[보고서]약제관련 악골괴사증 및 구강내병소의 비침습적 감압 처치를 위한 의료용 골내감압기와 골재생 치료기술 개발

김성민

약제관련 악골괴사증 및 구강내병소의 비침습적 감압 처치를 위한 의료용 골내감압기와 골재생 치료기술 개발
Development of intraossous decompression apparatus and bone regeneration therapy for the noninvasive decompressive drainage with therapeutic irrigation in the medication related osteonecrosis of jaw and other oral desease 원문보기

보고서 정보
주관연구기관	서울대학교 Seoul National University
연구책임자	김성민
참여연구자	이석근 , 권익재 , 박윤선 , 서미현 , 어미영 , 이수진 , 이용준 , 조윤주 , 김연숙 , 송지용 , 송희정 , 심한결 , 윤철수 , 이성현
보고서유형	최종보고서
발행국가	대한민국
언어	한국어
발행년월	2018-10
과제시작연도	2017
주관부처	보건복지부 [Ministry of Health & Welfare(MW)(MW)
등록번호	TRKO202200008588
과제고유번호	1465023936
사업명	질환극복기술개발
DB 구축일자	2022-09-24
키워드	약제관련 악골괴사증.구강내 병소.골재생.의료용 소형감압기.비침습적 감압처치.Medication.Intraoral pathology.Bone regeneration.Wifi controlled digitalized medical decompressive apparatus.Noninvasive decompression.

초록 ▼

□ 연구의 목적 및 내용
약제관련 악골괴사증 및 구강내병소의 비침습적 감압처치를 위한 의료용 골내감압기와 골재생 치료기술 개발하기 위하여 다음과 같이 8가지 세부목표를 설정하여 연구내용을 수행하였음.
1) 약제관련 악골괴사증의 동물실험모델 확립
2) 동물실험에서의 혈액학적 지표 개발
3) 임상에서의 혈액학적 지표 검증과 개념 증명
4) 펜톡시필린과 토코페를 복용 환자의 결과 분석
5) 의료용 소형감압기 (WDMDA) 의 임상적용
6) 구강악안면 병소에 사용되는 의료용 소형감압기 개발 및 골재생 촉진치료제 개발
7) 동물실험모델에서의 감압기와 약제 적용 효과검증 및 세포생물학적 내성 및 독성검사
8) 재구성된 수동 및 자동 소형감압기 (WDMDA)의 특허등록 및 골재생 촉진시키는 신의료기술 등록

□ 연구개발 성과
· 약제관련 악골괴사증 동물실험모델 외에 악골내 방사선골괴사증 모델, 세균감염 악골 골수염 모델 확립을 시작으로, 동물실험모델에서 혈액학적 지표 검증과 개념을 증명하였으며, IP-HPLC의 개념정립과 기본 측정 프로토콜 확립을 통해 임상환자의 혈액학적 지표검증에 있어 혈액 외에 술후 삼출액을 통해 치유과정을 검증하는 것이 가능하게 되었음
· 의료용 소형감압기 (WDMDA) 를 개발하여 발명명 ‘감압배농장치’로 특허 등록 및 PCT 출원하였으며, 시제품을 제작 및 의료용 소형감압기의 패키지를 구성하여 식약처 의료기기 허가 신청이 진행중에 있음.
· 골재생 촉진치료제 개발을 위하여 4-HR, Pamidronate, Phentoxifillyn 등 3가지 물질에 대하여 생쥐 RAW 274.7 세포와 사람의 HUVEC 세포에서의 단백질 발현에 대하여 분석하여 효과를 검증하였음.
· 본 연구기간 중 수행한 연구내용은 KCI급 5편, SCI(E)급 17편, SCOPUS 4편 논문게재하였으며, 국내 및 국제학술대회에서도 발표하였음.

□ 연구개발 성과의 활용계획 (기대효과)
기존의 수술적 접근, 침습적인 접근만이 고려되었던 다양한 형태의 악골 골수염 치료에서 본 연구결과로 개발한 의료용 소형감압기는 새로운 치료방법을 확립하고 진단목적으로도 응용할 수 있으며, 악골 골수염과 유사한 구강악안면 낭종병소들의 내압을 감소시키고 배농하는데 응용하여 사용할 수 있음.

(출처 : 요약문 13p)

Abstract ▼

□ Purpose & Contents
Eight detailed goals were set up as follows and the researches were conducted to development of intraosseous decompression apparatus and bone regeneration therapy for the noninvasive decompressive drainage with therapeutic irrigation in the medication-related osteonecrosis of jaws and other oral diseases.
1) Establishment of animal experiment model for medication-related osteonecrosis of the jaw
2) Development of hematologic indicators in animal experiment
3) Verification of hematologic indicators in clinical findings
4) Analysis of clinical outcomes of pentoxifyllin and tocopherol combined management in osteomyelitis patients
5) Clinical applications of the Wifi-controlled Digitalized Medical Decompressive Apparatus (WDMDA)
6) Development of the Wifi-controlled Digitalized Medical Decompressive Apparatus (WDMDA) and fast-healing agents in oral and maxillofacial pathologic lesions
7) Verification effectiveness of mini decompressor and drugs application in animal experiment models and along with the cytological immunity and toxicity
8) Patent registration of the Wifi controlled Digitalized Medical Decompressive Apparatus (WDMDA) and registration of new medical technology to promote bone regeneration.

