A review on gold nanoparticles as an innovative therapeutic cue in bone tissue engineering: Prospects and future clinical applications.

Bone damage is a complex orthopedic problem primarily caused by trauma, cancer, or bacterial infection of bone tissue. Clinical care management for bone damage remains a significant clinical challenge and there is a growing need for more advanced bone therapy options. Nanotechnology has been widely explored in the field of orthopedic therapy for the treatment of a severe bone disease. Among nanomaterials, gold nanoparticles (GNPs) along with other biomaterials are emerging as a new paradigm for treatment with excellent potential for bone tissue engineering and regenerative medicine applications. In recent years, a great deal of research has focused on demonstrating the potential for GNPs to provide for enhancement of osteogenesis, reduction of osteoclastogenesis/osteomyelitis, and treatment of bone cancer. This review details the latest understandings in regards to GNPs based therapeutic systems, mechanisms, and the applications of GNPs against various bone disorders. The present review aims to summarize i) the mechanisms of GNPs in bone tissue remodeling, ii) preparation methods of GNPs, and iii) functionalization of GNPs and its decoration on biomaterials as a delivery vehicle in a specific bone tissue engineering for future clinical application.

Eucalyptol induces osteoblast differentiation through ERK phosphorylation in vitro and in vivo.

Eucalyptol (EU) is monoterpene oxide that is the main component of the essential oil extracted from aromatic plants such as Eucalyptus globules. EU has therapeutic effects such as antibacterial, anti-inflammatory and antioxidant in chronic diseases including inflammation disorder, respiratory disease, and diabetic disease. However, the effects of EU on osteoblast differentiation and bone diseases such as osteoporosis have not been studied. The present study investigated the effects of EU on osteoblast differentiation and bone formation. EU induces mRNA and protein expression of osteogenic genes in osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts. EU also promoted alkaline phosphatase (ALP) activity and mineralization. Here, the osteoblast differentiation effect of EU is completely reversed by ERK inhibitor. These results demonstrate that osteoblast differentiation effect of EU is mediated by ERK phosphorylation. The efficacy of EU on bone formation was investigated using surgical bone loss-induced animal models. EU dose-dependently promoted bone regeneration in zebrafish caudal fin rays. In the case of ovariectomized mice, EU increased ERK phosphorylation and ameliorated bone loss of femurs. These results indicate that EU ameliorates bone loss by promoting osteoblast differentiation through ERK phosphorylation. We suggest that EU, plant-derived monoterpenoid, may be useful for preventing bone loss. KEY MESSAGES: Eucalyptol (EU) increases osteoblast differentiation in pre-osteoblasts. EU up-regulates the osteogenic genes expression via ERK phosphorylation. EU promotes bone regeneration in partially amputated zebrafish fin rays. Oral administration of EU improves ovariectomy-induced bone loss and increases ERK phosphorylation.

Can pretreatment platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios predict long-term oncologic outcomes after preoperative chemoradiation followed by surgery for locally advanced rectal cancer?

PURPOSE: Systemic inflammation is associated with various malignancies, including colorectal cancer, as possible prognostic predictors. We aimed to evaluate the correlation of pretreatment the platelet-to-lymphocyte (PLR) and the neutrophil-to-lymphocyte (NLR) ratio with long-term oncologic outcomes and pathologic complete response (pCR) in locally ad vanced rectal cancer patients who received neoadjuvant concurrent chemoradiotherapy (CRT) followed by curative resection. METHODS: Between October 1996 and December 2015, 168 rectal cancer patients treated with preoperative CRT followed by surgery were enrolled. The set cut-off/mean PLR and NLR were 170 and 2.8. We analyzed the relationship between PLR, NLR, and the 5-year overall survival (OS), disease-free survival (DFS), and pCR rate. RESULTS: The 5-year OS rates were 75.9% and 59.8% in the highand low-PLR groups. The 5-year DFS rates were 62.9% and 50.8% in the high- and low-PLR groups, with no significant difference. In addition, the 5-year OS rates were 75.7% and 58.4%, and the 5-year DFS rates were 62.5% and 50.0% in the high- and low-NLR groups, respectively, both without any significant difference. Multivariate analysis showed only pretreatment PLR as an independent prognostic factor for OS (hazard ratio, 1.850; 95% confidence interval, 1.041-3.287; P=0.036), and both serologic markers were not independent prognostic factors for 5-year DFS. CONCLUSION: Neither PLR nor NLR was associated with 5-year DFS nor pCR to neoadjuvant CRT. Only pretreatment PLR can be used in predicting OS in locally advanced rectal cancer patients who received neoadjuvant CRT followed by curative resection.

