Biodegradable Piezoelectric Force Sensor.

Measuring vital physiological pressures is important for monitoring health status, preventing the buildup of dangerous internal forces in impaired organs, and enabling novel approaches of using mechanical stimulation for tissue regeneration. Pressure sensors are often required to be implanted and directly integrated with native soft biological systems. Therefore, the devices should be flexible and at the same time biodegradable to avoid invasive removal surgery that can damage directly interfaced tissues. Despite recent achievements in degradable electronic devices, there is still a tremendous need to develop a force sensor which only relies on safe medical materials and requires no complex fabrication process to provide accurate information on important biophysiological forces. Here, we present a strategy for material processing, electromechanical analysis, device fabrication, and assessment of a piezoelectric Poly-l-lactide (PLLA) polymer to create a biodegradable, biocompatible piezoelectric force sensor, which only employs medical materials used commonly in Food and Drug Administration-approved implants, for the monitoring of biological forces. We show the sensor can precisely measure pressures in a wide range of 0-18 kPa and sustain a reliable performance for a period of 4 d in an aqueous environment. We also demonstrate this PLLA piezoelectric sensor can be implanted inside the abdominal cavity of a mouse to monitor the pressure of diaphragmatic contraction. This piezoelectric sensor offers an appealing alternative to present biodegradable electronic devices for the monitoring of intraorgan pressures. The sensor can be integrated with tissues and organs, forming self-sensing bionic systems to enable many exciting applications in regenerative medicine, drug delivery, and medical devices.

Wide-Range Motion Recognition Through Insole Sensor Using Multi-Walled Carbon Nanotubes and Polydimethylsiloxane Composites.

High linearity/sensitivity and a wide dynamic sensing range are the most desirable features for pressure sensors to accurately detect and respond to external pressure stimuli. Even though a number of recent studies have demonstrated a low-cost pressure sensing device for a smart insole system by using scalable and deformable conductive materials, they still lack stretchability and desirable properties such as high sensitivity, hysteresis, linearity, and fast response time to obtain accurate and reliable data. To resolve this issue, a flexible and stretchable piezoresistive pressure sensor with high linear response over a wide pressure range is developed and integrated in a wearable insole system. The sensor uses multi-walled carbon nanotubes and polydimethylsiloxane (MWCNT/PDMS) composites with gradient density double-stacked configuration as well as randomly distributed surface microstructure (RDSM). The randomly distributed surface of the MWCNT/PDMS composite is easily and non-artificially generated by the evaporation of residual IPA solvent during a composite curing process. Due to two functional features consisting of the double-stacked composite configuration with different gradient MWCNT density and RDSM, the pressure sensor shows high linear sensitivity (∼82.5 kPa) and a pressure range of 0-1 MPa, providing extensive potential applications in monitoring human motions. Moreover, for a practical wearable application detecting the user's real-time motions, a custom-designed output signal acquisition system has been developed and integrated with the insole pressure sensor. As a result, the insole sensor can successfully detect walking, running, and jumping movements and can be used in daily life to monitor gait patterns by virtue of its long-term stability.

Corticotomy-assisted decompensation for augmentation of the mandibular anterior ridge.

INTRODUCTION: This article introduces a technique combining corticotomy and orthodontic forces, or accelerated osteogenic orthodontics, for use in patients with a Class III occlusion and a thin alveolus who will undergo orthognathic surgery. METHODS: Two adults with Class III malocclusion undergoing anterior decompensation for mandibular setback surgery were selected. The first patient was treated with accelerated osteogenic orthodontics and conventional decompensation. The second patient was treated with accelerated osteogenic orthodontics and decompensation with a temporary skeletal anchorage device in concert with guided tissue regeneration. Decortication of bone was performed to the mandibular teeth with a low-speed round bur and piezosurgery. After hemostasis, bone graft material was placed into the decorticated area. In the severely thin alveolar ridge, a rigid scaffold was applied for immobilization of graft material. After approximation of the flap, an immediate orthodontic force was applied to the teeth to initiate rapid tooth movement. RESULTS: Rapid tooth movement into predetermined positions for orthognathic surgery was accomplished in all mandibular anterior teeth. Preoperative 3-dimensional imaging showed dehiscences on the facial aspects of the mandibular anterior teeth. Postoperative imaging demonstrated coverage of the denuded roots with radiodense material. CONCLUSIONS: The accelerated osteogenic orthodontic technique is a safe and effective treatment option for mandibular anterior decompensation treatment of these patients. When combined with a temporary skeletal anchorage device and bone augmentation, this technique facilitated the decompression of the mandibular anterior teeth in severely compromised dentitions.

