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Transport Tijdens Intraperitoneale Chemotherapie Modeling of Drug Modelleren van geneesmiddelenverdeling en -transport tijdens intraperitoneale chemotherapie Modeling of Drug Delivery and Transport during Intraperitoneal Chemotherapy Margo Steuperaert Promotoren: prof. dr. ir. P. Segers, prof. dr. W. Ceelen, prof. dr. ir. C. Debbaut Proefschrift ingediend tot het behalen van de graad van Doctor in de ingenieurswetenschappen: biomedische ingenieurstechnieken Vakgroep Elektronica en Informatiesystemen Voorzitter: prof. dr. ir. K. De Bosschere Faculteit Ingenieurswetenschappen en Architectuur Academiejaar 2019 - 2020 ISBN 978-94-6355-307-0 NUR 954 Wettelijk depot: D/2019/10.500/115 Supervisors: Prof. Dr. Ir. Patrick Segers Prof. Dr. Wim Ceelen Prof. Dr. Ir. Charlotte Debbaut Research lab: Institute Biomedical Technology Biofluid, Tissue and solid Mechanics for medical applications (bio- MMeda) Ghent University Corneel Heymanslaan 10 - blok B (entrance 36) B-9000 Gent, Belgium Members of the exam committee: Chairman: prof. Dr. Ir. Patrick De Baets Faculty of Engineering and Architecture, UGent Secretary: Prof. Dr. Christian Vanhove Faculty of Engineering and Architecture, UGent Reading committee: Prof. Dr. Christian Vanhove Faculty of Engineering and Architecture, UGent Prof. Dr. Katrien Remaut Faculty of Pharmaceutics, UGent Prof. Dr. Ir. Pascal Verdonck Faculty of Engineering and Architecture, UGent Prof. Dr. Ir. Geraldine Heynderickx Faculty of Engineering and Architecture, UGent Department of Medical Physics, Dr. Steven Sourbron University of Leeds (UK) This research was supported by the FWO grant: G012513N (Integrated Dy- namic Functional Imaging and Numerical Simulation of Mass Transport for the Assessment of Intraperitoneal Chemotherapy for Carcinomatosis) TABLEOF CONTENTS Table of Contents vii List of Figures xi List of Tables xiii Abbreviations and Symbols xv Samenvatting xix Summary xxvii Introduction and Problem Statement xxxiii I Introduction, background and goal of this dissertation 1 1 Anatomy and physiology of the peritoneum 3 1.1 Macroscopic anatomy . 3 1.2 Microscopic anatomy . 5 1.2.1 Mesothelial layer and basal lamina . 5 1.2.2 Submesothelial layer . 6 1.3 Physiology of the peritoneum . 8 1.3.1 Transmembrane transport . 8 1.3.2 Inflammation response . 9 1.3.3 Antigen presentation . 9 1.3.4 Tissue repair . 9 1.4 Peritoneal fluid flow . 10 2 Pathophysiology of peritoneal metastases 13 2.1 Origin of peritoneal carcinomatosis . 13 2.1.1 Primary peritoneal cancers . 14 2.1.2 Secondary peritoneal cancers . 18 vii TABLEOF CONTENTS 2.2 Methods of dissemination and tumor growth . 23 2.3 The role of imaging in the management of peritoneal meta- stases . 24 2.3.1 Ultrasound imaging . 25 2.3.2 Multidetector computed tomography imaging . 25 2.3.3 MRI imaging techniques . 26 2.3.4 PET and PET/CT scans . 28 2.3.5 Conclusion . 30 3 Intraperitoneal chemotherapy 31 3.1 Introduction . 31 3.2 Pharmakodynamic rationale of intraperitoneal chemother- apy................................. 32 3.2.1 Two-compartment model . 32 3.2.2 First pass effect . 34 3.2.3 Hallmarks of the ideal drug for intraperitoneal chemotherapy . 35 3.3 State of the art of IPC . 36 3.3.1 Introduction . 36 3.3.2 Therapeutic goal of IPC . 37 3.3.3 Patient selection for IPC . 37 3.3.4 Open, laparoscopic and closed intraperitoneal chemotherapy . 39 3.3.5 Timing of intraperitoneal chemotherapy . 40 3.3.6 Drugs used in intraperitoneal chemotherapy pro- tocols........................... 41 3.3.7 Hyper- versus normothermic IPC . 44 3.3.8 Duration and repetition . 45 3.3.9 Alternative delivery methods of intraperitoneal chemotherapy . 46 4 Drug transport during intraperitoneal chemotherapy 49 4.1 Introduction . 49 4.2 Basic mechanisms of tissue drug transport . 50 4.3 Strategies to improve interstitial drug transport . 52 4.3.1 Therapy related parameters . 53 4.3.2 Tissue related parameters . 56 4.3.3 Additional interventions . 57 5 Current challenges for intraperitoneal chemotherapy and re- search goals 59 5.1 Limitation 1: surface exposure . 59 5.1.1 Description of limitation . 59 viii Table of Contents 5.1.2 Research Objective 1 . 61 5.2 Limitation 2: penetration depth of drugs . 61 5.2.1 Description of limitation . 61 5.2.2 Research Objective 2 . 62 II Modeling intraperitoneal drug delivery and transport 65 6 A new drug delivery system for intraperitoneal chemother- apy: design, development and bench testing 67 6.1 Introduction . 68 6.2 Design of the catheter prototype . 69 6.2.1 Theoretical catheter design . 71 6.2.2 Computational validation of proposed designs . 74 6.3 In vitro testing of the prototypes . 78 6.3.1 In vitro test: single catheter . 78 6.3.2 In vitro test: full set-up . 79 6.3.3 Manufacturing methods and issues . 80 6.3.4 Numerical simulations of measured prototype . 82 6.4 Future directions . 83 7 Modelling drug transport during intraperitoneal chemotherapy 85 7.1 Introduction . 