Facile Preparation of ß-Cyclodextrin-grafted Chitosan Electrospun Nanofibrous Scaffolds as a Hydrophobic Drug Delivery Vehicle for Tissue Engineering Applications.

Despite advances in the bio-tissue engineering area, the technical basis to directly load hydrophobic drugs on chitosan (CTS) electrospun nanofibers (ENs) has not yet been fully established. In this study, we fabricated CTS ENs by using an electrospinning (ELSP) system, followed by surface modification using succinyl-beta-cyclodextrin (ß-CD) under mild conditions. The ß-CD-modified CTS (ßCTS) ENs had slightly increased hydrophobicity compared to pristine CTS ENs as well as decreased residual amine content on the surface. Through FTIR spectroscopy and thermogravimetric analysis (TGA), we characterized the surface treatment physiochemically. In the drug release test, we demonstrated the stable and sustained release of a hydrophobic drug (e.g., dexamethasone) loaded on ß-CD ENs. During in vitro biocompatibility assessments, the grafting of ß-CD was shown to not reduce cell viability compared to pristine CTS ENs. Additionally, cells proliferated well on ß-CD ENs, and this was confirmed by F-actin fluorescence staining. Overall, the material and strategies developed in this study have the potential to load a wide array of hydrophobic drugs. This could be applied as a drug carrier for a broad range of tissue engineering applications.

Overcome the barriers of the skin: exosome therapy.

Exosomes are nano-sized cargos with a lipid bilayer structure carrying diverse biomolecules including lipids, proteins, and nucleic acids. These small vesicles are secreted by most types of cells to communicate with each other. Since exosomes circulate through bodily fluids, they can transfer information not only to local cells but also to remote cells. Therefore, exosomes are considered potential biomarkers for various treatments. Recently, studies have shown the efficacy of exosomes in skin defects such as aging, atopic dermatitis, and wounds. Also, exosomes are being studied to be used as ingredients in commercialized skin treatment products. In this review, we discussed the need for exosomes in skin therapy together with the current challenges. Moreover, the functional roles of exosomes in terms of skin treatment and regeneration are overviewed. Finally, we highlighted the major limitations and the future perspective in exosome engineering.

Effect of laparoscopic surgery on the risk for surgical site infections in colorectal resection: results from the Health Insurance Review & Assessment Service Database.

PURPOSE: To compare the hospital length of stay (LOS), duration of antibiotic use, medical costs, and incidence of surgical site infection (SSI) between laparoscopic colorectal surgery (Lap-CRS) and open CRS (Open-CRS). METHODS: We retrospectively reviewed data of the Health Insurance Review and Assessment Service Surgical Antibiotic Prophylaxis assessment (7th assessment, 2015); the nationwide data were collected from patients who underwent CRS from September to November 2015 in low volume hospital to the tertiary hospital level in Korea. RESULTS: All 2,751 patients who underwent elective CRS were assessed. The mean hospital LOS (12.18 days vs. 14.16 days, P < 0.001) and mean postoperative LOS (8.21 days vs. 9.46 days, P < 0.001) were shorter in the Lap-CRS group than in the Open-CRS group. The mean duration of antibiotic use was shorter in the Lap-CRS group (2.91 days vs. 3.64 days, P = 0.033). The rate of SSI was lower in the Lap-CRS group, but there was no significant difference between the groups (3.57% vs. 5.01%, P = 0.133). Among the SSI group, the mean LOS (19.5 days vs. 24.9 days, P = 0.081), duration of antibiotic use (12.62 days vs. 15.46 days, P = 0.097), and medical costs showed no significant difference between the 2 groups. CONCLUSION: Lap-CRS is significantly associated with reduced hospital LOS and the duration of antibiotic use in this study. However, we could not identify significant differences in the incidence of SSI according to the type of surgery. To assess the overall benefits of Lap-CRS, studies including the rate of SSI up to 30 days postoperatively will be needed in the future.

