Bone formation around zirconia implants combined with rhBMP-2 gel in the canine mandible.

OBJECTIVE: The aim of this study was to estimate the effects of zirconia implants and recombinant human bone morphogenetic protein-2 (rhBMP-2) gel on the acceleration of local bone formation and osseointegration in the canine mandible. MATERIALS AND METHODS: Four groups of 48 implants with identical geometry were installed in the mandibles of beagle dogs: alumina-blasted zirconia implants applied with rhBMP-2, alumina-blasted zirconia implants applied with demineralized bone matrix (DBM), alumina-blasted zirconia implants, and resorbable blast media-treated titanium (Ti) implants. For the first two groups, zirconia implants were inserted after the surgical sites were filled with rhBMP-2 or DBM gel. For the other two groups, zirconia or Ti implants were installed with no adjunctive treatment. Fluorescent bone markers were administered to monitor bone remodeling at weeks 2, 4, and 5 postimplantation. After healing periods of 3 weeks and 6 weeks, the animals were sacrificed, and fluorescent microscopy, histology, and histomorphometric analyses were performed. RESULTS: Fluorescent microscopy showed that bone formation around the zirconia implants installed with rhBMP-2 gel was the most prominent at 2 weeks postimplantation, while the Ti implants acquired bone apposition mainly at week 5. No significant differences were found in bone area among the groups (P > 0.05). The zirconia implants showed similar bone-to-implant contact to the Ti implants. There were no significant differences in bone-to-implant contact between the zirconia implants with rhBMP-2 gel and those with DBM (P > 0.05). CONCLUSIONS: The zirconia implants with alumina-blasted surfaces may achieve osseointegration in much the same manner as the well-established Ti implants. The area influenced by rhBMP-2 gel, including the alveolar crest, may cause active remodeling and early bone formation.

Drug delivery by sonosensitive liposome and microbubble with acoustic-lens attached ultrasound: an in vivo feasibility study in a murine melanoma model.

Conventional chemotherapy methods have adverse off-target effects and low therapeutic efficiencies of drug release in target tumors. In this study, we proposed a combination therapy of doxorubicin (DOX)-loaded ultrasound (US)-sensitive liposomal nanocarriers (IMP301), microbubbles (MBs) under focused US exposure using convex acoustic lens-attached US (LENS) to tumor treatment. The therapeutic effects of each treatment in a murine melanoma model were evaluated using contrast-enhanced US (CEUS) and micro-computed tomography (micro-CT) imaging, bioluminescence and confocal microscopy imaging, and liquid chromatography-mass spectroscopy (LC/MS) analysis. Tumor-bearing mice were randomly assigned to one of the following groups: (1) G1: IMP301 only (n = 9); (2) G2: IMP301 + LENS (n = 9); (3) G3: IMP301 + MB + LENS (n = 9); (4) G4: DOXIL only (n = 9); and (5) G5: IMP301 without DOXIL group as a control group (n = 4). Ten days after tumor injection, tumor-bearing mice were treated according to each treatment strategy on 10th, 12th, and 14th days from the day of tumor injection. The CEUS images of the tumors in the murine melanoma model clearly showed increased echo signal intensity from MBs as resonant US scattering. The relative tumor volume of the G2 and G3 groups on the micro-CT imaging showed inhibited tumor growth than the reference baseline of the G5 group. DOX signals on bioluminescence and confocal microscopy imaging were mainly located at the tumor sites. LC/MS showed prominently higher intratumoral DOX concentration in the G3 group than in other treated groups. Therefore, this study effectively demonstrates the feasibility of the synergistic combination of IMP301, MBs, and LENS-application for tumor-targeted treatment. Thus, this study can enable efficient tumor-targeted treatment by combining therapy such as IMP301 + MBs + LENS-application.

Magnetic implants in vivo guiding sorafenib liver delivery by superparamagnetic solid lipid nanoparticles.

