The clinical use of some drugs, such as carbamazepine, phenytoin, and allopurinol, is often associated with adverse cutaneous reactions. The bioactivation of drugs into immunologically reactive metabolites by the liver is postulated to be the first step in initiating a downstream cascade of pathological immune responses. Current mechanistic understanding and the ability to predict such adverse drug cutaneous responses have been partly limited by the lack of appropriate cutaneous drug bioactivation experimental models. Although in vitro human liver models have been extensively investigated for predicting hepatotoxicity and drug–drug interactions, their ability to model the generation of antigenic reactive drug metabolites that are capable of eliciting immunological reactions is not well understood. Here, we employed a human progenitor cell (HepaRG)-derived hepatocyte model and established highly sensitive liquid chromatography-mass spectrometry analytical assays to generate and quantify different reactive metabolite species of three paradigm skin sensitizers, namely, carbamazepine, phenytoin, and allopurinol. We found that the generation of reactive drug metabolites by the HepaRG-hepatocytes was sensitive to the medium composition. In addition, a functional assay based on the activation of U937 myeloid cells into the antigen-presenting cell (APC) phenotype was established to evaluate the immunogenicity potential of the reactive drug metabolites produced by HepaRG-derived hepatocytes. We showed that the reactive drug metabolites of known skin sensitizers could significantly upregulate IL 8, IL 1β, and CD 86 expressions in U937 cells compared to the metabolites from a nonskin sensitizer (i.e., acetaminophen). Thus, the extent of APC activation by HepaRG-hepatocytes conditioned medium containing reactive drug metabolites can potentially be used to predict their skin sensitization potential.
: Polyvinylidene fluoride (PVDF), a piezoelectric material, is commonly used in tissue engineering due to its potential for mimicking the electrical microenvironment of biological conditions for tissue development. In this present research, polyvinyl alcohol (PVA) was introduced into electrospun PVDF fabrication through an electrospinning process, aiming to enhance the nanofibrous membrane's biocompatibility properties by improving the hydrophilicity properties to act as an artificial tissue scaffold. The electrospun PVDF/PVA membranes are found to be optimum at a PVDF-to-PVA ratio of 90:10 due to its excellent mechanical, morphological, and hydrophilicity conductivity properties. Fourier transform infrared (FTIR) spectroscopy verified strong hydrogen bonding interaction formed between the fluorine group of PVDF with oxygen-containing in the hydroxyl group of PVA. In-vitro cell culture showed that the enhanced hydrophilic property of electrospun PVDF/PVA could significantly enhance the cell growth. These positive results indicated that the scaffold could be implemented as artificial tissue material for tissue engineering applications. ABSTRAK: Polivinilidena fluorida (PVDF) adalah bahan piezoelektrik yang biasa digunakan dalam kejuruteraan tisu kerana potensinya menyerupai keadaan persekitaran mikro-elektrik biologi bagi perkembangan tisu. Dalam penyelidikan ini, polivinil alkohol (PVA) diperkenalkan ke dalam fabrikasi pintalan-elektro PVDF melalui proses pemintalan-elektro, yang bertujuan bagi mengembangkan sifat biokompatibiliti membran nanogentian dengan meningkatkan sifat hidrofilik bagi menjadi perancah tisu tiruan. Membran pintalan-elektro PVDF / PVA didapati optimum pada nisbah PVDF-ke-PVA, 90:10 kerana sifat kekonduksian, mekanikal, morfologi dan hidrofiliknya yang sangat baik. Spektroskopi transformasi inframerah Fourier (FTIR) mengesahkan interaksi ikatan hidrogen yang kuat terbentuk antara kumpulan fluoro PVDF dengan oksigen yang terkandung dalam kumpulan hidroksil PVA. Kultur sel secara in-vitro menunjukkan bahawa sifat hidrofilik pintalan-elektro PVDF / PVA dapat meningkatkan pertumbuhan sel secara signifikan. Hasil positif ini menunjukkan bahawa perancah ini dapat digunakan sebagai bahan tisu buatan bagi aplikasi kejuruteraan tisu.
Wound dressing have experienced continuous improvement and changes since ancient time. Electrospinning of polymeric nanofibers have captured the interest of researchers due to its simplicity and cost effective technique that able to produce wound dressing membrane that meet the requirement as ideal wound dressing and drug delivery carrier. In this work, polyvinyl alcohol (PVA) and poly (lactic acid) (PLA) were chosen polymer to produce wound dressing membrane through electrospinning and coating method. PVA was electrospun and then coated with PLA. Preliminary study had been conducted between 1, 4 and 8% concentration for the selection of optimum PLA coating concentration. PLA has been proposed for the use of coating materials at 4%, the coated nanofiber membrane started to exhibit high Ultimate Tensile Strength at 1022.5 ± 9.28 MPa, highest degree of swelling (1850 ± 3.7 %) and optimum water contact angle (60.9 ± 11.46˚). The aim of this study was to investigate the morphological properties of PVA/PLA wound dressing membrane. Based on the results from Atomic Force Microscope, PVA nanofiber coated with 4% PLA exhibit the highest value of Rq which is 0.47 ± 0.19 μm compared to neat PVA nanofibers membrane. Field Emission Scanning Electron Microscope (FE-SEM) image revealed that PVA nanofiber coated with 4% PLA shows porous fiber-like morphology and well incorporated with each other without any gap formed between them. This report clearly suggestive of the fact that synthetic biodegradable polymers such as PLA can be exploited for the synergistic combination with PVA nanofiber for wound dressing application.
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