R01AI168475

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 approximately 29% of reproductive-age women. It is linked with higher risks of adverse pregnancy outcomes, postsurgical infections, and sexually transmitted infections. In a healthy vagina, lactobacilli typically dominate, but BV is characterized by low levels of lactobacilli and an overgrowth of diverse anaerobic bacteria, often including Gardnerella and Prevotella.

Current oral or topical antibiotic treatments can alleviate symptoms in 80% of women, but most 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. However, current topically-applied formulations require repeated administrations, which can hinder female convenience and adherence to treatment, especially when undergoing multiple weeks of treatment that require administering both antibiotics and probiotics.

In this project, we will utilize 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 that sequentially release antibiotics targeting 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 focus on designing and evaluating 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 begin with a materials-based characterization of metronidazole-containing silicone (1A) or metronidazole-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 antibiotics (1B) or dual agents (2B) in a "virtual female reproductive tract" and ultimately in a mouse co-infection model.

We will evaluate metronidazole-silicone (1C) and metronidazole-silicone probiotic-gelatin alginate composites (2C) for cytotoxicity to the vaginal epithelium and their 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.

University Of Louisville

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Kentucky United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 293% from $772,879 to $3,037,595.