A Study on the Development and Effectiveness of ISO13485: 2016 Education Programs for Domestic Medical Device Manufacturers

Purpose As ISO 13485 was revised in 2016, the domestic GMP (Good Manufacturing Practice) system was also revised and implemented in 2019. However, there are many problems in the domestic medical device industry because most of the small and medium-sized enterprises lack human and material resources. Accordingly, this study was conducted to provide education programs for domestic medical device companies to induce information provision and improve the company’s quality management ability. Methods First, analyze existing education. Second, based on the revised GMP system, a survey paper was produced to investigate difficulties and problems experienced by companies. Third, a two-week survey was conducted on domestic medical device manufacturers, and a total of 77 companies responded to this survey. Fourth, educational program development was conducted based on the results of the survey. Results and Conclusion The developed education program consists of a total of five sessions. In this study, the educational program developed by grasping the needs of the company through a survey consists of a total of five sessions. The first session consisted of theoretical education and the second to fifth sessions of practical education. Through the education program developed in this study, it is expected to contribute to the overall development of medical device quality by establishing a domestic medical device manufacturing environment that secures the safety and performance of domestic medical device companies.ope

Hydrogel cross-linking-programmed release of nitric oxide regulates source-dependent angiogenic behaviors of human mesenchymal stem cell

Angiogenesis is stimulated by nitric oxide (NO) production in endothelial cells (ECs). Although proangiogenic actions of human mesenchymal stem cells (hMSCs) have been extensively studied, the mechanistic role of NO in this action remains obscure. Here, we used a gelatin hydrogel that releases NO upon crosslinking by a transglutaminase reaction ("NO gel"). Then, the source-specific behaviors of bone marrow versus adipose tissue-derived hMSCs (BMSCs versus ADSCs) were monitored in the NO gels. NO inhibition resulted in significant decreases in their angiogenic activities. The NO gel induced pericyte-like characteristics in BMSCs in contrast to EC differentiation in ADSCs, as evidenced by tube stabilization versus tube formation, 3D colocalization versus 2D coformation with EC tube networks, pericyte-like wound healing versus EC-like vasculogenesis in gel plugs, and pericyte versus EC marker production. These results provide previously unidentified insights into the effects of NO in regulating hMSC source-specific angiogenic mechanisms and their therapeutic applications. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).ope

A Micro-Costing Analysis of Flexible Bronchoscopic Intubation in a Korean Tertiary Hospital

Objectives: To evaluate the per-procedure cost of flexible bronchoscopic intubation in relation to the monetary value of the practice expense relative value units (RVUs) of the procedure. Methods: A micro-costing analysis of flexible bronchoscopic intubation was performed in the anesthesiology and pain medicine department of a Korean tertiary hospital over the fiscal year 2019. Cost records were collected and then categorized into three cost components: depreciation of reusable flexible bronchoscopes and video equipment, reprocessing, and repairs. The per-procedure cost was calculated by dividing the total annual cost by the annual number of flexible bronchoscopic intubations performed. The resulting per-procedure cost was then compared to the monetary value of the practice expense RVUs of the procedure. Considering that the annual procedural volume would significantly impact per-procedure costs and overall profitability, a deterministic sensitivity analysis (DSA) was conducted. Results: In total, 748 flexible bronchoscopic intubations were performed during the fiscal year. Total annual costs for depreciation of the bronchoscopes and video equipment, reprocessing, and repair were US$31,921, US$ 22,268, and US$22,948 respectively. The calculated per-procedure cost of the flexible bronchoscopic intubation in the period was US$ 103.1 while the fee listed in the fee schedule and the monetary value of the practice expense RVUs of the procedure were US$69.9 and US$ 52.2 respectively. Therefore, the procedure was performed at a loss over the period: the amount that the subject department lost with respect to the practice expense RVUs totaled as much as US$ 38,039. The DSA demonstrated that the procedure would remain unprofitable even if twice the volume of procedures were performed over the same duration (n=1,500). Conclusion: The findings suggest that HIRA’s determination of the practice expense RVUs of the procedure may have been underestimated and thus in need of review and recalculation to achieve adequate compensation. The per-procedure cost would vary by procedural volume and site of practice which indicates that a further multicenter study is required to confirm the study’s findings.ope

Selective inhibitory effect of epigallocatechin-3-gallate on migration of vascular smooth muscle cells

