3D-printed long-acting 5-fluorouracil implant to prevent conjunctival fibrosis in glaucoma.

OBJECTIVES: To develop a sustained release 5-fluorouracil (5-FU) implant by three-dimensional (3D) printing to effectively prevent conjunctival fibrosis after glaucoma surgery. METHODS: 3D-printed implants composed of polycaprolactone (PCL) and chitosan (CS) were fabricated by heat extrusion technology and loaded with 1% 5-FU. Light microscopy and scanning electron microscopy were used to study the surface morphology. The 5-FU concentration released over 8 weeks was measured by ultraviolet visible spectroscopy. The effects on cell viability, fibroblast contractility and the expression of key fibrotic genes were assessed in human conjunctival fibroblasts. KEY FINDINGS: The PCL-CS-5-FU implant sustainably released 5-FU over 8 weeks and the peak concentration was over 6.1 µg/ml during weeks 1 and 2. The implant had a smooth surface and its total weight decreased by 3.5% after 8 weeks. The PCL-CS-5-FU implant did not affect cell viability in conjunctival fibroblasts and sustainably suppressed fibroblast contractility and key fibrotic genes for 8 weeks. CONCLUSIONS: The PCL-CS-5-FU implant was biocompatible and degradable with a significant effect in suppressing fibroblast contractility. The PCL-CS-5-FU implant could be used as a sustained release drug implant, replacing the need for repeated 5-FU injections in clinic, to prevent conjunctival fibrosis after glaucoma surgery.

3D bioprinted scaffolds for diabetic wound-healing applications.

The treatment strategy required for the effective healing of diabetic foot ulcer (DFU) is a complex process that is requiring several combined therapeutic approaches. As a result, there is a significant clinical and economic burden associated in treating DFU. Furthermore, these treatments are often unsuccessful, commonly resulting in lower-limb amputation. The use of drug-loaded scaffolds to treat DFU has previously been investigated using electrospinning and fused deposition modelling (FDM) 3D printing techniques; however, the rapidly evolving field of bioprinting is creating new opportunities for innovation within this research area. In this study, 3D-bioprinted scaffolds with different designs have been fabricated for the delivery of an antibiotic (levoflocixin) to DFU. The scaffolds were fully characterised by a variety of techniques (e.g. SEM, DSC/TGA, FTIR, and mechanical characterisation), demonstrating excellent mechanical properties and providing sustained drug release for 4 weeks. This proof of concept study demonstrates the innovative potential of bioprinting technologies in fabrication of antibiotic scaffolds for the treatment of DFU.

Optimization of FDM 3D printing process parameters to produce haemodialysis curcumin-loaded vascular grafts.

3D printing has provided a new prospective in the manufacturing of personalized medical implants, including fistulas for haemodialysis (HD). In the current study, an optimized fused modelling deposition (FDM) 3D printing method has been validated, for the first time, to obtain cylindrical shaped fistulas. Printing parameters were evaluated for the manufacturing of fistulas using blank and 0.25% curcumin-loaded filaments that were produced by hot melt extrusion (HME). Four different fistula types have been designed and characterized using a variety of physicochemical characterization methods. Each design was printed three times to demonstrate printing process accuracy considering outer and inner diameter, wall thickness, width, and length. A thermoplastic polyurethane (TPU) biocompatible elastomer was chosen, showing good mechanical properties with a high elastic modulus and maximum elongation, as well as stability at high temperatures with less than 0.8% of degradation at the range between 25 and 250 °C. Curcumin release profile has been evaluated in a saline buffer, obtaining a low release (12%) and demonstrating drug could continue release for a longer period, and for as long as grafts should remain in patient body. Possibility to produce drug-loaded grafts using one-step method as well as 3D printing process and TPU filaments containing curcumin printability has been demonstrated.

The manufacturing of 3D-printed microfluidic chips to analyse the effect upon particle size during the synthesis of lipid nanoparticles.

