Byeong Cheol Kang

Safety of Intravenous Infusion of Human Adipose Tissue-Derived Mesenchymal Stem Cells in Animals and Humans

Adipose tissue-derived mesenchymal stem cells (AdMSCs) represent an attractive and ethical cell source for stem cell therapy. With the recent demonstration of MSC homing properties, intravenous applications of MSCs to cell-damaged diseases have increased. In the present study, the toxicity and tumorigenicity of human AdMSCs (hAdMSCs) were investigated for clinical application. Culture-expanded hAdMSCs showed the typical appearance, immunophenotype, and differentiation capacity of MSCs, and were genetically stable at least 12 passages in culture. Cells suspended in physiological saline maintained their MSC properties in a cold storage condition for at least 3 days. To test the toxicity of hAdMSCs, different doses of hAdMSCs were injected intravenously into immunodeficient mice, and the mice were observed for 13 weeks. Even at the highest cell dose (2.5×10(8) cells/kg body weight), the SCID mice were viable and had no side effects. A tumorigenicity test was performed in Balb/c-nu nude mice for 26 weeks. Even at the highest cell dose (2×10(8) MSCs/kg), no evidence of tumor development was found. In a human clinical trial, 8 male patients who had suffered a spinal cord injury >12 months previous were intravenously administered autologous hAdMSCs (4×10(8) cells) one time. None of the patients developed any serious adverse events related to hAdMSC transplantation during the 3-month follow-up. In conclusion, the systemic transplantation of hAdMSCs appears to be safe and does not induce tumor development.

Establishment of Efficacy and Safety Assessment of Human Adipose Tissue-Derived Mesenchymal Stem Cells (hATMSCs) in a Nude Rat Femoral Segmental Defect Model

Human adipose tissue-derived mesenchymal stem cell (hATMSC) have emerged as a potentially powerful tool for bone repair, but an appropriate evaluation system has not been established. The purpose of this study was to establish a preclinical assessment system to evaluate the efficacy and safety of cell therapies in a nude rat bone defect model. Segmental defects (5 mm) were created in the femoral diaphyses and transplanted with cell media (control), hydroxyapatite/tricalcium phosphate scaffolds (HA/TCP, Group I), hATMSCs (Group II), or three cell-loading density of hATMSC-loaded HA/TCP (Group III-V). Healing response was evaluated by serial radiography, micro-computed tomography and histology at 16 weeks. To address safety-concerns, we conducted a GLP-compliant toxicity study. Scanning electron microscopy studies showed that hATMSCs filled the pores/surfaces of scaffolds in a cell-loading density-dependent manner. We detected significant increases in bone formation in the hATMSC-loaded HA/TCP groups compared with other groups. The amount of new bone formation increased with increases in loaded cell number. In a toxicity study, no significant hATMSC-related changes were found in body weights, clinical signs, hematological/biochemical values, organ weights, or histopathological findings. In conclusion, hATMSCs loaded on HA/TCP enhance the repair of bone defects and was found to be safe under our preclinical efficacy/safety hybrid assessment system.

Modeling Parkinson's disease in the common marmoset (Callithrix jacchus): overview of models, methods, and animal care

The common marmoset (Callithrix jacchus) is a small-bodied, popular New World monkey and is used widely in reproductive biology, neuroscience, and drug development, due to its comparative ease of handling, high reproductive efficiency, and its unique behavioral characters. In this review, we discuss the marmoset models in Parkinsons disease (PD), which is a neurological movement disorder primarily resulting from a degeneration of dopaminergic neurons with clinical features of tremor, rigidity, postural instability, and akinesia. The most common PD models involve the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine to study the pathogenesis and to evaluate novel therapies. Following the systemic or local administration of these neurotoxins, the marmosets with very severe Parkinsons symptoms are recommended to be placed in an intensive care unit with artificial feeding to increase survival rate. All procedures with MPTP should be conducted in a special room with enclosed cages under negative-pressure by trained researchers with personal protection. Behavioral tests are conducted to provide an external measure of the brain pathology. Along with several biomarkers, including α-synuclein and DJ-1, non-invasive neuroimaging techniques such as positron emission tomography and magnetic resonance imaging are used to evaluate the functional changes associated with PD. With the recent growing interest in potential and novel therapies such as stem cell and gene therapy for PD in Korea, the marmoset can be considered as a suitable non-human primate model in PD research to bridge the gap between rodent studies and clinical applications.

Non‐invasive Transdermal Delivery Route Using Electrostatically Interactive Biocompatible Nanocapsules

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (03-PJ1-PG1-CH14-0001).

Insulin Facilitates the Recovery of Myocardial Contractility and Conduction during Cardiac Compression in Rabbits with Bupivacaine-Induced Cardiovascular Collapse

Bupivacaine inhibits cardiac conduction and contractility. Insulin enhances cardiac repolarization and myocardial contractility. We hypothesizes that insulin therapy would be effective in resuscitating bupivacaine-induced cardiac toxicity in rabbits. Twelve rabbits were tracheally intubated and midline sternotomy was performed under general anesthesia. Cardiovascular collapse (CVC) was induced by an IV bolus injection of bupivacaine 10 mg/kg. The rabbits were treated with either saline (control) or insulin injection, administered as a 2 U/kg bolus. Internal cardiac massage was performed until the return of spontaneous circulation (ROSC) and the time to the return of sinus rhythm (ROSR) was also noted in both groups. Arterial blood pressure, and electrocardiography were continuously monitored for 30 min and plasma bupivacaine concentrations at every 5 min. The ROSC, ROSR and normalization of QRS duration were attained faster in the insulin-treated group than in the control group. At the ROSC, there was a significant difference in bupivacaine concentration between two groups. Insulin facilitates the return of myocardial contractility and conduction from bupivacaine-induced CVC in rabbits. However, recovery of cardiac conduction is dependent mainly on the change of plasma bupivacaine concentrations.