Machine learning-based design strategy for 3D printable bioink: elastic modulus and yield stress determine printability.

Although three-dimensional (3D) bioprinting technology is rapidly developing, the design strategies for biocompatible 3D-printable bioinks remain a challenge. In this study, we developed a machine learning-based method to design 3D-printable bioink using a model system with naturally derived biomaterials. First, we demonstrated that atelocollagen (AC) has desirable physical properties for printing compared to native collagen (NC). AC gel exhibited weakly elastic and temperature-responsive reversible behavior forming a soft cream-like structure with low yield stress, whereas NC gel showed highly crosslinked and temperature-responsive irreversible behavior resulting in brittleness and high yield stress. Next, we discovered a universal relationship between the mechanical properties of ink and printability that is supported by machine learning: a high elastic modulus improves shape fidelity and extrusion is possible below the critical yield stress; this is supported by machine learning. Based on this relationship, we derived various formulations of naturally derived bioinks that provide high shape fidelity using multiple regression analysis. Finally, we produced a 3D construct of a cell-laden hydrogel with a framework of high shape fidelity bioink, confirming that cells are highly viable and proliferative in the 3D constructs.

Efficacy of a chitosan tampon in the loop electrosurgical excision procedure: A prospective randomized controlled study.

It has been reported that chitosan has a hemostatic effect and an antibiotic activity. This study aimed to evaluate the efficacy and feasibility of using a chitosan tampon (Hemoblock-Tampon) in preventing hemorrhage and enhancing wound healing after the loop electrosurgical excision procedure (LEEP).This single-blind, prospective, randomized study included 62 consecutive patients who underwent LEEP for cervical intraepithelial neoplasia. A chitosan tampon (31 patients; treatment group), or a general tampon (31 patients; control group) was applied to the uterine cervix immediately after LEEP. One patient in the treatment group declined to participate in this study. Thus, 30 patients in the treatment group and 31 patients in the control group completed this study. For objective analysis of hemorrhage in the postoperative 2 weeks, the amounts of bleeding were checked daily with a pictorial blood assessment chart. We evaluated vaginal discharge, abdominal pain, and impairment in daily living during the postoperative 2 weeks using 5 visual analogue scale questionnaires.The bleeding count was significantly lower in the treatment group than in the control group (21.37 ± 16.86 vs. 40.52 ± 16.55, p = 0.0014). The sum of the scores of the 5 questionnaires was significantly lower in the treatment group than in the control group (6.53 ± 2.84 vs. 8.59 ± 2.88, p = 0.0079). The incidence of vaginal discharge was significantly lower in the treatment group than in the control group (20.0% vs. 48.4%, p = 0.0207). According to logistic regression, only the use of chitosan tampon reduced the risk of moderate to severe vaginal bleeding 2 weeks after surgery (Odd ratio, 0.213; 95% confidence interval, 0.06-0.76; p = 0.0172). Complete healing of the uterine cervix occurred in 86.7% of patients in the treatment group and in 61.3% of patients in the control group at 4 weeks after surgery (p = 0.0255).The use of chitosan tampons can reduce hemorrhage, vaginal discharge, abdominal pain, and impairment of daily living after LEEP. Moreover, chitosan tampon may help enhance wound healing.

Management of large and surrounding tissue infiltrative anal fistula cancer: Two case reports.

