Modified Release 3D-Printed Capsules Containing a Ketoprofen Self-Nanoemulsifying System for Personalized Medical Application.

This study explores the realm of personalized medicine by investigating the utilization of 3D-printed dosage forms, specifically focusing on patient-specific enteric capsules designed for the modified release of ketoprofen, serving as a model drug. The research investigates two distinct scenarios: the modification of drug release from 3D-printed capsules crafted from hydroxypropyl methylcellulose phthalate:polyethylene glycol (HPMCP:PEG) and poly(vinyl alcohol) (PVA), tailored for pH sensitivity and delayed release modes, respectively. Additionally, a novel ketoprofen-loaded self-nanoemulsifying drug delivery system (SNEDDS) based on pomegranate seed oil (PSO) was developed, characterized, and employed as a fill material for the capsules. Through the preparation and characterization of the HPMCP:PEG based filament via the hot-melt extrusion method, the study thoroughly investigated its thermal and mechanical properties. Notably, the in vitro drug release analysis unveiled the intricate interplay between ketoprofen release, polymer type, and capsule thickness. Furthermore, the incorporation of ketoprofen into the SNEDDS exhibited an enhancement in its in vitro cylooxygenase-2 (COX-2) inhibitory activity. These findings collectively underscore the potential of 3D printing in shaping tailored drug delivery systems, thereby contributing significantly to the advancement of personalized medicine.

Advancements in Laser Wire-Feed Metal Additive Manufacturing: A Brief Review.

Laser Wire-Feed Metal Additive Manufacturing (LWAM) is a process that utilizes a laser to heat and melt a metallic alloy wire, which is then precisely positioned on a substrate, or previous layer, to build a three-dimensional metal part. LWAM technology offers several advantages, such as high speed, cost effectiveness, precision control, and the ability to create complex geometries with near-net shape features and improved metallurgical properties. However, the technology is still in its early stages of development, and its integration into the industry is ongoing. To provide a comprehensive understanding of the LWAM technology, this review article emphasizes the importance of key aspects of LWAM, including parametric modeling, monitoring systems, control algorithms, and path-planning approaches. The study aims to identify potential gaps in the existing literature and highlight future research opportunities in the field of LWAM, with the goal of advancing its industrial application.

3D-Printed Gentamicin-Releasing Poly-ε-Caprolactone Composite Prevents Fracture-Related Staphylococcus aureus Infection in Mice.

Bacterial infections are a serious healthcare complication in orthopedic and trauma surgery worldwide. Compared to systemic, local antibiotic prophylaxis has been shown to provide a higher antibiotic dose and bioavailability at the bone site with minimum toxic effects. However, there are still not enough biomaterial and antibiotic combinations available for personalized implant sizes for patients. The aim of this study was to develop a bone fixation plate coating made of a composite of poly-ε-caprolactone, hydroxyapatite and halloysite nanotubes loaded with gentamicin sulphate and fabricated via fused filament fabrication 3D printing technology. The mechanical and thermal properties of the biomaterial were analyzed. The in vitro release kinetics of gentamicin sulphate were evaluated for 14 days showing a burst release during the first two days that was followed by a sustained release of bactericidal concentrations. The composite loaded with 2 and 5% gentamicin sulphate exhibited complete antimicrobial killing of Staphylococcus aureus in an ex vivo mouse femur fixation plate infection model. Moreover, a fixation plate of the composite loaded with 5% of gentamicin sulphate was able to prevent S. aureus infection in the bone and surrounding tissue in an in vivo mouse bone fixation plate infection model 3 days post-surgery. In conclusion, the newly developed composite material successfully prevented infection in vivo. Additionally, the ability to use fused filament fabrication 3D printing to produce patient-specific implants may provide a wider range of personalized solutions for patients.

A Niclosamide-releasing hot-melt extruded catheter prevents Staphylococcus aureus experimental biomaterial-associated infection.

Biomaterial-associated infections are a major healthcare challenge as they are responsible for high disease burden in critically ill patients. In this study, we have developed drug-eluting antibacterial catheters to prevent catheter-related infections. Niclosamide (NIC), originally an antiparasitic drug, was incorporated into the polymeric matrix of thermoplastic polyurethane (TPU) via solvent casting, and catheters were fabricated using hot-melt extrusion technology. The mechanical and physicochemical properties of TPU polymers loaded with NIC were studied. NIC was released in a sustained manner from the catheters and exhibited in vitro antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. Moreover, the antibacterial efficacy of NIC-loaded catheters was validated in an in vivo biomaterial-associated infection model using a methicillin-susceptible and methicillin-resistant strain of S. aureus. The released NIC from the produced catheters reduced bacterial colonization of the catheter as well as of the surrounding tissue. In summary, the NIC-releasing hot-melt extruded catheters prevented implant colonization and reduced the bacterial colonization of peri-catheter tissue by methicillin sensitive as well as resistant S. aureus in a biomaterial-associated infection mouse model and has good prospects for preclinical development.

Can filaments, pellets and powder be used as feedstock to produce highly drug-loaded ethylene-vinyl acetate 3D printed tablets using extrusion-based additive manufacturing?

