Efficiency of a dexamethasone nanosuspension as an intratympanic injection for acute hearing loss.

Dexamethasone sodium phosphate (Dex-SP) is the most commonly used drug administered via intratympanic injection for the treatment of acute hearing loss, but its penetration efficiency into the inner ear is very low. To address this problem, we evaluated the possibility of administering dexamethasone nanosuspensions via intratympanic injection because hydrophobic drugs might be more effective in penetrating the inner ear. Three types of dexamethasone nanosuspensions were prepared; the dexamethasone nanoparticles in the three nanosuspensions were between approximately 250 and 350 nm in size. To compare the efficiency of Dex-SP and dexamethasone nanosuspension in delivering dexamethasone to the inner ear, the concentrations of dexamethasone in perilymph and cochlear tissues were compared by liquid chromatography-mass spectrometry. The dexamethasone nanosuspensions resulted in significantly higher drug concentrations in perilymph and cochlear tissues than Dex-SP at 6 h; interestingly, animals treated with nanosuspensions showed a 26-fold higher dexamethasone concentrations in their cochlear tissues than animals treated with Dex-SP. In addition, dexamethasone nanosuspension caused better glucocorticoid receptor phosphorylation than Dex-SP both in vitro and in vivo, and in the ototoxic animal model, the nanosuspension showed a significantly better hearing-protective effect against ototoxic drugs than Dex-SP. In the in vivo safety evaluation, the nanosuspension showed no toxicity at concentrations up to 20 mg/mL. In conclusion, a nanosuspension of dexamethasone was able to deliver dexamethasone to the cochlea very safely and efficiently and showed potential as a formula for intratympanic injection.

Overcoming the obstacles of current photodynamic therapy in tumors using nanoparticles.

Photodynamic therapy (PDT) has been applied in clinical treatment of tumors for a long time. However, insufficient supply of pivotal factors including photosensitizer (PS), light, and oxygen in tumor tissue dramatically reduces the therapeutic efficacy of PDT. Nanoparticles have received an influx of attention as drug carriers, and recent studies have demonstrated their promising potential to overcome the obstacles of PDT in tumor tissue. Physicochemical optimization for passive targeting, ligand modification for active targeting, and stimuli-responsive release achieved efficient delivery of PS to tumor tissue. Various trials using upconversion NPs, two-photon lasers, X-rays, and bioluminescence have provided clues for efficient methods of light delivery to deep tissue. Attempts have been made to overcome unfavorable tumor microenvironments via artificial oxygen generation, Fenton reaction, and combination with other chemical drugs. In this review, we introduce these creative approaches to addressing the hurdles facing PDT in tumors. In particular, the studies that have been validated in animal experiments are preferred in this review over proof-of-concept studies that were only performed in cells.

Optimized Combination of Photodynamic Therapy and Chemotherapy Using Gelatin Nanoparticles Containing Tirapazamine and Pheophorbide a.

In combination therapy, synergetic effects of drugs and their efficient delivery are essential. Herein, we screened 12 anticancer drugs for combination with photodynamic therapy (PDT) using pheophorbide a (Pba). On the basis of combination index (CI) values in cell viability tests, we selected tirapazamine (TPZ) and developed self-assembled gelatin nanoparticles (NPs) containing both Pba and TPZ. The resulting TPZ-Pba-NPs showed a synergetic effect to kill tumor cells because TPZ was activated under the hypoxic conditions that originated from the PDT with Pba and laser irradiation. After they were injected into tumor-bearing mice via the tail vein, TPZ-Pba-NPs showed 3.17-fold higher blood concentration and 4.12-fold higher accumulation in tumor tissue 3 and 24 h postinjection, respectively. Upon laser irradiation to tumor tissue, TPZ-Pba-NPs successfully suppressed tumor growth by efficient drug delivery and synergetic effects in vivo. These overall results suggest that in vitro screening of drugs based on CI values, mechanism studies in hypoxia, and real-time in vivo imaging are promising strategies in developing NPs for optimized combination therapy.

In vivo vocal fold augmentation using an injectable polyethylene glycol hydrogel based on click chemistry.