INTRODUCTION: Adenocarcinoma originating from chronic perianal fistulas is a rare disease. Due to the lack of evidence of this malignancy, no definitive diagnostic and treatment guidelines have been established. We present two cases of anal fistula cancer and discuss the diagnostic and treatment strategies. PRESENTATION OF CASE: A 79-year-old man was referred for a perianal mass. The patient had a history of chronic perianal fistula and was diagnosed with adenocarcinoma originating from a long-standing perianal fistula. The patient underwent laparoscopic abdominoperineal resection (APR) without any adjuvant therapy. The second case was a 42-year old man, who was referred for a prolapsed anal mass. The patient had recurrent perianal fistula over several years. He was diagnosed with mucinous adenocarcinoma originating from a long-standing perianal fistula, but he initially refused surgical treatment. Two years later, the patient revisited with a huge overgrown tumor and underwent laparoscopic APR with wide perineal skin excision, wound debridement and coverage with a bilateral V-Y advancement flap via a one-step procedure. DISCUSSION: High degree of clinical suspicion is crucial to diagnose this rare disease that can easily be missed at an early stage. Depending on the disease stage, surgical treatment, chemotherapy, and radiotherapy can be considered. CONCLUSION: Histopathological evaluation should be performed on recurrent and incurable anal fistulas over a long period of time. Intensive surgical treatment with or without neoadjuvant and adjuvant therapy should be considered in advanced cases.

Diminished Expression of P-glycoprotein Using Focused Ultrasound Is Associated With JNK-Dependent Signaling Pathway in Cerebral Blood Vessels.

MRI-guided focused ultrasound (MRgFUS) combined with microbubbles (MBs) is a promising technology that can facilitate drug delivery through a temporarily disrupted blood-brain barrier (BBB) and induce the down-regulation of P-glycoprotein (P-gp) expression on the blood vessels. Despite the increasing evidence regarding the down-regulation of P-gp expression after MRgFUS BBB disruption (BBBD), its underlying molecular events remain unclear. The aim of this study was to evaluate the underlying mechanism of FUS BBBD-mediated P-gp down-regulation. While our results showed down-regulation of P-gp at 24 h post-BBBD in transcriptional and translational levels, restoration to the normal expression appeared at different time points for transcriptional (72 h) and translational (120 h) levels. In addition, the signaling molecule, JNK, was significantly activated in the cerebral blood vessels at 24 h post-BBBD. Although P-gp levels were significantly decreased, the expression levels of proteins involved in the integrity of blood vessels, such as Glut1, ZO-1 and occludin, were not decreased at 24 h post-BBBD. Our study suggests that the JNK signaling pathway is involved in the regulation of FUS-induced P-gp expression, without affecting vessel integrity, and a detailed regulatory mechanism can provide the basis for clinical application of FUS to the treatment of neurological disease.

Synergistic Effects of Beta Tri-Calcium Phosphate and Porcine-Derived Decellularized Bone Extracellular Matrix in 3D-Printed Polycaprolactone Scaffold on Bone Regeneration.

Bone-derived extracellular matrix (ECM) is widely used in studies on bone regeneration because of its ability to provide a microenvironment of native bone tissue. However, a hydrogel, which is a main type of ECM application, is limited to use for bone graft substitutes due to relative lack of mechanical properties. The present study aims to fabricate a scaffold for guiding effective bone regeneration. A polycaprolactone (PCL)/beta-tricalcium phosphate (ß-TCP)/bone decellularized extracellular matrix (dECM) scaffold capable of providing physical and physiological environment are fabricated using 3D printing technology and decoration method. PCL/ß-TCP/bone dECM scaffolds exhibit excellent cell seeding efficiency, proliferation, and early and late osteogenic differentiation capacity in vitro. In addition, outstanding results of bone regeneration are observed in PCL/ß-TCP/bone dECM scaffold group in the rabbit calvarial defect model in vivo. These results indicate that PCL/ß-TCP/bone dECM scaffolds have an outstanding potential as bone graft substitutes for effective bone regeneration.

Full Thickness Skin Expansion ex vivo in a Newly Developed Reactor and Evaluation of Auto-Grafting Efficiency of the Expanded Skin Using Yucatan Pig Model.

