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.

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.

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.

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.

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.

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.

Biomimetic fiber mesh scaffolds based on gelatin and hydroxyapatite nano-rods: Designing intrinsic skills to attain bone reparation abilities.

Intrinsic material skills have a deep effect on the mechanical and biological performance of bone substitutes, as well as on its associated biodegradation properties. In this work we have manipulated the preparation of collagenous derived fiber mesh frameworks to display a specific composition, morphology, open macroporosity, surface roughness and permeability characteristics. Next, the effect of the induced physicochemical attributes on the scaffold's mechanical behavior, bone bonding potential and biodegradability were evaluated. It was found that the scaffold microstructure, their inherent surface roughness, and the compression strength of the gelatin scaffolds can be modulated by the effect of the cross-linking agent and, essentially, by mimicking the nano-scale size of hydroxyapatite in natural bone. A clear effect of bioactive hydroxyapatite nano-rods on the scaffolds skills can be appreciated and it is greater than the effect of the cross-linking agent, offering a huge perspective for the upcoming progress of bone implant technology.

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.

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.

Nanoscale surface characterization of biphasic calcium phosphate, with comparisons to calcium hydroxyapatite and ß-tricalcium phosphate bioceramics.

OBJECTIVES: It is our aim to understand the mechanisms that make calcium phosphates, such as bioactive calcium hydroxyapatite (HA), and biphasic calcium (BCP) and ß-tricalcium (ß-TCP) phosphates, desirable for a variety of biological applications, such as the filling of bone defects. METHODS: Here, we have characterized these materials by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), time-of-flight secondary ion mass spectroscopy (TOF-SIMS) and laser granulometry. RESULTS: SEM shows clearly that BCP is a matrix made of macro-organized microstructure, giving insight to the specially chosen composition of the BCP that offers both an adequate scaffold and good porosity for further bone growth. As revealed by laser granulometry, the particles exhibit a homogeneous size distribution, centered at a value somewhat larger than the expected 500 µm. XPS has revealed the presence of adventitious carbon at all sample surfaces, and has shown that Ca/P and O/Ca ratios in the outer layers of all the samples differ significantly from those expected. A peak-by-peak XPS comparison for all samples has revealed that TCP and BCP are distinct from one another in the relative intensities of their oxygen peaks. The PO3(-)/PO2(-) and CaOH+/Ca+ TOF-SIMS intensity ratios were used to distinguish among the samples, and to demonstrate that the OH- fragment, present in all the samples, is not formed during fragmentation but exists at the sample surface, probably as a contaminant. CONCLUSIONS: This study provides substantial insight into the nanoscale surface properties of BCP, HA and ß-TCP. Further research is required to help identify the effect of surfaces of these bioceramics with proteins and several biological fluids. CLINICAL RELEVANCE: The biological performance of implanted synthetic graft bone biomaterials is strongly influenced by their nanosurface characteristics, the structures and properties of the outer layer of the biomaterial.

Solid state synthesis of carbon-encapsulated iron carbide nanoparticles and their interaction with living cells.

Superparamagnetic carbon-encapsulated iron carbide nanoparticles (NPs), Fe7C3@C, with unique properties, were produced from pure ferrocene by high pressure-high temperature synthesis. These NPs combine the merits of nanodiamonds and SPIONs but lack their shortcomings which limit their use for biomedical applications. Investigation of these NPs by X-ray diffraction, electron microscopy techniques, X-ray spectroscopic and magnetic measurement methods has demonstrated that this method of synthesis yields NPs with perfectly controllable physical properties. Using magnetic and subsequent fractional separation of magnetic NPs from residual carbon, the aqueous suspensions of Fe7C3@C NPs with an average particle size of ∼25 nm were prepared. The suspensions were used for in vitro studies of the interaction of Fe7C3@C NPs with cultured mammalian cells. The dynamics of interaction of the living cells with Fe7C3@C was studied by optical microscopy using time-lapse video recording and also by transmission electron microscopy. Using novel highly sensitive cytotoxicity tests based on the cell proliferation assay and long-term live cell observations it was shown that the internalization of Fe7C3@C NPs has no cytotoxic effect on cultured cells and does not interfere with the process of their mitotic division, a fundamental property that ensures the existence of living organisms. The influence of NPs on the proliferative activity of cultured cells was not detected as well. These results indicate that the carbon capsules of Fe7C3@C NPs are air-tight which could offer great opportunities for future use of these superparamagnetic NPs in biology and medicine.

