Islet cell spheroids produced by a thermally sensitive scaffold: a new diabetes treatment.

The primary issues in treating type 1 diabetes mellitus (T1DM) through the transplantation of healthy islets or islet ß-cells are graft rejection and a lack of available donors. Currently, the majority of approaches use cell encapsulation technology and transplant replacement cells that can release insulin to address transplant rejection and donor shortages. However, existing encapsulation materials merely serve as carriers for islet cell growth. A new treatment approach for T1DM could be developed by creating a smart responsive material that encourages the formation of islet cell spheroids to replicate their 3D connections in vivo and controls the release of insulin aggregates. In this study, we used microfluidics to create thermally sensitive porous scaffolds made of poly(N-isopropyl acrylamide)/graphene oxide (PNIPAM/GO). The material was carefully shrunk under near-infrared light, enriched with mouse insulinoma pancreatic ß cells (ß-TC-6 cells), encapsulated, and cultivated to form 3D cell spheroids. The controlled contraction of the thermally responsive porous scaffold regulated insulin release from the spheroids, demonstrated using the glucose-stimulated insulin release assay (GSIS), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence assay. Eventually, implantation of the spheroids into C57BL/6 N diabetic mice enhanced the therapeutic effect, potentially offering a novel approach to the management of T1DM.

Monoclonal Antibody Delivery Using 3D Printed Biobased Hollow µNe3dle Arrays for the Treatment of Osteoporosis.

Transdermal microneedles have demonstrated promising potential as an alternative to typical drug administration routes for the treatment of various diseases. As microneedles offer lower administration burden with enhanced patient adherence and reduced ecological footprint, there is a need for further exploitation of microneedle devices. One of the main objectives of this work was to initially develop an innovative biobased photocurable resin with high biobased carbon content comprising isobornyl acrylate (IBA) and pentaerythritol tetraacrylate blends (50:50 wt/wt). The optimization of the printing and curing process resulted in µNe3dle arrays with durable mechanical properties and piercing capacity. Another objective of the work was to employ the 3D printed hollow µNe3dles for the treatment of osteoporosis in vivo. The 3D printed µNe3dle arrays were used to administer denosumab (Dmab), a monoclonal antibody, to osteoporotic mice, and the serum concentrations of critical bone minerals were monitored for six months to assess recovery. It was found that the Dmab administered by the 3D printed µNe3dles showed fast in vitro rates and induced an enhanced therapeutic effect in restoring bone-related minerals compared to subcutaneous injections. The findings of this study introduce a novel green approach with a low ecological footprint for 3D printing of biobased µNe3dles, which can be tailored to improve clinical outcomes and patient compliance for chronic diseases.

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.

Screening, Synthesis, and Characterization of a More Rapidly Dissolving Celecoxib Crystal Form.

The prevalence of poor solubility in active pharmaceutical ingredients (APIs) such as celecoxib (CEL) is a major bottleneck in the pharmaceutical industry, leading to a low concentration gradient, poor passive diffusion, and in vivo failure. This study presents the synthesis and characterization of a new cocrystal of the API CEL. CEL is a nonsteroidal anti-inflammatory drug used for the treatment of osteoarthritis and rheumatoid arthritis. Computational screening was completed for CEL against a large library of generally recognized as safe (GRAS) coformers, based on molecular complementarity and hydrogen bond propensity (HBP). The generated list of 17 coformers with a likelihood for cocrystallization with CEL were experimentally screened using four techniques: liquid-assisted grinding (LAG), solvent evaporation (SE), gas antisolvent crystallization (GAS), and supercritical enhanced atomization (SEA). One new crystalline form was isolated, employing the liquid coformer N-ethylacetamide (NEA). This novel form, celecoxib-di-N-ethylacetamide (CEL·2NEA), was characterized by a variety of different techniques. The crystal structure was determined through single-crystal X-ray diffraction. Both NEA molecules are evolved from the crystal structure at a desolvation temperature of approximately 65 °C. The CEL·2NEA cocrystal exhibited a dissolution rate, with more than a twofold improvement in comparison to as-received CEL after only 15 min.

An Advanced Twin-Screw Granulation Technology: The use of Non-Volatile Solvents with High Solubilizing Capacity.