Medical X-band linear accelerator for high-precision radiotherapy.

PURPOSE: Recently, high-precision radiotherapy systems have been developed by integrating computerized tomography or magnetic resonance imaging to enhance the precision of radiotherapy. For integration with additional imaging systems in a limited space, miniaturization and weight reduction of the linear accelerator (linac) system have become important. The aim of this work is to develop a compact medical linac based on 9.3 GHz X-band RF technology instead of the S-band RF technology typically used in the radiotherapy field. METHODS: The accelerating tube was designed by 3D finite-difference time-domain and particle-in-cell simulations because the frequency variation resulting from the structural parameters and processing errors is relatively sensitive to the operating performance of the X-band linac. Through the 3D simulation of the electric field distribution and beam dynamics process, we designed an accelerating tube to efficiently accelerate the electron beam and used a magnetron as the RF source to miniaturize the entire linac. In addition, a side-coupled structure was adopted to design a compact linac to reduce the RF power loss. To verify the performance of the linac, we developed a beam diagnostic system to analyze the electron beam characteristics and a quality assurance (QA) experimental environment including 3D lateral water phantoms to analyze the primary performance parameters (energy, dose rate, flatness, symmetry, and penumbra) The QA process was based on the standard protocols AAPM TG-51, 106, 142 and IAEA TRS-398. RESULTS: The X-band linac has high shunt impedance and electric field strength. Therefore, even though the length of the accelerating tube is 37 cm, the linac could accelerate an electron beam to more than 6 MeV and produce a beam current of more than 90 mA. The transmission ratio is measured to be approximately 30% ~ 40% when the electron gun operates in the constant emission region. The percent depth dose ratio at the measured depths of 10 and 20 cm was approximately 0.572, so we verified that the photon beam energy was matched to approximately 6 MV. The maximum dose rate was measured as 820 cGy/min when the source-to-skin distance was 80 cm. The symmetry was smaller than the QA standard and the flatness had a higher than standard value due to the flattening filter-free beam characteristics. In the case of the penumbra, it was not sufficiently steep compared to commercial equipment, but it could be compensated by improving additional devices such as multileaf collimator and jaw. CONCLUSIONS: A 9.3 GHz X-band medical linac was developed for high-precision radiotherapy. Since a more precise design and machining process are required for X-band RF technology, this linac was developed by performing a 3D simulation and ultraprecision machining. The X-band linac has a short length and a compact volume, but it can generate a validated therapeutic beam. Therefore, it has more flexibility to be coupled with imaging systems such as CT or MRI and can reduce the bore size of the gantry. In addition, the weight reduction can improve the mechanical stiffness of the unit and reduce the mechanical load.

Synthesis and evaluation of human serum albumin-modified exendin-4 conjugate via heterobifunctional polyethylene glycol linkage with protracted hypoglycemic efficacy.