The effect of ethylene oxide sterilization on the surface chemistry and in vitro cytotoxicity of several kinds of chitosan.

The surfaces of three chitosan samples, differing only in their degrees of deacetylation and of carboxyethyl chitosan were chemically characterized by X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectroscopy, X-ray diffraction, and Fourier transform infrared, both before and after sterilization with ethylene oxide. Unexpected elemental ratios suggest that surface chemical modification occurred during the processing of the original chitin, with further surface modification on subsequent sterilization, despite previous reports to the contrary. Cell viability was evaluated by direct contact methyl thiazole tetrazolium and lactate dehydrogenase assays between the chitosan particles and A549 human epithelial cells, which demonstrated that the modifications incurred on sterilization are reflected in biocompatibility changes. All the samples were found to be biocompatible and nontoxic before sterilization and remained so subsequently. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.

The effect of ethylene oxide sterilization on the surface chemistry and in vitro cytotoxicity of several kinds of chitosan.

The surfaces of three chitosan samples, differing only in their degrees of deacetylation and of carboxyethyl chitosan were chemically characterized by X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectroscopy, X-ray diffraction, and Fourier transform infrared, both before and after sterilization with ethylene oxide. Unexpected elemental ratios suggest that surface chemical modification occurred during the processing of the original chitin, with further surface modification on subsequent sterilization, despite previous reports to the contrary. Cell viability was evaluated by direct contact methyl thiazole tetrazolium and lactate dehydrogenase assays between the chitosan particles and A549 human epithelial cells, which demonstrated that the modifications incurred on sterilization are reflected in biocompatibility changes. All the samples were found to be biocompatible and nontoxic before sterilization and remained so subsequently.

Personalized implant for high tibial opening wedge: combination of solid freeform fabrication with combustion synthesis process.

In this work a new generation of bioceramic personalized implants were developed. This technique combines the processes of solid freeform fabrication (SFF) and combustion synthesis (CS) to create personalized bioceramic implants with tricalcium phosphate (TCP) and hydroxyapatite (HA). These porous bioceramics will be used to fill the tibial bone gap created by the opening wedge high tibial osteotomy (OWHTO). A freeform fabrication with three-dimensional printing (3DP) technique was used to fabricate a metallic mold with the same shape required to fill the gap in the opening wedge osteotomy. The mold was subsequently used in a CS process to fabricate the personalized ceramic implants with TCP and HA compositions. The mold geometry was designed on commercial 3D CAD software. The final personalized bioceramic implant was produced using a CS process. This technique was chosen because it exploits the exothermic reaction between P2O5 and CaO. Also, chemical composition and distribution of pores in the implant could be controlled. To determine the chemical composition, the microstructure, and the mechanical properties of the implant, cylindrical shapes were also fabricated using different fabrication parameters. Chemical composition was performed by X-ray diffraction. Pore size and pore interconnectivity was measured and analyzed using an electronic microscope system. Mechanical properties were determined by a mechanical testing system. The porous TCP and HA obtained have an open porous structure with an average 400 µm channel size. The mechanical behavior shows great stiffness and higher load to failure for both ceramics. Finally, this personalized ceramic implant facilitated the regeneration of new bone in the gap created by OWHTO and provides additional strength to allow accelerated rehabilitation.

Factors influencing alginate gel biocompatibility.

Alginate remains the most popular polymer used for cell encapsulation, yet its biocompatibility is inconsistent. Two commercially available alginates were compared, one with 71% guluronate (HiG), and the other with 44% (IntG). Both alginates were purified, and their purities were verified. After 2 days in the peritoneal cavity of C57BL/6J mice, barium (Ba)-gel and calcium (Ca)-gel beads of IntG alginate were clean, while host cells were adhered to beads of HiG alginate. IntG gel beads, however, showed fragmentation in vivo while HiG gel beads stayed firm. The physicochemical properties of the sodium alginates and their gels were thoroughly characterized. The intrinsic viscosity of IntG alginate was 2.5-fold higher than that of HiG alginate, suggesting a greater molecular mass. X-ray photoelectron spectroscopy indicated that both alginates were similar in elemental composition, including low levels of counterions in all gels. The wettabilities of the alginates and gels were also identical, as measured by contact angles of water on dry films. Ba-gel beads of HiG alginate resisted swelling and degradation when immersed in water, much more than the other gel beads. These results suggest that the main factors contributing to the biocompatibility of gels of purified alginate are the mannuronate/guluronate content and/or intrinsic viscosity.

Low thrombogenicity coating of nonwoven PET fiber structures for vascular grafts.

Vascular PET grafts (Dacron) have shown good performance in large vessels (≥ 6 mm) applications. To address the urgent unmet need for small-diameter (2-6 mm) vascular grafts, proprietary high-compliance nonwoven PET fiber structures were modified with various PEG concentrations using PVA as a cross-linking agent, to fabricate non-thrombogenic mechanically compliant vascular grafts. The blood compatibility assays measured through platelet adhesion (SEM and mepacrine dye) and platelet activation (morphological changes, P-selectin secretion, and TXB2 production) demonstrate that functionalization using a 10% PEG solution was sufficient to significantly reduce platelet adhesion/activation close to optimal literature-reported levels observed on carbon-coated ePTFE.

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.

Effect of sterilization on non-woven polyethylene terephthalate fiber structures for vascular grafts.

Non-woven polyethylene terephthalate (PET) fibers produced via melt blowing and compounded into a 6 mm diameter 3D tubular scaffold were developed with artery matching mechanical properties. This work compares the effects of ethylene oxide (EtO) and low temperature plasma (LTP) sterilization on PET surface chemistry and biocompatibility. As seen through X-ray photoelectron spectroscopy (XPS) analysis, LTP sterilization led to an increase in overall oxygen content and the creation of new hydroxyl groups. EtO sterilization induced alkylation of the PET polymer. The in vitro cytotoxicity showed similar fibroblastic viability on LTP- and EtO-treated PET fibers. However, TNF-α release levels, indicative of macrophage activation, were significantly higher when macrophages were incubated on EtO-treated PET fibers. Subcutaneous mice implantation revealed an inflammatory response with foreign body reaction to PET grafts independent of the sterilization procedure.

New predictive model for monitoring bone remodeling.

The aim of this article was to present a new thermodynamic-based model for bone remodeling which is able to predict the functional adaptation of bone in response to changes in both mechanical and biochemical environments. The model was based on chemical kinetics and irreversible thermodynamic principles, in which bone is considered as a self-organizing system that exchanges matter, energy and entropy with its surroundings. The governing equations of the mathematical model have been numerically solved using Matlab software and implemented in ANSYS software using the Finite Element Method. With the aid of this model, the whole inner structure of bone was elucidated. The current model suggested that bone remodeling was a dynamic process which was driven by mechanical loading, metabolic factors and other external contributions. The model clearly indicated that in the absence of mechanical stimulus, the bone was not completely resorbed and reaches a new steady state after about 50% of bone loss. This finding agreed with previous clinical studies. Furthermore, results of virtual computations of bone density in a composite femur showed the development of a dense cortical bone around the medullary canal and a dense trabeculae bone between the femoral head and the calcar region of the medial cortex due to compressive stresses. The comparison of the predicted bone density with the structure of the proximal femur obtained from X-rays and using strain energy density gave credibility to the current model.