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1.
J Control Release ; 366: 349-365, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38182058

RESUMO

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.


Assuntos
Doenças Transmissíveis , Infecção Hospitalar , Medicina , Humanos , Doenças Transmissíveis/tratamento farmacológico , Biofarmácia , Impressão Tridimensional
2.
Ann 3D Print Med ; 112023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37583971

RESUMO

Lactobacilli, play a beneficial role in the female reproductive tract (FRT), regulating pH via lactic acid metabolism to help maintain a healthy environment. Bacterial vaginosis (BV) is characterized by a dysregulated flora in which anaerobes such as Gardnerella vaginalis (Gardnerella) create a less acidic environment. Current treatment focuses on antibiotic administration, including metronidazole, clindamycin, or tinidazole; however, lack of patient compliance as well as antibiotic resistance may contribute to 50% recurrence within a year. Recently, locally administered probiotics such as Lactobacillus crispatus (L. crispatus) have been evaluated as a prophylactic against recurrence. To mitigate the lack of patient compliance, sustained probiotic delivery has been proposed via 3D-bioprinted delivery vehicles. Successful delivery depends on a variety of vehicle fabrication parameters influencing timing and rate of probiotic recovery; detailed evaluation of these parameters would benefit from computational modeling complementary to experimental evaluation. This study implements a novel simulation platform to evaluate sustained delivery of probiotics from 3D-bioprinted scaffolds, taking into consideration bacterial lactic acid production and associated pH changes. The results show that the timing and rate of probiotic recovery can be realistically simulated based on fabrication parameters that affect scaffold degradation and probiotic survival. Longer term, the proposed approach could help personalize localized probiotic delivery to the FRT to advance women's health.

3.
Eur J Pharm Biopharm ; 190: 81-93, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37479065

RESUMO

The emergence of probiotics as an alternative and adjunct to antibiotic treatment for microbiological disturbances of the female genitourinary system requires innovative delivery platforms for vaginal applications. This study developed a new, rapid-dissolving form using electrospun polyethylene oxide (PEO) fibers for delivery of antibiotic metronidazole or probiotic Lactobacillus acidophilus, and performed evaluation in vitro and in vivo. Fibers did not generate overt pathophysiology or encourage Gardnerella growth in a mouse vaginal colonization model, inducing no alterations in vaginal mucosa at 24 hr post-administration. PEO-fibers incorporating metronidazole (100 µg MET/mg polymer) effectively prevented and treated Gardnerella infections (∼3- and 2.5-log reduction, respectively, 24 hr post treatment) when administered vaginally. Incorporation of live Lactobacillus acidophilus (107 CFU/mL) demonstrated viable probiotic delivery in vitro by PEO and polyvinyl alcohol (PVA) fibers to inhibit Gardnerella (108 CFU/mL) in bacterial co-cultures (9.9- and 7.0-log reduction, respectively, 24 hr post-inoculation), and in the presence of vaginal epithelial cells (6.9- and 8.0-log reduction, respectively, 16 hr post-inoculation). Administration of Lactobacillus acidophilus in PEO-fibers achieved vaginal colonization in mice similar to colonization observed with free Lactobacillus. acidophilus. These experiments provide proof-of-concept for rapid-dissolving electrospun fibers as a successful platform for intra-vaginal antibiotic or probiotic delivery.


Assuntos
Nanofibras , Probióticos , Feminino , Animais , Camundongos , Antibacterianos/uso terapêutico , Metronidazol , Resultado do Tratamento , Lactobacillus acidophilus/fisiologia
4.
ACS Biomater Sci Eng ; 9(7): 4277-4287, 2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37367532

RESUMO

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.