Albumin conjugation is considered to be one of the most effective means of protracting the short in vivo lifespans of peptides and proteins. Here, we present a new long-acting antidiabetic exendin-4 conjugate linked with human serum albumin (HSA) via polyethylene glycol (PEG). As a first step toward synthesizing this conjugate, three artificial sulfhydryl groups were introduced in HSA using 2-iminothiolane at pH 8.0. This thiolated HSA was further reacted with the monomer fraction of exendin-4 (6 equiv) conjugated with maleimide-PEG(5k)-N- hydroxysuccinimide (MAL-PEG(5k)-NHS) for 3 h. Because of the presence of PEG molecules, the resulting conjugate (HSA-PEG-Ex4) was found to have a greater apparent molecular weight and a larger particle size (ca. 195 kDa and 9.48 +/- 0.74 nm) than those of HSA-exendin-4 without the PEG linker (HSA-Ex4, ca. 84.3 kDa and 7.77 +/- 0.98 nm). Although the receptor binding affinity of HSA-PEG-Ex4 on RIN-m5F cells was significantly lower than that of Ex4, its antihyperglycemic efficacy was slightly higher than that of Ex-4 and HSA-Ex4 in type 2 diabetic db/db mice. Furthermore, HSA-PEG-Ex4 had greater circulating t(1/2) and AUC(inf) values than HSA-Ex and native exendin-4 by 2.1- and 10.3-fold, respectively. Accordingly, its hypoglycemic duration was greatly increased to 31.0 h at a dose of 250 nmol/kg vs that of native Ex4 (7.0 h). Results show that the HSA-PEG-Ex4 conjugate produced has distinct advantages over HSA-Ex4 without PEG. We believe that this exendin-4 derivative, which has the merits of albumin conjugation and PEGylation, has considerable potential as a novel type 2 antidiabetic agent.

A Behavior-Learned Cross-Reactive Sensor Matrix for Intelligent Skin Perception.

Mimicking human skin sensation such as spontaneous multimodal perception and identification/discrimination of intermixed stimuli is severely hindered by the difficulty of efficient integration of complex cutaneous receptor-emulating circuitry and the lack of an appropriate protocol to discern the intermixed signals. Here, a highly stretchable cross-reactive sensor matrix is demonstrated, which can detect, classify, and discriminate various intermixed tactile and thermal stimuli using a machine-learning approach. Particularly, the multimodal perception ability is achieved by utilizing a learning algorithm based on the bag-of-words (BoW) model, where, by learning and recognizing the stimulus-dependent 2D output image patterns, the discrimination of each stimulus in various multimodal stimuli environments is possible. In addition, the single sensor device integrated in the cross-reactive sensor matrix exhibits multimodal detection of strain, flexion, pressure, and temperature. It is hoped that his proof-of-concept device with machine-learning-based approach will provide a versatile route to simplify the electronic skin systems with reduced architecture complexity and adaptability to various environments beyond the limitation of conventional "lock and key" approaches.

Two-component mini-implant as an efficient tool for orthognathic patients.

A new type of orthodontic mini-implant called the C-implant can be an effective alternative to conventional 1-component screws in orthognathic patients because of its particular design. Its small size and 2-component structure make it easily applicable for various types of difficult intermaxillary fixation cases such as 2-jaw orthognathic surgery, 1-jaw surgery with genioplasty, and orthognathic surgery without presurgical orthodontic treatment. The 2-part design highly resists fracture or deformation during placement and removal, and the long-span head allows the patient to easily attach intermaxillary elastics for traction. This mini-implant can be used not only as an intermaxillary fixation screw but also as anchorage during presurgical and postsurgical orthodontic treatment. Better osseointegration potential of the surface-treated screw part allows it to endure heavy and dynamic forces. In this article, we attempted to show that this mini-implant is a good tool for effective anchorage in presurgical treatment, intermaxillary fixation during surgery, and postsurgical treatment of orthognathic patients.

Evaluation of apically positioned dental implants with a sandblasted with large grit and acid-etched surface 1 day after initial placement using micro-CT images and nondecalcified tissue slide images in a rabbit model.