□ Results
· Besides the animal model of medication-related osteonecrosis of the jaw, experimental model of radiation-related osteonecrosis of the jaw, and bacterial osteomyelitis of the jaw was established. The animal experiment models proved the concept and verification of the hematologic indicators, help to establish the concept of IP-HPLC and basic measurement protocol, make it's possible to verify the healing process by using the postoperative exudate in the difficulty of verifyinghematologic indicators of clinical patients.
· Developed the Wifi controlled Digitalized Medical Decompressive Apparatus (WDMDA), which was patent registered and PCT applied as invention name ‘Deconpressive pus drainage apparatus’. Moreover, the WDMDA prototype production and package are being applied for approval of the Korea Food and Drug Administration
· The effects of 4-HR, Pamidronate, and Pentoxifylline on protein expression were analyzed and verified for the development of bone regeneration promoting drugs in mouse RAW 274.7 cells and human HUVEC cells.
· The contents of the research carried out during this research period have been published on 5 KCI articles, 17 SCI(E) articles and 4 SCOPUS articles. Also the researches were presented at domestic and international conferences.

□ Expected Contribution
Recently, there are many interests and researches in bisphosphonate- or medication-related osteonecrosis of jaws, however many limitations also existed in the basic and transitional research of this fields. For overcoming these limitations, our new intraosseous decompressive and drainage apparatus will bring many good positive contributions in the effective management of osteomyelitis and other cystic pathology of the jaw.

(source : SUMMARY 14p)

목차 Contents

표지 ... 1
보고서요약 ... 2
제 출 문 ... 11
보고서 요약서 ... 12
국문 요약문 ... 13
SUMMARY ... 14
Contents ... 15
목차 ... 16
1. 연구개발과제의 개요 ... 18
1-1. 연구개발 목적 ... 18
1-2. 연구개발의 필요성 ... 18
1-3. 연구개발 범위 ... 23
2. 국내외 기술개발 현황 ... 25
3. 연구수행 내용 및 결과 ... 27
3-1. 연구개발 추진전략 및 방법 ... 28
3-2. 연구개발 추진일정 ... 29
3-3. 연구수행 내용 및 결과 ... 30
3-4. 연구성과 ... 131
4. 목표달성도 및 관련분야 기여도 ... 132
4-1. 목표달성도 ... 132
4-2. 관련분야 기여도 ... 132
5. 연구결과의 활용계획 ... 133
6. 연구과정에서 수집한 해외과학기술정보 ... 134
7. 연구개발성과의 보안등급 ... 134
8. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 134
9. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 135
10. 연구개발과제의 대표적 연구실적 ... 136
11. 기타사항 ... 137
12. 참고문헌 ... 138
끝페이지 ... 143

표/그림 (143)

