3D-Printed Wearable Personalized Orthodontic Retainers for Sustained Release of Clonidine Hydrochloride.

Orthodontic retainers are wearable customizable medical devices for dental protection or alignment. Here, clonidine hydrochloride (CH)-loaded wearable personalized 3D printed orthodontic retainers were studied for local sustained-release of drugs. CH powders were mixed with PEG 4000, Tween 80, poly(lactic acid), and polycaprolactone. The mixture was hot-melt extruded to form a filament that was 3D printed to a customizable original orthodontic retainer with the fused deposition modeling (FDM) method. The original retainer showed a burst release of CH in the early stage of the dissolution process though a sustained release appeared in the late stage. The in vivo burst release of CH would lead to unexpected side effect. The original retainer was modified by coating with hydrophilic polymers or washing with buffered solutions to obtain the coated or washed retainer. The coated retainer still showed a burst release while the washed retainer showed an optimal sustained release. Many CH microparticles existed on the surface of original retainers according to the scanning electron microscopic image so that the burst release was unavoidable. The hydrophilic polymer coating method did not change the release profile because the polymer was also rapidly dissolved. However, most of the surface CH can be eliminated by washing so that the burst release dissappeared in the washed retainer. Furthermore, the simulated CH concentration-time profiles in the circulation of humans of the washed retainer showed the stable and appropriate drug levels for more than 3 days. Wearable personalized 3D printed drug-loaded orthodontic retainers are a promising drug-device for sustained release of drugs.

Intratumorally Injected Photothermal Agent-Loaded Photodynamic Nanocarriers for Ablation of Orthotopic Melanoma and Breast Cancer.

Traditional chemotherapy of cancers may lead to serious adverse reactions due to little drug distribution in tumors. Here, a combination of photothermal therapy (PTT) and photodynamic therapy (PDT) was used for local treatment of orthotopic melanoma and breast cancer via intratumoral (i.t.) injection of photothermal agent-loaded photodynamic nanocarriers. A hydrophobic derivative of indocyanine green, DCC, was synthesized and entrapped into a pH-sensitive photosensitizer-core copolymer, PDCZP, to form DCC@PDCZP. The nanocarriers showed remarkable fluorescence, high singlet oxygen quantum yields, and a strong photothermal effect. Flow cytometry suggested that the nanocarriers were efficiently internalized by cancer cells. Near infrared thermal imaging and fluorescence self-imaging showed that the i.t. injected DCC@PDCZP mainly remained in the tumors, but the intravenous (i.v.) nanocarriers were distributed a little. One i.t. injection of DCC@PDCZP was enough to ablate the orthotopic B16-F10 and 4T1 mouse tumors under 830 and 660 nm irradiation at 4 h postinjection. More importantly, no local recurrences were found, though swabs were formed at 9 days post-treatment. The major anticancer mechanisms included improvement of cancer cell necrosis due to hyperthermia, inhibition of neovascularization, and enhancement of cell apoptosis. The i.t. injection of PTT/PDT nanoformulations is thus a promising local treatment of superficial tumors.

3D printed mold-based capsaicin candy for the treatment of oral ulcer.

Oral ulcer is one common mucosal disease with high prevalence. Here, capsaicin candies were prepared based on the stereolithographically (SLA) 3D printed molds. The molds can be freely designed depending on the needs of patients, involving symmetric shapes (e.g., round, four-lead clover and cube), asymmetric shapes (e.g., car) and various color (e.g., blue, red and yellow). A two-part-combined mold was filled with the xylitol-based material and separated to obtain hard candies. Capsaicin was amorphous in the candies according to the differential scanning calorimetry and X-ray diffraction. Poloxamer 188 improved the release of capsaicin from the candies. Rat oral ulcer models were established on the tongue with phenol liquids. The blank candy, 0.05% capsaicin candy and dexamethasone were respectively administered on the ulcer once daily. On Day 7, a healing rate of 97.8% was achieved by the capsaicin candy, much higher than those in the other groups. Moreover, the blank candy also showed the remarkable ulcer healing effect due to the presence of xylitol and poloxamer. Capsaicin remarkably enhanced the reepithelialization of ulcer tissues and showed strong anti-inflammatory effect by reducing the expressions of THF-α and IL-6. 3D printing-based capsaicin candies provide an interesting therapeutic choice for the people with oral ulcer.

Combination of 3D printing technologies and compressed tablets for preparation of riboflavin floating tablet-in-device (TiD) systems.

Gastric floating tablets are a multifunctional dosage form with the merits of long-term gastric retention, sustained release and improved bioavailability though floating time and sustained release are usually not satisfied. Here we designed a novel gastric floating system by combining compressed tablets with 3D printed devices, wherein a riboflavin tablet was filled into a device. The table-filled device can be called a tablet-in-device (TiD) system. Commercial poly(lactic acid) filaments were used for fused deposition modeling (FDM) 3D printing of the body and cap of the device. Four types of TiD systems were prepared. The basic structures of them involved non-net, centrally symmetric double-net (including a peripheral sealed air-filled chamber and a centric net-on-both-sides chamber), single-net (including a sealed air-filled chamber on the top side and a net-on-one-side chamber on the bottom side), and eccentric double-net (including an eccentric net-on-both-sides chamber and an air-filled chamber). They were exquisitely designed after precise calculations of every chamber parameters according to the buoyant principle. All of them showed good floating ability, although only the latter two TiD systems were selected due to appropriate drug release. Compressed riboflavin tablets, consisting of riboflavin, lactose, hydroxypropyl methylcellulose (HPMC) and magnesium stearate, were prepared with the direct compaction method. All the tablets showed rapid drug release though the release was highly hindered by the devices in the TiD systems due to the barrier effect of devices and the tablet slurry formation. The single-net and double-net TiD systems achieved the cumulative release of 41% and 62% at 72 h, respectively, along with simultaneously well floating. In vivo long-term (>72 h) gastric floating function of TiD systems was further demonstrated on the rabbit models by the CT investigation. TiD systems are appropriate for oral administration of drugs with super long-term floating and controlled release in the gastric route.