Vaginal chemokine delivery system for pelvic floor muscular dysfunction and urinary incontinence prophylaxis and therapy

Physiology 2021 (2021) Proc Physiol Soc 48, PC033

Poster Communications: Vaginal chemokine delivery system for pelvic floor muscular dysfunction and urinary incontinence prophylaxis and therapy

Juliana Ferreira Floriano1, 2, Sofia Vega1, Angélica Barbosa1, 3, Luis Sobrevia1, 4, 5, 6, 7, Marilza Vieira Rudge1

1 Botucatu Medical School - Sao Paulo State University, Botucatu, Brazil 2 National Heart and Lung Institute, Imperial College London, London, UK , London, United Kingdom 3 Department of Physiotherapy and Occupational Therapy, School of Philosophy and Sciences, São Paulo State University (UNESP), Marilia, Brazil , Marilia, Brazil 4 Cellular and Molecular Physiology Laboratory (CMPL), Departme of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile. , Santiago, Chile 5 Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain. , Seville, Spain 6 University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia. , Queensland,, Australia 7 Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands. , Groningen, The Netherlands

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Gestational diabetes mellitus (GDM) associates with high risk factor of gestational hyperglycemic myopathy (GHM) leading to pelvic floor muscular dysfunction (PFMD) and urinary incontinence (UI) at two years postpartum (PP) [1,2]. There are new approaches for the treatment of PFMD and UI based on regenerative medicine and mesenchymal stem cell therapy (MSCs) [3]. The MSCs therapy has limitations and challenges such as homing and retention of the injected MSCs. Thus, the sustained release of the chemotactic chemokine like CCL7 provides a great prospect for endogenous stem cell homing and improvement of the response to MSCs therapy in the prophylaxis in women at high risk of developing PP and UI and treatment of PFMD and UI. Our goal was developing an CCL7 sustained-release vaginal delivery device in the preclinical phase (experimental model in female rats), which can be used later translationally in humans. The in vivo study was approved by Botucatu Medical School ethics committee (protocol number 1234/2017-CEUA). Aliquots of 2 mL natural rubber latex (NRL) were mixed with a solution containing 0.2 µg/µL CCL7. During polymerization the devices were molded according to the rat vaginal anatomy and dried at 37°C during 48 h. In vitro release kinetics were evaluated by mimicking the vaginal environment. Elisa was used to evaluate sustained release of CCL7 over 10 days. Scanning electron microscopy analyzes were performed to analyze the structure of the vaginal devices. The in vivo release kinetics were evaluated by insertion of the devices into the animals vagina during 10 days. Virgin and young female rats (45) were used in the experiment in three different groups (n = 5): with device + CCL (CL+), with device without CCL7 (CL–) and control without the device and without CCL7 (CC). The groups were subdivided by 3 collection period (1, 7 and 10 days). The plasma, vagina, urethra, bladder and caudal portion of rectus abdominis muscle (RAM) were collected in these periods after the device insertion. The In vitro release kinetics results shows sustained CCL7 release over ~9 days without burst 2,500 ± 100 S.D pg/mL. CCL7 level in the vagina, urethra, bladder and RAM increased exponentially up to 10 days after the use of the device in the group CL+. The CCL7 level observed in the 10 days period using the vaginal device was 193± 83 S.D pg/mL (ANOVA and Tukey’s post hoc test) in bladder, 45 ± 10 S.D pg/mL in vagina/urethra, and 16 ± 6 S.D pg/mL RAM. However, CCL7 concentration was lower in the RAM when compared with the bladder (15 ±  2,5 fold  p<0.01) and with the vagina/urethra (2.81±  1,5 fold  p<0.01). There was no systemic release since no CCL7 was detected in the plasma. In the group CL- and CC the CCL7 was not detected in the tissues. The results show that the implanted vaginal device allows delivering CCL7 through the vagina with a sustained and continuous release increasing the CCL7 bioavailability in all regions of interest for prophylaxis and treatment.  



Where applicable, experiments conform with Society ethical requirements.

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