Develope of Ultrasound Elastography for Nondestructive And
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DEVELOPE OF ULTRASOUND ELASTOGRAPHY FOR NONDESTRUCTIVE AND NONINVASIVE CHARACTERIZATION OF STIFFER POLYMERIC BIOMATERIALS By HAOYAN ZHOU Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Dr. Agata Exner Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY January, 2016 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Haoyan Zhou _______________________________________________________ candidate for the _________________________________Doctor of Philosophy degree *. (signed) ________________________________________________Horst von Recum (chair of the committee) ________________________________________________Agata A. Exner ________________________________________________Stuart Rowan ________________________________________________Joseph M. Mansour ________________________________________________Anant Madabhushi (date) __________________________03 August 2015 *We also certify that written approval has been obtained for any Proprietary material contained therein. To my wife, father, and mother Table of Contents Table of Contents……………………………………………………………i List of Tables………………………………………………………………..v List of Figure………………………………………………………………..vi Acknowledgements…………………………………………………............viii List of Abbreviations……………………………………………………….ix Abstract……………………………………………………………………..xii Overview…………………………………………………………………....xiv Chapter 1: Background and Introduction 1.1 Polymer degradation and erosion……………………………………….1 1.1.1 Polymer degradation………………………………………..1 1.1.2 Polymer erosion…………………………………………….4 1.1.3 Traditional and current methods……………………………5 1.2 In Situ forming drug delivery systems…………………………………..7 1.3 Ultrasound elastography………………………………………………...11 1.4 References………………………………………………………………14 Chapter 2: Biomedical Imaging in Implantable Drug Delivery ………..23 Systems (DDS)………………..……………………………….……….…...24 2.1 Introduction………………………………………………….………......25 2.2 Biomedical Imaging Modalities…………………………….…………...29 i 2.2.1 Ultrasound………………………………………………….…29 2.2.2 Magnetic Resonance Imaging (MRI)………………….……...33 2.2.3 Optical imaging and Optical Coherence Tomography (OCT)..37 2.2.4 X-ray Imaging and Computed Tomography (CT)…….……...40 2.3 Conclusion…………………………………………...………….……...43 2.4 References……………………………………………………………....46 Chapter 3: Validation of Ultrasound Elastography Imaging for Nondestructive Characterization of Stiffer Biomaterials…..…………..60 3.1 Introduction……………………………………………………….…….61 3.2 Materials and Methods……………………………………………….....64 3.2.1 PDMS Sample Fabrication…………………………………....64 3.2.2 Phantom Preparation………………..…………………….…..65 3.2.3 Mechanical Testing…………………………………….……..66 3.2.4 Strain Imaging……………………………………….……......68 3.2.5 Statistics………………………………………………….…...69 3.2.6 Region of Interest (ROI) study…………………………….…70 3.3 Results………………………………………………………………….70 3.3.1 Mechanical Testing………………………………………......70 3.3.2 Ultrasound Elastography (UE)…………………………..…..73 ii 3.3.3 Strain Data and Statistics Evaluation………………………..74 3.3.4 Modulus and Strain Correlation………………………..……77 3.4 Discussion……………………………………………………………..79 3.5 Conclusion…………………………………………………………….83 3.6 References……………………………………………………………..84 Chapter 4: Nondestructive Characterization of Biodegradable Polymer Erosion in Vivo Using Ultrasound Elastography Imaging ……….......89 4.1 Introduction…………………………………………………………...90 4.2 Materials and Methods………………………………………………..93 4.2.1 Materials…………………………………………………….93 4.2.2 In Situ Forming Implant (ISFI) Solution Preparation………93 4.2.3 Phantom Fabrication and ISFI Injection……………………94 4.2.4 In Vitro UE Scan and Image Analysis………………….......95 4.2.5 In Vitro Mechanical Testing………………………………..96 4.2.6 In Vitro Erosion Study………………………………….......97 4.2.7 Animal Preparation and Implant Injection…………………97 4.2.8 In Vivo UE Scan……………………………………………98 4.2.9 In Vivo Erosion Study……………………………………...99 4.2.10 Predication of Implant erosion in vitro……………….......99 iii 4.3 Results………………………………………………….