Chang-Yong Ko

Heparin‐Coated Gold Nanoparticles for Liver‐Specific CT Imaging

Since computed tomography (CT) was developed and its resolution, sensitivity, and scan speed rapidly improved, the use of CT in the diagnosis of hepatic disease has been evaluated by various investigators. In particular, liver-specific X-ray CT imaging has attracted much attention in cancer diagnosis and cancer treatment because liver metastases are a common occurrence in the history of a patient affected by various cancers. The liver is the organ most frequently involved in metastases due to its high volume of blood flow, the suitable size of sinusoids for trapping metastatic cells, and rich environment for rapid growth. The sensitivity of liver imaging needs to be guaranteed in cancer detection because diagnosis of liver metastasis at an early stage mainly relies on imaging and all liver metastases begin with a microscopic-sized tumor. However, in CT imaging, the detection of liver lesions is impossible without the use of contrast-enhancing agents, although, even then, the problem of distinguishing between small vessels and small liver tumors is an issue. For this reason, the demand for a tissue-specific X-ray contrast agent has increased, although there are a few products available they have limitations for clinical application. Although low-molecular-weight iodinated contrast agents are generally used in CT imaging, they have serious limitations in clinical applications due to their low liver uptake, rapid renal excretion, and lack of membrane permeation; this leads to renal toxicity and high viscosity of the injectable formulation. To overcome the undesirable pharmacokinetics and limitations, low-molecular-weight iodinates have been chemically conjugated to high-molecular-weight polymers or encapsulated into liposomes and polymeric micelles. These macromolecular and nanosized contrast agents display enhanced blood-circulating characteristics in vivo as well as providing liver-specific CT images. However, they still show a lower imaging resolution with respect to differentiating liver tissues from other vessels, organs, and cancers because iodine-based contrast agents inherently possess a lower X-ray absorption coefficient. Another novel inorganic nanoparticle-based CT contrast agent has been proposed. Polymer-coated bismuth sulfide (Bi2S3) nanoparticles showed high X-ray absorption compared with iodinated imaging agents, but their size and shape were not easy to [a] I.-C. Sun, J. H. Na, Dr. S. Lee, Dr. I.-C. Youn, Dr. K. Choi, Dr. I. C. Kwon, Dr. K. Kim Biomedical Research Center Korea Institute of Science and Technology 39-1 Hawolgok-dong, Seongbuk-gu, Seoul, 136-791 (Korea) Fax: (+82)2-958-5909 E-mail : kim@kist.re.kr [b] D.-K. Eun, Dr. C.-H. Ahn Research Institute of Advanced Materials (RIAM) Department of Materials Science and Engineering Seoul National University San 56-1, Sillim, Gwanak, Seoul, 151-744 (Korea) Fax: (+82)2-883-8197 E-mail : chahn@snu.ac.kr [c] I.-J. Kim Department of Chemistry, College of Science, Korea University Anam-dong, Seongbuk-gu, Seoul 136-791 (Korea) [d] Dr. C.-Y. Ko, Dr. H.-S. Kim Department of Biomedical Engineering, Yonsei University Wonju, Ganwondo, 220-710 (Korea) [e] Dr. D. Lim Silver Technology Center, Korea Institute of Industrial Technology 35-5 Hongcheon, Ipjang, Cheonan, Chungnam (Korea) [f] Dr. P. B. Messersmith Biomedical Engineering, Northwestern University 2145 Sheridan Road, Evanstron, IL 60208 (USA) [g] Dr. T. G. Park Department of Biological Sciences Korea Advanced Institute of Science Technology Daejeon 305-701 (Korea) [h] Dr. S. Y. Kim Department of Otolaryngology-Head and Neck Surgery Asan Medical Center, College of Medicine, University of Ulsan Seoul 138-736 (South Korea) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902344.

Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice

Regulation of the formation and function of bone-resorbing osteoclasts (OCs) is a key to understanding the pathogenesis of skeletal disorders. Gene-targeting studies have shown that the RANK signaling pathway plays a critical role in OC differentiation and function. Although pharmaceutical blockade of RANK may be a viable strategy for preventing bone destruction, RANK is implicated in multiple biological processes. Recently, a cytoplasmic motif of RANK was identified that may be specifically involved in OC differentiation. Here, we developed a cell-permeable inhibitor termed the RANK receptor inhibitor (RRI), which targets this motif. The RRI peptide blocked RANKL-induced OC formation from murine bone marrow-derived macrophages. Furthermore, RRI inhibited the resorptive function of OCs and induced OC apoptosis. Treatment with the peptide impaired downstream signaling of RANK linked to Vav3, Rac1, and Cdc42 and resulted in disruptions of the actin cytoskeleton in differentiated OCs. In addition, RRI blocked inflammation-induced bone destruction and protected against ovariectomy-induced bone loss in mice. These data may be useful in the development of selective therapeutic agents for the treatment of osteoporosis and other bone diseases.

