PreSS/MD: Predictor of Skin Sensitization Caused by Chemicals Leaching from Medical Devices

Safety evaluation for medical devices includes the toxicity assessment of chemicals used in device manufacturing, cleansing and/or sterilization that may leach into a patient. According to international standards on biocompatibility assessments (ISO 10993), chemicals that could be released from medical devices should be evaluated for their potential to induce skin sensitization/allergenicity, and one of the commonly used approaches is the guinea pig maximization test (GPMT). However, there is growing trend in regulatory science to move away from costly animal assays to employing New Approach Methodologies including computational methods. Herein, we developed a new computational tool for rapid and accurate prediction of the GPMT outcome that we named PreSS/MD (Predictor of Skin Sensitization for Medical Devices). To enable model development, we (i) collected, curated, and integrated the largest publicly available dataset for GPMT; (ii) succeeded in developing externally predictive (balanced accuracy of 70-74% as evaluated by both 5-fold external cross-validation and testing of novel compounds) Quantitative Structure-Activity Relationships (QSAR) models for GPMT using machine learning algorithms, including Deep Learning; and (iii) developed a publicly accessible web portal integrating PreSS/MD models that enables the prediction of GPMT outcomes for any molecules using. We expect that PreSS/MD will be used by both researchers and regulatory agencies to support safety assessment for medical devices and help replace, reduce or refine the use of animals in toxicity testing. PreSS/MD is freely available at https://pressmd.mml.unc.edu/. Keywords: sensitization, GPMT, QSAR, deep learning,

Evaluation of skin irritation and skin sensitization potential of Venusia max lotion (paraben-free, alcohol-free, mineral oil-free, animal origin free) using human repeat insult patch test

<p class="abstract"><strong>Background:</strong> Topical exposure to chemicals from cosmetics can lead to adverse skin effects or skin irritation. This study aimed to investigate the skin irritation and sensitizing potential of a moisturizer Venusia max lotion (paraben-free, alcohol-free, mineral oil-free, animal origin free (PAMA) free).</p><p class="abstract"><strong>Methods:</strong> In this single-center, non-randomized, observational study, skin irritation, and skin sensitization potential of a test product was assessed using the human repeat insult patch test (HRIPT) technique. Approximately 0.04 g of the test product and filter papers dipped in 0.9% isotonic saline solution (~0.04 ml of solution) were filled in different wells of patch chambers and applied occlusively, on the back of each participant. Scoring of the skin reactions in the induction phase and challenge phase was done using Draize and international contact dermatitis research group (ICDRG) scales respectively. Scores were compared to the baseline and the negative control (isotonic saline).<strong></strong></p><p class="abstract"><strong>Results:</strong> In total 234 participants (50 with sensitive skin), 224 and 221 participants completed the induction phase and challenge phase respectively. Scores for the induction phase for Venusia max lotion (PAMA free) and isotonic saline were 0.46 and 0.06 respectively. The mean cumulative score of erythema and oedema for Venusia max lotion (PAMA free) was below 2. For the challenge phase, none of the participants showed any positive reactions at any time point for test product and isotonic saline.</p><p class="abstract"><strong>Conclusions:</strong> Test product Venusia max lotion (PAMA free) found to be non-irritant and hypoallergenic. Thus, it can be used without fear of skin irritation or sensitization.</p>

Evaluation of the Skin-Sensitizing Potential of Brazilian Green Propolis

Propolis is a resinous mixture produced by bees from their secretions and plant material, so its composition varies depending on its botanical origin. Propolis has several beneficial bioactivities, but its skin sensitization properties have long been suspected. Nevertheless, the skin sensitization potency of Brazilian green propolis (BGP) has not been scientifically evaluated. Here, we used scientifically reliable tests to evaluate it. In vitro antigenicity test based on the human cell line activation test (OECD TG 442E) was performed by measuring the expression of CD54 and CD86, which are indicators of the antigenicity of test substances, on THP-1 and DC2.4 cells. BGP did not affect the expression of either marker on THP-1 cells, but upregulated the expression of CD86 on DC2.4 cells, suggesting that BGP may be a skin sensitizer. Then, we performed local lymph node assay (LLNA, OECD TG 429) as a definitive in vivo test. LLNA showed that 1.70% BGP primed skin sensitization and is a “moderate sensitizer”. Our results indicate scientific proof of the validity of arbitrary concentrations (1–2%), which have been used empirically, and provide the first scientific information on the safe use of BGP.