PURPOSE: Optimal positioning of implant placement is difficult in several conditions. In cases of thin alveolar ridges or irregular alveolar crests, the dental implant thread is not always fully submerged in the alveolar bone. The response of surrounding bone to dental implants placed apically several days after the initial surgery has yet to be fully revealed. This study evaluated apically positioned dental implants with sandblasted with large grit and acid-etched (SA) surfaces 1 day after initial placement with treatment of saline or tetracycline. MATERIALS AND METHODS: Twelve rabbits were used in this study, and the surgeries were performed on both sides of the mandibular bone. Twenty-four implants were placed and classified into three groups. In the control group, implant placement was performed following recommendations, with the SA surface submerged in the bone. In the saline and tetracycline groups, 1 mm of the SA surface was exposed above the cortical bone. On the following day, the implants were apically positioned after treatment using a cotton pellet soaked with sterile saline (saline group) or tetracycline solution (tetracycline group). The images from the nondecalcified tissue slide were compared with microcomputed tomography (micro-CT) images. The bone-to-implant contact ratio and bone area ratio were measured using micro-CT images 4 weeks after implant placement. RESULTS: The bone-to-implant contact ratio (mean ± standard deviation, %) of the control group was 87.9 ± 13.7, and those of the saline and tetracycline groups were 83.7 ± 15.46 and 86.9 ± 18.5, respectively. No statistically significant differences were noted among the three groups (P > .05). The bone area ratio (mean ± standard deviation, %) was 90.1 ± 12.2, 96.6 ± 4.3, and 88.7 ± 22.3 for the control, saline, and tetracycline groups, respectively (P > .05). The results from the transverse plane showed no significant differences among the three groups. CONCLUSION: This study evaluated the effects of apically positioned dental implants with SA surfaces 1 day after initial placement, and uneventful healing was observed irrespective of treatment with saline or tetracycline. Apical positioning of the dental implant within a few days of initial placement may be acceptable without compromising osseointegration. However, further studies in large animal models with larger sample sizes may be necessary before clinical application is recommended.

Assessment of stem cell viability in the initial healing period in rabbits with a cranial bone defect according to the type and form of scaffold.

PURPOSE: Increased bone regeneration has been achieved through the use of stem cells in combination with graft material. However, the survival of transplanted stem cells remains a major concern. The purpose of this study was to evaluate the viability of transplanted mesenchymal stem cells (MSCs) at an early time point (24 hours) based on the type and form of the scaffold used, including type I collagen membrane and synthetic bone. METHODS: The stem cells were obtained from the periosteum of the otherwise healthy dental patients. Four symmetrical circular defects measuring 6 mm in diameter were made in New Zealand white rabbits using a trephine drill. The defects were grafted with 1) synthetic bone (ß-tricalcium phosphate/hydroxyapatite [ß-TCP/HA]) and 1×105 MSCs, 2) collagen membrane and 1×105 MSCs, 3) ß-TCP/HA+collagen membrane and 1×105 MSCs, or 4) ß-TCP/HA, a chipped collagen membrane and 1×105 MSCs. Cellular viability and the cell migration rate were analyzed. RESULTS: Cells were easily separated from the collagen membrane, but not from synthetic bone. The number of stem cells attached to synthetic bone in groups 1, 3, and 4 seemed to be similar. Cellular viability in group 2 was significantly higher than in the other groups (P<0.05). The cell migration rate was highest in group 2, but this difference was not statistically significant (P>0.05). CONCLUSIONS: This study showed that stem cells can be applied when a membrane is used as a scaffold under no or minimal pressure. When space maintenance is needed, stem cells can be loaded onto synthetic bone with a chipped membrane to enhance the survival rate.

Evaluation of the bisphosphonate effect on stem cells derived from jaw bone and long bone rabbit models: A pilot study.