In order to prevent restenosis after angioplasty or stenting, one of the most popular targets is suppression of the abnormal growth and excess migration of vascular smooth muscle cells (VSMCs) with drugs. However, the drugs also adversely affect vascular endothelial cells (VECs), leading to the induction of late thrombosis. We have investigated the effect of epigallocatechin-3-gallate (EGCG) on the proliferation and migration of VECs and VSMCs. Both cells showed dose-dependent decrease of viability in response to EGCG while they have different IC(50) values of EGCG (VECs, 150 mM and VSMCs, 1050 mM). Incubating both cells with EGCG resulted in significant reduction in cell proliferation irrespective of cell type. The proliferation of VECs were greater affected than that of VSMCs at the same concentrations of EGCG. EGCG exerted differential migration-inhibitory activity in VECs vs. VSMCs. The migration of VECs was not attenuated by 200 mM EGCG, but that of VSMCs was significantly inhibited at the same concentration of EGCG. It is suggested that that EGCG can be effectively used as an efficient drug for vascular diseases or stents due to its selective activity, completely suppressing the proliferation and migration of VSMCs, but not adversely affecting VECs migration in blood vessels.ope

Ethyl-3,4-dihydroxybenzoate with a dual function of induction of osteogenic differentiation and inhibition of osteoclast differentiation for bone tissue engineering.

The current approach in biomaterial design of bone implants is to induce in situ regeneration of bone tissue, thus improving integration of the implants and reducing their failure. Therefore, ethyl-3,4-dihydroxybenzoate (EDHB), which stimulates differentiation of osteoblasts and the resultant bone formation, should be studied. In this study, the osteoinductive ability of EDHB in preosteoblasts and human mesenchymal stem cells was examined. EDHB for future use in bone tissue engineering was evaluated by examination of early markers of differentiation (such as alkaline phosphatase [ALP] activity and collagen type I expression) and late markers of osteoblast differentiation (bone nodule formation). As bone remodeling and implant osteointegration depend not only on osteoblast response but also on interaction of the biomaterial with bone-resorbing osteoclasts, differentiation of osteoclasts in response to the compounds was also observed. For in vivo study, alginate gel comprised of EDHB and cells was transplanted into the back subcutis of mice. Our results show that EDHB might have beneficial effects through regulation of both osteoblast and osteoclast differentiation. Therefore, we suggest that EDHB could be a strong candidate for dual regulation to increase osteoblast differentiation and decrease osteoclast differentiation.ope

Mitogenesis of Vascular Smooth Muscle Cell Stimulated by Platelet-Derived Growth Factor-bb Is Inhibited by Blocking of Intracellular Signaling by Epigallocatechin-3-O-Gallate

Epigallocatechin gallate (EGCG) is known to exhibit antioxidant, antiproliferative, and antithrombogenic effects and reduce the risk of cardiovascular diseases. Key events in the development of cardiovascular disease are hypertrophy and hyperplasia according to vascular smooth muscle cell proliferation. In this study, we investigated whether EGCG can interfere with PDGF-bb stimulated proliferation, cell cycle distribution, and the gelatinolytic activity of MMP and signal transduction pathways on RAOSMC when it was treated in two different ways—cotreatment with PDGF-bb and pretreatment of EGCG before addition of PDGF-bb. Both cotreated and pretreated EGCG significantly inhibited PDGF-bb induced proliferation, cell cycle progression of the G0/G1 phase, and the gelatinolytic activity of MMP-2/9 on RAOSMC. Also, EGCG blocked PDGF receptor- (PDGFR-) phosphorylation on PDGF-bb stimulated RAOSMC under pretreatment with cells as well as cotreatment with PDGF-bb. The downstream signal transduction pathways of PDGFR-, including p42/44 MAPK, p38 MAPK, and Akt phosphorylation, were also inhibited by EGCG in a pattern similar to PDGFR- phosphorylation. These findings suggest that EGCG can inhibit PDGF-bb stimulated mitogenesis by indirectly and directly interrupting PDGF-bb signals and blocking the signaling pathway via PDGFR- phosphorylation. Furthermore, EGCG may be used for treatment and prevention of cardiovascular disease through blocking of PDGF-bb signaling.ope

Locally delivered ethyl-2,5-dihydroxybenzoate using 3D printed bone implant for promotion of bone regeneration in a osteoporotic animal model

