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The Effect and Limitation of Drug Diffusion by a Novel Pressurized Intraperitoneal Aerosol Chemotherapy in an Ex Vivo Model Mimicking the Human Abdominal Cavity : 새로운 가압 복강 내 에어로졸 화학 요법에 의한 인간 복강을 모방 한 Ex Vivo 모델에서의 약물 확산의 효과와 한계

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dc.contributor.advisor이마리아-
dc.contributor.author박금란-
dc.date.accessioned2022-04-20T07:58:19Z-
dc.date.available2022-04-20T07:58:19Z-
dc.date.issued2021-
dc.identifier.other000000166396-
dc.identifier.urihttps://hdl.handle.net/10371/179053-
dc.identifier.urihttps://dcollection.snu.ac.kr/common/orgView/000000166396ko_KR
dc.description학위논문(박사) -- 서울대학교대학원 : 의과대학 의학과, 2021.8. 이마리아.-
dc.description.abstractBackground: Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has been introduced as a novel technique of intraperitoneal chemotherapy for the treatment of peritoneal metastasis (PM) caused by advanced or recurrent solid tumors. PIPAC has been implemented in clinical medicine mainly in Europe. But the PIPAC machine has not been imported to South Korea and is not affordable in market. So, before conducting this part of ex vivo experiment, we collaborated with medical biomechanics and design laboratory in Seoul National University redesigned and reconstructed the well-established prototype and this project implemented to investigate the pattern of tissue penetration according to different nozzle position and to find the best position resulting in best drug delivery.
Material and Methods: Fresh postmortem peritoneum tissues were cut into 8 identical pieces and fixed at different spatial places A-H considering the asymmetrical abdominal cavity in 2cm-,4cm- and 8cm- ex vivo models. Ex vivo experiment performed using a novel prototype, that sprayed about 30-μm droplets at flow rate of 30ml/min under the pressure of 7 bars. Methylene blue staining aera on six faces in the three ex vivo models were observed with naked eyes. The penetration depth was evaluated with the depth of concentrated diffusion (DCD) and the depth of maximal diffusion (DMD) of doxorubicin using confocal laser scanning microscopy after the application of 4,6-diamidino-2-phenylindole to the tissue specimens. The counted highest number of DCD and DMD was performed to compare the score of three ex vivo models.
Results: In terms of the distribution, the 4cm- and 8cm-ex vivo models showed more stained faces than the 2cm-ex vivo model, the closer nozzle to the bottom of the model, the more unevenly distributed methylene blue was observed. With different nozzle positions, the best tissue penetration found at different tissue sample and the pattern of doxorubicin penetration in the 8 sample tissues change accordingly. After we counted the number of the highest DCD and DMD values and found that 4cm-ex vivo model showed the highest score of 5 (62.5%).
Conclusion: Drug delivery into the peritoneum tissue during PIPAC differs according to different nozzle position and the optional nozzle position for best drug delivery should be determined in consideration of the three-dimensional structure of the abdominal cavity. Further in vivo study is needed to determine optional nozzle position and rotated nozzle can be expected to improve diffusion and penetration of aerosol during PIPAC
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dc.description.abstract배경: 가압복강내에어로졸항암요법은 solid종양의 복강내 전이종양의 새로운 치료방법으로 잘 알려져 있다. 가압복강내에어로졸항암요법은 현재 주로 유럽에서 잘 사용되고 있다. 그러나 가압복강내에어로졸항암요법은 현재 국내에 도입이 되여있지 않고 시중에서 구매할수 없다. 본 실험을 진행하기 앞서 서울대학교 의공학과와 콜라보를 하여 새로운 PIPAC prototype을 만들었으며 본 prototype을 사용해 prototype의 노즐의 위치가 변함에 따라 조직의 penetration이 어떻게 변화를 하는지 어떤 위치에 있을 경우에 가장 이상적인 delivery를 얻어낼 수 있는지 알아보려고 한다.
자료와 방법: 8개의 똑 같은 크기의 신선한 사후 실험돼지의 복막조직(A-H)을 인체의 비대칭구조를 모방하여 만든 ex vivo 모델의 부동한 공간위치에 부착을 하였다. 노즐과 ex vivo모델의 밑부분과의 거리 2cm-,4cm-,8cm를 선택했다. 본 ex vivo 모델에서 새로운 prototype를 사용했으며 본 prototype은 30-μm 크기의 에어로졸들을 30ml/min의 유속으로 7 bar의 압력아래 분사한다. Ex vivo 모델내에 약물의 분포도는 methylene blue로 축정했으며 눈으로 관찰하여 측정하였다. 조직의 약물 침투는 depth of concentrated diffusion (DCD)와 depth of maximal diffusion (DMD)를 측정하여 confocal laser scanning microscopy로 관찰하였고 부동한 ex vivo 모델끼리 비교 분석하였다. 각 모델의 가장 높은 DCD와 DMD를 카운트한결과 4cm-ex vivo 모델에서 가장 이상적인 약물delivery가 측정되었다.