BACKGROUND AND OBJECTIVE: Bisphosphonates have been widely used and the number of patients experiencing medication-related osteonecrosis of the jaw (MRONJ) has been increasing. This study was designed to evaluate the effect of zoledronate on stem cells derived from different tissues. DESIGN: Stem cells derived from four different tissues were compared using rabbit models (JPO: periosteum from the jaw bone (mandible), JBM: bone marrow from the jaw bone, LPO: periosteum from long bone (tibia), and LBM: bone marrow from long bone). Stem cells were grown in the presence of zoledronate at final concentrations ranging from 10-6M to 10-10M. Morphology was viewed under an inverted microscope, and the analysis of cell proliferation was performed using a Cell Counting Kit-8 (CCK-8) on days 1, 2, 4, and 7. RESULTS: The CCK-8 results for LBM showed that the increase of CCK-8 values was correlated with a longer incubation time. Compared to the untreated control, growth in the presence of zoledronate at 10-10M and 10-8M resulted in decreased CCK-8 values for LBM on day 7 (P<0.05). The CCK-8 results for JBM, LPO, and JPO on days 1, 2, 4, and 7 showed that the presence of zoledronate did not produce statistically significant changes compared with the untreated control. CONCLUSION: Zoledronate in the tested concentrations from JBM, LPO, and JPO did not produce noticeable alterations in the viability of mesenchymal stem cells. This in vitro experiment suggests that the occurrence of MRONJ solely in the oral cavity is not due to differences in the cellular proliferation of stem cells in the response to zoledronate.

Associations between the number of natural teeth and the maternal age at childbirth or history of parity in postmenopausal women: The 2010-2012 Korea national health and nutrition examination survey.

BACKGROUND: The relationship between reproductive factors, including pregnancy and delivery, and the number of teeth in postmenopausal women remains to be revealed. OBJECTIVES: The aim of this study was to evaluate the relationship between age at first and last delivery, parity and the number of natural teeth in postmenopausal women, using nationally representative data. MATERIAL AND METHODS: Data from the Korea National Health and Nutrition Examination Survey between 2010 and 2012 were used, and the analysis in this study was confined to a total of 4,060 respondents who had gone through menopause and had no missing values for the reproductive factors and outcome variables. The total number of natural teeth was then calculated after excluding third molars, and frequency of tooth brushing was recorded as oral health behavior. Univariate and multivariate logistic regression analyses were used to assess the associations between the number of natural teeth and reproductive factors. RESULTS: Both a woman's age at her last childbirth and the number of pregnancies had statistically significant effects on the number of natural teeth remaining after menopause. With each one-year increase of age at a woman's last delivery, the number of natural teeth decreased by a value of 0.12 (p < 0.05). Similar trends were seen with increases in parity, which resulted in decreases in the number of natural teeth by 0.65 (p < 0.05). The odds ratios of the percentage of individuals with a 20 or fewer teeth tended to increase with increases in the woman's age at her last childbirth. CONCLUSIONS: This study identified an association between the number of natural teeth and a woman's age at her last childbirth as well as between the number of natural teeth and parity. Higher ages at last childbirth and higher parity were found to be potential risk indicators for tooth loss in postmenopausal women.

Performance assessment of a submerged membrane bioreactor using a novel microbial consortium.

The performance of a submerged membrane bioreactor (MBR) with and without a novel microbial consortium (NMBR vs. CMBR) was compared to provide deeper insights into the effects of changes in water quality and dissolved organic matter (DOM) characteristics by a novel microbial consortium on the fouling characteristics of MBR processes. Despite similar operating conditions and identical DOM properties in the feed waters, NMBR exhibited a lower propensity to release polysaccharide-like compounds with low molecular weight by bacterial activities compared to CMBR. These compounds have a great fouling potential for MBR processes. Therefore, an increase in the transmembrane pressure (TMP) of NMBR (normalized TMP (TMP/TMP0): 1.14) was much slower and less significant than that observed in CMBR (TMP/TMP0: 2.61). These observations imply that the novel microbial consortium can efficiently mitigate membrane fouling by hydrophilic DOM in MBR processes.

