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1.  Co-localized confocal Raman spectroscopy and optical coherence tomography (CRS-OCT) for depth-resolved analyte detection in tissue 
Biomedical Optics Express  2015;6(6):2022-2035.
We report the development of a combined confocal Raman spectroscopy (CRS) and optical coherence tomography (OCT) instrument (CRS-OCT) capable of measuring analytes in targeted biological tissues with sub-100-micron spatial resolution. The OCT subsystem was used to measure depth-resolved tissue morphology and guide the acquisition of chemically-specific Raman spectra. To demonstrate its utility, the instrument was used to accurately measure depth-resolved, physiologically-relevant concentrations of Tenofovir, a microbicide drug used to prevent the sexual transmission of HIV, in ex vivo tissue samples.
PMCID: PMC4473741  PMID: 26114026
(170.5660) Raman spectroscopy; (170.4500) Optical coherence tomography; (170.6935) Tissue characterization
2.  Quantitative Analysis of Microbicide Concentrations in Fluids, Gels and Tissues Using Confocal Raman Spectroscopy 
PLoS ONE  2013;8(12):e85124.
Topical vaginal anti-HIV microbicides are an important focus in female-based strategies to prevent the sexual transmission of HIV. Understanding microbicide pharmacokinetics is essential to development, characterization and implementation of efficacious microbicide drug delivery formulations. Current methods to measure drug concentrations in tissue (e.g., LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry) are highly sensitive, but destructive and complex. This project explored the use of confocal Raman spectroscopy to detect microbicide drugs and to measure their local concentrations in fluids, drug delivery gels, and tissues. We evaluated three candidate microbicide drugs: tenofovir, Dapivirine and IQP-0528. Measurements were performed in freshly excised porcine buccal tissue specimens, gel vehicles and fluids using two Horiba Raman microscopes, one of which is confocal. Characteristic spectral peak calibrations for each drug were obtained using serial dilutions in the three matrices. These specific Raman bands demonstrated strong linear concentration dependences in the matrices and were characterized with respect to their unique vibrational signatures. At least one specific Raman feature was identified for each drug as a marker band for detection in tissue. Sensitivity of detection was evaluated in the three matrices. A specific peak was also identified for tenofovir diphosphate, the anti-HIV bioactive product of tenofovir after phosphorylation in host cells. Z-scans of drug concentrations vs. depth in excised tissue specimens, incubated under layers of tenofovir solution in a Transwell assay, showed decreasing concentration with depth from the surface into the tissue. Time-dependent concentration profiles were obtained from tissue samples incubated in the Transwell assay, for times ranging 30 minutes - 6 hours. Calibrations and measurements from tissue permeation studies for tenofovir showed good correlation with gold standard LC-MS/MS data. These results demonstrate that confocal Raman spectroscopy holds promise as a tool for practical, minimally invasive, label-free measurement of microbicide drug concentrations in fluids, gels and tissues.
PMCID: PMC3875564  PMID: 24386455
3.  Identification of Personal Lubricants That Can Cause Rectal Epithelial Cell Damage and Enhance HIV Type 1 Replication in Vitro 
AIDS Research and Human Retroviruses  2011;27(9):1019-1024.
Over-the-counter personal lubricants are used frequently during vaginal and anal intercourse, but they have not been extensively tested for biological effects that might influence HIV transmission. We evaluated the in vitro toxicity anti-HIV-1 activity and osmolality of popular lubricants. A total of 41 lubricants were examined and compared to Gynol II and Carraguard as positive and negative controls for toxicity, respectively. Cytotoxicity was assessed using the XTT assay. The MAGI assay with R5 and X4 HIV-1 laboratory strains was used to evaluate antiviral activity. The effect of the lubricants on differentiated Caco-2 cell monolayers (transepithelial electrical resistance, TEER) was also measured. None of the lubricants tested showed significant activity against HIV-1. Surprisingly, four of them, Astroglide Liquid, Astroglide Warming Liquid, Astroglide Glycerin & Paraben-Free Liquid, and Astroglide Silken Secret, significantly enhanced HIV-1 replication (p<0.0001). A common ingredient in three of these preparations is polyquaternium-15. In vitro testing of a chemically related compound (MADQUAT) confirmed that this similarly augmented HIV-1 replication. Most of the lubricants were found to be hyperosmolar and the TEER value dropped approximately 60% 2 h after exposure to all lubricants tested. Cells treated with Carraguard, saline, and cell controls maintained about 100% initial TEER value after 2–6 h. We have identified four lubricants that significantly increase HIV-1 replication in vitro. In addition, the epithelial damage caused by these and many other lubricants may have implications for enhancing HIV transmission in vivo. These data emphasize the importance of performing more rigorous safety testing on these products.
PMCID: PMC3161103  PMID: 21309617
4.  Design and validation of a multiplexed low coherence interferometry instrument for in vivo clinical measurement of microbicide gel thickness distribution 
Biomedical Optics Express  2011;2(10):2850-2858.
We present a multiplexed, Fourier-domain low coherence interferometry (mLCI) instrument for in vivo measurement of intravaginal microbicide gel coating thickness distribution over the surface of the vaginal epithelium. The mLCI instrument uses multiple delivery fibers to acquire depth resolved reflection profiles across large scanned tissue areas. Here mLCI has been adapted into an endoscopic system with a custom imaging module for simultaneous, co-registered measurements with fluorimetric scans of the same surface. The resolution, optical signal-to-noise, and cross-talk of the mLCI instrument are characterized to evaluate performance. Validation measurements of gel thickness are made using a calibration socket. Initial results from a clinical study are presented to show the in vivo capability of the dual-modality system for assessing the distribution of microbicide gel vehicles in the lower human female reproductive tract.
PMCID: PMC3191450  PMID: 22025989
(120.3180) Interferometry; (120.3890) Medical optics instrumentation; (170.4500) Optical coherence tomography
5.  Optimal imaging and analysis of human vaginal coating by drug delivery gels 
Contraception  2006;75(2):142-151.
We used a new optical imaging technique to compare human intravaginal coating distributions of Conceptrol® and Advantage™. These gels are surrogates for future microbicidal gels, differing in molecular structures and biophysical properties.
For each protocol, a 3-mL gel bolus was inserted to the posterior fornix while the woman was in the supine position. She then either: (1) remained supine (10 min); or (2) sat up (1 min), stood up (1 min), sat down (1 min), and returned to supine for a net elapsed time of 10 min. The imaging device is sized/shaped like a phallus, and measurements while the device was inserted provide data that simulate peri-intromission coating.
Coating by Advantage™ was more extensive and uniform than coating by Conceptrol®, with smaller bare spots of uncoated epithelium. Change in posture tended to increase extent and uniformity of coating, details differing between gels.
Results are consistent with predictions of mechanistic coating theory, using gel rheological data as inputs.
PMCID: PMC3072785  PMID: 17241845
Vaginal gel; Contraceptive agents; Microbicide; Fluorimeter; Epithelial coating

Results 1-5 (5)