BACKGROUND: Skin grafts are required in numerous clinical procedures, such as reconstruction after skin removal and correction of contracture or scarring after severe skin loss caused by burns, accidents, and trauma. The current standard for skin defect replacement procedures is the use of autologous skin grafts. However, donor-site tissue availability remains a major obstacle for the successful replacement of skin defects and often limits this option. The aim of this study is to effectively expand full thickness skin to clinically useful size using an automated skin reactor and evaluate auto grafting efficiency of the expanded skin using Yucatan female pigs. METHODS: We developed an automated bioreactor system with the functions of real-time monitoring and remote-control, optimization of grip, and induction of skin porosity for effective tissue expansion. We evaluated the morphological, ultra-structural, and mechanical properties of the expanded skin before and after expansion using histology, immunohistochemistry, and tensile testing. We further carried out in vivo grafting study using Yucatan pigs to investigate the feasibility of this method in clinical application. RESULTS: The results showed an average expansion rate of 180%. The histological findings indicated that external expansion stimulated cellular activity in the isolated skin and resulted in successful grafting to the transplanted site. Specifically, hyperplasia did not appear at the auto-grafted site, and grafted skin appeared similar to normal skin. Furthermore, mechanical stimuli resulted in an increase in COL1A2 expression in a suitable environment. CONCLUSIONS: These findings provided insight on the potential of this expansion system in promoting dermal extracellular matrix synthesis in vitro. Conclusively, this newly developed smart skin bioreactor enabled effective skin expansion ex vivo and successful grafting in vivo in a pig model.

Controlled release of paclitaxel using a drug-eluting stent through modulation of the size of drug particles in vivo.

Drug-eluting stents (DESs) are generally used in percutaneous coronary intervention. Paclitaxel (PTX) is widely used in DESs to suppress neointima, which causes restenosis. However, the PTX release profile is slow owing to its hydrophobic properties, resulting in negative effects on re-endothelialization in vessels. In this study, we assessed the effects of the controlled release of PTX particles of specific sizes on in-stent restenosis (ISR). PTX particle sizes were controlled by adjusting the evaporating temperature of the solvent from 25 to 80°C during ultrasonic coating, and DESs were prepared. The properties of prepared films and DESs were analyzed, and cell viability was assessed in vitro and in vivo. Poly(lactic-co-glycolic acid) (PLGA)/PTX500-loaded stents showed the most rapid release for 58 days, and smaller drug particles exhibited lower PTX release rates. In vivo, PLGA/PTX50-, PLGA/PTX250-, and PLGA/PTX500-loaded stents showed good efficacy for alleviating ISR as compared with bare metal stents and PLGA/PTX5-loaded stents. However, PLGA/PTX250- and PLGA/PTX500-loaded stents exhibited strut exposure and reduced recovery of the vascular compared with PLGA/PTX50-loaded stents. PTX drug particles of approximately 50 nm were most effective in vivo, and the control of particle size is a promising strategy for improving the performance of PTX-eluting stents. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2275-2283, 2018.

Rapid expansion and auto-grafting efficiency of porcine full skin expanded by a skin bioreactor ex vivo.

Full skin auto-grafts are required for reconstruction of skin burns and trauma scars. However, currently available clinical approaches such as sheet skin graft, mesh skin grafts, artificial skin graft, and in vivo skin expansion have limitations due to their potential danger for secondary damage and scar formation at the donor site, and discomfort during skin expansion. We developed an advanced bioreactor system and evaluated its function in skin expansion using porcine full skin. The reactor was designed as a pneumatic cylinder type, was programmed to adjust the pressure and the operating time. The system was composed of culture chamber unit, environmental control unit, and monitoring unit. Skins were expanded at 200 kPa pneumatic force and the expanded skins were analyzed by immunohistochemistry and histology. Furthermore we carried out auto-grafting experiment of the expanded skins in vivo using Yucatan pigs and skins were harvested and histologically analyzed after 8 weeks. The results showed that the bioreactor expanded skins to 160% in 4 hours. Histological analysis of the expanded skins revealed that epidermal cells and dermal fibroblasts were viable and remained integrity. The results of auto-grafting experiment indicated that fibrosis and scars were not detected in the grafted skins. This study demonstrates that the newly developed skin bioreactor enabled to obtain large sized full skin rapidly and successful grating.

Porous zirconia/hydroxyapatite scaffolds for bone reconstruction.