OBJECTIVES: The process of 3D printing to produce microfluidic chips is becoming commonplace, due to its quality, versatility and newfound availability. In this study, a UV liquid crystal display (LCD) printer has been implemented to produce a progression of microfluidic chips for the purpose of liposomal synthesis. The emphasis of this research is to test the limitations of UV LCD printing in terms of resolution and print speed optimisation for the production of microfluidic chips. KEY FINDINGS: By varying individual channel parameters such as channel length and internal geometries, the essential channel properties for optimal liposomal formulation are being investigated to act as a basis for future experimentation including the encapsulation of active pharmaceutical ingredients. Using the uniquely designed chips, liposomes of ≈120 nm, with polydispersity index values of ≤0.12 are able to be reproducibly synthesised. CONCLUSIONS: The influence of total flow rates and lipid choice is investigated in depth, to provide further clarification on how a microfluidic setup should be optimised. In-depth explanations of the importance of each channel parameter are also explained throughout, with reference to their importance for the properties of a successful liposome.

In-House Innovative "Diamond Shaped" 3D Printed Microfluidic Devices for Lysozyme-Loaded Liposomes.

Nanotechnology applications have emerged as one of the most actively researched areas in recent years. As a result, substantial study into nanoparticulate lipidic systems and liposomes (LPs) has been conducted. Regardless of the advantages, various challenges involving traditional manufacturing processes have hampered their expansion. Here, the combination of microfluidic technology (MF) and 3D printing (3DP) digital light processing (DLP) was fruitfully investigated in the creation of novel, previously unexplored "diamond shaped" devices suitable for the production of LPs carrying lysozyme as model drug. Computer-aided design (CAD) software was used designing several MF devices with significantly multiple and diverse geometries. These were printed using a high-performance DLP 3DP, resulting in extremely high-resolution chips that were tested to optimize the experimental condition of MF-based LPs. Monodisperse narrow-sized lysozyme-loaded PEGylated LPs were produced using in-house devices. The developed formulations succumbed to stability tests to determine their consistency, and then an encapsulation efficacy (EE) study was performed, yielding good findings. The in vitro release study indicated that lysozyme-loaded LPs could release up to 93% of the encapsulated cargo within 72 h. Therefore, the proficiency of the association between MF and 3DP was demonstrated, revealing a potential growing synergy.

3D printing in Ophthalmology: From medical implants to personalised medicine.

3D printing was invented thirty years ago. However, its application in healthcare became prominent only in recent years to provide solutions for drug delivery and clinical challenges, and is constantly evolving. This cost-efficient technique utilises biocompatible materials and is used to develop model implants to provide a greater understanding of human anatomy and diseases, and can be used for organ transplants, surgical planning and for the manufacturing of advanced drug delivery systems. In addition, 3D printed medical devices and implants can be customised for each patient to provide a more tailored treatment approach. The advantages and applications of 3D printing can be used to treat patients with different eye conditions, with advances in 3D bioprinting offering novel therapy applications in ophthalmology. The purpose of this review paper is to provide an in-depth understanding of the applications and advantages of 3D printing in treating different ocular conditions in the cornea, glaucoma, retina, lids and orbits.

Stereolithography 3D printed implants: A preliminary investigation as potential local drug delivery systems to the ear.

The current study is a preliminary investigation on the use of stereolithography 3D printing technology in the field of personalized medicines and specifically for delivering drugs locally, which can for example usefully be applied to ear infections. The main aim is the development of drug-loaded implants for the treatment of ear diseases, to improve patient compliance and to overcome the limitations of current delivery approaches. Multiple prototypes of implant geometries have been created and printed using a flexible resin containing 0.5% w/v of Levofloxacin. Physicochemical characterization of the printed implants was carried out using a variety of techniques (e.g., microscopic, spectroscopic, and mechanical analysis). Finally, preliminary in vitro tests were performed to evaluate the release profile of Levofloxacin, the prototype implant's stability, and their antimicrobial property. The results obtained show that there is no interaction between the resin and the drug, which is perfectly solubilized in the device. In addition, the results of the mechanical tests show that the material used resists compression without compromising the design itself, and the diffusion test has shown that the drug diffused through the matrix prototype at 50% over 3 weeks. The selected designs showed higher antimicrobial activity on E. coli than on S. aureus.

Fused deposition modelling 3D printing proof-of-concept study for personalised inner ear therapy.

