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.

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.

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.

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.

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.

Impact of residual contamination on the biofunctional properties of purified alginates used for cell encapsulation.

Alginate is frequently used for cell encapsulation, but its biocompatibility is neither optimal nor reproducible. Purifying the alginate is critical for achieving a suitable biocompatibility. However, published purification methods vary in efficiency and may induce changes in polymer biofunctionality. Applying X-ray photoelectron spectroscopy, we showed that commercial alginates, purified by in-house and industrial methods, contained elemental impurities that contributed 0.41-1.73% of their atomic composition. Residual contaminants were identified to be proteins (nitrogen/COOH), endotoxins (phosphorus), and fucoidans (sulphur). Studies using attenuated total reflectance Fourier transform infrared spectroscopy suggested that trace contamination did not alter the alginate molecular structure. Alginate hydrophilicity increased by 19-40% after purification, in correlation with a reduction in protein and polyphenol content. Solution viscosity of the alginate increased by 28-108% after purification, in correlation with a reduction in protein content. These results demonstrate that commercial alginates contain potentially immunogenic contaminants that are not completely eliminated by current purification methods. Moreover, these contaminants alter the functional properties of the alginate in a manner that may compromise biocompatibility: Hydrophilicity may affect protein adsorption and solution viscosity influences the morphology of alginate-based microcapsules. These findings highlight the need to improve and better control alginate purity to ensure a reproducible biofunctionality and optimal biocompatibility of alginate and microcapsules.

Evaluation of alginate purification methods: effect on polyphenol, endotoxin, and protein contamination.

Alginate, a polysaccharide extracted from brown seaweed, is widely used for the microencapsulation of islets of Langerhans, allowing their transplantation without immunosuppression. This natural polymer is known to be largely contaminated. The implantation of islets encapsulated using unpurified alginate leads to the development of fibrotic cell overgrowth around the microcapsules and normalization of the blood glucose is restricted to a very short period if it is achieved at all. Several research groups have developed their own purification method and obtained relatively good results. No comparative evaluation of the efficiencies of these methods has been published. We conducted an evaluative study of five different alginate preparations: a pharmaceutical-grade alginate in its raw state, the same alginate after purification according to three different published methods, and a commercially available purified alginate. The results showed that all purification methods reduced the amounts of known contaminants, that is, polyphenols, endotoxins, and proteins, although with varying efficiencies. Increased viscosity of alginate solutions was observed after purification of the alginates. Despite a general efficiency in decreasing contamination levels, all of the purified alginates contained relatively high residual amounts of protein contaminants. Because proteins may be immunogenic, these residual proteins may have a role in persisting microcapsule immunogenicity.

Applications of carbon nanotubes-based biomaterials in biomedical nanotechnology.

One of the facets of nanotechnology applications is the immense opportunities they offer for new developments in medicine and health sciences. Carbon nanotubes (CNTs) have particularly attracted attention for designing new monitoring systems for environment and living cells as well as nanosensors. Carbon nanotubes-based biomaterials are also employed as support for active prosthesis or functional matrices in reparation of parts of the human body. These nanostructures are studied as molecular-level building blocks for the complex and miniaturized medical device, and substrate for stimulation of cellular growth. The CNTs are cylindrical shaped with caged molecules which can act as nanoscale containers for molecular species, well required for biomolecular recognition and drug delivery systems. Endowed with very large aspect ratios, an excellent electrical conductivity and inertness along with mechanical robustness, nanotubes found enormous applications in molecular electronics and bioelectronics. The ballistic electrical behaviour of SWNTs conjugated with functionalization promotes a large variety of biosensors for individual molecules. Actuative response of CNTs is considered very promising feature for nanodevices, micro-robots and artificial muscles. An description of CNTs based biomaterials is attempted in this review, in order to point out their enormous potential for biomedical nanotechnology and nanobiotechnology.

Biomechanical stability of a retrotubercle opening-wedge high tibial osteotomy.