85 7.2 Drug transport steps during intraperitoneal chemotherapy 87 7.3 Whole body level: Compartmental models . 89 7.4 Tissue level: distributed models . 92 7.5 Cellular models . 95 7.6 Conclusions and future directions . 97 8 Mathematical modeling of intraperitoneal drug delivery: sim- ulation of drug distribution in a single tumor nodule 101 8.1 Introduction . 101 8.2 Materials and Methods . 104 8.2.1 Model geometry . 104 8.2.2 Governing equations . 104 8.2.3 Baseline model . 107 8.2.4 Parameter study . 108 8.2.5 Numerical methods . 110 8.2.6 Analyzed variables . 110 8.3 Results . 111 8.3.1 Baseline Cases . 111 8.3.2 Drug type . 113 8.3.3 Vascular Normalization . 114 ix TABLEOF CONTENTS 8.3.4 Necrotic core . 114 8.3.5 Permeability . 115 8.4 Discussion and Conclusion . 115 9 A 3D CFD-model of the interstitial fluid pressure and drug dis- tribution in heterogeneous tumor nodules during intraperi- toneal chemotherapy 121 9.1 Introduction . 121 9.2 Material and methods . 123 9.2.1 Cell line . 124 9.2.2 Mouse model . 125 9.2.3 MRI protocol . 125 9.2.4 Intraperitoneal chemotherapy . 126 9.2.5 Interstitial fluid pressure measurement . 126 9.2.6 Data processing, fitting and interpolation . 126 9.2.7 Computational model . 129 9.2.8 Reported parameters . 131 9.3 Results . 131 9.3.1 Geometry and segmentation . 131 9.3.2 Data Processing . 132 9.3.3 Pressure measurement . 133 9.3.4 Pressure simulation . 133 9.3.5 Drug distribution . 135 9.4 Discussion . 135 III Conclusions and future perspectives 143 Bibliography 201 x LISTOF FIGURES 1.1 Sagittal section of the sub-diaphragmatic space . 4 1.2 Sagittal views of the male and female pelvis demonstrating the peritoneal covering . 4 1.3 Microscopic anatomy of the peritoneum showing the three distinctive layers . 6 1.4 Scanning electron microscopy images of mesothelium of the human pelvic peritoneum . 7 1.5 Microscopic anatomy of the peritoneum showing both types of mesothelial cells and the structure of the submesothelial layer 7 1.6 The peritoneal cavity . 10 2.1 Overview of primary peritoneal cancers with subdivision based on their origins . 15 2.2 Overview of secondary peritoneal cancers that give rise to peritoneal metastases . 18 2.3 Example of ultrasound imaging of peritoneal metastases . 26 2.4 Example of the use of DW-MRI for imaging peritoneal metastases 28 2.5 Example of the use of PET-CT for imaging peritoneal metastases 29 3.1 Two-compartment model of intraperitoneal chemotherapy . 33 3.2 Schematic representation of the first-pass effect in the liver that occurs during intraperitoneal chemotherapy . 35 3.3 Illustration of the peritoneal cancer index scoring system . 39 3.4 Three different approaches to intraperitoneal chemotherapy . 40 3.5 Pressurized intraperitoneal aerosol chemotherapy set-up . 47 4.1 Schematic representation of drug transport during intraperi- toneal chemotherapy . 52 4.2 Schematic representation of the different parameters that in- fluence drug penetration during intraperitoneal chemotherapy 54 6.1 Placement of intraperitoneal catheter in the pelvis . 68 xi LISTOF FIGURES 6.2 Single perforated catheter for intraperitoneal dialysis or drug delivery . 69 6.3 Full set-up for intraperitoneal drug delivery . 70 6.4 Section of a catheter arm along its long axis . 72 6.5 Outflow at all perforations in function of distance to inlet for geometries with uniform perforations . 76 6.6 Graphical representation of the outflow in function of distance to inlet for geometries with different perforation diameters along the length of the catheter . 77 6.7 Comparison between experimental and simulated flow profiles 78 6.8 Experimental set-up of the full catheter . 79 6.9 Outflow for each perforation after three days of infusion at 500 ml/day . 80 6.10 Flow profiles for three manufactured catheters with identical design specifications . 81 6.11 Microscopic images of the microdrilled perforations showing the presence of burrs and uneven perforations . 82 6.12 Model validation using experimentally measured geometry . 83 7.1 Schematic representation of the drug transport process during intraperitoneal chemotherapy and some of its determining factors. 87 7.2 Schematic representation of the five different compartmental models highlighting their mutual relationships . 92 7.3 Spatially varying cisplatin concentration after intraperitoneal chemotherapy in a spherical tumor nodule. 93 7.4 Schematic representation of the lattice used in the described cellular Potts model . 96 8.1 Visualization of the six used geometries in our model in chapter 8105 8.2 Summary of model output and analysed variables in chapter 8 112 8.3 Interstitial fluid pressure distribution profiles of the six baseline cases in chapter 8 . 113 8.4 Normalized concentration profiles in which both length along the axis and concentration are normalized in chapter 8 . 115 9.1 Schematic illustration of the workflow described in chapter 9 124 9.2 Visualization of the three segmented tumor geometries and their different zones on a common scale in chapter 9 .
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