Personalized medicine, produced through 3D printing, is a promising approach for delivering the required drug dose based on the patient's profile. The primary purpose of this study was to investigate the potential of two different extrusion-based additive manufacturing techniques - fused filament fabrication (FFF) and screw-based 3D printing, also known as direct extrusion additive manufacturing (DEAM). Different ethylene-vinyl acetate (EVA) copolymers (9 %VA, 12 %VA, 16 %VA, 18 %VA, 25 %VA, 28 %VA, and 40 %VA) were selected and loaded with 50% (w/w) metoprolol tartrate (MPT). Hot-melt extrusion was performed to produce the drug-loaded filaments. These filaments were used for FFF in which the mechanical and rheological properties were rate-limiting steps. The drug-loaded filament based on the 18 %VA polymer was the only printable formulation due to its appropriate mechanical and rheological properties. As for the highest VA content (40 %VA), the feeding pinch rolls cause buckling of the filaments due to insufficient stiffness, while other filaments were successfully feedable towards the extrusion nozzle. However, poor flowability out of the extrusion nozzle due to the rheological limitation excluded these formulations from the initial printing trials. Filaments were also pelletized and used for pellets-DEAM. This method showed freedom in formulation selection because the screw rotation drives the material flow with less dependence on their mechanical properties. All drug-loaded pellets were successfully printed via DEAM, as sufficient pressure was built up towards the nozzle due to single screw extrusion processing method. In contrast, filaments were used as a piston to build up the pressure required for extrusion in filament-based printing, which highly depends on the filament's mechanical properties. Moreover, printing trials using a physical mixture in powder form were also investigated and showed promising results. In vitro drug release showed similar release patterns for MPT-loaded 3D printed tablets regardless of the printing technique. Additionally, pellets-DEAM enabled the production of tablets with the highest VA content, which failed in FFF 3D printing but showed an interesting delayed release profile.

Coupling Additive Manufacturing with Hot Melt Extrusion Technologies to Validate a Ventilator-Associated Pneumonia Mouse Model.

Additive manufacturing is widely used to produce highly complex structures. Moreover, this technology has proven its superiority in producing tools which can be used in different applications. We designed and produced an extrusion nozzle that allowed us to hot melt extrude drug-loaded tubes. The tubes were an essential part of a new mouse ventilator-associated pneumonia (VAP) model. Ciprofloxacin (CPX) was selected for its expected activity against the pathogen Staphylococcus aureus and ease of incorporation into thermoplastic polyurethane (TPU). TPU was selected as the carrier polymer for its biocompatibility and use in a variety of medical devices such as tubing and catheters. The effect of loading CPX within the TPU polymeric matrix and the physicochemical properties of the produced tubes were investigated. CPX showed good thermal stability and in vitro activity in preventing S. aureus biofilm formation after loading within the tube's polymeric matrix. Moreover, the produced tubes showed anti-infective efficacy in vivo. The produced tubes, which were extruded via our novel nozzle, were vital for the validation of our mouse VAP model. This model can be adopted to investigate other antibacterial and antibiofilm compounds incorporated in polymeric tubes using hot melt extrusion.

3D-Printed Drug Delivery Systems: The Effects of Drug Incorporation Methods on Their Release and Antibacterial Efficiency.

Additive manufacturing technologies have been widely used in the medical field. More specifically, fused filament fabrication (FFF) 3D-printing technology has been thoroughly investigated to produce drug delivery systems. Recently, few researchers have explored the possibility of directly 3D printing such systems without the need for producing a filament which is usually the feedstock material for the printer. This was possible via direct feeding of a mixture consisting of the carrier polymer and the required drug. However, as this direct feeding approach shows limited homogenizing abilities, it is vital to investigate the effect of the pre-mixing step on the quality of the 3D printed products. Our study investigates the two commonly used mixing approaches-solvent casting and powder mixing. For this purpose, polycaprolactone (PCL) was used as the main polymer under investigation and gentamicin sulfate (GS) was selected as a reference. The produced systems' efficacy was investigated for bacterial and biofilm prevention. Our data show that the solvent casting approach offers improved drug distribution within the polymeric matrix, as was observed from micro-computed topography and scanning electron microscopy visualization. Moreover, this approach shows a higher drug release rate and thus improved antibacterial efficacy. However, there were no differences among the tested approaches in terms of thermal and mechanical properties.

Production of Drug Delivery Systems Using Fused Filament Fabrication: A Systematic Review.

Fused filament fabrication (FFF) 3D printing technology is widely used in many fields. For almost a decade, medical researchers have been exploring the potential use of this technology for improving the healthcare sector. Advances in personalized medicine have been more achievable due to the applicability of producing drug delivery devices, which are explicitly designed based on patients' needs. For the production of these devices, a filament-which is the feedstock for the FFF 3D printer-consists of a carrier polymer (or polymers) and a loaded active pharmaceutical ingredient (API). This systematic review of the literature investigates the most widely used approaches for producing drug-loaded filaments. It also focusses on several factors, such as the polymeric carrier and the drug, loading capacity and homogeneity, processing conditions, and the intended applications. This review concludes that the filament preparation method has a significant effect on both the drug homogeneity within the polymeric carrier and drug loading efficiency.