Assuntos
Anti-Infecciosos , Lacticaseibacillus rhamnosus , Infecções Urinárias , Humanos , Infecções Urinárias/prevenção & controle , Infecções Urinárias/microbiologia , Cateteres Urinários/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias , Silicones
5.
Biomed Eng Adv ; 52023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37123989

RESUMO

Sustained vaginal administration of antibiotics or probiotics has been proposed to improve treatment efficacy for bacterial vaginosis. 3D printing has shown promise for development of systems for local agent delivery. In contrast to oral ingestion, agent release kinetics can be fine-tuned by the 3D printing of specialized scaffold designs tailored for particular treatments while enhancing dosage effectiveness via localized sustained release. It has been challenging to establish scaffold properties as a function of fabrication parameters to obtain sustained release. In particular, the relationships between scaffold curing conditions, compressive strength, and drug release kinetics remain poorly understood. This study evaluates 3D printed scaffold formulation and feasibility to sustain the release of metronidazole, a commonly used antibiotic for BV. Cylindrical silicone scaffolds were printed and cured using three different conditions relevant to potential future incorporation of temperature-sensitive labile biologics. Compressive strength and drug release were monitored for 14d in simulated vaginal fluid to assess long-term effects of fabrication conditions on mechanical integrity and release kinetics. Scaffolds were mechanically evaluated to determine compressive and tensile strength, and elastic modulus. Release profiles were fitted to previous kinetic models to differentiate potential release mechanisms. The Higuchi, Korsmeyer-Peppas, and Peppas-Sahlin models best described the release, indicating similarity to release from insoluble or polymeric matrices. This study shows the feasibility of 3D printed silicone scaffolds to provide sustained metronidazole release over 14d, with compressive strength and drug release kinetics tuned by the fabrication parameters.

6.
Int J Pharm ; 641: 123054, 2023 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-37207856

RESUMO

Bacterial vaginosis (BV) is a highly recurrent vaginal condition linked with many health complications. Topical antibiotic treatments for BV are challenged with drug solubility in vaginal fluid, lack of convenience and user adherence to daily treatment protocols, among other factors. 3D-printed scaffolds can provide sustained antibiotic delivery to the female reproductive tract (FRT). Silicone vehicles have been shown to provide structural stability, flexibility, and biocompatibility, with favorable drug release kinetics. This study formulates and characterizes novel metronidazole-containing 3D-printed silicone scaffolds for eventual application to the FRT. Scaffolds were evaluated for degradation, swelling, compression, and metronidazole release in simulated vaginal fluid (SVF). Scaffolds retained high structural integrity and sustained release. Minimal mass loss (<6%) and swelling (<2%) were observed after 14 days in SVF, relative to initial post-cure measurements. Scaffolds cured for 24 hr (50 °C) demonstrated elastic behavior under 20% compression and 4.0 N load. Scaffolds cured for 4 hr (50 °C), followed by 72 hr (4 °C), demonstrated the highest, sustained, metronidazole release (4.0 and 27.0 µg/mg) after 24 hr and 14 days, respectively. Based upon daily release profiles, it was observed that the 24 hr timepoint had the greatest metronidazole release of 4.08 µg/mg for scaffolds cured at 4 hr at 50 °C followed by 72 hr at 4 °C. For all curing conditions, release of metronidazole after 1 and 7 days showed > 4.0-log reduction in Gardnerella concentration. Negligible cytotoxicity was observed in treated keratinocytes comparable to untreated cells, This study shows that pressure-assisted microsyringe 3D-printed silicone scaffolds may provide a versatile vehicle for sustained metronidazole delivery to the FRT.


