title: Uterine perfusion model for analyzing barriers to transport in fibroids.
abstract: This project uses an ex vivo human perfusion model for studying transport in benign, fibrous tumors. The uterine arteries were cannulated to perfuse the organ with a buffer solution containing blood vessel stain and methylene blue to analyze intratumoral transport. Gross examination revealed tissue expansion effects and a visual lack of methylene blue in the fibroids. Some fibroids exhibited regions with partial methylene blue penetration into the tumor environment. Histological analysis comparing representative sections of fibroids and normal myometrium showed a smaller number of vessels with decreased diameters within the fibroid. Imaging of fluorescently stained vessels exposed a stark contrast between fluorescence within the myometrium and relatively little within the fibroid tissues. Imaging at higher magnification revealed that fibroid blood vessels were indeed perfused and stained with the lipophilic membrane dye; however, the vessels were only the size of small capillaries and the blood vessel coverage was only 12% that of the normal myometrium. The majority of sampled fibroids had a strong negative correlation (Pearson's r=-0.68 or beyond) between collagen and methylene blue staining. As methylene blue was able to passively diffuse into fibroid tissue, the true barrier to transport in these fibroids is likely high interstitial fluid pressure, correlating with high collagen content and solid stress observed in the fibroid tissue. Fibroids had an average elevated interstitial fluid pressure of 4mmHg compared to -1mmHg in normal myometrium. Our findings signify relationships between drug distribution in fibroids and between vasculature characteristics, collagen levels, and interstitial fluid pressure. Understanding these barriers to transport can lead to developments in drug delivery for the treatment of uterine fibroids and tumors of similar composition.
authors.affiliation: Department of Bioengineering, University of Utah, United States.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Stirland
authors.affiliation: Department of Bioengineering, University of Utah, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Nichols
authors.affiliation: Department of Obstetrics and Gynecology, University of Utah, United States; Department of Pathology, University of Utah, United States.
authors.forename: Elke
authors.initials: E
authors.lastname: Jarboe
authors.affiliation: Department of Obstetrics and Gynecology, University of Utah, United States.
authors.forename: Marisa
authors.initials: M
authors.lastname: Adelman
authors.affiliation: Department of Obstetrics and Gynecology, University of Utah, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Dassel
authors.affiliation: Department of Bioengineering, University of Utah, United States; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, United States; Department of Obstetrics and Gynecology, University of Utah, United States. Electronic address: margit.janat-amsbury@hsc.utah.edu.
authors.forename: Margit-Maria
authors.initials: MM
authors.lastname: Janát-Amsbury
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, United States; Utah-Inha DDS and Advanced Therapeutics Research Center, Incheon, Korea. Electronic address: you.bae@utah.edu.
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
mesh_terms: D002196:Capillaries / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004396:Coloring Agents; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D006874:Hydrostatic Pressure; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007889:Leiomyoma / Q000098:blood supply* / Q000473:pathology; D008751:Methylene Blue; D008954:Models, Biological; D009215:Myometrium / Q000378:metabolism; D010477:Perfusion; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012039:Regional Blood Flow; D055988:Uterine Artery / Q000378:metabolism; D014599:Uterus / Q000098:blood supply* / Q000473:pathology
chemical_list: D004396:Coloring Agents; D004364:Pharmaceutical Preparations; D003094:Collagen; D007770:L-Lactate Dehydrogenase; D008751:Methylene Blue
keywords: Clinical tumor model; Drug delivery; Ex vivo model; Interstitial fluid pressure; Intratumoral distribution; Uterine fibroid