표 다양한 BRONJ 환자들의 임상적 모습
표 미국에서 흔히 사용하는 골흡수억제제
표 혈관신생억제, 혈관 내피 성장 인자 (Vascular Endothelial Growth Factor, VEGF)를 target한 항암제
표 AAOMS 제시하는 BRONJ의 3가지 기준
표 BRONJ의 영향요인들
표 Relative potency of bisphosphonates (Coleman RE. Cancer Treat Rev. 2001:27:165-176)
표 Structures of bisphosphonate Frequency of ONJ Over Time http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM270958.pdf
표 Staging and Treatment Strategies [American Association of Oral and Maxillofacial Surgeons (AAOMS) 의 Update Position Paper 2014 참조]
표 술전 의료용 소형감압기 초창기 모식도
표 술후 의료용 소형감압기 초창기 모식도
표 새로운 의료용 소형감압기를 통해 악골내 결손부를 최소화하여 치료를 도모하게 됨
표 진공음압창상처치 모식도 (좌), 국내에서 사용되고 있는 전동식의료용흡인기와 본 연구에서 개발한 의료용 소형감압기 (우)
표 InfoV.A.C therapy unit 와 V.A.C granufoam dressing kit 의 식약처 허가 내용
표 비스포스포네이트 악골괴사 모델 실험에 사용한 약제 및 경구투여모델 실험 타임테이블
표 시기별로 희생하여 상하악골 발치부위를 임상적, Micro CT 및 조직학적 분석을 시행하였음
표 비스포스 포네이트 악골괴사 모델 실험에 사용한 약제 및 복강투여모델 실험 타임테이블
표 Artificial rat BRONJ lesion treated with no cessation of bisphosphonate therapy. A: Suppurative osteomyelitis with sequestrum (S, arrow) in the central area. E: High magnification of panel A, denoting a sequestrum (s, arrow) floated in suppurative inflammatory exudate. B, C, D: Osteonecrotic bony lesion with multiple reversal lines (arrows) and thin rims of immature bone in the periphery of trabecular bones. F, G, and H: Polarizing microscope images of B, C, and D, respectively. The reversal lines (arrows) in panel B showed almost no birefringence in panel F. The peripheral zone of trabecular bones (arrow heads) in panel C and D showed rare birefringence (arrow heads) in panel G and H
표 Artificial rat BRONJ lesion treated with cessation of bisphosphonate therapy. The granulomatous bony lesion was gradually organized with active osteophytic new bones. The necrotic exudate in the marrow space was gradually disappeared and replaced by granulation tissue rich in capillaries. A, B, and C were inflamed bony lesion, and they were observed under polarizing microscope in D, E, and F, respectively. The peripheral zone of trabecular bones (arrow heads) in panel B and C showed strong birefringence (arrow heads) in panel E and F
표 휴지기를 지닌 실험군에서의 골치유가 재현되는 Micro CT 모습과 BMD 비교 모습
표 기존의 방사선골괴사 동물모델을 정리하여 본 연구진의 모델을 확립함
표 외부방사선조사 골괴사 동물모델을 위한 타임테이블과 시행모습
표 비교 분석한 군별 조건과 실제 측정된 방사선량 및 체중변화에 대한 도표
표 점막염 확인을 위한 피부탈모의 임상모습
표 Micro CT 분석을 통한 시티 이미지 및 BMD 통계 그래프
표 Histological findings with 16 Gy irradiation showing resorption line (A1; arrow), micro abscess (A2,A3;arrow) and dead bone (C1,C2,E1,E2; arrow) with empty osteocytic lacunae (B,D,E1; arrowhead) in the defect site. A1 arrow: resorption line, A2 arrow, A3: abscess border line and abscess area; B arrow head: empty osteocytic lacunae; C1, C2 arrow: dead bone border line; D, E1 arrow head: empty osteocytic lacunae; E1, E2 arrow: dead bone border line
표 Histological findings with 18 Gy irradiation showing more dead bone than the bones irradiated with 16 Gy dose and the presence of resorption with osteoclast cells. The abscess (A1, A2, A3; arrow), inflammatory infiltrate (B1; arrow) and empty osteocytic lacunae (B2, B3; arrow head) were observed. The close-up of box in the C1 was magnified as C2. There are numerous osteoclast cells was observed in radionecrotic lesions border line. A1, A2 arrow, A3: abscess and abscess border line; B1 arrow: inflammatory cell; B2, B3 arrow head: empty osteocytic lacunae; C1,C2 arrow: osteoclast cells C3: internal osteoclast cells. A1,A2: resorption line; A3 arrow: inflammatory cell; B1,B2,B3 arrow head: empty osteocytic lacunae; C1,C2,C3 arrow: osteoclast cells; C3 arrow head: dead bone border line
표 Histological findings with 20 Gy irradiation. The histological features with 20 Gy irradiation showed the presence of resorption line (A1, A2) with osteoclast cells (C1, C2, C3; arrow), inflammatory infiltrate (A3) and empty osteocytic lacunae (B1, B2, B3; arrow head). A1, A2: resorption line; A3 arrow: inflammatory cell; B1, B2, B3 arrow head: empty osteocytic lacunae; C1, C2, C3 arrow: osteoclast cells; C3 arrow head: dead bone border line
표 세균 수 및 농도 설정에 사용된 장비 및 기구 그리고 진행 과정
표 그린플라스트를 활용하여 세균의 골결손부위에 유지시킴
표 백서 하악골의 골 결손부위를 임상적, 방사선학적으로 파악하는 모습
표 실험동물에서 미정맥 및 경정맥 채혈 모습
