Biology subjects

Benoit, D.

Publications and source records attributed to Benoit, D..

4 recordsLinked to original sources

bioRxiv2026

Design and Application of a μSiM Outer Blood-Retinal Barrier (OBRB) Model as a Drug Development Tool

The outer blood-retinal barrier (OBRB) is the primary interface through which systemically circulating drugs reach the retina. A tool that measures delivery across this barrier would support the development of targeted therapies as alternatives to repeated intravitreal injection, and the screening of drugs that reach the retina as an off-target toxicity. Such a tool should deliver drugs fluidically through a vascular compartment, measure transport across the retinal pigment epithelium (RPE), and display disease phenotypes relevant to efficacy. Here we adapt the SiM platform, which places epithelium and endothelium in direct juxtaposition across a permeable, optically transparent silicon nitride nanomembrane. ARPE-19 and human umbilical vein endothelial cells (HUVECs) were used as development cell sources. ARPE-19 monocultures reached a transepithelial electrical resistance of 68 {+/-} 26 {Omega} cm2 by 28 days, and ARPE-19 + HUVEC co-cultures reached a small-molecule permeability of 6.34 {+/-} 1.3 x 10-4 cm min-1 within 14 days, a state reported elsewhere only after longer culture. The barriers developed an intervening basement membrane. Drugs perfused through the basal vascular channel crossed into an open apical well, where sampling and mass spectrometry showed transport correlating with lipophilicity, as reported in vivo. The device also displayed two clinically relevant phenotypes. Digoxin at a clinically toxic concentration reduced viability in the co-barrier by about half and doubled permeability. In a vascularized configuration, VEGF drove endothelial invasion of the RPE layer, as seen in neovascular AMD. The SiM-OBRB therefore satisfies basic design criteria for measurement of drug bioavailability, toxicity, and efficacy.

bioengineering↗

bioRxiv2024

Drivers of plant-associated invertebrate community structure in West-European coastal dunes

The organisation of species assemblages is affected by environmental factors acting at different spatial scales. To understand the drivers behind the community structure of invertebrates associated with marram grass -the dominant dune-building ecosystem engineer in European coastal dunes-, we set up a stratified sampling scheme in six biogeographic sectors along the North Sea. We tested to which degree local invertebrate species composition is affected by the spatial organisation of marram grass tussocks. We used distance-based RDA and a joint species distribution modelling approach to understand how species traits and their phylogeny contribute to invertebrate community composition. We show biogeography to be the most important driver, followed by species-specific responses to marram grass cover and vitality. Traits and phylogeny had a minor influence on the species distribution patterns. The residual species covariation suggests negative interactions between groups of specialist and generalist species. From an applied perspective, our research indicates that the biological value of nature-based solutions for the restoration and design of coastal dunes can be optimized by the design of a heterogeneous marram grass planting scheme and/or development.

ecology↗

bioRxiv2023

Identifying novel radioprotective drugs via salivary gland tissue chip screening

During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence ({beta}-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.

bioengineering↗

bioRxiv2023

Radioprotective drug screening in a salivary gland tissue chip.

Ionizing radiation damage to the salivary glands during head and neck cancer treatment often causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients experience difficulty with eating, speaking, and swallowing and are predisposed to oral infections and tooth decay. While the radioprotective drug amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use and motivate research into discovering alternatives. To address this issue, we have developed a salivary gland mimetic (SGm) tissue chip platform for use in high-content drug discovery. Here, we report on the development and validation of in-chip assays to quantify reduced glutathione and cellular senescence ({beta}-galactosidase) as measures of radiation damage and protection using WR-1065, the active form of amifostine. Following validation, we next tested our assays using other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine, Rapamycin, Ex-Rad, and Palifermin. The validated assays were then used to screen a library of FDA-approved compounds for radioprotection. We screened 438 compounds, obtained 25 hits that were further tested for EC50 values and downselected using information from the PubChem database. Lead compounds were identified that are being tested in preclinical models.

bioengineering↗