Sustained dual delivery of metronidazole and viable Lactobacillus crispatus from 3D-printed silicone shells.

Bacterial vaginosis (BV) is an imbalance of the vaginal microbiome in which there are limited lactobacilli and an overgrowth of anaerobic and fastidious bacteria such as Gardnerella. The propensity for BV recurrence is high, and therapies involving multiple treatment modalities are emerging to meet this need. However, current treatments requiring frequent therapeutic administration are challenging for patients and impact user compliance. Three-dimensional (3D)-printing offers a novel alternative to customize platforms to facilitate sustained therapeutic delivery to the vaginal tract. This study designed a novel vehicle intended for dual sustained delivery of both antibiotic and probiotic. 3D-printed compartmental scaffolds consisting of an antibiotic-containing silicone shell and a core containing probiotic Lactobacillus were developed with multiple formulations including biomaterials sodium alginate (SA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyethylene oxide (PEO), and kappa-carrageenan (KC). The vehicles were loaded with 50 µg of metronidazole/mg polymer and 5 × 107 CFU of L. crispatus/mg scaffold. Metronidazole-containing shells exhibited cumulative drug release of 324.2 ± 31.2 µg/mL after 14 days. Multiple polymeric formulations for the probiotic core demonstrated cumulative L. crispatus recovery of >5 × 107 CFU/mg scaffold during this timeframe. L. crispatus-loaded polymeric formulations exhibited ≥2 log CFU/mL reduction in free Gardnerella in the presence of VK2/E6E7 vaginal epithelial cells. As a first step towards the goal of facilitating patient compliance, this study demonstrates in vitro effect of a novel 3D-printed dual antibiotic and probiotic delivery platform to target BV.

Rising role of 3D-printing in delivery of therapeutics for infectious disease.

Modern drug delivery to tackle infectious disease has drawn close to personalizing medicine for specific patient populations. Challenges include antibiotic-resistant infections, healthcare associated infections, and customizing treatments for local patient populations. Recently, 3D-printing has become a facilitator for the development of personalized pharmaceutic drug delivery systems. With a variety of manufacturing techniques, 3D-printing offers advantages in drug delivery development for controlled, fine-tuned release and platforms for different routes of administration. This review summarizes 3D-printing techniques in pharmaceutics and drug delivery focusing on treating infectious diseases, and discusses the influence of 3D-printing design considerations on drug delivery platforms targeting these diseases. Additionally, applications of 3D-printing in infectious diseases are summarized, with the goal to provide insight into how future delivery innovations may benefit from 3D-printing to address the global challenges in infectious disease.

Development and Characterization of Lactobacillus rhamnosus-Containing Bioprints for Application to Catheter-Associated Urinary Tract Infections.

Catheter-associated urinary tract infections (CAUTI) are a significant healthcare burden affecting millions of patients annually. CAUTI are characterized by infection of the bladder and pathogen colonization of the catheter surface, making them especially difficult to treat. Various catheter modifications have been employed to reduce pathogen colonization, including infusion of antibiotics and antimicrobial compounds, altering the surface architecture of the catheter, or coating it with nonpathogenic bacteria. Lactobacilli probiotics offer promise for a "bacterial interference" approach because they not only compete for adhesion to the catheter surface but also produce and secrete antimicrobial compounds effective against uropathogens. Three-dimensional (3D) bioprinting has enabled fabrication of well-defined, cell-laden architectures with tailored release of active agents, thereby offering a novel means for sustained probiotic delivery. Silicone has shown to be a promising biomaterial for catheter applications due to mechanical strength, biocompatibility, and its ability to mitigate encrustation on the catheter. Additionally, silicone, as a bioink, provides an optimum matrix for bioprinting lactobacilli. This study formulates and characterizes novel 3D-bioprinted Lactobacillus rhamnosus (L. rhamnosus)-containing silicone scaffolds for future urinary tract catheterization applications. Weight-to-weight (w/w) ratio of silicone/L. rhamnosus was bioprinted and cured with relative catheter dimensions in diameter. Scaffolds were analyzed in vitro for mechanical integrity, recovery of L. rhamnosus, antimicrobial production, and antibacterial effect against uropathogenic Escherichia coli, the leading cause of CAUTI. The results show that L. rhamnosus-containing scaffolds are capable of sustained recovery of live bacteria over 14 days, with sustained production of lactic acid and hydrogen peroxide. Through the use of 3D bioprinting, this study presents a potential alternative strategy to incorporate probiotics into urinary catheters, with the ultimate goal of preventing and treating CAUTI.