표 IP-HPLC 장비사진과 측정결과를 데이터화하여 분석함
표 다양한 골 질환별 창상치유 물질
표 BRONJ 환자에 대한 의무기록 리뷰에 대한 IRB 승인서 (좌측) 및 본 연구에서 진행한 혈액검사 지수 및 평균화한 수치와 통계방법의 명시 (우측)
표 Clinical data of 50 patients with BRONJ, 16 patients with chronic osteomyelitis, and patients data including chronic osteomyelitis, BRONJ, and ORN
표 Laboratory data including preoperative(좌상단), after biopsy(우상단), postoperative 1day(좌하단), and postoperative 5 to 7 days(우하단)
표 One-way ANOVA(좌) 및 Post-hoc test 결과(우)를 이용한 임상검사 수치의 통계분석 결과
표 Normalized ESR의 비교
표 Positive and negative predictive value for nESR values (nESR>0.45,0.50,0.55)
표 평균 Monocyte 및 normalized Monocyte 의 군별 비교
표 Positive and negative predictive value for nMonocyte values (nMonocyte>0.)
표 Index O = nESR + nMonocyte 의 골수염 형태별 비교
표 Clinical data of 20 patients with chronic osteomyelitis of jaws
표 The multiple reversal lines (arrows) of bisphosphonate (BP)-involved bones showed no birefringence. The immature bony matrix of bisphosphonate-related osteonecrosis of the jaws (BRONJ) also showed rudimentary or rare birefringence under the polarizing microscope in the histochemical staining with toluidine blue, Giemsa, Safranin O, van Gieson, and Masson″s trichrome (magnification 20e100 with scale bar). A and B, Toluidine blue staining disclosed multiple reversal lines (arrows) in BPinvolved bones (A), which were much thicker and irregularly curved compared to the control bone E and rare birefringence under the polarizing microscope (B). C and D (same section of A), Giemsa staining also disclosed multiple reversal lines (arrows) in BP-involved bones (C), which were much thicker and irregularly curved compared to the control bone (E) and rare birefringence under the polarizing microscope (D). E and F, Toluidine blue staining of ordinary chronic osteomyelitic bone under the polarizing microscope. The reversal lines (arrows) of chronic osteomyelitic bone were thin and linear, and gradually compressed and thinned as the lamellate bone mineralization advanced (E). The reversal lines (arrows) of chronic osteomyelitic bone showed strong birefringence under the polarizing microscope (F). G (same section of A) and H, The multiple reversal lines (arrows) of BPinvolved bone were strongly stained with Safranin O, indicating that they were immature with abundant organic elements (G and H). I and J, van Gieson staining also disclosed immature collagenous bony matrices not only in the reversal lines (arrows) but also in the woven bone matrix of BP-involved bones (#). K and L, Masson trichrome staining in the border area between normal lamellar bone (&) and BP-involved bone (@). The immature woven bone (@) of BRONJ was usually stained blue (K) and showed rare birefringence under the polarizing microscope (L)
표 Multiple reversal lines associated with immature woven bone in bisphosphonate (BP)-involved bones compared with none BP-involved osteomyelitic bones of the jaws (magnification 20e100 with scale bar). A and C, Masson trichrome stain. B and D, Under polarizing microscope, the immature woven bones (arrows) in BRONJ. E and G, Hematoxylin and eosin (H&E) stain. F and H, Under polarizing microscope, thick, irregular, and multiple reversal lines associated with immature woven bones (arrows) in bisphosphonate-related osteonecrosis of the jaws (BRONJ). I and K, H&E stain. J and L, Under polarizing microscope, thin reverse lines in noneBP-involved bone of chronic osteomyelitis which were gradually compressed and thinned between osteon structures (arrows)
표 Photomicrography of BRONJ in decalcified microsections stained with hematoxylin and eosin. A, Necrotic dead bones heavily infected by bacterial colonies, which subsequently extended into Volkmann canals (arrows) of bone. B, The filamentous bacterial colonies could directly destroy the bony matrix (arrow). C, A thick reversal line (arrows) was found in the woven bone infected by bacteria. Also, note the relatively homogenous bacterial flora. D, The reversal lines (arrows) were easily destroyed by bacterial infection. E, Thick basophilic lines (arrows) similar to reversal lines appeared in the marginal bones demineralized by bacterial infection. F, Note the thick reversal line (arrows) demarcating the outer woven bone, which was gradually resorbed by the bacterial infection
