A new ex vivo model for optimizing distribution of therapeutic aerosols: the (inverted) bovine urinary bladder

Abstract

Background: Development of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) requires adequate preclinical models. Methods: The model should be easy to use, reproducible and cost-effective. It should have a volume similar to the human abdominal cavity, and an oval shape. The inner surface should be lined with serosa. The model should allow pharmacological and biological analysis, including histology. No living animals should be used. Results: The fresh urinary bladder is explanted from an adult bovine in the slaughterhouse. A 4-cm incision is performed into the bladder neck. The bladder can be inverted through the incision, which allows exposition of the serosa on its inner side. A balloon trocar is inserted through the incision and a ligature placed, ensuring full tightness. The therapeutic capnoperitoneum is installed. The bovine bladder has a volume somewhat smaller (2-3 L) than the human abdominal cavity (3-5 L). Costs are minimal. There is no significant bacteriological contamination. Manipulation is simple. Conclusions: The (inverted) bovine urinary bladder is an innovative and versatile ex vivo model for optimizing drug delivery with therapeutic aerosols both onto the mucosa or the serosa. This model can be used for pharmaceutical Quality-by-Design approaches and will replace a large number of experiments in the animal.

Establishment of a rat ovarian peritoneal metastasis model to study pressurized intraperitoneal aerosol chemotherapy (PIPAC)

“…An in vitro model consisting of aerosol generation in a plastic box that contains human peritoneum with PM was used to study tissue penetration of doxorubicin, as well as the effect of treatment parameters such as nebulizer position, pressure, and drug dose [14, 15]. Schnelle et al developed an interesting ex vivo model that consists of an inverted bovine urinary bladder, resulting in a serosa-lined cavity that can be used to study PIPAC [16]. Solass and coworkers demonstrated the technical proof of principle of PIPAC in a pig model [17].…”

Pressurized intraperitoneal aerosol chemotherapy: a review of the introduction of a new surgical technology using the IDEAL framework

“…Overall, the search identified: 23 stage 0 studies; 18 stage 1 studies and two protocol papers for stage 1 studies; 25 stage 2a studies, one protocol paper and five trial registrations (NCT01854255, NCT02735928, NCT03246321, NCT02604784 and NCT03124394) for stage 2a studies; six stage 2b studies and three protocol papers for stage 2b studies; and three protocol papers for stage 3 studies. Fig .…”

Enhanced Intraperitoneal Delivery of Charged, Aerosolized Curcumin Nanoparticles by Electrostatic Precipitation

“…For this purpose, CUR-PLGA-NPs were coated with chitosan to create a positive versus negative ζ-potential. We then used an established ex vivo model of the peritoneal cavity, the eIBUB model [18,19], to compare the efficacy of ePIPAC versus PIPAC for delivering these CUR-PLGA-NPs. The main finding of our study is that both a positive charge and the electrostatic precipitation increase the depth of tissue penetration of CUR-PLGA-NPs.…”

“…The nanoparticles were delivered as pressurized aerosols. Freshly prepared animal organs were used for testing [19]. The null hypotheses were that particle charge and electrostatic precipitation do not modify tissue uptake of CUR-PLGA-NPs.…”

“…For this study, we used the previously established enhanced inverted bovine urinary bladder (eIBUB) model [19]. The bovine urinary bladder as an intraperitoneal organ is almost entirely covered by a visceral peritoneal layer.…”