OBJECTIVES: There is a requirement within ear therapeutics for a delivery system capable of safely delivering controlled doses to the inner ear. However, the anatomy and sensitivity of the inner ear make current delivery systems problematic and often ineffective. Therefore, a new delivery system is required to overcome these issues and provide a more efficacious system in the treatment of inner ear disease. This study assesses the potential of 3D printing (3DP) as a fabrication method for an implantable drug delivery system (DDS) to the inner ear. KEY FINDINGS: Three implantable designs of varying geometry were produced with fused deposition modelling (FDM) 3DP, each loaded with 0.25%, 0.5% and 1% levofloxacin; filaments prepared by hot-melt extrusion. Each implant was effective in providing sustained, therapeutic release of levofloxacin for at least 4 days and as such would be effective in therapeutic treatment of many common inner ear diseases, such as otitis media or Ménière's disease. CONCLUSIONS: This proof-of-concept research was successful in utilising FDM as a fabrication method for a DDS capable of providing prolonged release directly to the inner ear and highlights the viability of 3DP in the fabrication of an inner ear DDS.

3D Printing: an appealing technology for the manufacturing of solid oral dosage forms.

OBJECTIVES: The traditional manufacturing methods of solid oral dosage forms (SODFs) are reported to be time-consuming, highly expensive and not tailored to the patient's needs. Three-dimensional printing (3DP) is an innovative emerging technology that can help to overcome these issues. The aim of this review is to describe the most employed 3DP technologies, materials and the state of the art on 3DP SODFs. Characterization techniques of 3DP SODFs, challenges and regulatory issues are also discussed. KEY FINDINGS: The interest in the investigation of the suitability of 3DP as an alternative strategy for the fabrication of SODFs is growing. Different 3DP technologies and starting materials have been investigated for the development of SODFs. Numerous SODFs with complex geometries and composition, and with different release patterns, have been successfully manufactured via 3DP. Despite that, just one 3DP SODF has reached the market. SUMMARY: 3DP can be a promising alternative to the classical SODFs manufacturing methods. However, numerous technically and regulatory challenges still need to be addressed in order 3DP to be extensively used in the pharmaceutical sector.

Melt-extrusion 3D printing of resorbable levofloxacin-loaded meshes: Emerging strategy for urogynaecological applications.

Current surgical strategies for the treatment of pelvic floor dysfunctions involve the placement of a polypropylene mesh into the pelvic cavity. However, polypropylene meshes have proven to have inadequate mechanical properties and have been associated to the arising of severe complications, such as infections. Furthermore, currently employed manufacturing strategies are unable to produce compliant and customisable devices. In this work, polycaprolactone has been used to produce resorbable levofloxacin-loaded meshes in two different designs (90° and 45°) via melt-extrusion 3D printing. Drug-loaded meshes were produced using a levofloxacin concentration of 0.5% w/w. Drug loaded meshes were successfully produced with highly reproducible mechanical and physico-chemical properties. Tensile test results showed that drug-loaded 45° meshes possessed a mechanical behaviour close to that of the vaginal tissue (E ≃ 8.32 ± 1.85 MPa), even after 4 weeks of accelerated degradation. Meshes released 80% of the loaded levofloxacin in the first 3 days and were capable of producing an inhibitory effect against S. Aureus and E. coli bacterial strains with an inhibition zone equal to 12.8 ± 0.45 mm and 15.8 ± 0.45 mm respectively. Thus, the strategy adopted in this work holds great promise for the manufacturing of custom-made surgical meshes with antibacterial properties.

Optimization of Printing Parameters for Digital Light Processing 3D Printing of Hollow Microneedle Arrays.

3D printing is an emerging technology aiming towards personalized drug delivery, among many other applications. Microneedles (MN) are a viable method for transdermal drug delivery that is becoming more popular for delivery through the skin. However, there is a need for a faster fabrication process with potential for easily exploring different geometries of MNs. In the current study, a digital light processing (DLP) method of 3D printing for fabrication of hollow MN arrays using commercial UV curable resin was proposed. Print quality was optimised by assessing the effect of print angle on needle geometries. Mechanical testing of MN arrays was conducted using a texture analyser. Angled prints were found to produce prints with geometries closer to the CAD designs. Curing times were found to affect the mechanical strength of MNs, with arrays not breaking when subjected to 300 N of force but were bent. Overall, DLP process produced hollow MNs with good mechanical strength and depicts a viable, quick, and efficient method for the fabrication of hollow MN arrays.