표 Measure area rectangle을 이용하여 평균 흑화도를 분석하는 기본적인 예시
표 골수염환자의 흑화도 비교 (좌측상단), 한 개의 파노라마에서 최대 및 최소 흑화도 값 (우측상단), 대조군인 정상 환자의 양측부위의 흑화도 비교 (좌측하단), 및 동일 환자에서 다른 시간 촬영한 경우의 비교 (우측하단)
표 골수염 환자와 대조군의 연령 분포의 통계적 유의성 검증
표 Conditional inference trees showing comparison between osteomyelitis patient and control group (A), between suppurative bacterial osteomyelitis, suppurative BRONJ, and control group (B), between osteoradionecrosis, sclerosing bacterial osteomyelitis, sclerosing BRONJ, and control group (C)
표 Schematic time tables of duration of latent, onset of osteoradionecrosis
표 A serial panoramic views of various surgical procedures in the left tongue cancer patient, after glossectomy with radial forearm flap reconstruction state (A), ORN suspicious state after radiotherapy (B), after wound debridement state (C), after sequestrectomy states (D, E), after decortication with seqestrectomy state (F, G), and reconstruction with fibular free flap state (H)
표 악골내 방사선골괴사증의 핵심 정리 내용
표 방사선골괴사증의 대표적인 임상적 분류
표 Scoring system of osteoradionecrosis
표 펜톡시필린의 화학적 구조로 메틸-크산틴 유도체로서 본 과제에서 기대되는 골내 세척수 후보제로 고려하였음
표 α-토코페롤의 화학식 구조와 연질의 액체로서 체내 흡수가 우수한 성상을 보여줌
표 악골내 방사선골괴사증 환자에 대한 분석연구 (좌측) 및 펜톡시필린과 토코페롤 처방한 환자와 처방하지 않은 환자의 비교연구 (우측) IRB 승인서
표 The method used in this study to quantify the densities of defects in the panoramic views. These analyses were performed using Adobe Photoshop CS6®Histogram(AdobeSyste mInc.,SanJose,CA,USA)
표 Serial occlusal clinical photos and panoramic views after using PTX and tocopherol in the Case No. 2 patient who had not undergone any surgery and had taken medication for ORN for 315 days, A,E; Before prescription, B, F; Three months after drug administration, C, G; Six months after drug administration, D, H; One year after drug administration
표 펜톡시필린과 토코페롤을 투여한 25명의 환자에 대한 테이터
표 Serial radiographic changes after using PTX and tocopherol in the Case No. 7 patient who began medications after surgical wound healing (56 days), A. Before surgical treatment, B. After surgery including extraction and saucerization and before beginning medications, C. Three months after drug administration, D. Six months after drug administration with the figure showing an extended osteolytic lesion
표 Serial radiographic changes with clinical photos after using PTX and tocopherol in the Case No. 10 patient who began PTX and tocopherol after surgical wound healing for treatment of BRONJ for 8 months, A. Clinical picture showing the pathologic lesion before surgery, B. One year after surgery and drug administration, C. Preoperative panorama showing the lesion extending to the mandibular border, D, One week after surgery, at the beginning treatment of PTX and tocopherol, E; Six months after drug administration, F; One year after drug administration
표 PTX와 토코페롤 사용 기간에 따른 방사선 사진의 변화의 비교
표 시간 경과에 따른 ESR의 변화
표 Clinical data of ten chronic mandibular osteomyelitis patients
표 Clinical data of 27 bisphosphonate-related osteonecrosis of mandible patients
표 Representative IP-HPLC chromatographic data demonstrating the changes of protein expression in the BRONJ POE compared to the CMO POE that was used as the control. In the BRONJ POE, the inflammation regulating protein TNFa was less expressed in the postoperative 6 h sample, but gradually recovered when the postoperative 2-day sample (a). The inflammation inhibitor IL-10 was overexpressed in the postoperative 6 h sample but dramatically decreased in the postoperative 1- and 2-day samples (b). The protein expressions of b-defensin-1, LL-37, VEGF-A, and bFGF gradually increased until the postoperative 2-day sample compared to the control (c-f)
표 Histopathologic photomicrographs of the BRONJ lesion. The involved bone was severely resorbed in the absence of osteocytes in their lacuna spaces and became necrotic (NB) and sequestered (a). In the high magnification of a, the dead bone was severely resorbed by the decomposition of its bony matrix with marked infiltration of inflammatory cells (b). On the other hand, the osteophytic new bone (arrow) was deposited in the fibrous granulomatous area (c). In the high magnification of c, the newly formed bone was abnormally condensed with immature osteocytes, producing woven bones demarcated by irregular and thick reversal lines (arrows, d)