The Research of Toxicity and Sensitization Potential of PEGylated Silver and Gold Nanomaterials

Polyethylene glycol (PEG) is a polymer used for surface modification of important substances in the modern pharmaceutical industry and biopharmaceutical fields. Despite the many benefits of PEGylation, there is also the possibility that the application and exposure of the substance may cause adverse effects in the body, such as an immune response. Therefore, we aimed to evaluate the sensitization responses that could be induced through the intercomparison of nanomaterials of the PEG-coated group with the original group. We selected gold/silver nanomaterials (NMs) for original group and PEGylated silver/gold NMs in this study. First, we measured the physicochemical properties of the four NMs, such as size and zeta potential under various conditions. Additionally, we performed the test of the NM’s sensitization potential using the KeratinoSens™ assay for in vitro test method and the LLNA: 5-bromo-2-deoxyuridine (BrdU)-FCM for in vivo test method. The results showed that PEGylated-NMs did not lead to skin sensitization according to OECD TG 442 (alternative test for skin sensitization). In addition, gold nanomaterial showed that cytotoxicity of PEGylated-AuNMs was lower than AuNMs. These results suggest the possibility that PEG coating does not induce an immune response in the skin tissue and can lower the cytotoxicity of nanomaterials.

Lessons learned in integrating traditional and NAM-based evidence to assess skin sensitization potential

Classification of chemicals as skin sensitizers have traditionally relied on a small set of in vivo tests. Difficult to test substances, such as poorly soluble, mildly irritating, or those of Unknown or Variable Composition Complex reaction products or Biological Materials (UVCBs), producing weak or borderline results in Local Lymph Node Assay (LLNA), often benefit from additional data integration in a weight of evidence (WOE) approach. Advances in multiple testing and non-testing methodologies (in vivo, in vitro, and in silico) can now provide clarity and confidence in concluding on skin sensitization potential. Here we present several case studies using a WOE approach with difficult to test substances and highlight the utility of Toxicological Prioritization IndexTM (ToxPi™) as a comparative visualization and integration tool of toxicology studies. The three test chemicals chosen represent two poorly soluble substances, tetrakis (2-ethylbutyl) orthosilicate and decyl palmitate, and one UVCB substance, alkylated anisole. Data from in vivo and in vitro assays representing multiple key events within the skin sensitization adverse outcome pathway (e.g., direct peptide reactivity assay, human cell line activation test, GARD®Skin, LLNA) were either gathered from publicly available sources or specifically generated. Incorporating the data on our test chemicals as well as chemicals of a known sensitization class (sensitizer, irritating non-sensitizer, non-sensitizer) into ToxPi™ revealed biological activity profiles which were used to support class prediction for the three test chemicals. Using this method, the biological activity profiles for all three test chemicals were most consistent with a non-sensitizing class. This paper demonstrates that visualizing the WOE using mechanistic data maximizes the value of all data to the overall assessment of skin sensitization potential by reducing the uncertainty associated with any one individual assay.

Biocompatibility evaluation for the developed hydrogel wound dressing – ISO-10993-11 standards – InVitro and InVivo study

Assessment of biocompatibility for the developed wound dressing plays a significant role in translational studies. In the present research work, a wound dressing has been developed using gelatin, hyaluronic acid and chondroitin sulfate using EDC as crosslinker in a specific manner. The characterized hydrogel wound dressing was evaluated for its biocompatibility studies by means of ISO-10993-11 medical device rules and standards. Various parameters like skin sensitization test, acute systemic toxic test, implantation study, intracutaneous reactivity test, in vitro cytotoxicity test and bacterial reverse mutation test, were evaluated and the results demonstrated its safety for the pre-clinical investigation.