In recent years, opening-wedge osteotomy has gained popularity. However, the complication rate reported is high. Opening-wedge osteotomy was modified to remedy the problems seen with the conventional technique including loss of correction, delayed healing, and patella infera. This biomechanical study evaluates the response of a new opening-wedge osteotomy in a static and dynamic mode of human cadavers. Results were compared to the stability of the conventional technique. Six preserved pairs of human cadaveric knees were tested. Specimens of the same pair were randomly assigned to either the modified or conventional osteotomy. Internal fixation was used to ensure precise correction and prevent bone collapse. Each tibia was loaded on a material testing system from 0 to 700 N for 10,000 cycles to simulate immediate full weight bearing in a walking individual. Specimens were then loaded to failure to determine ultimate load and stiffness of the construct. Displacement of the articular fragment and stiffness were measured during dynamic loading. Load to failure, displacement, and stiffness were measured during static testing. The modified osteotomy provided significantly greater stiffness (1392 N/mm) and smaller loss of correction (.68 mm) than the conventional osteotomy (741 N/mm; 1.76 mm) under cyclic loading conditions (P<.05). The modified retrotubercle osteotomy provides greater stiffness than the conventional osteotomy, increasing stability by 62% and minimizing loss of correction to <1 mm. The modified osteotomy eliminates the need for bone graft and provides additional strength to allow accelerated rehabilitation.

Corrosion behaviour of a beta-titanium alloy.

The beta-titanium alloy, a particular type of titanium, has been investigated as a biomaterial because of its good mechanical performances and its high corrosion resistance and biocompatibility. This work focuses on the corrosion performance of a beta-titanium alloy of composition Ti-11Mo-2V-4Nb-3Al in Hank's physiological solution. Potentiodynamic tests were performed from -0.25 V to 3.5 V; the breakdown potential was not reached. To observe the behaviour of the alloy while submitted to long-term aggressive conditions, 1, 4 and 8 cycles of cyclic polarization were carried out. Results show a high resistance of the alloy to corrosion and a stabilization of the surface after several corrosion cycles. Pitting was not observed and a fast ability of the surface to repassivate was noticed. The surface was characterized by different techniques before and after corrosion testing. Following the corrosion tests, X-ray Photoelectron Spectroscopy (XPS) showed the presence of calcium and phosphorus, an increase of the oxide layer was measured by Auger Electron Spectroscopy (AES), a relatively smooth surface was visualised by Scanning Electron Microscopy (SEM) and contact-angle measurements showed that the surface energy increased.

Washing effect on superparamagnetic iron oxide nanoparticles.

Much recent research on nanoparticles has occurred in the biomedical area, particularly in the area of superparamagnetic iron oxide nanoparticles (SPIONs); one such area of research is in their use as magnetically directed prodrugs. It has been reported that nanoscale materials exhibit properties different from those of materials in bulk or on a macro scale [1]. Further, an understanding of the batch-to-batch reproducibility and uniformity of the SPION surface is essential to ensure safe biological applications, as noted in the accompanying article [2], because the surface is the first layer that affects the biological response of the human body. Here, we consider a comparison of the surface chemistries of a batch of SPIONs, before and after the supposedly gentle process of dialysis in water.

A comparative physicochemical, morphological and magnetic study of silane-functionalized superparamagnetic iron oxide nanoparticles prepared by alkaline coprecipitation.

The characterization of synthetic superparamagnetic iron oxide nanoparticle (SPION) surfaces prior to functionalization is an essential step in the prediction of their successful functionalization, and in uncovering issues that may influence their selection as magnetically targeted drug delivery vehicles (prodrugs). Here, three differently functionalized magnetite (Fe3O4) SPIONs are considered. All were identically prepared by the alkaline coprecipitation of Fe(2+) and Fe(3+) salts. We use X-ray photoelectron spectroscopy, electron microscopy, time-of-flight SIMS, FTIR spectroscopy and magnetic measurements to characterize their chemical, morphological and magnetic properties, in order to aid in determining how their surfaces differ from those prepared by Fe(CO)5 decomposition, which we have already studied, and in assessing their potential use as drug delivery carriers.