표 Graphs plotted from the IP-HPLC data for the inflammationrelated proteins of the BRONJ POE samples taken 6 h, 1 day, and 2 days after surgical intervention compared to the 6 h CMO POE sample used as the control-bar (a) and line (b) graph. In the postoperative 6 h sample, the BRONJ exudate showed a greater expression of IL-10 and IL-28, but decreased the expression of TNFa and LL-37 compared to the control. In the postoperative 1-day sample, the BRONJ exudate showed more expression of TNFa, IL-6, -8, -12, -28, and a1-antitrypsin but less expression of CD68 and lysozyme than the control. In the postoperative 2-day sample, the BRONJ exudate consistently showed a greater expression of LL-37 and b-defensin-1 than the control. The macrophage markers, CD68, lysozyme, and a1-antitrypsin were relatively reduced in the BRONJ exudates compared to the control
표 Graphs plotted from the IP-HPLC data for the osteogenesis and angiogenesis-related proteins of the BRONJ POE sample taken 6 h, 1 day, and 2 days after surgical intervention compared to the CMO POE in 6 h as the control—-bar (a) and line (b) graph. In the BRONJ exudate taken 6 h after surgical intervention, a greater expression of OPG and osteocalcin was observed with a decreased expression of bFGF and ALP than the control. In the postoperative 1 day BRONJ exudate sample, an increased expression of VEGF-A and VEGF-C was observed, but a decreased expression of RANKL, bFGF, and ALP was seen compared to the control. In the BRONJ exudate taken 2 days after surgical intervention, a consistently greater expression of VEGF-A with a smaller expression of RANKL was observed compared to the control. The expressions of bFGF and ALP in the BRONJ exudates were almost recovered to the level of the control
표 Schematic demonstration of molecular signaling found in the BRONJ POE compared to the CMO as the control. The red arrows are the signals in the POE 6 h after surgical intervention, and indicate the primarystatus of BRONJ. The blue arrows are the signals in the POE 1 and 2 days after surgery and indicate the wound healing progress of BRONJ. A linear line represents a direct influence, and a dotted line means an indirect influence. The primary status of the BRONJ POE sample taken 6 h after surgery shows the inhibition of macrophage activation, osteogenesis, and angiogenesis, the upregulation of IL-10, and the downregulation of TNFa, IL-1, -6, -8, and -28, and antimicrobial proteins. The wound healing progress of BRONJ 1 and 2 days after surgery shows the increase of macrophage activation, osteogenesis, and angiogenesis, the downregulation of IL-10, and the upregulation of TNFa, IL-1, -6, -8, and -28, and antimicrobial proteins. Compared to the control, the BRONJ POE discloses the rapid elevation of inflammatory signaling followed by the increase of angiogenesis and osteogenesis for the wound healing progress of the BRONJ lesion
표 Measurement of radiographic density using Adobe Photoshop CS5 (Adobe Systems Inc., San Jose, CA)
표 Patient Characteristics According to Group
표 Radiographic views of the bony regeneration process at postoperative day 1 (A), 3 months (B) and 12 months (C) in group 1, and at postoperative day 1 (D), 3 months (E) and 12 months (F) in group 3
표 Panoramic views of the bony regeneration process in group 2, preoperative (A), endodontic treatment of involved molar (B), postoperative day 1 (C), 1 month (D) 3 months (E), 6 months (F), 12 months (G), 2 years (H), and 3 years (I)
표 Schematic representation of CNF classification based on clinical appearances limited to the neck and extended to the upper thoracic region
표 Representative photomicrographs of limited to neck type of CNF showing acute type with hematogenous spread within 2 weeks (a), subacute type with suppuration over 2–.4 weeks (b), and chronic type without suppuration over 4–.6 weeks (C)
표 Representative case of partial skin necrosis in the upper chest with thoracic extension showing multiple necrotic skin islands on frontal (a), left lateral (b), and right lateral views ©