Effects of alveolar bone displacement with segmental osteotomy: micro-CT and histomorphometric analysis in rats.

The purpose of this study was to evaluate the effects of segmental osteotomy on the blood vessels and osteoclasts in rats using micro-computed tomography (micro-CT) and histomorphometric analysis. After segmental osteotomy was performed around the maxillary first molars of 36 male Sprague-Dawley rats (n = 72), the samples were divided into a control group (no displacement), 0.5 D group (0.5 mm buccal displacement) and 1.0 D group (1.0 mm buccal displacement) (n = 24/group). At 1, 2, 4 and 8 weeks after surgery, changes in the blood vessel volume were investigated using micro-CT with perfusion of radiopaque silicone rubber. Tartrate-resistant acid phosphatase (TRAP) staining was used for histomorphometric analysis. Two-way repeated measures analysis of variance (rmANOVA) was performed to compare the volume of blood vessels and number of TRAP-positive osteoclasts among the groups. Regarding blood vessel volume, the displacement groups had no significant effects, while the time points had significant effects (p = 0.014). The blood vessel volume at 1 week was significantly smaller than that at 2, 4, and 8 weeks (p = 0.004, p = 0.026, and p = 0.005, respectively). Regarding TRAP cell count, the displacement groups had no significant effects, while the time points had significant effects (p < 0.001). The number of TRAP-positive osteoclasts at 8 weeks was significantly smaller than that at 1, 2, and 4 weeks (p < 0.001, p < 0.001, and p = 0.002, respectively), and the count at 4 weeks was smaller than that at 1 week (p = 0.011). Therefore, a regional osteoclast-related acceleratory phenomenon was maintained until 4 weeks after surgery.

PEGylated apoptotic protein-loaded PLGA microspheres for cancer therapy.

The aim of the current study was to investigate the antitumor potential of poly (D,L-lactic-co-glycolic acid) microspheres (PLGA MSs) containing polyethylene glycol (PEG)-conjugated (PEGylated) tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL). PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 µm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively). The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer.

In situ facile-forming PEG cross-linked albumin hydrogels loaded with an apoptotic TRAIL protein.

The key to making a practicable hydrogel for pharmaceutical or medical purposes is to endow it with relevant properties, i.e., facile fabrication, gelation time-controllability, and in situ injectability given a firm basis for safety/biocompatibility. Here, the authors describe an in situ gelling, injectable, albumin-cross-linked polyethylene glycol (PEG) hydrogel that was produced using a thiol-maleimide reaction. This hydrogel consists of two biocompatible components, namely, thiolated human serum albumin and 4-arm PEG20k-maleimide, and can be easily fabricated and gelled in situ within 60s by simply mixing its two components. In addition, the gelation time of this system is controllable in the range 15s to 5min. This hydrogel hardly interacted with an apoptotic TRAIL protein, ensuring suitable release profiles that maximize therapeutic efficacy. Specifically, tumors (volume: 278.8mm(3)) in Mia Paca-2 cell-xenografted BALB/c nu/nu mice treated with the TRAIL-loaded HSA-PEG hydrogel were markedly smaller than mice treated with the hydrogel prepared via an amine-N-hydroxysuccinimide reaction or non-treated mice (1275.5mm(3) and 1816.5mm(3), respectively). We believe that this hydrogel would be a new prototype of locally injectable sustained-release type anti-cancer agents, and furthermore offers practical convenience for a doctor and universal applicability for a variety of therapeutic proteins.

Four-arm PEG cross-linked hyaluronic acid hydrogels containing PEGylated apoptotic TRAIL protein for treating pancreatic cancer.