OBJECTIVE: Highly porous apatite-based bioceramic scaffolds have been widely investigated as three-dimensional (3D) templates for cell adhesion, proliferation, and differentiation promoting the bone regeneration. Their fragility, however, limits their clinical application especially for a large bone defect. METHODS: To address the hypothesis that using a ZrO(2)/hydroxyapatite (HAp) composite might improve both the mechanical properties and cellular compatibility of the porous material, we fabricated ZrO(2)/HAp composite scaffolds with different ZrO(2)/HAp ratios, and evaluated their characteristics. In addition, porous ZrO(2)/HAp scaffolds containing bone marrow derived stromal cells (BMSCs) were implanted into critical-size bone defects for 6 weeks in order to evaluate the bone tissue reconstruction with this material. RESULTS: The porosity of a ZrO(2)/HAp scaffold can be adjusted from 72% to 91%, and the compressive strength of the scaffold increased from 2.5 to 13.8MPa when the ZrO(2) content increased from 50 to 100wt%. The cell adhesion and proliferation in the ZrO(2)/HAp scaffold was greatly improved when compared to the scaffold made with ZrO(2) alone. Moreover, in vivo study showed that a BMSCs-loaded ZrO(2)/HAp scaffold provided a suitable 3D environment for BMSC survival and enhanced bone regeneration around the implanted material. SIGNIFICANCE: We thus showed that a porous ZrO(2)/HAp composite scaffold has excellent mechanical properties, and cellular/tissue compatibility, and would be a promising substrate to achieve both bone reconstruction and regeneration needed in the treatment of large bone defects.

Chitooligosaccharides decreases plasma lipid levels in healthy men.

Chitosan, which is derived from chitin, has drawn much attention due to its low toxicity and potential use in medical and pharmaceutical applications. The biological activities of chitosan have been shown to depend on its molecular weight (MW) and degree of deacetylation. In this study, we investigated whether oral chitooligosaccharides, which are easily absorbed into the body, can reduce the plasma level of lipid in smokers and non-smokers because smoking is a high-risk factor for cardiovascular diseases. All healthy men (11 smokers and 8 non-smokers) consumed 500 mg of chitooligosaccharides in water twice daily before a meal (breakfast and dinner) over a 6-week period. Total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased in both the smoker group and non-smoker group when compared with baseline. These results suggest that low MW chitooligosaccharides would be an effective dietary supplement for lowering cholesterol level.

Zirconia-hydroxyapatite composite material with micro porous structure.

OBJECTIVES: Titanium plates and apatite blocks are commonly used for restoring large osseous defects in dental and orthopedic surgery. However, several cases of allergies against titanium have been recently reported. Also, sintered apatite block does not possess sufficient mechanical strength. In this study, we attempted to fabricate a composite material that has mechanical properties similar to biocortical bone and high bioaffinity by compounding hydroxyapatite (HAp) with the base material zirconia (ZrO(2)), which possesses high mechanical properties and low toxicity toward living organisms. METHODS: After mixing the raw material powders at several different ZrO(2)/HAp mixing ratios, the material was compressed in a metal mold (8 mm in diameter) at 5 MPa. Subsequently, it was sintered for 5 h at 1500°C to obtain the ZrO(2)/HAp composite. The mechanical property and biocompatibility of materials were investigated. Furthermore, osteoconductivity of materials was investigated by animal studies. RESULTS: A composite material with a minute porous structure was successfully created using ZrO(2)/HAp powders, having different particle sizes, as the starting material. The material also showed high protein adsorption and a favorable cellular affinity. When the mixing ratio was ZrO(2)/HAp=70/30, the strength was equal to cortical bone. Furthermore, in vivo experiments confirmed its high osteoconductivity. SIGNIFICANCE: The composite material had strength similar to biocortical bones with high cell and tissue affinities by compounding ZrO(2) and HAp. The ZrO(2)/HAp composite material having micro porous structure would be a promising bone restorative material.

Crystallinity of anodic TiO2 nanotubes and bioactivity.