PURPOSE: Twin-screw wet granulation (TSWG) is a manufacturing process that offers several advantages for the processing of water-insoluble active pharmaceutical ingredients (APIs) and has been used for increasing the solubility and dissolution rates. Here we introduce a novel TSWG approach with reduced downstream processing steps by using non-volatile solvents as granulating binders. METHODS: Herein, TSWG was carried out using Transcutol a non-volatile protic solvent as a granulating binder and dissolution enhancer of ibuprofen (IBU) blends with cellulose polymer grades (Pharmacoat® 603, Affinisol™, and AQOAT®). RESULTS: The physicochemical characterisation of the produced granules showed excellent powder flow and the complete transformation of IBU into the amorphous state. Dissolution studies presented immediate release rates for all IBU formulations due to the high drug-polymer miscibility and the Transcutol solubilising capacity. CONCLUSIONS: Overall, the study demonstrated an innovative approach for the development of extruded granules by processing water-insoluble APIs with non-volatile solvents for enhanced dissolution rates at high drug loadings.

In Vitro Profile of Hydrocortisone Release from Three-Dimensionally Printed Paediatric Mini-Tablets.

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire® 44/14 and Precirol® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages.

Personalised oral dosage forms using an ultra-compact tablet press at the point of care.

Over the last 10 years there is an increasing need for the design of personalised medicines at the point of care (PoC) that meet the specific needs of individual patients. A plethora of technologies has been introduced for making affordable personalised pharmaceutical products, which however, do not address manufacturing and regulatory challenges. Here we introduce a novel ultra-compact tablet press which was used for the design and compression of rosuvastatin-aspirin and amiloride-lysonipril bilayer tablets respectively. By applying precision dosing, it was feasible to manufacture tablets of different dose strengths and control features such as hardness, friability and disintegration times. The compaction of on-demand personalised multidrug pills that meet quality standards could revolutionised the treatment of patients at the point of care.

Exosome-like genistein-loaded nanoparticles developed by thin-film hydration and 3D-printed Tesla microfluidic chip: A comparative study.

Exosomes are naturally derived information carriers that present interest as drug delivery systems. However, their vague cargo and isolation difficulties hinder their use in clinical practice. To overcome these limitations, we developed exosome-like nanoparticles, consisted of the main lipids of exosomes, using two distinct methods: thin-film hydration and 3D-printed microfluidics. Our novel microfluidic device, fabricated through digital light processing printing, demonstrated a favorable architecture to produce exosome-like nanoparticles. We compared these two techniques by analyzing the physicochemical characteristics (size, size distribution, and ζ-potential) of both unloaded and genistein-loaded exosome-like nanoparticles, using dynamic and electrophoretic light scattering. Our findings revealed that the presence of small lipophilic molecules, cholesterol and/or genistein, influenced the characteristics of the final formulations differently based on the development approach. Regardless of the initial differences of the formulations, all exosome-like nanoparticles, whether loaded with genistein or not, exhibited remarkable colloidal stability over time. Furthermore, an encapsulation efficiency of over 87% for genistein was achieved in all cases. Additionally, thermal analysis uncovered the presence of metastable phases within the membranes, which could impact the drug delivery efficiency. In summary, this study provides a comprehensive comparison between conventional and innovative methods for producing complex liposomal nanosystems, exemplified by exosome-like nanoparticles.

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.

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 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.

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.

In vivo evaluation of nanostructured lipid carrier systems (NLCs) in mice bearing prostate cancer tumours.

Nanostructure lipid carriers (NLCs) were developed for the delivery of curmumin (CRN), a potent anticancer agent with low bioavailability, for the treatment of prostate cancer. NLCs prepared using high pressure homogenization (HPH) with around 150 nm particle size, - 40 V ζ-potential and excellent long-term stability. Cellular uptake of CRN-SLN showed nanoparticle localization in the cytoplasm around the nucleus. CRN-NLCs were assessed using flow cytometry and found to cause early and late apoptotic events at 100 µg/ml CRN concentrations. CRN-NLC nanoparticles were administrated to nude mice with LNCaP prostate cancer xenografts and demonstrated substantial tumour volume suppression (40%) with no weight loss compared to pure CRN (ethanolic solution). Overall, NLCs were proved a suitable carrier for passive drug delivery and cancer treatment.

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.

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.

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.

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.

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.