3D Printed Flavor-Rich Chewable Pediatric Tablets Fabricated Using Microextrusion for Point of Care Applications.

Over the past few years, 3D printing technologies have gained interest in the development of medicinal products for personalized use at the point of care. The printing of drug products offers personalization and flexibility in dose, shape/design, and flavor, potentially enhancing acceptability in pediatric populations. In this study, we present the design and development of ibuprofen (IBU) chewable flavor-rich personalized dosage forms by using microextrusion for the processing of powdered blends. The optimization processing parameters such as applied pneumatic pressure and temperature resulted in high quality printable tablets of various designs with a glossy appearance. Physicochemical characterization of the printed dosages revealed that IBU was molecularly dispersed in the methacrylate polymer matrix and the formation of H bonding. A panelist's study demonstrated excellent taste masking and aroma evaluation when using strawberry and orange flavors. Dissolution studies showed very fast IBU dissolution rates of more than 80% within the first 10 min in acidic media. Microextrusion is a 3D printing technology that can be effectively used to generate pediatric patient centric dosage forms at the point of care.

Sustained release of 3D printed bupropion hydrochloride tablets bearing Braille imprints for the visually impaired.

3D printing has been introduced as a novel approach for the design of personalized dosage forms and support patient groups with special needs that require additional assistance for enhanced medication adherence. In this study liquid crystal display (LCD) is introduced for the development of sustained release bupropion.HCl printed tablets. The optimization of printing hydrogel inks was combined with the display of Braille patterns on the tablet surface for blind or visually impaired patients. Due to the high printing accuracy, the Braille patterns could be verified by blind patients and provide the required information. Further characterization revealed the presence of BUP in amorphous state within the photopolymerized resins. The selection of poly(ethylene glycol) (PEG)-diacrylate (PEGDA) of different molecular weights and the presence of surfactants or solubilizers disrupted the resin photopolymerization, thus controlling the BUP dissolution rates. A small batch scale-up study demonstrated the capacity of LCD to print rapidly a notable number of tablets within 24 min.

3D-Printed Melatonin Tablets with Braille Motifs for the Visually Impaired.

An innovative approach for creating customized dosage forms and supporting patient populations with specific requirements who need additional support to improve drug adherence is 3D printing. This work introduces liquid crystal display (LCD) 3D printing as a means of developing melatonin (MLT) tablets. For patients who are blind or visually challenged, Braille patterns were displayed on the tablet surface in addition to the optimization of printing hydrogel inks. Owing to the great printing accuracy, blind patients could validate the Braille patterns that provided the required information. Upon further examination MLT was found to be present in the photopolymerized resins in an amorphous state. The choice of poly(ethylene glycol)-diacrylate (PEGDA) with varying molecular weights and the inclusion of surfactants or solubilizers interfered with the photopolymerization of the resin, hence controlling the rates of MLT dissolution towards the sought sustained release. Nuclear magnetic resonance (NMR) analysis showed that photopolymerization of the PEGDA resins in the printed dosage forms has taken place. A small batch scale-up investigation showed that LCDs could print a significant number of tablets quickly-about twenty-four minutes.

3D printing of LEGO® like designs with tailored release profiles for treatment of sleep disorder.

3D printed LEGO®-like designs are an attractive approach for the development of compartmental delivery systems due to their potential for dose personalisation through the customisation of drug release profiles. Additive manufacturing technologies such as Fused Deposition Modelling (FDM) are ideal for the printing of structures with complex geometries and various sizes. This study is a paradigm for the fabrication of 3D printed LEGO® -like tablets by altering the design of the modular units and the filament composition for the delivery of different drug substances. By using a combination of placebo and drug loaded compartments comprising of immediate release (hydroxypropyl cellulose) and pH dependant polymers (hypromellose acetate succinate) we were able to customise the release kinetics of melatonin and caffeine that can potentially be used for the treatment of sleep disorders. The LEGO® -like compartments were designed to achieve immediate release of melatonin followed by variable lag times and controlled release of caffeine.

Three-Dimensionally Printed Vaginal Rings: Perceptions of Women and Gynecologists in a Cross-Sectional Survey.