Systemic transplantation of human adipose-derived stem cells stimulates bone repair by promoting osteoblast and osteoclast function

Systemic transplantation of adipose‐derived stem cells (ASCs) is emerging as a novel therapeutic option for functional recovery of diverse damaged tissues. This study investigated the effects of systemic transplantation of human ASCs (hASCs) on bone repair. We found that hASCs secrete various bone cell‐activating factors, including hepatocyte growth factor and extracellular matrix proteins. Systemic transplantation of hASCs into ovariectomized mice induced an increased number of both osteoblasts and osteoclasts in bone tissue and thereby prevented bone loss. We also observed that conditioned medium from hASCs is capable of stimulating proliferation and differentiation of osteoblasts via Smad/extracellular signal‐regulated kinase (ERK)/JNK (c‐jun NH2‐terminal kinase) activation as well as survival and differentiation of osteoclasts via ERK/JNK/p38 activation in vitro. Overall, our findings suggest that paracrine factors secreted from hASCs improve bone repair and that hASCs can be a valuable tool for use in osteoporosis therapy.

Low-intensity ultrasound stimulation prevents osteoporotic bone loss in young adult ovariectomized mice†

Osteoporosis is a disease characterized by low bone mass, increased bone fragility, and a greater risk for bone fracture. Currently, pharmacological intervention can generally aid in the prevention and treatment of osteoporosis, but these therapies are often accompanied by undesirable side effects. Therefore, alternative therapies that minimize side effects are necessary. Biophysical stimuli, especially low‐intensity ultrasound stimulation (LIUS), may be potential alternatives to drug‐based therapies for osteoporosis. Hence, we sought to address whether LIUS therapy can effectively prevent or treat osteoporotic bone loss induced by estrogen deficiency. LIUS (1.5 MHz frequency, 1.0 kHz pulse repetition on frequency, 30 mW/cm2 intensity, 200 µs pulse length) was applied to right tibiae of eight 14‐week‐old ovariectomized virgin ICR female mice for 20 min per day, 5 days per week, over a 6‐week period. Changes in 3D structural bone characteristics were detected using in vivo micro‐computed tomography. Left tibiae served as controls. Structural characteristics including bone volume/tissue volume, trabecular number, trabecular bone pattern factor, and mean polar moment inertia were significantly enhanced 6 weeks after LIUS compared to the control, nonstimulated group (p < 0.05). In particular, the bone volume/tissue volume in the region exposed directly to LIUS was significantly higher in the treated group (p < 0.05). These findings indicate that new bone formation may be activated or that bone structure may be maintained by LIUS, and that LIUS may be effective for preventing estrogen deficiency‐induced bone loss.

Low-level laser therapy using the minimally invasive laser needle system on osteoporotic bone in ovariectomized mice.

This study tested the effectiveness of low-level laser therapy (LLLT) in preventing and/or treating osteoporotic trabecular bone. Mice were ovariectomized (OVX) to induce osteoporotic bone loss. The tibiae of eight OVX mice were treated for 5 days each week for 2 weeks by LLLT (660 nm, 3 J) using a minimally invasive laser needle system (MILNS) which is designed to minimize loss of laser energy before reaching bone (LASER group). Another eight mice received a sham treatment (SHAM group). Structural parameters of trabecular bone were measured with in vivo micro-computed tomography images before and after laser treatment. After LLLT for 2 weeks, the percentage reduction (%R) was significantly lower in BV/TV (bone volume fraction) and Tb.N (trabecular number, p<0.05 and p<0.05) and significant higher in Tb.Sp (trabecular separation) and SMI (structure model index, p<0.05 and p<0.05) than in the SHAM group. The %R in BV/TV at sites directly treated by LLLT was significantly lower in the LASER group than the SHAM group (p<0.05, p<0.05). These results indicated that LLLT using MILNS may be effective for preventing and/or treating trabecular bone loss and the effect may be site-dependent in the same bone.

Trabecular bone response to mechanical loading in ovariectomized Sprague-Dawley rats depends on baseline bone quantity

Mechanical loading is one of the determining factors for bone modulation, and is therefore frequently used to treat or prevent bone loss; however, there appears to be no data on the effects of baseline bone quantity on this response. This study aimed to verify whether baseline bone quantity affects osteoporotic trabecular bone adaptive response to mechanical stimulation. Twenty-four female Sprague-Dawley (SD) rats were ovariectomized (OVX). After 3 weeks of OVX, rats were divided into a high bone quantity and a low bone quantity group, and rats in each group were then subdivided into 4 groups that were exposed to different loading strategies. In the loading groups, tibiae were stimulated through axial loading at 2000με of strain, for 1500 cycles each of 75s, 150s, or 250s. The sham treatment groups received no loading. Changes in BV/TV for trabecular bone in the tibia were measured at the baseline (before loading), and at 3 weeks and 6 weeks after loading. BV/TVs in loading groups of the low baseline bone quantity group were significantly increased at 6 weeks, compared with those in the no-loading groups (p<0.05), while those in the high quantity groups were not increased (p>0.05). A significant negative correlation was observed between baseline BV/TV and its relative variations at 3 weeks or 6 weeks (p<0.05). These results indicate that adaptive responses of osteoporotic trabecular bone to mechanical loading depend on baseline bone quantity.

