Development and characterization of 3D printed ethylene vinyl acetate (EVA) as drug delivery device for the treatment of overactive bladder.

The overactive bladder is a condition characterized by a sudden urge to urinate, even with small volumes of urine present in the bladder. The current treatments available for this pathology consist on conservative approaches and the continuous administration of drugs, which when made by conventional methods has limitations related to the first pass metabolism, bioavailability, severe side effects, and low patient adherence to treatments, ultimately leading to low effectiveness. Within this context, the present work proposes the design, manufacture, and characterization of an intravesical implant for the treatment of overactive bladder pathology, using EVA copolymer as a matrix and oxybutynin as a drug. The fabrication of devices through two manufacturing techniques (extrusion and additive manufacturing by fused filament fabrication, FFF) and the evaluation of the implants through characterization tests was proposed. The usability and functionality were evaluated through simulated insertion of the device/prototype in a bladder model through catheter insertion tests. The safety and effectiveness of the devices was investigated from mechanical testing as well as drug release assays. Drug release assays presented a burst release in the first 24 h, followed by a release of 1.8 and 2.8 mg/d, totalizing 32 d. Mechanical tests demonstrated an increase in the stiffness of the specimens due to the addition of the drug, showing a change in maximum stress and strain at break. The released dose was higher than that usually presented when considering the oral administration route, showing the optimization of the development of this implant has the potential to improve the quality of life of patients with overactive bladder.

3D-Printed EVA Devices for Antiviral Delivery and Herpes Virus Control in Genital Infection.

Herpes viruses are widespread in the human population and can cause many different diseases. Genital herpes is common and can increase the risk of HIV infection and neonatal herpes. Acyclovir is the most used drug for herpes treatment; however, it presents some disadvantages due to its poor oral bioavailability. In this study, some ethylene vinyl acetate devices with different acyclovir amounts (0, 10, and 20 wt.%) were manufactured by fused filament fabrication in two different geometries, an intrauterine device, and an intravaginal ring. Thermal analyses suggested that the crystallinity of EVA decreased up to 8% for the sample loaded with 20 wt.% of acyclovir. DSC, SEM, and FTIR analyses confirmed that the drug was successfully incorporated into the EVA matrix. Moreover, the drug release tests suggested a burst release during the first 24 h followed by a slower release rate sustained up to 80 days. Biological assays showed the biocompatibility of the EVA/ACV device, as well as a 99% reduction in vitro replication of HSV-1. Finally, the EVA presented a suitable performance for 3D printing manufacturing that can contribute to developing personalized solutions for long-term herpes treatment.

Influence of Breast Implant Surface Finishing on Physicochemical and Mechanical Properties before and after Extreme Degradation Studies.

The influence of the surface finishing of breast implants on physicochemical and mechanical properties, before and after extreme degradation experiments, was investigated in this study. Removal of superficial layers after degradation was verified for both smooth and rough membranes, in which local erosion was verified. FTIR results demonstrated the generation of low-molecular-weight structures in all samples due to exposure to acidic and basic environments. Furthermore, smooth samples presented higher degrees of crosslinking than rough samples. Considering the mechanical properties, no difference was verified between smooth and rough samples as received and after degradation studies. However, the pH of the degradation solution had an influence on mechanical properties of the material and a basic environment caused greater deterioration of the mechanical properties compared to acidic conditions.

Polymeric implants with drug-releasing capabilities: a mapping review of laboratory research.

PURPOSE: To provide a systematic map of the nature and extent of preclinical research concerning drug-releasing polymeric implants. SIGNIFICANCE: By summarizing available data, this mapping review can guide the development of new drug-delivery devices. METHODS: In-vitro studies assessing drug-delivery implants were reviewed. A study protocol was registered at Open Science Framework. The association of polymers with prominent drugs, manufacturing processes, geometries, treatments, and anatomical locations was assessed using the VOSviewer software. The release periods were also evaluated. RESULTS: A total of 423 articles, published between 1975 and 2020, were included and grouped into a framework with nine main categories. More than half of studies were published between 2010 and 2020. Among 201 individual polymers or combinations, the most investigated were PLGA, PCL, PLA, Silicone (SIL), EVA, and PU. Similarly, from 232 individual drugs or combinations, the most prominent were dexamethasone (DEX; anti-inflammatory), paclitaxel (PTX; anticancer), fluoruracil (anticancer), ciprofloxacin (CFX) hydrochloride (antibiotic), and gentamicin (GS; antibiotic). A total of 51 manufacturing processes were encountered, of which the most reported were solvent evaporation, compression molding (CM), extrusion (EX), electrospinning (ELS), and melt molding (MM). Among 38 implant geometries, cylinder (CIL) was the most prominent, followed by disk, square film, circular film (FCIR), and undefined film. Release times varied greatly, although the majority of articles ranged between 5 and 300 d. CONCLUSIONS: Drug-delivery implants were highly heterogeneous due to its applicability for multiple health conditions. Most implants were made of PLGA and most drugs assessed presented anti-inflammatory, antibiotic, or anticancer effects. Solvent evaporation and CIL were the most prominent manufacturing process and geometry, respectively.

Thermomechanical and in vitro biological characterization of injection-molded PLGA craniofacial plates.

PURPOSE:: To evaluate the thermomechanical and in vitro biological response of poly(lactic-co-glycolic acid) (PLGA) plates for craniofacial reconstructive surgery. METHODS:: PLGA 85/15 craniofacial plates were produced by injection molding by testing two different temperatures (i.e., 240°C, PLGA_lowT, and 280°C, PLGA_highT). The mechanical properties of the produced plates were characterized by three-point bending tests, dynamic mechanical analysis, and residual stress. Crystallinity and thermal transitions were investigated by differential scanning calorimetry. Finally, in vitro cell interaction was evaluated by using SAOS-2 as cell model. Indirect cytotoxicity tests (ISO 10-993) were performed to prove the absence of cytotoxic release. Cells were then directly seeded on the plates and their viability, morphology, and functionality (ALP) checked up to 21 days of culture. RESULTS:: A similar performance of PLGA_lowT and PLGA_highT plates was verified in the three-point bending test and dynamic mechanical analyses. Also, the two processing temperatures did not influence the in vitro cell interaction. Cytotoxicity and ALP activity were similar for the PLGA plates and control. Cell results demonstrated that the PLGA plates supported cell attachment and proliferation. Furthermore, energy-dispersive X-ray spectroscopy revealed the presence of sub-micron particles, which were identified as inorganic mineral deposits resulting from osteoblast activity. CONCLUSION:: The present work demonstrated that the selected processing temperatures did not affect the material performance. PLGA plates showed good mechanical properties for application in craniofacial reconstructive surgery and adequate biological properties.

Glucosamine Hydrochloride and N-Acetylglucosamine Influence the Response of Bovine Chondrocytes to TGF-ß3 and IGF in Monolayer and Three-Dimensional Tissue Culture.

BACKGROUND: Glucosamine hydrochloride (GlcN·HCl) has been shown to inhibit cell growth and matrix synthesis, but not with N-acetyl-glucosamine (GlcNAc) supplementation. This effect might be related to an inhibition of critical growth factors (GF), or to a different metabolization of the two glucosamine derivatives. The aim of the present study was to evaluate the synergy between GlcN·HCl, GlcNAc, and GF on proliferation and cartilage matrix synthesis. METHOD: Bovine chondrocytes were cultivated in monolayers for 48 h and in three-dimensional (3D) chitosan scaffolds for 30 days in perfusion bioreactors. Serum-free (SF) medium was supplemented with either growth factors (GF) TGF-ß (5 ng mL-1) and IGF-I (10 ng mL-1), GlcN·HCl or GlcNAc at 1mM each or both. Six groups were compared according to medium supplementation: (a) SF control; (b) SF + GlcN·HCl; (c) SF + GlcNAc; (d) SF + GF; (e) SF + GF + GlcN·HCl; and (f) SF + GF + GlcNAc. Cell proliferation, proteoglycan, collagen I (COL1), and collagen II (COL2) synthesis were evaluated. RESULTS: The two glucosamines showed opposite effects in monolayer culture: GlcN·HCl significantly reduced proliferation and GlcNAc significantly augmented cellular metabolism. In the 30 days 3D culture, the GlcN·HCl added to GF stimulated cell proliferation more than when compared to GF only, but the proteoglycan synthesis was smaller than GF. However, GlcNAc added to GF improved the cell proliferation and proteoglycan synthesis more than when compared to GF and GF/GlcN·HCl. The synthesis of COL1 and COL2 was observed in all groups containing GF. CONCLUSION: GlcN·HCl and GlcNAc increased cell growth and stimulated COL2 synthesis in long-time 3D culture. However, only GlcNAc added to GF improved proteoglycan synthesis.

Effect of Injection Molding Melt Temperatures on PLGA Craniofacial Plate Properties during In Vitro Degradation.

The purpose of this article is to present mechanical and physicochemical properties during in vitro degradation of PLGA material as craniofacial plates based on different values of injection molded temperatures. Injection molded plates were submitted to in vitro degradation in a thermostat bath at 37 ± 1°C by 16 weeks. The material was removed after 15, 30, 60, and 120 days; then bending stiffness, crystallinity, molecular weights, and viscoelasticity were studied. A significant decrease of molecular weight and mechanical properties over time and a difference in FT-IR after 60 days showed faster degradation of the material in the geometry studied. DSC analysis confirmed that the crystallization occurred, especially in higher melt temperature condition. DMA analysis suggests a greater contribution of the viscous component of higher temperature than lower temperature in thermomechanical behavior. The results suggest that physical-mechanical properties of PLGA plates among degradation differ per injection molding temperatures.

Influence of Processing Conditions on the Mechanical Behavior and Morphology of Injection Molded Poly(lactic-co-glycolic acid) 85:15.

Two groups of PLGA specimens with different geometries (notched and unnotched) were injection molded under two melting temperatures and flow rates. The mechanical properties, morphology at the fracture surface, and residual stresses were evaluated for both processing conditions. The morphology of the fractured surfaces for both specimens showed brittle and smooth fracture features for the majority of the specimens. Fracture images of the notched specimens suggest that the surface failure mechanisms are different from the core failure. Polarized light techniques indicated birefringence in all specimens, especially those molded with lower temperature, which suggests residual stress due to rapid solidification. DSC analysis confirmed the existence of residual stress in all PLGA specimens. The specimens molded using the lower injection temperature and the low flow rate presented lower loss tangent values according to the DMA and higher residual stress as shown by DSC, and the photoelastic analysis showed extensive birefringence.

Graft tendon slippage with metallic and bioabsorbable interference screws under cyclic load: a biomechanical study in a porcine model

Introduction The rupture of the anterior cruciate ligament (ACL) is the most common type of knee injury. Reconstructive surgery is the ‘gold standard’ treatment. During the immediate post-operative period, the fixation of the graft is entirely dependent on the ability of the grafted implant to be secured inside the bone tunnel under the cyclical loads associated with daily tasks. Poor fixation can lead to graft slippage, thus impairing the healing and integration of the graft. The aim of this study was to evaluate the biomechanical performance of tendon graft fixation devices with metallic and bioabsorbable interference screws. Methods Twenty ACL reconstructions were carried out in porcine tibias using deep flexor tendons to fix 9 × 20 mm metallic (n=10) and PLLA 70/30 bioabsorbable screws (n=10). To verify the ability of a construct to resist immediate postoperative (PO) rehabilitation protocols for immediate load bearing, a cyclic loading test was applied with 50-250 N of tensile force at 1 Hz for 1000 cycles, and the displacement was measured at 10, 50, 100, 500 and 1000 load cycles to quantify the slippage of the graft during the test. After the cyclic loading test, a single-cycle load-to-failure test was applied. Results The slippage of the graft using metallic screws did not differ (P = 0.616) from that observed when using bioabsorbable screws. Conclusion The results obtained in this experiment indicate that metallic screws may promote a similar amount of graft slippage during low cyclic loading as bioabsorbable screws. Additionally, there was no difference in the biomechanical performance of these two types of screws during high failure loads.

Production and characterization of cornstarch/cellulose acetate/silver sulfadiazine extrudate matrices.

The production and evaluation of cornstarch/cellulose acetate/silver sulfadiazine extrudate matrices are reported herein. The matrices were melt extruded under nine different conditions, altering the temperature and the screw speed values. The surface morphology of the matrices was examined by scanning electron microscopy. The micrographs revealed the presence of non-melted silver sulfadiazine microparticles in the matrices extruded at lower temperature and screw speed values. The thermal properties were evaluated and the results for both the biopolymer and the drug indicated no thermal degradation during the melt extrusion process. The differential scanning analysis of the extrudate matrices showed a shift to lower temperatures for the silver sulfadiazine melting point compared with the non-extruded drug. The starch/cellulose acetate matrices containing silver sulfadiazine demonstrated significant inhibition of the growth of Pseudomonas aeruginosa and Staphylococcus aureus. In vivo inflammatory response tests showed that the extrudate matrices, with or without silver sulfadiazine, did not trigger chronic inflammatory processes.