Three-dimensional printing technologies can be implemented for the fabrication of personalized vaginal rings (VRs) as an alternative approach to traditional manufacturing. Although several studies have demonstrated the potential of additive manufacturing, there is a lack of knowledge concerning the opinions of patients and clinicians. This study aimed to investigate the perception of women and gynecologists regarding VRs with personalized shapes. The devices were printed with different designs (traditional, "Y", "M", and flat circle) by Fused Deposition Modeling for a cross-sectional survey with 155 participants. Their anticipated opinion was assessed through a questionnaire after a visual/tactile analysis of the VRs. The findings revealed that most women would feel comfortable using some of the 3D-printed VR designs and demonstrated good acceptability for the traditional and two innovative designs. However, women presented multiple preferences when the actual geometry was assessed, which directly related to their age, previous use of the vaginal route, and perception of comfort. In turn, gynecologists favored prescribing traditional and flat circle designs. Overall, although there was a difference in the perception between women and gynecologists, they had a positive opinion of the 3D-printed VRs. Finally, the personalized VRs could lead to an increase in therapeutic adherence, by meeting women's preferences.

3D Printing of Personalised Carvedilol Tablets Using Selective Laser Sintering.

Selective laser sintering (SLS) has drawn attention for the fabrication of three-dimensional oral dosage forms due to the plurality of drug formulations that can be processed. The aim of this work was to employ SLS with a CO2 laser for the manufacturing of carvedilol personalised dosage forms of various strengths. Carvedilol (CVD) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) blends of various ratios were sintered to produce CVD tablets of 3.125, 6.25, and 12.5 mg. The tuning of the SLS processing laser intensity parameter improved printability and impacted the tablet hardness, friability, CVD dissolution rate, and the total amount of drug released. Physicochemical characterization showed the presence of CVD in the amorphous state. X-ray micro-CT analysis demonstrated that the applied CO2 intensity affected the total tablet porosity, which was reduced with increased laser intensity. The study demonstrated that SLS is a suitable technology for the development of personalised medicines that meet the required specifications and patient needs.

Development of 3D printed drug-eluting contact lenses.

OBJECTIVES: The aim of the work was to introduce 3D printing technology for the design and fabrication of drug-eluting contact lenses (DECL) for the treatment of glaucoma. The development of 3D printed lenses can effectively overcome drawbacks of existing approaches by using biocompatible medical grade polymers that provide sustained drug release of timolol maleate for extended periods. METHODS: Hot melt extrusion was coupled with fusion deposition modelling (FDM) to produce printable filaments of ethylene-vinyl acetate copolymer-polylactic acid blends at various ratios loaded with timolol maleate. Physicochemical and mechanical characterisation of the printed filaments was used to optimise the printing of the contact lenses. KEY FINDINGS: 3D printed lenses with an aperture (opening) and specified dimensions could be printed using FDM technology. The lenses presented a smooth surface with good printing resolution while providing sustained release of timolol maleate over 3 days. The findings of this study can be used for the development of personalised DECL in the future.

Personalised paediatric chewable Ibuprofen tablets fabricated using 3D micro-extrusion printing technology.

Three-dimensional (3D) printing is becoming an attractive technology for the design and development of personalized paediatric dosage forms with improved palatability. In this work micro-extrusion based printing was implemented for the fabrication of chewable paediatric ibuprofen (IBU) tablets by assessing a range of front runner polymers in taste masking. Due to the drug-polymer miscibility and the IBU plasticization effect, micro-extrusion was proved to be an ideal technology for processing the drug/polymer powder blends for the printing of paediatric dosage forms. The printed tablets presented high printing quality with reproducible layer thickness and a smooth surface. Due to the drug-polymer interactions induced during printing processing, IBU was found to form a glass solution confirmed by differential calorimetry (DSC) while H-bonding interactions were identified by confocal Raman mapping. IBU was also found to be uniformly distributed within the polymer matrices at molecular level. The tablet palatability was assessed by panellists and revealed excellent taste masking of the IBU's bitter taste. Overall micro-extrusion demonstrated promising processing capabilities of powder blends for rapid printing and development of personalised dosage forms.

Evaluation of 3D Printability and Biocompatibility of Microfluidic Resin for Fabrication of Solid Microneedles.

In this study, we have employed Digital Light Processing (DLP) printing technology for the fabrication of solid microneedle (MN) arrays. Several arrays with various geometries, such as cones, three-sided pyramids and four-sided pyramids, with different height to aspect ratios of 1:1, 2:1 and 3:1, were printed. Post-processing curing optimizations showed that optimal mechanical properties of the photocurable resin were obtained at 40 °C and 60 min. Ex vivo skin studies showed that piercing forces, penetration depth and penetration width were affected by the MN geometry and height to aspect ratio. Cone-shaped MNs required lower applied forces to penetrate skin and showed higher penetration depth with increasing height to aspect ratio, followed by three-sided and four-sided printed arrays. Cytotoxicity studies presented 84% cell viability of human fibroblasts after 2.5 h, suggesting the very good biocompatibility of the photocurable resin. Overall, DLP demonstrated excellent printing capacity and high resolution for a variety of MN designs.

Coupling of Fused Deposition Modeling and Inkjet Printing to Produce Drug Loaded 3D Printed Tablets.

In the current study, we have coupled Fused Deposition Modelling (FDM) for the fabrication of plain polyvinyl alcohol (PVA) tablets followed by dispensing of minoxidil ethanolic solutions using inkjet printing. The use of a drop-on-solid printing approach facilitates an accurate and reproducible process while it controls the deposition of the drug amounts. For the purpose of the study, the effect of the solvent was investigated and minoxidil ink solutions of ethanol 70% v/v (P70) or absolute ethanol (P100) were applied on the plain PVA tablets. Physicochemical characterization showed that solvent miscibility with the polymer substrate plays a key role and can lead to the formation of drug crystals on the surface or drug absorption in the polymer matrix. The produced minoxidil tablets showed sustained release profiles or initial bursts strongly affected by the solvent grade used for dispensing the required dose on drug loaded 3D printed tablets. This paradigm demonstrates that the coupling of FDM and inkjet printing technologies could be used for rapid development of personalized dosage forms.

3D Bioprinting of Complex, Cell-laden Alginate Constructs.

Biofabrication has been receiving a great deal of attention in tissue engineering and regenerative medicine either by manual or automated processes. Different automated biofabrication techniques have been used to produce cell-laden alginate hydrogel structures, especially bioprinting approaches. These approaches have been limited to 2D or simple 3D structures, however. In this chapter, a novel bioprinting technique is disclosed for the production of more complex alginate hydrogel structures. This was achieved by dividing the alginate hydrogel cross-linking process into three stages: primary calcium ion cross-linking for printability of the gel, secondary calcium ion cross-linking for rigidity of the alginate hydrogel immediately after printing, and tertiary barium ion cross-linking for the long-term stability of the alginate hydrogel in the culture medium.

3D printing advances in the development of stents.

3D printing technologies have found several applications within the biomedical sector including in the fabrication of medical devices, advanced visualization, diagnosis planning and simulation of surgical procedures. One of the areas in which of 3D printing is anticipated to revolutionised is the manufacturing of implantable bioresorbable drug-eluting scaffolds (stents). The ability to customize and create personalised tailor-made bioresorbable scaffolds has the potential to help solve many of the challenges associated with stenting, such as inappropriate stent sizing and design, abolish late stent thrombosis and help artery growth; 3D printing offers a rapid prototyping and effective method of producing stents making customization of designs feasible. This review provides an overview of the subjects and summarizes the latest research in the 3D printing technologies employed for the design and fabrication of bioresorbable stents including materials with the required printable and mechanical properties. Finally, we present a regulatory perspective on the development and engineering of 3D printed implantable stents.

Investigation on hot melt extrusion and prediction on 3D printability of pharmaceutical grade polymers.

The development of printable filaments has been identified as a critical aspect for the processing of pharmaceutical grade polymers and the fabrication of oral solid dosage forms. In this study a range of plain and drug loaded polymers were investigated and assessed for their printability in comparison to commercial filaments. Physicochemical characterizations of the polymers included differential scanning calorimetry (DSC) thermogravimetric analysis (TGA) and rheology were studied prior to Hot Melt Extrusion processing for the filament fabrication. A texture analyser was used to study the filament mechanical properties in order to derive the maximum tensile strength, Young's Modulus and elongation at break. Principal component analysis was used to compare the printability of the polymer and to identify the contribution of each mechanical property. The analysis showed that maximum tensile strength with a threshold between 15 and 20 MPa is the most critical property for the prediction of the printability. Furthermore, printable filaments were processed using Fusion Deposition Modelling technology and optimal printing parameters were identified. The study demonstrated that the prediction of filament printability is feasible by evaluating the mechanical properties.

Personalised Tasted Masked Chewable 3D Printed Fruit-Chews for Paediatric Patients.

The development of personalised paediatric dosage forms using 3D printing technologies has gained significant interest over the last few years. In the current study extruded filaments of the highly bitter Diphenhydramine Hydrochloride (DPH) were fabricated by using suitable hydrophilic carries such as hydroxypropyl cellulose (Klucel ELFTM) and a non-ionic surfactant (Gelucire 48/16TM) combined with sweetener (Sucralose) and strawberry flavour grades. The thermoplastic filaments were used to print 3D fruit-chew designs by Fused Deposition Modelling (FDM) technology. Physicochemical characterisation confirmed the formation of glass solution where DPH was molecularly dispersed within the hydrophilic carriers. DPH was released rapidly from the 3D printed fruit-chew designs with >85% within the first 30 min. Trained panellists performed a full taste and sensory evaluation of the sweetener intensity and the strawberry aroma. The evaluation showed complete taste masking of the bitter DPH and revealed a synergistic effect of the sweetener and the strawberry flavour with enhanced sweet strawberry, fruity and aftertaste perception. The findings of the study can be used for the development of paediatric dosage forms with enhanced organoleptic properties, palatability and medication adherence.

Bioprinting and Preliminary Testing of Highly Reproducible Novel Bioink for Potential Skin Regeneration.

Three-dimensional (3D) bioprinting is considered as a novel approach in biofabricating cell-laden constructs that could potentially be used to promote skin regeneration following injury. In this study, a novel crosslinked chitosan (CH)-genipin (GE) bioink laden with keratinocyte and human dermal fibroblast cells was developed and printed successfully using an extruder-based bioprinter. By altering the composition and degree of CH-GE crosslinking, bioink printability was further assessed and compared with a commercial bioink. Rheological analysis showed that the viscosity of the optimised bioink was in a suitable range that facilitated reproducible and reliable printing by applying low pressures ranging from 20-40 kPa. The application of low printing pressures proved vital for viability of cells loaded within the bioinks. Further characterisation using MTT assay showed that cells were still viable within the printed construct at 93% despite the crosslinking, processing and after subjecting to physiological conditions for seven days. The morphological study of the printed cells showed that they were mobile within the bioink. Furthermore, the multi-layered 3D printed constructs demonstrated excellent self-supportive structures in a consistent manner.

Three-dimensional bioprinting of complex cell laden alginate hydrogel structures.

Different bioprinting techniques have been used to produce cell-laden alginate hydrogel structures, however these approaches have been limited to 2D or simple three-dimension (3D) structures. In this study, a new extrusion based bioprinting technique was developed to produce more complex alginate hydrogel structures. This was achieved by dividing the alginate hydrogel cross-linking process into three stages: primary calcium ion cross-linking for printability of the gel, secondary calcium cross-linking for rigidity of the alginate hydrogel immediately after printing and tertiary barium ion cross-linking for long-term stability of the alginate hydrogel in culture medium. Simple 3D structures including tubes were first printed to ensure the feasibility of the bioprinting technique and then complex 3D structures such as branched vascular structures were successfully printed. The static stiffness of the alginate hydrogel after printing was 20.18 ± 1.62 KPa which was rigid enough to sustain the integrity of the complex 3D alginate hydrogel structure during the printing. The addition of 60 mM barium chloride was found to significantly extend the stability of the cross-linked alginate hydrogel from 3 d to beyond 11 d without compromising the cellular viability. The results based on cell bioprinting suggested that viability of U87-MG cells was 93 ± 0.9% immediately after bioprinting and cell viability maintained above 88% ± 4.3% in the alginate hydrogel over the period of 11 d.