Four-arm polyethylene glycol (PEG) cross-linked hyaluronic acid (HA) hydrogels containing PEGylated tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL) were fabricated, and their antitumor effects were evaluated in pancreatic cell (Mia Paca-2)-xenografted mice. HA was conjugated with 4-arm PEG(10k)-amine (a cross-linker) at ratios of 100:1 and 100:2 using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a cross-linker, and TRAIL or PEG-TRAIL was incorporated into these HA hydrogels. HA hydrogels at a 100:1 ratio were prepared in good yields (>88%), were moderately stiff, and gradually released PEG-TRAIL over ~14 days in vitro and over ~7 days in vivo (as determined by high-pressure liquid chromatography and infrared imaging). The released PEG-TRAIL was found to have obvious apoptotic activity in Mia Paca-2 cells. PEG-TRAIL HA hydrogels displayed remarkably more antitumor efficacy than TRAIL HA hydrogels in Mia Paca-2 cell-xenografted mice in terms of tumor volumes (size) and weights (453.2mm(3) and 1.03 g vs. 867.5mm(3) and 1.86 g). Furthermore, this improved antitumor efficacy was found to be due to the apoptotic activity of PEG-TRAIL in vivo (determined by a TUNEL assay) despite its substantially lower cytotoxicity than native TRAIL (IC50 values: 71.8 and 202.5 ng ml(-1), respectively). This overall enhanced antitumor effect of PEG-TRAIL HA hydrogels appeared to be due to the increased stability of PEGylated TRAIL in HA hydrogels. These findings indicate that this HA hydrogel system combined with PEG-TRAIL should be considered a potential candidate for the treatment of pancreatic cancer.

The effect of systemically administered bisphosphonates on bony healing after tooth extraction and osseointegration of dental implants in the rabbit maxilla.

PURPOSE: To evaluate the effects of bisphosphonates on bone healing after tooth extraction and osseointegration of dental implants in a rabbit model. MATERIALS AND METHODS: Twenty-four rabbits were divided into four groups; one control and three experimental. The experimental were treated with intravenous zoledronic acid (ZA, 0.1 mg/kg) twice per week starting 4 (Z4 group) and 8 (Z8 group) weeks before surgery until the end of the experiments. The experimental ZD4 group was treated with intravenous ZA (0.01 mg/kg) and intramuscular dexamethasone (1 mg/kg) twice per week starting 4 weeks before surgery until the end of the experiments. The maxillary first premolar was extracted, and an implant with a diameter of 1.5 mm was placed between the incisor and the premolar of each maxilla. Healing of the extraction socket was evaluated and histomorphometric analysis around the implant was performed, using the bone-to-implant contact ratio (BIC) and bone area ratio (BA) 4 and 8 weeks after the surgery. RESULTS: The control group underwent a normal healing process, but all experimental groups showed necrotic bone with hollow lacunae. BIC and BA in the control group increased from the 4- to 8-week evaluations, but decreased in the experimental groups from 4 to 8 weeks. BIC and BA of the Z8 and ZD4 groups were higher than those of the control group at the 4-week evaluation, but were lower than the control at the the 8-week evaluation. CONCLUSIONS: This study showed that administration of bisphosphonates interferes with normal bone remodeling after tooth extraction. The experimental groups showed good initial stability, but long-term healing around the implants was impaired. Within the limits of this study, it may be suggested that patients taking bisphosphonates should be treated with caution when performing tooth extraction or placing dental implants.

Long-acting inhalable chitosan-coated poly(lactic-co-glycolic acid) nanoparticles containing hydrophobically modified exendin-4 for treating type 2 diabetes.

