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.

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 (L. rhamnosus)-containing silicone scaffolds for future urinary tract catheterization applications. Weight-to-weight (w/w) ratio of silicone/ was bioprinted and cured with relative catheter dimensions in diameter. Scaffolds were analyzed for mechanical integrity, recovery of , antimicrobial production, and antibacterial effect against uropathogenic , the leading cause of CAUTI. The results show that -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.

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.

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.

Breast cancer accounts for almost one in four cancer diagnoses in women. Studies in breast cancer patients have identified several molecular markers, indicators of aggressiveness, which help toward more individual therapeutic approaches. In triple-negative breast cancer (TNBC), epidermal growth factor receptor (EGFR) overexpression is associated with increased metastatic potential and worst survival rates. Specifically, abnormal EGFR activation leads to altered matrix metalloproteinases' (MMPs) expression and, hence, extracellular matrix (ECM) degradation, resulting in induced migration and invasion. The use of matrix substrates for cell culture gives the opportunity to mimic the natural growth conditions of the cells and their microenvironment, as well as cell-cell and cell-matrix interactions. The aim of this study was to evaluate the impact of EGFR inhibition, estrogen receptor beta (ERβ) and different matrix substrates [type I collagen and fibronectin (FN)] on the functional properties, expression of MMPs and cell morphology of ERβ-positive TNBC cells and shERβ ones. Our results highlight EGFR as a crucial regulator of the expression and activity levels of MMPs, while ERβ emerges as a mediator of MMP7 and MT1-MMP expression. In addition, the EGFR/ERβ axis impacts the adhesion and invasion potential of breast cancer cells on collagen type I. Images obtained by scanning electron microscope (SEM) from cultures on the different matrix substrates revealed novel observations regarding various structures of breast cancer cells (filopodia, extravesicles, tunneling nanotubes, etc.). Moreover, the significant contribution of EGFR and ERβ in the morphological characteristics of these cells is also demonstrated, hence highlighting the possibility of dual pharmacological targeting.

Breast cancer is the most common malignancy among women worldwide. The role of epidermal growth factor receptor (EGFR) in many epithelial malignancies has been established, since it is dysregulated, overexpressed or mutated. Its overexpression has been associated with increased aggressiveness and metastatic potential in breast cancer. The well-established interplay between EGFR signaling pathway and estrogen receptors (ERs) as well as major extracellular matrix (ECM) mediators is crucial for regulating basic functional properties of breast cancer cells, including migration, proliferation, adhesion and invasion. EGFR activation leads to endocytosis of the receptor with implications in the regulation of downstream signaling effectors, the modulation of autophagy and cell survival. Therefore, EGFR is considered as a promising therapeutic target in breast cancer. Several anti-EGFR therapies (i.e. monoclonal antibodies and tyrosine kinase inhibitors) have been evaluated both in vitro and in vivo, making their way to clinical trials. However, the response rates of anti-EGFR therapies in the clinical trials is low mainly due to chemoresistance. Novel drug design, phytochemicals and microRNAs (miRNAs) are assessed as new therapeutic approaches against EGFR. The main goal of this review is to highlight the importance of targeting EGFR signaling pathway in terms of its crosstalk with ERs, the involvement of ECM effectors and epigenetics. Moreover, recent insights into the design of specialized delivery systems contributing in the development of novel diagnostic and therapeutic approaches in breast cancer are addressed.

BACKGROUND: Titanium mesh is a popular material for cranioplasty. However, long-term outcomes of these reconstructions remain unknown. We aimed to compare long-term outcomes between patients undergoing both (1) skull reconstruction with titanium mesh and other commonly used cranioplasty materials and (2) scalp reconstructions with locoregional flaps and free tissue transfers.

METHODS: A retrospective review of patients treated with 466 cranioplasties (401 patients) between 2002 and 2014 was performed.

RESULTS: Materials used for reconstructions included nontitanium alloplast (52.0%), titanium mesh (38%), and autologous bone (10%). Median cranial defect size was 58.4 cm. Eighty-three reconstructions (18%) included full-thickness scalp defect with a median area of 155.4 cm. Median follow-up was 3.9 years. Retention rate for isolated cranioplasty was 90%, 89.9%, and 77.1% for titanium mesh, nontitanium alloplast, and autologous bone, respectively (P > 0.05). In composite defect cases, retention rate for autologous bone was comparable, 81.8% (P > 0.05), whereas for titanium mesh and nontitanium alloplast it was significantly lower, 46.8% and 72.0%, respectively (P < 0.05). The retention rate of titanium mesh cranioplasty with free fascio- and myocutaneous flaps was higher when compared with locoregional and free muscle flaps (P < 0.05).

CONCLUSIONS: Titanium mesh offers a durable repair of isolated bone defects. However, in high-risk patients with soft-tissue defect, the outcomes are significantly worse. In these cases, free tissue transfer for soft-tissue coverage tends to be more successful, especially when using a myocutaneous or fasciocutaneous free flap. This is the first study to identify a high complication rate of this popular material, especially when it is combined with a locoregional scalp flap or free muscle flap. Therefore, in these cases, titanium mesh should be used with caution.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/β(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .