Fabrication of 3D-Printed Contact Lens Composed of Polyethylene Glycol Diacrylate for Controlled Release of Azithromycin.

Since three-dimensional (3D)-printed tablets were approved by the United States Food and Drug Administration (FDA), 3D printing technology has garnered increasing interest for the fabrication of medical and pharmaceutical devices. With various dosing devices being designed for manufacture by 3D printing, 3D-printed ophthalmic formulations to release drugs have been one such target of investigation. In the current study, 3D-printed contact lenses designed for the controlled release of the antibiotic azithromycin were produced by vat photopolymerization, and the effect of the printer ink composition and a second curing process was investigated. The azithromycin-loaded contact lenses were composed of the cross-linking reagent polyethylene glycol diacrylate (PEGDA), PEG 400 as a solvent, a photoinitiator, and azithromycin. The 3D-printed contact lenses were fabricated successfully, and formulations with lower PEGDA concentrations produced thicker lenses. The mechanical strength of the PEGDA-based contact lenses was dependent on the amount of PEGDA and was improved by a second curing process. Drug release from 3D-printed contact lenses was reduced in the samples with a second curing process. The azithromycin-loaded contact lenses exhibited antimicrobial effects in vitro for both Gram-positive and -negative bacteria. These results suggest that 3D-printed contact lenses containing antibiotics are an effective model for treating eye infections by controlling drug release.

Lyophilized ophthalmologic patches as novel corneal drug formulations using a semi-solid extrusion 3D printer.

3D printing technology is a novel and practical approach for producing unique and complex industrial and medical objects. In the pharmaceutical field, the approval of 3D printed tablets by the US Food and Drug Administration has led to other 3D printed drug formulations and dosage forms being proposed and investigated. Here, we report novel ophthalmologic patches for controlled drug release fabricated using a semi-solid material extrusion-type 3D printer. The patch-shaped objects were 3D printed using hydrogel-based printer inks composed of hypromellose (HPMC), sugar alcohols (mannitol, xylitol), and drugs, then freeze-dried. The viscous properties of the printer inks and patches were dependent on the HPMC and sugar alcohol concentrations. Then, the physical properties, surface structure, water uptake, antimicrobial activity, and drug release profile of lyophilized patches were characterized. Lyophilized ophthalmologic patches with different dosages and patterns were fabricated as models of personalized treatments prepared in hospitals. Then, ophthalmologic patches containing multiple drugs were fabricated using commercially available eye drop formulations. The current study indicates that 3D printing is applicable to producing novel dosage forms because its high flexibility allows the preparation of patient-tailored dosages in a clinical setting.

Developing spray-freeze-dried particles containing a hyaluronic acid-coated liposome-protamine-DNA complex for pulmonary inhalation.

The liposome-protamine-DNA complex (LPD) is an effective cationic carrier of various nucleic acid constructs such as plasmid DNA and small interfering RNA (siRNA). Hyaluronic acid coated on LPD (LPDH) reduces cytotoxicity and maintains the silencing effect of LPD-encapsulated siRNA. Herein, we aim to develop LPD- or LPDH-containing spray-freeze-dried particles (SFDPs) for therapeutic delivery of siRNA to the lungs. LPD- or LPDH-containing SFDPs (LPD- or LPDH-SFDPs) were synthesized and their structure and function as gene carriers were evaluated using physical and biological methods. The particle size of LPDH, but not of LPD, was constant after re-dispersal from the SFDPs and the amount of siRNA encapsulated in LPDH was larger than that in LPD after re-dispersal from the SFDPs. The in vitro pulmonary inhalation properties of LPDH-SFDPs and LPD-SFDPs were almost the same. The cytotoxicity of LPDH-SFDPs in human umbilical vein endothelial cells (HUVEC) was greatly decreased compared with that of LPD-SFDPs. In addition, Bcl-2 siRNA in LPDH-SFDPs had a significant gene silencing effect in human lung cancer cells (A549), whereas Bcl-2 siRNA in LPD-SFDPs had little effect. These results indicate that compared with LPD, LPDH is more useful for developing SFDPs for siRNA pulmonary inhalation.

Fabrication of Muco-Adhesive Oral Films by the 3D Printing of Hydroxypropyl Methylcellulose-Based Catechin-Loaded Formulations.

Pharmaceutical applications of three dimensional (3D) printing technology are increasing following the approval of 3D-printed tablets by the U.S. Food and Drug Administration. Semi-solid extrusion-type 3D printers are used to 3D print hydrogel- and paste-based materials. We previously developed tablet formulations for semi-solid extrusion-type 3D bioprinters. In the present study, we extended our study to the preparation of muco-adhesive oral film formulations to 3D bioprint mouth ulcer pharmaceuticals. We focused on hydroxypropyl methylcellulose (HPMC)-based catechin (model drug)-loaded hydrogel formulations and found that the viscosity of a hydrogel formulation is dependent on the HPMC concentration, and that viscosity is important for facile 3D printing. HPMC-based films were prepared using two different drying methods (air drying and freeze drying). The films exhibited different drug dissolution profiles, and increasing the amount of HPMC in the film delayed drug dissolution. The fabrication of HPMC-based catechin-loaded films with different shapes provides a model of individualized, on-demand pharmaceuticals. Our results support the flexible application of 3D bioprinters (semi-solid extrusion-type 3D printers) for preparing film formulations.