Development of a shear measurement sensor for measuring forces at human-machine interfaces.

Measuring shear force is crucial for investigating the pathology and treatment of pressure ulcers. In this study, we introduced a bi-axial shear transducer based on strain gauges as a new shear sensor. The sensor consisted of aluminum and polyvinyl chloride plates placed between quadrangular aluminum plates. On the middle plate, two strain gauges were placed orthogonal to one another. The shear sensor (54 mm × 54 mm × 4.1 mm), which was validated by using standard weights, displayed high accuracy and precision (measurement range, -50 to 50 N; sensitivity, 0.3N; linear relationship, R(2)=0.9625; crosstalk error, 0.635% ± 0.031%; equipment variation, 4.183). The shear force on the interface between the human body and a stand-up wheelchair was measured during sitting or standing movements, using two mats (44.8 cm × 44.8 cm per mat) that consisted of 24 shear sensors. Shear forces on the sacrum and ischium were almost five times higher (15.5 N at last posture) than those on other sites (3.5 N on average) during experiments periods. In conclusion, the proposed shear sensor may be reliable and useful for measuring the shear force on human-machine interfaces.

The Effects of Partial Vibration on Tibia of Osteoporosis Induced Rat

The pharmacological therapies and whole body vibration as non-pharmacological therapies were known to have adverse side effects. Therefore, partial stimulation was suggested and its effects were evaluated. This study aimed to evaluate the site-specific effects of partial stimulator for treatment of osteoporosis induced by estrogen deficiency. Sixteen virginal Sprague-Dawley rats (12 weeks old) were divided into 2 groups(no stimulation, stimulation groups). All rats were ovariectomised to induce osteoporosis. After 3 weeks of operation, the right tibiae in rats of stimulation group (frequency: 10Hz, cycle: 1500, strain on bone surface: 2000µe) were stimulated perpendicularly at right tibia by using partial stimulator for 6 weeks (3days/week). The right tibiae in rats were scanned, before stimulation (0 week) and at 6 weeks after stimulation by using invivo micro computed tomography. For investigation of changes in morphological characteristics, structural parameters were measured and calculated. At 6 weeks the morphological characteristics (relative value) in stimulation group were significantly enhanced than those in no stimulation group (p<0.05). In this study, we find that after 6 weeks of partial stimulation, the morphological characteristics of tibia trabecular bone were enhanced. Thus, we concluded that partial stimulation could be used to treat osteoporosis.

Bilateral asymmetry in microarchitecture of trabecular bone in male c57bl/6 mouse tibia: implication for experimental sample size estimations

This study aimed to determine whether there is bilateral asymmetry between the left and right tibiae in the microarchitectural characteristics of the trabecular bone and estimate a moderate sample size for detections of such bilateral differences. The left and right tibiae of 20 C57BL/6 mice (12 weeks old) were scanned by micro-computed tomography, and the structural parameters of the trabecular bone were measured. There were significant differences in the structural parameters between the left and right tibiae (p<0.05); specifically, the microarchitecture was greater in quantity and quality in the left tibia than in the right tibia. Moreover, the percent of bilateral differences between the left and right tibiae ranged from 2.26% to 22.52%. For most of the structural parameters except for trabecular bone thickness (Tb.Th) and trabecular bone separation (Tb.Sp), the 20 mice involved in this study were enough to detect differences. These results show that the directional left–right asymmetry in the microarchitecture of the trabecular bone may exist despite the samples being from an inbred strain. Furthermore, we estimated a sample size for detections of such differences between the left and right tibiae.

Effects of Combined Stimulus on Stress Relief

This study was designed to investigate the effect of a combined stimulus which was composed of chi- ropractic massage and thermotherapy on the relief of mental and physical stress. Fifteen healthy male subjects were treated with three type of stimuli; control (without any stimulus), a single stimulus (only chiropractic) and a combined stimulus. To evaluate the effects of stimuli, visual analogue scale (VAS), trunk extension, electromyogram (EMG) on erector spinae muscle and electrocardiogram (ECG) were measured and analyzed before and after stimuli. In the control group, there were no significant changes in EMG root mean square (RMS) value and low Frequency / high Frequency (LF/HF) ratio (p > 0.05, p > 0.05). However, both stimulus groups showed significant increases in trunk extension and EMG RMS values (p < 0.05, p < 0.05), but significant decreases in LF/HF ratios (p < 0.05). Partic- ularly the decrement rate in LF/HF ratio was significantly higher in the combined stimulus group than that in the single stimulus group (p < 0.05). Also, a significantly lower VAS was recorded after combined stimulus. Our findings indicate that the combined stimulus might not only improve flexibility and strength of muscle, but also active para- sympathetic nerve activity. The combined stimulus may thus contribute to relieve the stress and to enhance the mus- cle function.