Manufacturing of 3D-Printed Microfluidic Devices for the Synthesis of Drug-Loaded Liposomal Formulations.

Microfluidic technique has emerged as a promising tool for the production of stable and monodispersed nanoparticles (NPs). In particular, this work focuses on liposome production by microfluidics and on factors involved in determining liposome characteristics. Traditional fabrication techniques for microfluidic devices suffer from several disadvantages, such as multistep processing and expensive facilities. Three-dimensional printing (3DP) has been revolutionary for microfluidic device production, boasting facile and low-cost fabrication. In this study, microfluidic devices with innovative micromixing patterns were developed using fused deposition modelling (FDM) and liquid crystal display (LCD) printers. To date, this work is the first to study liposome production using LCD-printed microfluidic devices. The current study deals with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes with cholesterol (2:1) prepared using commercial and 3D-printed microfluidic devices. We evaluated the effect of microfluidic parameters, chip manufacturing, material, and channel design on liposomal formulation by analysing the size, PDI, and ζ-potential. Curcumin exhibits potent anticancer activity and it has been reported that curcumin-loaded liposomes formulated by microfluidics show enhanced encapsulation efficiency when compared with other reported systems. In this work, curcumal liposomes were produced using the developed microfluidic devices and particle sizing, ζ-potential, encapsulation efficiency, and in vitro release studies were performed at 37 °C.

Thermally reactive N-(2-hydroxypropyl)methacrylamide (HPMA) amphiphiles for drug solubilisation.

Thermally active polymers, can respond structurally to temperature changes, making them interesting as potential drug delivery vehicles. Polymers of N-(3-aminopropyl) methacrylamide hydrochloride (APMA) are cationic with primary amine groups in their structure, which have been explored in biomedical applications via post-polymerisation modifications. In this work, we synthesised amphiphilic APMA monomers using hydrophobic pendant groups via conjugation onto their primary amine group. The pendant groups chosen in this study were palmitoyl, dansyl and cholesteryl moieties. The amphiphilic monomers were subsequently copolymerized with N-(2-hydroxypropyl)methacrylamide (HPMA) using varied monomer feed ratios resulting in a thermo-responsive system. The ability of the resultant aggregates in aqueous solution to encapsulate and liberate model drugs (e.g., propofol, griseofulvin and prednisolone) was then determined. Our data showed that the HPMA based formulations were capable of loading the model drug molecules inside their lipophilic core; HPMA-co-(APMA-Dansyl 2%) exhibited the largest drug encapsulation ability. Subsequently, poly(ethylene glycol) (PEG) was incorporated into the intrinsic polymer structure. This resulted in a more rapid drug release profile, whereby 100% of griseofulvin and prednisolone were liberated after only 4 h, which was only 5% and 10% before the PEG inclusion, respectively. Similarly, propofol showed 70% liberation from the polymer aggregate after 24 h, compared with only 30% liberation pre-PEGylation. These studies give an insight into the potential of the HMPA based amphiphiles as thermally responsive cargo carrier/release systems which could be exploited in the delivery of poorly soluble drugs.

Antimicrobial 3D Printed Objects in the Fight Against Pandemics.

The uncharted nature of the COVID-19 pandemic has caused uncertainty globally, resulting in many health care professionals and key-workers being left with supply shortages in medical consumables and personal protective equipment, exacerbated by supply line issues and in some cases delays resulting from governmental policies. 3D printing (3DP) has played an important role in providing essential items to hospitals and the wider communities, such as visors, face masks, and ventilator components. This short-review article covers the potential of antimicrobial materials in the manufacturing of 3DP essential products, as an approach for added protection against pandemics.

3D printed estradiol-eluting urogynecological mesh implants: Influence of material and mesh geometry on their mechanical properties.

