Cervicovaginal mucus barrier properties during pregnancy are impacted by the vaginal microbiome

IntroductionMucus in the female reproductive tract acts as a barrier that traps and eliminates pathogens and foreign particles via steric and adhesive interactions. During pregnancy, mucus protects the uterine environment from ascension of pathogens and bacteria from the vagina into the uterus, a potential contributor to intrauterine inflammation and preterm birth. As recent work has demonstrated the benefit of vaginal drug delivery in treating women’s health indications, we sought to define the barrier properties of human cervicovaginal mucus (CVM) during pregnancy to inform the design of vaginally delivered therapeutics during pregnancy.MethodsCVM samples were self-collected by pregnant participants over the course of pregnancy, and barrier properties were quantified using multiple particle tracking. 16S rRNA gene sequencing was performed to analyze the composition of the vaginal microbiome.ResultsParticipant demographics differed between term delivery and preterm delivery cohorts, with Black or African American participants being significantly more likely to delivery prematurely. We observed that vaginal microbiota is most predictive of CVM barrier properties and of timing of parturition. Lactobacillus crispatus dominated CVM samples showed increased barrier properties compared to polymicrobial CVM samples.DiscussionThis work informs our understanding of how infections occur during pregnancy, and directs the engineering of targeted drug treatments for indications during pregnancy

Cervicovaginal mucus barrier properties during pregnancy are impacted by the vaginal microbiome

Introduction Mucus in the female reproductive tract acts as a barrier that traps and eliminates pathogens and foreign particles via steric and adhesive interactions. During pregnancy, mucus protects the uterine environment from ascension of pathogens and bacteria from the vagina into the uterus, a potential contributor to intrauterine inflammation and preterm birth. As recent work has demonstrated the benefit of vaginal drug delivery in treating women’s health indications, we sought to define the barrier properties of human cervicovaginal mucus (CVM) during pregnancy to inform the design of vaginally delivered therapeutics during pregnancy. Methods CVM samples were self-collected by pregnant participants over the course of pregnancy, and barrier properties were quantified using multiple particle tracking. 16S rRNA gene sequencing was performed to analyze the composition of the vaginal microbiome. Results Participant demographics differed between term delivery and preterm delivery cohorts, with Black or African American participants being significantly more likely to delivery prematurely. We observed that vaginal microbiota is most predictive of CVM barrier properties and of timing of parturition. Lactobacillus crispatus dominated CVM samples showed increased barrier properties compared to polymicrobial CVM samples. Discussion This work informs our understanding of how infections occur during pregnancy, and directs the engineering of targeted drug treatments for indications during pregnancy

Vaginal Delivery of Paclitaxel via Nanoparticles with Non-Mucoadhesive Surfaces Suppresses Cervical Tumor Growth

Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface

Nanofiber-coated, tacrolimus-eluting sutures inhibit post-operative neointimal hyperplasia in rats

Post-operative complications of vascular anastomosis procedures remain a significant clinical challenge and health burden globally. Each year, millions of anastomosis procedures connect arteries and/or veins in vascular bypass, vascular access, organ transplant, and reconstructive surgeries, generally via suturing. Dysfunction of these anastomoses, primarily due to neointimal hyperplasia and the resulting narrowing of the vessel lumen, results in failure rates of up to 50% and billions of dollars in costs to the healthcare system. Non-absorbable sutures are the gold standard for vessel anastomosis; however, damage from the surgical procedure and closure itself causes an inflammatory cascade that leads to neointimal hyperplasia at the anastomosis site. Here, we demonstrate the development of a novel, scalable manufacturing system for fabrication of high strength sutures with nanofiber-based coatings composed of generally regarded as safe (GRAS) polymers and either sirolimus, tacrolimus, everolimus, or pimecrolimus. These sutures provided sufficient tensile strength for maintenance of the vascular anastomosis and sustained drug delivery at the site of the anastomosis. Tacrolimus-eluting sutures provided a significant reduction in neointimal hyperplasia in rats over a period of 14 days with similar vessel endothelialization in comparison to conventional nylon sutures. In contrast, systemically delivered tacrolimus caused significant weight loss and mortality due to toxicity. Thus, drug-eluting sutures provide a promising platform to improve the outcomes of vascular interventions without modifying the clinical workflow and without the risks associated with systemic drug delivery

The Microstructure and Bulk Rheology of Human Cervicovaginal Mucus Are Remarkably Resistant to Changes in pH

The protective barrier, lubricant, and clearance functions of mucus are intimately coupled to its microstructure and bulk rheology. Mucus gels consist of a network of mucin biopolymers along with lipids, salts, and other proteins and exhibit similar biochemical and physical properties across diverse mucosal surfaces. Nevertheless, mucus is exposed to a broad range of pH values throughout the human body. Protein functions are typically sensitive to small changes in pH, and prior investigations using reconstituted, purified mucin gels suggested mucus undergoes a transition from a low-viscosity liquid at neutral pH to a highly viscoelastic solid at low pH. We sought to determine whether those observations hold for fresh, minimally perturbed human mucus <i>ex vivo</i> by using different-sized muco-inert nanoparticles to probe microstructure and cone-and-plate rheometry to measure bulk rheology. We demonstrate that both the microstructure and bulk rheology of fresh, undiluted, and minimally perturbed cervicovaginal mucus exhibit relatively minor changes from pH 1–2 to 8–9, in marked contrast with the pH sensitivity of purified mucin gels. Our work also suggests additional components in mucus secretions, typically eliminated during mucin purification and reconstitution, may play an important role in maintaining the protective properties of mucus