HYPOTHESIS: Solid lipid nanoparticles (SLNs), co-encapsulating superparamagnetic iron oxide nanoparticles and sorafenib, have been exploited for magnetic-guided drug delivery to the liver. Two different magnetic configurations, both comprising two small magnets, were under-skin implanted to investigate the effect of the magnetic field topology on the magnetic SLNP accumulation in liver tissues. A preliminary simulation analysis was performed to predict the magnetic field topography for each tested configuration. EXPERIMENTS: SLNs were prepared using a hot homogenization approach and characterized using complementary techniques. Their in vitro biological behavior was assessed in HepG-2 liver cancer cells; wild-type mice were used for the in vivo study. The magnet configuration that resulted in a higher magnetic targeting efficiency was investigated by evaluating the iron content in homogenated murine liver tissues. FINDINGS: SLNs, characterized by an average size smaller than 200 nm, retained their superparamagnetic behavior and relevant molecular resonance imaging properties as negative contrast agents. The evaluation of iron accumulation in the liver tissues was consistent with the magnetic induction profile of each magnet configuration, concurring with the results predicted by simulation analysis and obtained by measurements in living mice.

Preparation and in vivo evaluation of a highly skin- and nail-permeable efinaconazole topical formulation for enhanced treatment of onychomycosis.

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes-infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.

Development of finasteride polymer microspheres for systemic application in androgenic alopecia.

The use of finasteride for alleviating hair loss has been investigated, and it has been applied as an oral dose medication. However, due to the inconvenience of daily drug administration over long period of time, novel controllable finasteride delivery has been actively investigated. As a novel method of finasteride delivery, the development of finasteride­loaded microspheres for subcutaneous administration is becoming increasingly pharmaceutically important. Therefore, the present study aimed to use finasteride­loaded microspheres in a controlled manner in an attempt to overcome the limitations of the oral administration of finasteride and to cause fewer adverse effects. Finasteride­loaded microspheres containing poly(lactic­co­glycolic acid) and finasteride at a ratio of 4:1 were prepared, and a testosterone­induced androgenic alopecia mouse model was used. Following observation for 10 weeks, the percentage hair growth was 86.7% (total hair growth 60%, partial hair growth 26.7%) in the orally­applied finasteride­treated group as a positive control, and 93.3% (total hair growth 60%, partial hair growth 33.3%) in the finasteride­loaded microspheres­treated group. Serum dihydrotestosterone levels began to decrease at week 6 in the orally­applied finasteride­ and finasteride­loaded microsphere­treated groups. In addition, the finasteride­loaded microspheres­treated group exhibited similar follicular number, follicular length, anagen/telogen ratio and hair bulb diameter values to those of the orally­applied finasteride­treated group. Furthermore, the finasteride­loaded microspheres increased the activities of phosphoinositide 3­kinase/protein kinase B and Wnt/ß­catenin in relation to hair follicle cell growth signaling in mouse skin, and suppressed the apoptosis of hair follicle cells by reducing the expression of transforming growth factor­ß2 and caspase­3, which are indicators of apoptosis. In conclusion, the administration of a single injection of finasteride­loaded microspheres was effective in treating testosterone­induced alopecia. Furthermore, it led to equivalent hair growth effects when compared with orally­applied finasteride, thus revealing the possibility of effective treatment via different routes of administration.

Biostimulatory effects of polydioxanone, poly-d, l lactic acid, and polycaprolactone fillers in mouse model.

BACKGROUND: Numerous fillers are increasingly used for augmentation of volume loss and relaxation of facial wrinkles. Collagen stimulators are the latest next-generation dermal fillers that can induce neocollagenesis. To investigate biophysical characteristics, safety, and efficacy of newly developed polydioxanone (PDO) filler in comparison with poly-l lactic acid (PLLA) and polycaprolactone (PCL) fillers. METHODS: In vitro assay, morphology of particles, and rheological property of fillers were measured. A total of 24 female hairless mice (SKH1-Hrhr ) were randomly divided into three groups and injected with PDO, PLLA, or PCL fillers. Durability of fillers was assessed at 0, 3 days, and 1, 4, 8, 12 weeks after injection using folliscope and PRIMOS. To determine biocompatibility and neocollagenesis, histologic evaluation was performed at 1, 4, 8, and 12 weeks after injection. Efficacy was also evaluated based on skin surface roughness changes using PRIMOS in a hairless mouse photoaging model. RESULTS: In the particle morphology test, PDO microspheres had an irregular surface and were spherical and uniformly sized. PDO filler demonstrated similar neocollagenesis and inflammatory response to other collagen stimulators. PDO filler showed better biodegradability than PLLA and PCL fillers. In the hairless mouse photoaging model, there was a statistically significant decrease in skin surface roughness after PDO filler injection. CONCLUSIONS: Our data suggest that newly developed collagen stimulating PDO filler might be a safe and effective option for correction of volume loss and rejuvenation of photoaging skin.