It is important to focus on urgent needs in clinics and develop optimal materials. For successful augmentation of vocal folds, the ideal filler should be injectable through a syringe, and should stably maintain its volume for a long time without toxicity. To achieve these criteria, a click chemistry-based PEG (polyethylene glycol) hydrogel was developed and applied for vocal fold augmentation in vivo. The PEG hydrogel enables fast gelation in vivo after injection and provides long-term stability. Azide- and dibenzocyclooctyne (DBCO)-modified 4-arm PEG were cross-linked by chemical conjugation via click chemistry and yielded gelation within several minutes. After subcutaneous injection into mice and rats, the PEG hydrogel showed higher stability after 1 month compared to the traditionally used calcium hydroxyapatite-carboxymethyl cellulose (CaHA-CMC) filler. In rabbit models with vocal fold paralysis, the PEG hydrogel stably fixed the paralyzed vocal fold in 4 months and minimized the glottic gap. It was an improved therapeutic result compared to CaHA-CMC, demonstrating the potential of a click chemistry-based PEG hydrogel for vocal fold therapy.

Influence of posteromedial corner injuries on clinical outcome and second-look arthroscopic findings after allograft transtibial anterior cruciate ligament reconstruction.

BACKGROUND: The purpose of this study was to evaluate the influence of posterior medial corner (PMC) injuries on clinical outcome and second-look arthroscopic findings after anterior cruciate ligament (ACL) reconstruction. METHODS: Seventy-eight consecutive patients underwent a second-look arthroscopic surgery after ACL reconstruction and magnetic resonance imaging (MRI) examination of the PMC. The patients were divided into a PMC intact group (n = 42) and a PMC injured group (n = 36). The stability and clinical outcomes were evaluated using the Lachman test, pivot-shift test, a KT-2000 arthrometer, and the Lysholm knee scoring scale. Graft tension and synovial coverage were evaluated in second-look arthroscopy. RESULTS: The clinical function showed no significant differences regarding PMC injury. Although the graft tendon tension revealed no significant differences (p = 0.141), the second-look arthroscopic findings indicated that the PMC intact group showed better synovial coverage compared to the PMC injured group (p = 0.012). CONCLUSION: Patients who injured the PMC had poor synovial coverage as assessed by second-look arthroscopic findings after transtibial ACL reconstruction, even though clinical outcomes and stability showed no significant differences.

Chlorin e6-Loaded PEG-PCL Nanoemulsion for Photodynamic Therapy and In Vivo Drug Delivery.

We fabricated poly (ethylene glycol)-block-polycaprolactone (PEG-b-PCL) nanoemulsion for drug delivery and photodynamic therapy. PEG-b-PCL effectively stabilized the interface between water and soybean oil, and the resulting nanoemulsion was about 220.3 nm in diameter with spherical shape. For photodynamic therapy (PDT), chlorin e6 (Ce6) was loaded into the nanoemulsion as a photosensitizer (PS). These chlorin e6-loaded PEG-PCL nanoemulsions (Ce6-PCL-NEs) showed efficient cellular uptake and, upon laser irradiation, generated singlet oxygen to kill tumor cells. Particularly, Ce6-PCL-NEs showed prolonged blood circulation and about 60% increased tumor accumulation compared to free Ce6 after intravenous injection to 4T1 tumor-bearing mice. These results demonstrate the promising potential of Ce6-PCL-NEs for efficient PDT and in vivo drug delivery to tumor tissue.

Critical shoulder angle and greater tuberosity angle according to the partial thickness rotator cuff tear patterns.