결과: 4cm-와8cm-ex vivo모델에서 2cm-ex vivo모델보다 약물의 분포가 가장 잘 측정되었다. 노즐위치가 다름에 따라 각 조직의 약물침투패턴이 다르며 각 위치에서 가장 높은 약물침투가 측정되는 조직 또한 다르다. 항암제의 약물전달은 4cm-ex vivo 모델에서 가장 훌륭한 DCD와 DMD 5 (62.5%)이 측정되었다.
결론: 본 prototype을 사용했을 때 노즐위치에 따본 ex vivo model의 각 타깃조직의 penetration패턴이 다르며 노즐위치가 다름에 따라 약물침투가 가장 많이 되는 조직 또한 다르다. 인체 복강의 복잡한 three-dimensional구조를 고려했을 때 노즐위치를 위아래로 바꾸거나 각도를 바꾸는 방법으로 더 우월한 delivery를 얻을 수 있을 것이다. 향후 in vivo실험을 더 진행해야 할 필요성이 있다.
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dc.description.tableofcontentsChapter 1. Ex vivo Experiment of Pressurized Intraperitoneal Aerosol Chemotherapy: A Review 6
1.1 Introduction 6
1.1.1 Ovarian cancer 6
1.1.2 Peritoneal metastasis 6
1.2 Diagnosis of Peritoneal Metastasis 7
1.3 Treatment of Peritoneal Metastasis 8
1.3.1 Intravenous chemotherapy (IV) 8
1.3.2 Intraperitoneal chemotherapy (IP) 8
1.3.3 Hyperthermic intraperitoneal chemotherapy 10
1.3.4 Pressurized intraperitoneal aerosol chemotherapy 11
1.4 Methodological Aspects of PIPAC 12
1.5 The Microinjection Pump 13
1.6 Ex Vivo Experiment of PIPAC 14
1.6.1 Ex vivo model of PIPAC 15
1.6.2 Position to detect drug penetration depth 16
1.6.3 Nozzle position 16
1.7 Previous Studies of Ex Vivo Experiment of PIPAC 16
1.7.1 Effect of MIP position on drug delivery in the ex vivo model of PIPAC 16
1.7.2 Effect of internal pressure on the drug delivery in the ex vivo model of PIPAC 17
1.7.3 Effect of drug dosage on drug delivery in the ex vivo model of PIPAC 17
1.7.4 Exploring drug distribution in the ex vivo model 17
1.7.5 Effect of irradiation on the tissue penetration depth in the ex vivo model of PIPAC 18
1.7.5 Exploring particle stability and structure during the ex vivo experiment of PIPAC 18
1.7.6 Research about particle application range during ex vivo experiment of PIPAC 19
1.8 Discussion 19
1.9 Conclusion 21
Chapter 2. Evaluation of Drug Delivery into the Peritoneum Based on Nozzle Position during Pressurized Intraperitoneal Aerosol Chemotherapy in an ex vivo Model 22
2.1 Study Background 22
2.2 Purpose of Research 24
2.3 Materials and Method 26
2.3.1 Novel PIPAC system developed in Seoul National University 26
2.3.2 Novel ex vivo model of PIPAC 27
2.3.3 Procedure of ex vivo experiment of PIPAC 29
2.3.4 The distance between nozzle and the bottom of the model 30
2.3.5 Detection of doxorubicin penetration depth using confocal fluorescence microscopy 30
2.3.6 Distribution analysis 31
2.3.7 Statistical analysis 31
2.4 Results 32
2.4.1 Microscopic confocal laser analysis of DCD and DMD at various nozzle positions according to the distance between nozzle and the bottom 32
2.4.2 Comparison of DCD at various nozzle positions according to the distance between the nozzle and the bottom 32
2.4.3 Comparison of DMD at various nozzle positions according to distance between the nozzle and the bottom 33
2.4.4 Spatial distribution pattern of methylene blue in the novel ex vivo model of PIPAC 34
2.5 Discussion 44
2.6 Acknowledgements 49
References 50
Chapter 3. 초록 56
Chapter 4. Thank You Letters 57
Chapter 5. Abbreviations 58
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dc.format.extentii, 59-
dc.language.isoeng-
dc.publisher서울대학교 대학원-
dc.subjectPressurized intraperitoneal chemotherapy-
dc.subjectPeritoneal metastasis-
dc.subjectEx vivo-
dc.subjectNozzle-
dc.subject.ddc610-
dc.titleThe Effect and Limitation of Drug Diffusion by a Novel Pressurized Intraperitoneal Aerosol Chemotherapy in an Ex Vivo Model Mimicking the Human Abdominal Cavity-
dc.title.alternative새로운 가압 복강 내 에어로졸 화학 요법에 의한 인간 복강을 모방 한 Ex Vivo 모델에서의 약물 확산의 효과와 한계-
dc.typeThesis-
dc.typeDissertation-
dc.contributor.AlternativeAuthorJINLAN PIAO-
dc.contributor.department의과대학 의학과-
dc.description.degree박사-
dc.date.awarded2021-08-
dc.contributor.major산부인과학-
dc.identifier.uciI804:11032-000000166396-
dc.identifier.holdings000000000046▲000000000053▲000000166396▲-
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