Study on steric transition in asymmetrical flow field-flow fractionation and application to characterization of high-energy material.

In field-flow fractionation (FFF), there is the 'steric transition' phenomenon where the sample elution mode changes from the normal to steric/hyperlayer mode. Accurate analysis by FFF requires understanding of the steric transition phenomenon, particularly when the sample has a broad size distribution, for which the effect by combination of different modes may become complicated to interpret. In this study, the steric transition phenomenon in asymmetrical flow FFF (AF4) was studied using polystyrene (PS) latex beads. The retention ratio (R) gradually decreases as the particle size increases (normal mode) and reaches a minimum (Ri) at diameter around 0.5µm, after which R increases with increasing diameter (steric/hyperlayer mode). It was found that the size-based selectivity (Sd) tends to increase as the channel thickness (w) increases. The retention behavior of cyclo-1,3,5-trimethylene-2,4,6-trinitramine (commonly called 'research department explosive' (RDX)) particles in AF4 was investigated by varying experimental parameters including w and flow rates. AF4 showed a good reproducibility in size determination of RDX particles with the relative standard deviation of 4.1%. The reliability of separation obtained by AF4 was evaluated by transmission electron microscopy (TEM).

Nanoparticles modified by encapsulation of ligands with a long alkyl chain to affect multispecific and multimodal imaging.

UNLABELLED: The attachment of specific ligands to the surfaces of nanoparticles is important for medical and biologic imaging. However, covalent modification of nanoparticles has inherent problems in reproducibility because of many factors such as temperature, pH, concentration, and reaction time. Thus, we developed a method for modifying nanoparticles by encapsulation with specific ligand-conjugated amphiphiles. METHODS: We synthesized special amphiphiles with a hydrophilic head and a long single-alkyl chain, such as arginine-glycine-aspartic acid-C(18), mannose-C(18), lactose-C(18), and 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-C(18). And then we produced stable quantum dots (QDs) encapsulated with polysorbate 60 (a branched polyethylene glycol head with a C(18) tail) and the synthesized special amphiphiles. The prepared encapsulated QDs were subject to in vitro and in vivo animal biodistribution studies and small-animal PET studies to confirm their specific binding. RESULTS: The encapsulated QDs could specifically bind to target cells in vitro and in vivo and could be labeled with (68)Ga (a positron emitter) easily and with high efficiency. CONCLUSION: The nanoparticles encapsulated with special amphiphiles could provide a straightforward and novel imaging solution with multimodality and multispecificity.

A case of painful hemimasticatory spasm with masseter muscle hypertrophy responsive to botulinum toxin.

Hemimasticatory spasm (HMS) is a rare disorder of the trigeminal nerve characterized by paroxysmal involuntary contractions of the unilateral jaw-closing muscles. HMS has been frequently described in association with facial hemiatrophy or localized scleroderma. A 42-year-old female presented with involuntary paroxysmal spasms of the left face, of 6 months duration. Her lower face on the left was markedly hypertrophied without skin lesions. An electrophysiological study indicated that the masseter reflexes and masseteric silent period were attenuated on the affected side. Surface electromyography demonstrated irregular bursts of motor unit potentials at high frequencies up to 200 Hz. Magnetic resonance imaging of the head showed marked hypertrophy of the left masseter muscle. Biopsy of the hypertrophied masseter muscle was normal. Repeated local injections of botulinum toxin noticeably reduced the size of the hypertrophied muscle as well as improved the patient's symptoms.