3D-bioprinting of sustained- and phased-release antibiotic and probiotic scaffolds to treat bacterial vaginosis - PROJECT SUMMARY
Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that affects ~29% of reproductive age women
and is linked with higher risks of adverse pregnancy outcomes, postsurgical infections, and sexually transmitted
infections. While lactobacilli typically dominate the healthy vagina, BV is characterized by low lactobacilli levels
and an overgrowth of diverse anaerobic bacteria, most often including Gardnerella and Prevotella. Current oral
or topical antibiotic treatments alleviate symptoms in 80% of women, at least temporarily. However, most women
will experience a recurrence of BV within one-year post-treatment. A recent clinical study showed that a vaginal
probiotic treatment regimen (with Lactobacillus crispatus), used following a vaginal course of antibiotics
(metronidazole), significantly improved long-term treatment efficacy. Unfortunately, current topically-applied
formulations require repeated administrations (once to twice daily), which can hinder female convenience and
adherence to treatment, particularly when undergoing multiple weeks of treatment (required to administer both
antibiotic and probiotics).
In this project we will use 3D printing and computational modeling, iteratively enabled by functional investigation
of prototype scaffolds in vitro and in vivo, to design long-acting products that sustain therapeutic delivery, while
enabling phased-delivery of antibiotics and probiotics to the female reproductive tract. Our team brings together
female reproductive tract-specific expertise in delivery vehicle design, computational modeling, and preclinical
BV models. The ultimate goal is to use 3D-bioprinting to incorporate different device compartments, which
sequentially release antibiotics that target anaerobic overgrowth, followed by live probiotics that restore balance
back in favor of vaginal lactobacilli. In Aim 1, we will design and characterize 3D-printed silicone scaffolds that
sustain antibiotic-only delivery. Aim 2 will design and evaluate 3D-printed silicone and gelatin alginate
composites that sequentially release antibiotics followed by probiotics, providing a “1-2 punch” strategy to kill BV
bacteria and provide a ‘healthy’ Lactobacillus alternative. Each aim will focus first on a materials-based
characterization of Met-containing silicone (1A) or Met-silicone probiotic-gelatin alginate composites (2A).
Measurements from in vitro release experiments will be used to develop and test computational models that
predict the delivery of antibiotic (1B) or dual agents (2B) in a “virtual female reproductive tract” and ultimately in
a mouse co-infection model. We will evaluate Met-silicone (1C) and Met-silicone probiotic-gelatin alginate
composites (2C) for cytotoxicity to the vaginal epithelium and ability to stimulate soluble proinflammatory
mediators and downstream histopathology. In our mouse model, we will measure levels of viable Gardnerella
and Prevotella recovered from vaginal and uterine tissues following treatment with blank or active agent-
containing 3D-printed scaffolds. If successful, this project will support the development of multipurpose platforms
to prevent and treat BV as well as other female reproductive tract applications.