표 Representative case of broad type CNF with whole skin necrosis and thoracic extension showing the whole skin necrosis from neck to upper chest (a), left lateral view (b), right lateral view with extension to upper and lateral neck ©
표 Clinical and radiological findings of case number 16, showing a preoperative panoramic view (A), surgical specimens (B), and the intraoral wound with drain insertion (C)
표 Representative IP-HPLC data demonstrating the changes in proteins expression of IL-1, IL-10, and LL-37 in the CSO POE. The primary POE at 6 h postsurgery was used as the control. The inflammation-regulating cytokine IL-1 was decreased 1 day postoperative but was markedly increased 2 days postoperative, while the anti-inflammatory cytokine IL-10 was increased 1 day postoperative but markedly decreased 2 days postoperative compared to the control. The innate immune protein LL-37 was decreased 1 day postoperative but was markedly increased 2 days postoperative compared to the control. The area values (mAU*s) of each chromatography peak are presented relative to the control (%)
표 Clinical data of the 16 chronic suppurative osteomyelitis patients in this study
표 Histopathologic photomicrographs of the infected CSO in patient number 16. The marrow space of the dead bone was filled with bacterial colonies (arrows, A), and suppurative necrotic inflammation with the diffuse infiltration of polymorphonuclear leukocytes, macrophages, and plasma cells in the marrow space (B)
표 Graphs plotted with the results of IP-HPLC analysis for the expression of inflammation-related proteins in the CSO POE at 6 h, 1 day, and 2 days post-surgery. A and B: Bar and line graphs, respectively, plotted with the same data, which were collected in triplicate. The CSO POE at 6 h showed the primary status of bony inflammation just after the surgical treatment, and it was used as a control in this study. In the CSO POE, the expressions of TNF-a, IL-8, IL-12, and lysozyme were slightly higher than the control until 1 day postoperative, but became lower than the control at 2 days postoperative, and the expression of macrophage factors, CD31 and CD68, were markedly decreased 1 day postoperative and remained reduced 2 days postoperative compared to the control. The expressions of innate immunity-related proteins, IL-1, IL-6, IL-28, and LL-37, were gradually increased at 2 days postoperative compared to the control, while the expression of inflammation inhibitory factor, IL-10, was markedly increased 1 day postoperative but rapidly decreased to the control level by day 2. The regulating proteins for immune reaction, NFkB, was slightly increased, but its inhibitor protein, IKK, was slightly decreased 2 days postoperative compared to the control
표 Graphs plotted with the results of the IP-HPLC analysis for angiogenesis- and osteogenesis-related protein expression in the CSO POE 6 h, 1 day, and 2 days after surgery. A and B: Bar and line graphs, respectively, plotted with the same data, which were collected in triplicate. The CSO POE at 6 h showed the primary status of bony inflammation just after the surgical interventions, and it was used as a control in this study. The CSO POE showed consistently increased expression of angiogenesis-related proteins, VEGF-A, VEGF-C, and bFGF, and remarkably increased expression of TGF-b1 at day 2 compared to the control. In addition, the CSO POE showed slightly increased expression of osteogenesis-related proteins, OPG and ALP, but decreased expression of RANKL at day 2 compared to the control
표 Schematic demonstration of molecular signaling found in the CSO POE at 1 day and 2 days compared to that of 6 h. The red arrows point to the signals in the control, indicating the primary status of CSO. The blue arrows point to the signals in the POE at 1 and 2 days, indicating the wound healing progress of CSO. The suppression of the innate immune system, angiogenesis, and osteogenesis by the bacterial infection in the bone marrow was gradually restored during the 2 days following surgery
표 Schematic drawing showing the autoinflammatory organ involvement of chronic recurrent multifocal osteomyelitis (CRMO)
