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The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue.

ABSTRACT: Pharmaceutical excipients are widely used in vaginal drug products. The epithelial integrity of the cervicovaginal tissue is important for HIV-1 prevention. However, the effects of excipients on cervicovaginal epithelium remain unknown. This study aims at assessing the effects of vaginal product excipients on the integrity of human cervicovaginal epithelium and on a lead HIV prevention antiretroviral drug, tenofovir (TFV). In the current study, nine excipients commonly used in vaginal formulations were incubated for 6?h with excised human ectocervical tissue. The effects of the excipients were examined by measuring the transepithelial electrical resistance (TEER), epithelial morphology, paracellular/transcellular permeability, and cell viability. The efficacy of TFV for preventing HIV-1 infection in the ex vivo cultured ectocervix was also tested. We found that disodium ethyl-enediaminetetraacetate (EDTA), sorbic acid, and benzoic acid had no effect on the tissue TEER. Butylated hydroxyanisole, glycerin, propylene glycol, methylparaben, and propylparaben slightly to moderately decreased tissue TEER, whereas citric acid significantly decreased the TEER in a time-dependent manner. Tissue morphology observed post-exposure strongly correlated with TEER data; however, a less strong correlation was observed between paracellular permeability and TEER data after exposure to different excipients. In addition, treatment with EDTA, methylparaben, and propylene glycol at tested levels had no effect on the efficacy of TFV in preventing tissue HIV-1 infection. In conclusion, the combined measurements of TEER, morphology, permeability, and viability using human cervicovaginal tissue represent a clinically relevant platform for safety evaluation of excipients and formulated products for HIV-1 prevention.

SUBMITTER: Hu M

PROVIDER: S-EPMC5067878 | biostudies-other | 2016 Oct/Nov

REPOSITORIES: biostudies-other

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The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue.

Hu Minlu M Zhou Tian T Dezzutti Charlene S CS Rohan Lisa C LC

AIDS research and human retroviruses 20161001 10-11

Pharmaceutical excipients are widely used in vaginal drug products. The epithelial integrity of the cervicovaginal tissue is important for HIV-1 prevention. However, the effects of excipients on cervicovaginal epithelium remain unknown. This study aims at assessing the effects of vaginal product excipients on the integrity of human cervicovaginal epithelium and on a lead HIV prevention antiretroviral drug, tenofovir (TFV). In the current study, nine excipients commonly used in vaginal formulatio ...[more]

PMID: 27611224

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Project description:Simple Summary As global efforts to use eco-friendly and reusable materials increase, the use of lignin from waste biomass will continue to intensify. Lignin is an underutilized biowaste macromolecule that is gaining considerable interest in biomedical research. However, the source of lignin and the extraction process heavily influence its chemistry, which can influence a cell’s reaction to lignin. Organosolv lignin is extracted via an eco-friendly process from leftover waste material. Few studies have tested the biocompatibility of organosolv lignins with human cells. We extensively characterized fractionated organosolv lignin and performed in vitro cytotoxicity safety screening on diverse primary human cell types commonly used in tissue engineering. This is the first study to show that, at a balanced concentration, fractionated low MW beechwood-derived organosolv lignin is non-cytotoxic to highly relevant human cell types used in tissue engineering including human bone marrow-derived mesenchymal stromal cells (MSCs), chondrocytes, osteoblasts, periodontal ligament fibroblasts, gingival fibroblasts and keratinocytes. Additionally, we show that organosolv lignin can be used to fabricate cell scaffolds and that addition of lignin increased the stiffness and viscosity of the scaffolds as well as cell attachment. This suggests that organosolv lignin may be used in the generation of tissue-like biomaterial-based constructs for tissue repair. Abstract There is limited data assessing the cytotoxic effects of organosolv lignin with cells commonly used in tissue engineering. Structural and physico-chemical characterization of fractionated organosolv lignin showed that a decrease of the molecular weight (MW) is accompanied by a less branched conformation of the phenolic biopolymer (higher S/G ratio) and an increased number of aliphatic hydroxyl functionalities. Enabling stronger polymer−solvent interactions, as proven by the Hansen solubility parameter analysis, low MW organosolv lignin (2543 g/mol) is considered to be compatible with common biomaterials. Using low MW lignin, high cell viability (70–100%) was achieved after 2 h, 24 h and 7 days using the following lignin concentrations: MSCs and osteoblasts (0.02 mg/mL), gingival fibroblasts and keratinocytes (0.02 to 0.04 mg/mL), periodontal ligament fibroblasts and chondrocytes (0.02 to 0.08 mg/mL). Cell viability was reduced at higher concentrations, indicating that high concentrations are cytotoxic. Higher cell viability was attained using 30/70 (w/v) NaOH vs. 40/60 (w/v) EtOH as the initial lignin solvent. Hydrogels containing low MW lignin (0.02 to 0.3 mg/mL) in agarose dose-dependently increased chondrocyte attachment (cell viability 84–100%) and hydrogel viscosity and stiffness to 3–11 kPa, similar to the pericellular matrix of chondrocytes. This suggests that low MW organosolv lignin may be used in many tissue engineering fields.

Dataset Information

The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue.

Publications

The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue.

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