Current treatment for pelvic organ prolapse (POP) and stress urinary incontinence (SUI) involves transvaginal implantation of surgical mesh, conventionally made of polypropylene (PP). However, it has recently become apparent that the mechanical properties of PP are unsuitable, resulting in serious complications such as tissue erosion. In this study, thermoplastic polyurethane (TPU) was chosen as an alternative material, and hormone-loaded meshes were produced by fused deposition modelling (FDM). Filaments containing various concentrations (0%, 0.25%, 1%) of 17-ß-estradiol (E2) were prepared by hot-melt extrusion (HME) and were 3D printed into meshes with various geometries. The resulting meshes were characterised through a variety of instruments such as attenuated total reflection-Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), thermal analysis, fracture force and in vitro release studies. The results showed that E2 was homogeneously distributed throughout the TPU matrix. Moreover, the thermogravimetric analysis (TGA) showed degradation temperatures above those used during the FDM process, showing that the meshes can be produced below the degradation temperatures of the materials. The fracture force testing showed that material and mesh geometry influence mechanical properties, with TPU meshes appearing more elastic and therefore more suitable for pelvic floor repair than PP mesh. However, interestingly the mechanical properties of the TPU70 filament was not affected by the inclusion of E2. In addition, the 3D printed meshes showed a linear E2 release profile over a two weeks period, which can be modified according to the percentage of E2 added to the 3D printed construct. This proof of concept study demonstrates the potential of using FDM to create a new generation of safer mesh implants.

3D Printing of Pharmaceuticals and Drug Delivery Devices.

The process of 3D printing (3DP) was patented in 1986; however, the research in the field of 3DP did not become popular until the last decade. There has been an increasing research into the areas of 3DP for medical applications for fabricating prosthetics, bioprinting and pharmaceutics. This novel method allows the manufacture of dosage forms on demand, with modifications in the geometry and size resulting in changes to the release and dosage behaviour of the product. 3DP will allow wider adoption of personalised medicine due to the diversity and simplicity to change the design and dosage of the products, allowing the devices to be designed specific to the individual with the ability to alternate the drugs added to the product. Personalisation also has the potential to decrease the common side effects associated with generic dosage forms. This Special Issue Editorial outlines the current innovative research surrounding the topic of 3DP, focusing on bioprinting and various types of 3DP on applications for drug delivery as well advantages and future directions in this field of research.

Fused Deposition Modeling as an Effective Tool for Anti-Infective Dialysis Catheter Fabrication.

Catheter-associated infections are a common complication that occurs in dialysis patients. Current strategies to prevent infection include catheter coatings containing heparin, pyrogallol, or silver nanoparticles, which all have an increased risk of causing resistance in bacteria. Therefore, a novel approach for manufacture, such as the use of additive manufacturing (AM), also known as three-dimensional (3D) printing, is required. Filaments were produced by extrusion using thermoplastic polyurethane (TPU) and tetracycline hydrochloride (TC) in various concentrations (e.g., 0, 0.25, 0.5, and 1%). The extruded filaments were used in a fused deposition modeling (FDM) 3D printer to print catheter constructs at varying concentrations. Release studies in phosphate-buffered saline, microbiology studies, thermal analysis, contact angle, attenuated total reflection-Fourier transform infrared, scanning electron microscopy, and X-ray microcomputer tomography (µCT) analysis were conducted on the printed catheters. The results suggested that TC was uniformly distributed within the TPU matrix. The microbiology testing of the catheters showed that devices containing TC had an inhibitory effect on the growth of Staphylococcus aureus NCTC 10788 bacteria. Catheters containing 1% TC maintained inhibitory effect after 10 day release studies. After an initial burst release in the first 24 h, there was a steady release of TC in all concentrations of catheters. 3D-printed antibiotic catheters were successfully printed with inhibitory effect on S. aureus bacteria. Finally, TC containing catheters showed resistance to S. aureus adherence to their surfaces when compared with catheters containing no TC. Catheters containing 1% of TC showed a bacterial adherence reduction of up to 99.97%. Accordingly, the incorporation of TC to TPU materials can be effectively used to prepare anti-infective catheters using FDM. This study highlights the potential for drug-impregnated medical devices to be created through AM.