Inhalable glycol chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing palmitic acid-modified exendin-4 (Pal-Ex4) (chitosan Pal-Ex4 PLGA NPs) were prepared and characterized. The surface morphology, particle size, and zeta potential of chitosan Pal-Ex4 PLGA NPs were investigated, and the adsorption and cytotoxicity of chitosan Pal-Ex4 PLGA NPs were evaluated in human lung epithelial cells (A549). Finally, the lung deposition characteristics and hypoglycemia caused by chitosan Pal-Ex4 PLGA NPs were evaluated after pulmonary administration in imprinting control region (ICR) and type 2 diabetic db/db mice. Results showed that chitosan Pal-Ex4 PLGA NPs were spherical, compact and had a diameter of ~700 nm and a positive surface charge of +28.5 mV Chitosan-coated PLGA NPs were adsorbed onto A549 cells much more so than non-coated PLGA NPs. Pal-Ex4 release from chitosan-coated PLGA NPs was delayed by as much as 1.5 days as compared with chitosan-coated Ex4 PLGA NPs. In addition, chitosan-coated PLGA NPs remained in the lungs for ~72 hours after pulmonary administration, whereas most non-coated PLGA NPs were lost at 8 hours after administration. Furthermore, the hypoglycemic efficacy of inhaled chitosan Pal-Ex4 PLGA NPs was 3.1-fold greater than that of chitosan Ex4 PLGA NPs in db/db mice. The authors believe chitosan Pal-Ex4 PLGA NPs have considerable potential as a long-acting inhalation delivery system for the treatment of type 2 diabetes.

Doxorubicin-loaded porous PLGA microparticles with surface attached TRAIL for the inhalation treatment of metastatic lung cancer.

Inhalable highly porous large PLGA microparticles with incorporated doxorubicin and surface-attached with TRAIL (TRAIL/Dox PLGA MP) were fabricated using a w/o/w double emulsification method using ammonium bicarbonate as a gas-foaming agent for the treatment of lung cancer. The TRAIL/Dox PLGA MP produced were highly porous and 11.5 ± 0.4 µm in diameter, and the loading efficiencies of Dox and TRAIL were 86.5 ± 6.5% and 91.8 ± 2.4%, respectively. TRAIL and doxorubicin were gradually released by TRAIL/Dox PLGA over 7 days, and pulmonary administration resulted in the deposition of TRAIL/Dox PLGA MP in mouse lungs, and they remained in situ for up to a week. The anti-tumor efficacy of pulmonary administered TRAIL/Dox PLGA MP was evaluated in a BALB/c nu/nu mice mouse model of H226 cell metastasis. Tumors in H226-implanted mice treated with TRAIL/Dox PLGA MP were markedly smaller and fewer in number than mice treated with TRAIL or Dox PLGA MP alone. Furthermore, this improved performance was found to be due to the synergistic apoptotic effects of the two drugs. We believe that TRAIL/Dox PLGA MP offer a promise of a sustained-release, long-acting, inhalable anti-lung cancer agent. Furthermore, the synergism observed between TRAIL and doxorubicin suggests that the doxorubicin dosage could be substantially reduced and its side effects minimized.

Doxorubicin-loaded highly porous large PLGA microparticles as a sustained- release inhalation system for the treatment of metastatic lung cancer.

Doxorubicin-loaded highly porous large PLGA microparticles (Dox PLGA MPs) were prepared using a w/o/w double emulsification method using ammonium bicarbonate effervescent salt. The prepared Dox PLGA MPs were characterized by particle size analysis, scanning electron microscopy, and confocal microscopy. In vitro cytotoxicity to B16F10 melanoma cells and lung deposition in C57BL/6 mice were examined, and finally the anti-tumor efficacy of pulmonary administered Dox PLGA MPs was evaluated in a mouse model of B16F10 melanoma metastasis. Results showed that Dox PLGA MPs were highly porous, had high encapsulation efficiency, and good aerosolization characteristics. Doxorubicin was gradually released from Dox PLGA MPs over 2 weeks, and after pulmonary administration, Dox PLGA MPs were deposited in lungs and remained in situ for up to 14 days. Furthermore, exposure to Dox PLGA MPs killed B16F10 cells in vitro within 24 h. In particular, tumors in B16F10-implanted mice treated with Dox PLGA MPs were remarkably smaller in terms of mass and number than those in non-treated B16F10-implanted mice. We believe that doxorubicin-loaded highly porous large PLGA microparticles have great potential as a long-term inhalation agent for the treatment of lung cancer.