표 Representative computed tomographic views of chronic recurrent multifocal steomyelitis in jaw case showing the lesion in the right mandible, axial (A), coronal (B), and sagittal (C)
표 Active bone lesion in the right mandible, L1, left iliac bone, left clavicle, right distal femur and right proximal tibia (좌), Some trabecular bones were thickened and deposited with osteophyticnew bones, butmostof marrow bones were thinned and shortened with the features of gradual bony resorption. These reactive bony reaction was coincident with degenerative fibrous marrow connective tissue slightly infiltrated with chronic inflammatory cells. But diffused granulomatous lesion or inflammatory abscess was not found (우)
표 감압기의 전체 크기 및 튜브의 단면 모식도
표 충전식 케이스 장착으로 삼성휴대폰 OTG 젠더로 쉽게 충전할 수 있음
표 논문에 기재한 모식도로 와이파이 조절이 가능하여 병원에서 지시한 시간, 빈도 및 내용으로 기능 중인 휴대용 감압기의 패용 모습
표 System and process specification for decompressive apparatus
표 Piezoelectric micropump 의 기본 재원 및 내외면 구조
표 Main features and specification of SDMP320® micro piezopump
표 의료용 소형감압기 (WDMDA) 전체 모식도와 실물사진, 그리고 ㈜메디움사에서 요청한 시제품 명세서
표 4-hexylresorcinol (4-HR)의 화학 구조식
표 KSMCB 2018 International conference 초록집 표지 및 발표한 포스터
표 동물실험모델의 대조군과 실험군의 예시
표 세균감염 동물모델의 배액관 및 세척수 치료 실험 타임테이블
표 UV/VIS 분광광도계 (Spectrophotometer, Perkin Elmer Col. Korea) 장비를 사용하여 산란광 측정범위 600nm에서 OD 0.8의 S. aureus 희석액 준비
표 결손부 위치는 앞니 루트의 손상을 피하기 위해 루트 아래쪽에 위치하며, 3대구치 위치와 하악골 하연의 선을 따라 산을 이루는 점을 기준으로 뒤쪽에 직경 4mm의 결손부를 만듬
표 4-Hexylresorcinol 98% 의 모습과 4-Hexylresorcinol 98% 194.27 mg을 100% alcohol 100ml에 희석하여 사용하는 모습
표 피부 및 근육 절개, 박리시행 및 round bur를 이용하여 직경 4 mm 의 결손부를 생성하고, 107 CFU/ml 농도의 S. aureus 희석액 20ul 주입한 후, S. aureus 희석액 주입 후 유실방지를 위해 fibrin glue를 위치시키고 근육층과 피부층을 봉합하는 실험모습
표 감염 후 2주 감염치료 시행하여 주사기를 이용하여 pus 제거, 이후 절개 후 괴사조직 제거 및 괴사골의 curettage 시행후 배액관 삽입 후 봉합하거나, 또는 배액관 통해 세척하는 모습
표 체중 측정하여 증감량을 체크. 감염수술후 1주, 감염치료후1주차에 체중감소를 보이며, 전체동물의 체중을 비교한것과 실험군별로 비교하였을때 비슷한 패턴을 보였음
표 Micro CT 의 리컨스트럭션을 위한 부위 기준과 BMD 측정, 그리고 군별 비교모습
표 H&E 염색에 의한 군별 조직화학적 검사의 비교 모습
표 1차년도부터 자체 제작한 골내삽입튜브의 prototype 과 단면 모습
표 전체 골내삽입튜브의 길이 및 외형 모습
표 기존 2개의 도관으로 연결할 수 있는 튜브를 일체형으로 제작한 단면과 투명한 단면 모습
표 다양한 병소내에 삽입된 일체형 및 분리형 튜브 모습
표 감압기를 통해 배농시킨 삼출액을 IP-HPLC 를 통한 Protein expression profile을 직접 확인함으로서 앞으로 개발할 세척수 등의 효과를 직접 확인하고, 병소 부위의 치유과정 등을 수치화된 데이터로 분석하는 전 과정의 모습
표 생물학적 안전성 시험항목 선택을 위한 접촉부위에 따른 분류와 접촉기간에 따른 분류의 예시(의료기기 생물학적 안전성 통합 가이드라인 참조)
표 치의생명과학연구원 및 의생명연구원의 견적서 내용으로 1억여원이 요구됨을 확인함
표 하악골 대부분을 차지하는 큰 병소에서 Z11 골내삽입튜브가 장착된 임상 (A) 및 방사선사진 (B) 모습과 만 7일이 경과한 후에 제거된 튜브 모습 (C)
표 표준과학연구원의 시험인증서 및 외부기관에서의 시험분석인증서의 예시
표 의료용 소형감압기에서 제일 중요한 압력시험에 대한 표준과학연구원의 시험인증서 및 결과
표 감압기 내부 회로 구성 및 애플리케이션 설치 모식도
표 작동모드를 압력별로 최소한의 단계별로 표시하고 간헐 및 연속 모드 등으로 나누어 세팅함
표 압력과 작동시간 및 간격이 녹색램프로 표시됨
표 넥서스비 온라인 화면 및 자료실에 프로그램이 등록된 화면
표 프로그램 파일 다운로드 후 압축해제 후 휴대폰에 전송 후 앱을 설치 후 실행한 모습
표 한국기계전기전자시험연구원에서 승인된 전자파 안정성 실험 결과지
표 PCT 출원에 포함된 일체형 감압배농튜브 및 트로카의 모식도
표 감압배농장치의 도면 및 특허증
표 참여기업 ㈜신흥의 GMP 사본 및 의료용 소형감압기 (WDMDA) 제조 견적서 사본
표 의료용 소형감압기 (WDMDA) system의 구성
표 식품의약품안전처 의료기기안전국 온라인 화면으로 세운메디칼의 의료기기 제품정보 (좌), Barovac 제품의 품목정보 (우)
표 세운메디칼에서 제조 및 판매하는 Wound drainage system 제품
표 Input drain system 구성품으로 Trocar needle (좌), Round type wound tube (중간), Jackson pratt wound tube (우) 사진
표 구강내 사용을 위해 향후 구성이 필요한 Trocar needle의 디자인
표 본 연구실에서 규격 사이즈를 조사한 Container 종류 (좌) 및 사용할 container의 최종 디자인 (우)
표 의료용 소형감압기 (WDMDA) 와 구성되는 drain system 의 세부 내용
표 국내 의료기기의 개발-허가-시판 후 관리 절차 (좌측) 및 의료기기 2등급 허가절차 과정 (우측)
표 의료용 소형감압기 (WDMDA) 의 전체 구성 및 WDMDA 시제품 명세서
표 식약처 의료기기 전자민원창구 온라인 신청 화면
표 신의료기술 시장진입 절차도
표 신의료기술 등재 과정
표 건강보험심사평가원 기존기술여부 확인 신청 화면 및 신청서
표 한국보건의료연구원 신의료기술평가 신청서 제출 화면
표 한국보건의료연구원 신의료기술평가 온라인 신청서 및 오프라인 신청서

과제명(ProjectTitle) :	-
연구책임자(Manager) :	-
과제기간(DetailSeriesProject) :	-
총연구비 (DetailSeriesProject) :	-
키워드(keyword) :	-
과제수행기간(LeadAgency) :	-
연구목표(Goal) :	-
연구내용(Abstract) :	-
기대효과(Effect) :	-

내보내기 구분	파일저장 인쇄 메일전송
구성항목	기본정보 상세정보 관리번호, 제목(한글), 저자명(한글), 발행일자, 전자원문, 초록(한글), 초록(영문) 관리번호, 제목(한글), 제목(영문), 저자명(한글), 저자명(영문), 주관연구기관(한글), 주관연구기관(영문), 발행일자, 총페이지수, 주관부처명, 과제시작일, 보고서번호, 과제종료일, 주제분류, 키워드(한글), 전자원문, 키워드(영문), 입수제어번호, 초록(한글), 초록(영문), 목차
저장형식	Text(ASCII format) Excel format
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

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