Osteoporosis is a disease characterized by low bone mass, most commonly caused by an increase in bone resorption that is not matched by sufficient bone formation. The most common complications of postmenopausal osteoporosis are bone-related defects and fractures. Fracture healing is a multifactorial bone regeneration process, influenced by both biological and mechanical factors related to age, osteoporosis and stability of the osteosynthesis. During the treatment of bone defects in osteoporotic conditions, imbalanced bone remodeling is the leading cause for implant failure. To overcome these problems, ethyl-2,5-dihydroxybenzoate (E-2,5-DHB), a drug that promotes bone formation and inhibits bone resorption, was used. E-2,5-DHB-incorporating titanium (Ti) implants using poly(lactic-co-glycolic acid) (PLGA) coating for local delivery of E-2,5-DHB were developed and the effects on bone healing of femoral defects were evaluated in an osteoporotic model. The release of E-2,5-DHB resulted in decreased bone resorption and increased bone formation around the implant. Thus, it was confirmed that, in the osteoporotic model, bone healing was increased and implant fixation was enhanced. These results suggested that E-2,5-DHB-coated Ti implants have great potential as an ultimate local drug delivery system for bone tissue scaffolds.ope

Methods for Evaluation of the Chemotactic Migration of the Cells in 3D Biomimetic Matrix

Cell migration plays a critical role in various biological processes such as embryogenesis, metastasis of tumor cells and wound healing. Therefore, the migratory behavior of the cells has been researched with various influencing factors including chemoattractants. Most researches have done with 2 dimensional (2D) structured stratums to investigate the cell migration, however, this study suggests three different methods for in vitro studies of cell migratory behavior which are performed in biomimetic 3D structural environment by using collagen matrix. In the firstly introduced method, wound model was built up with a silicon insert and the chemoattractant, PDGF-bb was applied. Then, the movement of the cells to the wound area was observed. It was designed for examination of the potential of wound healing effect of certain agents. Other two methods are to study chemotactic migration of the cells in the 3D matrix in the presence of the chemoattractant. The orientation of the cell migration was examined by the under-agarose cell migration assay as the cells were seeded between the control collagen gel and PDGF-bb containing collagen gel. The cells located in the middle of the migrating chamber were affected by the components in both sides and the direction of their movement was determined. The last method was also performed in a 3D collagen matrix and the cell suspension was directly contacted to the chemoattractant. Therefore, the movement behavior of the cells was influenced by the agent. These protocols have different characteristics to evaluate the migration of the cells, and thus an appropriate method would be chosen for various studies of migration.ope

Titanium surface modification by using microwave-induced argon plasma in various conditions to enhance osteoblast biocompatibility

BACKGROUND: Titanium is a well proven implantable material especially for osseointegratable implants by its biocompatibility and anti-corrosive surface properties. Surface characteristics of the implant play an important role for the evolution of bone tissue of the recipient site. Among the various surface modification methods, plasma treatment is one of the promising methods for enhance biocompatibility. We made microwave-induced argon plasma at atmospheric pressure to improve in titanium surface biocompatibility. RESULTS: Various states of emission spectra from excited species-argon, nitrogen atoms and oxygen atoms were observed. The electron energy band structures are the unique characteristics of atoms and functional groups. Microwave-induced argon plasma treatment changed the titanium surface to be very hydrophilic especially on the 5 s short treatment and 30 s, 90 s long treatment samples that detected by contact angle measurement. MC3T3-E1 attachment and proliferation assay significantly increased in 5 s at short treatment, 30 s, and 90 s at long treatment after 5 days incubation. CONCLUSIONS: Result indicated that microwave-induce argon plasma treatment would be an effective method to modify titanium surface for enhancing cell-material interactions.ope

Homogeneity evaluation of mesenchymal stem cells based on electrotaxis analysis

Stem cell therapy that can restore function to damaged tissue, avoid host rejection and reduce inflammation throughout body without use of immunosuppressive drugs. The established methods were used to identify and to isolate specific stem cell markers by FACS or by immunomagnetic cell separation. The procedures for distinguishing population of stem cells took a time and needed many preparations. Here we suggest an electrotaxis analysis as a new method to evaluate the homogeneity of mesenchymal stem cells which can observe the stem cell population in culture condition and wide use to various types of stem cells. Human mesenchymal stem cell, adipose derived stem cell, tonsil derived stem cell and osteogenic differentiated cells migrated toward anode but the migration speed of differentiated cells was significantly decreased versus that of stem cells. In mixture of stem cells and differentiated cells condition, we identified that the ratio of stem cell versus differentiated cell was matched with the homogeneity evaluation data of stem cells based on electrotaxis analysis. As a result, our evaluation tool has the possibility of the wide use to stem cell homogeneity evaluation and might be used as the stem cell quality control during stem cell culture without any additional antibodies.ope