Fabrication of Naftopidil-Loaded Tablets Using a Semisolid Extrusion-Type 3D Printer and the Characteristics of the Printed Hydrogel and Resulting Tablets.

The production of three-dimensional (3D)-printed drugs holds promise for future personalized medicine. Here, we prepared tablets containing naftopidil as a model drug using a semisolid extrusion-type 3D bioprinter applicable for tissue engineering. A hydrogel is typically used as the printer ink for 3D bioprinters, and we incorporated various amounts of hydroxypropyl methylcellulose hydrogel (30%, 40%, and 50% gel) into the printer ink. The resulting 3D-printed gel product was dried to obtain tablets. The rheological properties of the printer ink changed as its composition was changed, and tablets were prepared successfully from several formulations. Increasing the amount of hydroxypropyl methylcellulose hydrogel in the printer ink led to delayed drug dissolution, decreased weight, and decreased hardness of the tablets. Delayed drug dissolution was also observed when the amount of disintegrating agent typically used in powder compression tablets was increased in the ink, and increasing the incorporated amount of the disintegrating agent crospovidone increased the hardness of the tablets. Our results will provide useful information for the preparation of tablets using semisolid extrusion-type 3D printers.

Activation of sensory neurons contributes to reduce spinal cord injury in rats.

We previously demonstrated that activation of sensory neurons increases endothelial prostaglandin I(2) (PGI(2)) production by releasing calcitonin gene-related peptide (CGRP). Since PGI(2) reduces post-traumatic spinal cord injury (SCI) by inhibiting tumor necrosis factor (TNF) production, activation of sensory neurons in the spinal cord tissue may ameliorate spinal cord injury. This study examines these possibilities using rat models of compression trauma-induced SCI. Both SB366791, a specific vanilloid receptor antagonist, and CGRP (8-37), a CGRP receptor antagonist, significantly inhibited trauma-induced increases in spinal cord tissue 6-keto-PGF(1alpha) levels. SB366791, CGRP (8-37) and indomethacin (IM) enhanced increases in spinal cord tissue TNF levels at 2h after trauma and exacerbated motor disturbances. Administration of CGRP significantly reduced motor disturbances and inhibited increases in spinal cord tissue TNF levels through enhancement of increases in tissue levels of 6-keto-PGF(1alpha). These observations strongly suggest that activation of sensory neurons might ameliorate compression trauma-induced SCI, inhibiting TNF production through enhancement of endothelial PGI(2) production. Thus, although the spinal cord sensory neurons function as nociceptive neurons, they could also be critically involved in the cytoprotective system that attenuates SCI development and, thus, pharmacological stimulation of spinal cord sensory neurons might contribute to reduce spinal cord injury.

Unicortical transverse osteochondral fracture of the patella: a case report.

Chondral lesions are relatively common and they usually occur as a result of high energy trauma. Chondral fractures of the patella ordinarily occur during an acute dislocation of the patella. Patellar chondral fractures without either a dislocation or a patella fracture are extremely rare. We have treated a 25-year-old male who had a unicortical transverse osteochondral fracture of the patella without a dislocation which was produced by high energy trauma. Chondral fractures of the patella are often overlooked because they are difficult to detect on plain radiographs. A persistent cartilaginous irregularity from either a chondral or osteochondral fracture may lead to the development of secondary osteoarthrosis. In this case, restoration of the articular surface was achieved by elevation of the compressed osteochondral fragment. This case demonstrates that understanding the mechanism of injury can be helpful in the treatment of osteochondral lesions.

The assessment of three methods to verify tracheal tube placement in the emergency setting.

We studied prospectively the reliability of clinical methods, end-tidal carbon dioxide (ETCO(2)) detection, and the esophageal detector device (EDD) for verifying tracheal intubation in 137 adult patients in the emergency department. Immediately after intubation, the tracheal tube position was tested by the EDD and ETCO(2) monitor, followed by auscultation of the chest. The views obtained at laryngoscopy were classified according to the Cormack grade. Of the 13 esophageal intubations that occurred, one false-positive result occurred in the EDD test and auscultation. In the non-cardiac arrest patients (n=56), auscultation, the ETCO(2), and EDD test correctly identified 89.3, 98.2*, and 94.6%* of tracheal intubations, respectively (*, P<0.05 vs. the cardiac arrest patients). In the cardiac arrest patients (n=81), auscultation, the ETCO(2), and the EDD tests correctly identified 92.6**, 67.9, and 75.3% of tracheal intubations, respectively (**, P<0.05 vs. EDD and ETCO(2)). The frequencies of Cormack grade 1 or 2 were 83.9% in the non-cardiac arrest, and 95.1% in the cardiac arrest patients. In conclusion, the ETCO(2) monitor is the most reliable method for verifying tracheal intubation in non-cardiac arrest patients. During cardiac arrest and cardiopulmonary resuscitation, however, negative results by the ETCO(2) or the EDD are not uncommon, and clinical methods are superior to the use of these devices.