Assuntos
Antibacterianos , Vaginose Bacteriana , Humanos , Feminino , Metronidazol , Administração Intravaginal , Vaginose Bacteriana/tratamento farmacológico , Impressão Tridimensional
7.
Eur J Pharm Biopharm ; 187: 68-75, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37086869

RESUMO

Bacterial vaginosis (BV) is a common condition that affects one-third of women worldwide. BV is characterized by low levels of healthy lactobacilli and an overgrowth of common anaerobes such as Gardnerella. Antibiotics for BV are administered orally or vaginally; however, approximately half of those treated will experience recurrence within 6 months. Lactobacillus crispatus present at high levels has been associated with positive health outcomes. To address the high recurrence rates following BV treatment, beneficial bacteria have been considered as an alternative or adjunct modality. This study aimed to establish proof-of-concept for a new long-acting delivery vehicle for L. crispatus. Here, it is shown that polyethylene oxide (PEO) fibers loaded with L. crispatus can be electrospun with poly(lactic-co-glycolic acid) (PLGA) fibers (ratio 1:1), and that this construct later releases L. crispatus as metabolically viable bacteria capable of lactic acid production and anti-Gardnerella activity. Probiotic-containing fibers were serially cultured in MRS (deMan, Rogosa, Sharpe) broth with daily media replacement and found to yield viable L. crispatus for at least 7 days. Lactic acid levels and corresponding pH values generally corresponded with levels of L. crispatus cultured from the fibers and strongly support the conclusion that fibers yield viable L. crispatus that is metabolically active. Cultures of L. crispatus-loaded fibers limited the growth of Gardnerella in a dilution-dependent manner during in vitro assays in the presence of cultured vaginal epithelial cells, demonstrating bactericidal potential. Exposure of VK2/E6E7 cells to L. crispatus-loaded fibers resulted in minimal loss of viability relative to untreated cells. Altogether, these data provide proof-of-concept for electrospun fibers as a candidate delivery vehicle for application of vaginal probiotics in a long-acting form.


Assuntos
Lactobacillus crispatus , Vaginose Bacteriana , Feminino , Humanos , Gardnerella vaginalis , Gardnerella , Vaginose Bacteriana/tratamento farmacológico , Vaginose Bacteriana/microbiologia , Bactérias , Vagina , Antibacterianos/farmacologia , Ácido Láctico
8.
J Control Release ; 357: 545-560, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37076014

RESUMO

Bacterial vaginosis (BV) is characterized by low levels of lactobacilli and overgrowth of potential pathogens in the female genital tract. Current antibiotic treatments often fail to treat BV in a sustained manner, and > 50% of women experience recurrence within 6 months post-treatment. Recently, lactobacilli have shown promise for acting as probiotics by offering health benefits in BV. However, as with other active agents, probiotics often require intensive administration schedules incurring difficult user adherence. Three-dimensional (3D)-bioprinting enables fabrication of well-defined architectures with tunable release of active agents, including live mammalian cells, offering the potential for long-acting probiotic delivery. One promising bioink, gelatin alginate has been previously shown to provide structural stability, host compatibility, viable probiotic incorporation, and cellular nutrient diffusion. This study formulates and characterizes 3D-bioprinted Lactobacillus crispatus-containing gelatin alginate scaffolds for gynecologic applications. Different weight to volume (w/v) ratios of gelatin alginate were bioprinted to determine formulations with highest printing resolution, and different crosslinking reagents were evaluated for effect on scaffold integrity via mass loss and swelling measurements. Post-print viability, sustained-release, and vaginal keratinocyte cytotoxicity assays were conducted. A 10:2 (w/v) gelatin alginate formulation was selected based on line continuity and resolution, while degradation and swelling experiments demonstrated greatest structural stability with dual genipin and calcium crosslinking, showing minimal mass loss and swelling over 28 days. 3D-bioprinted L. crispatus-containing scaffolds demonstrated sustained release and proliferation of live bacteria over 28 days, without impacting viability of vaginal epithelial cells. This study provides in vitro evidence for 3D-bioprinted scaffolds as a novel strategy to sustain probiotic delivery with the ultimate goal of restoring vaginal lactobacilli following microbiological disturbances.


Assuntos
Lactobacillus crispatus , Probióticos , Vaginose Bacteriana , Feminino , Humanos , Gelatina , Vagina , Vaginose Bacteriana/tratamento farmacológico , Vaginose Bacteriana/microbiologia , Lactobacillus/metabolismo , Alginatos
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