BACKGROUND: Current studies suggest that radiographic markers such as the critical shoulder angle (CSA) and the greater tuberosity angle (GTA) are associated with rotator cuff tears (RCTs). However, because the analysis of CSAs and GTAs according to the partial thickness rotator cuff tear patterns is limited, the purpose of the present study was to evaluate the relationship of CSAs and GTAs with partial thickness rotator cuff tear (PTRCT) patterns. METHOD: This retrospective study included 1,069 patients from 2013 to 2017. The subjects were divided into 4 groups: Group A, control group; Group B, articular-sided PTRCTs; Group C, bursal-sided PTRCTs; and Group D, full thickness rotator cuff tears (FTRCTs). RCTs were diagnosed with magnetic resonance imaging and the CSA and GTA were measured on simple radiographs. Multivariable analyses were used to clarify the potential risks for these pathologies. RESULTS: The mean CSAs of articular-sided PTRCTs (34.2°±4.7°) and FTRCTs (34.7°±4.4°) were significantly larger than those of the control group (32.3°±4.3°) and the bursal-sided PTRCTs (31.5°±4.6°), (P<0.001). Multivariable analysis also showed that larger CSAs had a significantly increased risk of both articular-sided PTRCTs and FTRCTs, with odds ratios of 1.12 and 1.17 per degree, respectively. The mean GTAs of bursal-sided PTRCTs (73.2°±4.8°) and FTRCTs (72.3°±5.4°) were significantly larger than that of the control group (70.5°±5.1°) (P<0.001), although the mean GTA of articular-sided PTRCTs (71.5°±6.9°) did not show a significant difference when compared with the other groups. Multivariable analysis also showed that larger GTAs had a significantly increased risk of both bursal-sided PTRCTs and FTRCTs, with odds ratios of 1.13 and 1.07 per degree, respectively. CONCLUSION: A large critical shoulder angle was associated more with articular-sided PTRCTs than bursal-sided PTRCTs. A large greater tuberosity angle was associated more with bursal-sided PTRCTs than with articular-sided PTRCTs. Both critical shoulder angle and greater tuberosity angle were positively associated with the occurrence of full thickness rotator cuff tears. LEVEL OF EVIDENCE: IV, Retrospective study.

Effect of Surgical-Site, Multimodal Drug Injection on Pain and Stress Biomarkers in Patients Undergoing Plate Fixation for Clavicular Fractures.

BACKGROUND: Surgical-site, multimodal drug injection has recently evolved to be a safe and useful method for multimodal pain management even in patients with musculoskeletal trauma. METHODS: Fifty consecutive patients who underwent plating for mid-shaft and distal clavicular fractures were included in the study. To evaluate whether surgical-site injections (SIs) have pain management benefits, the patients were divided into two groups (SI and no-SI groups). The injection was administered between the deep and superficial tissues prior to wound closure. The mixture of anesthetics consisted of epinephrine hydrochloride (HCL), morphine sulfate, ropivacaine HCL, and normal saline. The visual analogue scale (VAS) pain scores were measured at 6-hour intervals until postoperative hour (POH) 72; stress biomarkers (dehydroepiandrosterone sulfate [DHEA-S], insulin, and fibrinogen) were measured preoperatively and at POH 24, 48, and 72. In patients who wanted further pain control or had a VAS pain score of 7 points until POH 72, 75 mg of intravenous tramadol was administered, and the intravenous tramadol requirements were also recorded. Other medications were not used for pain management. RESULTS: The SI group showed significantly lower VAS pain scores until POH 24, except for POH 18. Tramadol requirement was significantly lower in the SI group until POH 24, except for POH 12 and 18. The mean DHEA-S level significantly decreased in the no-SI group (74.2 ± 47.0 µg/dL) at POH 72 compared to that in the SI group (110.1 ± 87.1 µg/dL; p = 0.046). There was no significant difference in the insulin and fibrinogen levels between the groups. The correlation values between all the biomarkers and VAS pain scores were not significantly different between the two groups (p > 0.05). CONCLUSIONS: After internal fixation of the clavicular fracture, the surgical-site, multimodal drug injection effectively relieved pain on the day of the surgery without any complications. Therefore, we believe that SI is a safe and effective method for pain management after internal fixation of a clavicular fracture.

Electrical and mechanical properties of poly(L-lactide)/carbon nanotubes/clay nanocomposites.

An organoclay containing epoxy groups, twice-functionalized organoclay (TFC), was synthesized by reacting (glycidoxypropyl)trimethoxy silane with Cloisite25A (C25A), which had already been modified with an amine compound. The introduction of epoxy groups to the clay surface and carboxylic group-functionalized multiwalled carbon nanotubes (MWCNTs) improved the interfacial adhesion between the poly(L-lactide) (PLLA) and nano-sized fillers when melt-compounded. The PLLA/MWCNTs/TFC nanocomposites showed superior tensile properties to those of PLLA and PLLA/CNTs. The dispersion of MWCNTs in the PLLA matrix decreased the electrical resistivity of the composite substantially due to the higher MWCNT loading. However, the introduction of TFC to the PLLA/MWCNTs nanocomposites resulted in a slight increase in volume resistivity. This increase was attributed to the individual MWCNTs being blocked by the TFC. The clays in the PLLA/MWCNTs/TFC nanocomposites prevented direct contact between the neighboring MWCNTs, which increased the electrical resistivity of the nanocomposites.

Synthesis and properties of multiwalled carbon nanotubes incorporated organic silk fibroin cryogels.

A new monolithic organic cryogel was synthesized from a silk fibroin/multiwalled carbon nanotube (MWCNT) hydrogel by the freeze-drying method in order to maintain the silk fibroin network. The silk fibroin/MWCNT hydrogel was prepared by the regeneration of silk fibroin using an aqueous silk fibroin solution in which MWCNTs were dispersed by in-situ methods. It was observed that the formation of the silk fibroin/MWCNT hydrogel was accelerated by increasing the MWCNT concentration. Fourier transform infrared spectrum analysis, X-ray diffraction, nitrogen adsorption-desorption, and electron microscopy analysis techniques were used to characterize the silk fibroin/MWCNT cryogel. The MWCNTs were embedded in the silk fibroin based cryogel with disordered porous structures. In addition, the MWCNTs induced a change in the crystal structure of the silk fibroin and also increased the proportions of micropores and mesopores in the supermacroporous cryogels when they were introduced in the appropriate amounts.

pH-sensitive multiwalled carbon nanotube dispersion with silk fibroins.

Multiwalled carbon nanotubes (MWCNTs) are considered to be ideal multifunctional materials for biorelated applications, but there is still some controversy regarding their toxicity. In addition, the poor dispersibility of MWCNTs in either water or organic solvents has limited their practical applications. Therefore, obtaining a good dispersion is one of the key issues in their applications. In this study, MWCNTs were dispersed in an aqueous solution using silk fibroin without chemical modification. An optical analyzer, Turbiscan, was used to confirm the stability of the MWCNT aqueous dispersion. Transmission electron microscopy showed individual MWCNTs coated with silk fibroin molecules. Silk fibroin in the sol state can interact with nanotubes through hydrophobic interactions. Therefore, silk fibroin molecules coat the nanotubes, which allow their dispersion in water. Under basic conditions (pH 12.0), an aqueous dispersion of MWCNTs with silk fibroin was stable without sedimentation or gelation. However, the MWCNT/silk fibroin dispersion was unstable under acidic conditions (pH 4.0). In addition, the MWCNT dispersion showed reversible changes with variations in pH. Under acidic conditions, the MWCNTs settled due to conformation changes in the silk fibroin. However, the stability of the MWCNTs had recovered fully under basic conditions. It is believed that silk fibroin has sol-like behavior under basic conditions and gel-like behavior under acidic conditions. Ultraviolet circular dichroism was used to determine the conformation of the silk fibroin molecules with pH. Overall, the pH-sensitive properties of the carbon nanotubes dispersed with silk fibroin can lead to a new class of novel biomaterials for cancer detection and treatment.

Preparation and characterization of silicone rubber/functionalized carbon nanotubes composites via in situ polymerization.

The dispersion of the nanometer-sized multiwalled carbon nanotubes (MWCNTs) in a silicone matrix leads to a marked improvement in the properties of the silicone based composite. In this study, silicone rubber/MWCNTs nanocomposite was successfully prepared by functionalizing MWCNTs with silane compound. This allowed a homogeneous dispersion of functionalized MWCNTs in the silicone matrix. The morphology of functionalized MWCNTs was observed using transmission electron microscopy and scanning electron microscopy with energy dispersive spectrometer. The silicone rubber/functionalized MWCNTs (1 wt%) composites showed that the tensile strength and modulus of the composites improved dramatically by about 50% and 28%, respectively, compared with silicone rubber.