy (AAS), and X-ray photoelectron spectroscopy (XPS). Under these experimental conditions, the studies have shown that after 400 million cycles, the tested stents did not demonstrate any mechanical failure. Moreover, the surface did not undergo any changes in its chemical composition. However, we did observe an increase in roughness and signs of pitting corrosion.

Characterization of endotoxins on orthopaedic fixation screws, using physicochemical surface analyses.

The objective of this study was to determine if surface analysis techniques could be used to detect endotoxin on stainless steel malleolus screws. New malleolus screws were compared to ones that had been coated in purified lipopolysaccharide (LPS) or Artificial Test Soil (ATS) containing lipopolysaccharide. X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and time-of flight secondary ion mass spectrometry (TOF-SIMS) were used to assess the fixation screws surface. Organic material was visualized on the LPS and ATS-LPS inoculated screws but not on the new unsoiled screws. This was further supported by the peaks observed at masses between 40 and 100 D in TOF-SIMS spectra of the LPS and ATS-LPS inoculated screws. After deconvolution of N1s high resolution XPS spectra, the LPS inoculated screws showed amide groups whereas the ATS-LPS inoculated screws showed predominantly nitroso groups (C-NO). Our data demonstrate that surface analysis can be used to detect organic residuals present on fixation screws. The XPS data confirmed that LPS reacted predominantly with positively charged surface metallic ions (Fe and Cr), whereas proteins reacted with the surface oxide layer of fixation screws, forming C-NO groups. The application of these surface analysis techniques will be helpful in determining if the reprocessing of such items results in an accumulation of organic material that might lead to aseptic loosening, when implanted. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:240-247, 2017.

Untargeted next-generation sequencing-based first-line diagnosis of infection in immunocompromised adults: a multicentre, blinded, prospective study.

OBJECTIVE: Infections are the major cause of morbidity and mortality in immunocompromised patients. Improving microbiological diagnosis in these patients is of paramount clinical importance. METHODS: We performed this multicentre, blinded, prospective, proof-of-concept study, to compare untargeted next-generation sequencing with conventional microbiological methods for first-line diagnosis of infection in 101 immunocompromised adults. Patients were followed for 30 days and their blood samples, and in some cases nasopharyngeal swabs and/or biological fluids, were analysed. At the end of the study, expert clinicians evaluated the results of both methods. The primary outcome measure was the detection rate of clinically relevant viruses and bacteria at inclusion. RESULTS: Clinically relevant viruses and bacteria identified by untargeted next-generation sequencing and conventional methods were concordant for 72 of 101 patients in samples taken at inclusion (κ test=0.2, 95% CI 0.03-0.48). However, clinically relevant viruses and bacteria were detected in a significantly higher proportion of patients with untargeted next-generation sequencing than conventional methods at inclusion (36/101 (36%) vs. 11/101 (11%), respectively, p <0.001), and even when the latter were continued over 30 days (19/101 (19%), p 0.003). Untargeted next-generation sequencing had a high negative predictive value compared with conventional methods (64/65, 95% CI 0.95-1). CONCLUSIONS: Untargeted next-generation sequencing has a high negative predictive value and detects more clinically relevant viruses and bacteria than conventional microbiological methods. Untargeted next-generation sequencing is therefore a promising method for microbiological diagnosis in immunocompromised adults.