Anodic TiO2 nanotubes were produced on titanium at 20 V using 1 M Na2SO4 and 0.5 wt% NaF. Oxidation for 3 hours produced amorphous tubes of diameter 100 nm and thicknesses 2 microm. Heat-treatments were done for 3 hours at different temperatures. 300 degrees C treatment converted the amorphous coatings to anatase. 550 and 700 degrees C treatments formed dual anatase and rutile; 850 degrees C treatment crystallized to rutile. The treatment at 700 degrees C produced an oxide surface with higher roughness, lower wetting angle and higher coating adhesion. Bioactivity of the as-oxidized and heated coatings were evaluated by treating them in a simulated body fluid (SBF) to form hydroxyapatite (HA) and the rates of HA formation were compared. Deposits of HA could be seen on the dual oxide structure within 3 days. HA was detected after 7 days in the anatase structure and only after 21 days in the amorphous and rutile structures. In vitro cell culture tests done using mouse osteoblasts indicated that, the 700 degrees C-heated surface showed higher levels of cell activity than the other surfaces. It is concluded that the dual rutile and anatase structure formed by heating the oxide at 700 degrees C is the best of the five surfaces tested.

Hydrogel-based biomimetic environment for in vitro modulation of branching morphogenesis.

The mechanical properties of the cellular microenvironment dramatically alter during tissue development and growth. Growing evidence suggests that physical microenvironments and mechanical stresses direct cell fate in developing tissue. However, how these physical cues affect the tissue morphogenesis remains a major unknown. We explain here that the physical properties of the cell and tissue microenvironment, biomimetically reproduced by using hydrogel, guide the tissue morphogenesis in the developmental submandibular gland (SMG). In particular, the softer gel enhances the bud expansion and cleft formation of SMG, whereas the stiffer gel attenuates them. These morphological changes in SMG tissue are led by soluble factors (FGF7/10) induction regulated by cell traction force derived from the tissue deformation. Our findings suggest that cells sense the mechanics of their surrounding environment and alter their properties for self-organization and the following tissue morphogenesis. Also, physically designed hydrogel material is a valuable tool for producing the biomimetic microenvironment to explore how physical cues affect tissue morphogenesis and to modulate tissue morphogenesis for in vitro tissue synthesis.

Treadmill exercise suppresses muscle cell apoptosis by increasing nerve growth factor levels and stimulating p-phosphatidylinositol 3-kinase activation in the soleus of diabetic rats.

We investigated the effects of treadmill exercise performed regularly for 6 weeks on the levels of nerve growth factor (NGF), tyrosine kinase A and p75 receptors, phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase/extracellular signal-regulated kinase (Erk) 1,2, cyclic AMP response element-binding protein (CREB), and caspase-3 in the soleus of rats with streptozotocin (STZ)-induced diabetes. Thirty-two male Sprague-Dawley rats were divided into the following four groups: (1) normal control group (NCG; n = 8), (2) normal exercise group (NEG; n = 8), (3) diabetes control group (DCG; n = 8), and (4) diabetes exercise group (DEG; n = 8). Diabetes was induced by intraperitoneal injection of STZ (55 mg/kg dissolved in 0.05 M citrate buffer, pH 4.5). Rats were subjected to treadmill exercise 5 days a week for 6 weeks. The protein level of NGF significantly increased in the NEG and DEG (p < 0.001), whereas the levels of tyrosine kinase A and p75 receptors significantly increased in the NEG (p < 0.001). The levels of t-PI3-K, p-PI3-K, and p-CREB, and the p-CREB/t-CREB ratio significantly increased in the NEG (p < 0.001, respectively). The p-PI3-K/t-PI3-K ratio significantly increased in the DEG (p < 0.001). The p-Erk1/t-Erk1 ratio significantly increased in the NEG (p < 0.001), whereas the p-Erk2/t-Erk2 ratio significantly decreased in the DCG and DEG (p < 0.001). The caspase-3 level significantly increased in the DCG compared with that in the DEG (p < 0.001). These results suggest that treadmill exercise increases NGF levels and accelerates p-PI3-K activation in order to suppress apoptotic cell death in the soleus muscle of diabetic rats.