…………...100 4.3.1 Implant Erosion In Vitro………………………………….100 4.3.2 Implant Erosion In Vivo………………………………......103 4.3.3 Predication of Implant erosion in vitro…………………...106 4.4 Discussion………………………………………………………......106 4.5 Conclusion………………………………………………………….111 4.6 References………………………………………………………......112 Chapter 5: Conclusions and Future Directions……………………...116 5.1 Conclusions…………………………………………………………116 5.2 Limitations………………………………………………………….118 5.3 Future Directions……………………………………………………119 5.4 References………………………………………………………......121 Bibliography……………………………………………………………122 Appendix………………………………………………………………..154 iv List of Tables Table 2.1 - Current tools for biomaterial characterization…………………….27 Table 2.2 - Properties of biomedical imaging modalities……………………..28 Table 3.1 - PDMS sample elastic modulus…………………………………....72 Table 3.2 - UE experiment statistics…………………………………………..77 Table 4.1 - Summary of erosion measurements………………………………106 v List of Figures Figure 1.1 - Schematic illustration of bulk erosion and surface erosion…………4 Figure 1.2 - Schematic illustration of phase inversion process…………………..9 Figure 1.3 - Release of fluorescein from a 29kDa PLGA ISFI formulation……..10 Figure 1.4 - Algorithm of strain estimation used in quasi-static elastography.......12 Figure 1.5 - Working flow of UE……………………………………………...…14 Figure 2.1 - Examples of ultrasound in implantable DDS……………………......31 Figure 2.2 - MRI images of an intravitreal implant………………………………35 Figure 2.3 - In vitro–in vivo erosion profiles of PEG:dextran implants……….….39 Figure 2.4 - Pre- and peri-operative imaging for transarterial chemoembolization.43 Figure 2.5 - Summary of biomedical imaging in implantable DDS………………46 Figure 3.1 - PDMS sample fabrication process………………………………...…66 Figure 3.2 - Ultrasound elastography scan setup………………………………….69 Figure 3.3 - Representative strain-stress curve of PDMS samples………………..71 Figure 3.4 - Elastic modulus of polyacrylamide tissue mimicking phantom……...73 Figure 3.5 - B-mode and UE color coded strain map of PDMS samples………....74 Figure 3.6 - Strain results from UE………………………………………………..75 Figure 3.7 - Elastic modulus and 1/strain correlations in both phantoms…………78 vi Figure 3.8 Average strain value comparison…………………………………..79 Figure 3.9 Finite element analysis of transducer-subject interface …………...83 Figure 4.1 - Void creation and ISFI implant injection process…………………95 Figure 4.2 - Animal study design……………………………………………….98 Figure 4.3 - Young’s modulus of 34 kDa PLGA implants…………………….101 Figure 4.4 - In vitro: Color coded strain map of implant over time……………102 Figure 4.5 - In vitro strain and erosion…………………………………………103 Figure 4.6 - In vivo: Color coded strain map of implant over time…………….104 Figure 4.7 - In vivo strain and erosion…………………………………………..105 Figure 4.8 - In vitro/In vivo erosion and strain correlation…………………………...109 vii Acknowledgements I would like to take the opportunity to express my deepest appreciation and thanks to my advisor Dr. Agata Exner for her guidance and mentorship. I would like to thank you for encouraging my research and for allowing me to grow as a research scientist. Your advice on both research as well as on my career have been invaluable. I would also like to thank all the members of the Exner lab past and present: Luis Solorio, Hanping Wu, Christopher Hernandez, Monika Goss and Reshani Perera. You have made the Exner lab an amazing environment to be a part of. I am also grateful for the guidance and support I have received from my Ph.D committee: Dr. Horst von Recum, Dr. Stuart Rowan, Dr. Joseph Mansour and Dr. Anant Madabhushi. Your time, academic support and input are greatly appreciated. Thank you. For the non-scientific side, a special thanks to my family. Words cannot express how grateful I am to your love and support. Without my wife Ning, my father Yong, and my mother Li I would not have been able to accomplish any of my goals or dreams. Thank you. viii List of Abbreviations DDS Drug delivery system PDMS Polydimethylsiloxane PEVA Poly(ethylene-co-vinyl acetate) IVIVC In vitro- in vivo correlation ISFI In situ forming implant DSC Differential scanning calorimetry GPC Gel permeation chromatography US Ultrasound MRI Magnetic Resonance Imaging MR Magnetic Resonance MRF Magnetic resonance fingerprinting BT-MRI Bench top- Magnetic Resonance Imaging EPR Electron paramagnetic resonance OCT Optical coherence tomography CT Computed tomography IVUS Intravascular ultrasound SWEI Shear wave elasticity imaging UE Ultrasound elastography TACE Transarterial chemoembolization kDa kilodaltons m meter cm centimeter mm millimeter μm micrometer g gram kg kilogram mg milligram μg microgram l liter ix ml milliliter μl microliter dl deciliters ᵒ C degree centigrade S second h hour d day keV kiloelectronvolts kPa kilopascal MPa megapascal Pa pascal N newton MHz megahertz wt weight w weight v volume E Young’s modulus Eq Equation TEMED tetramethyl ethylenediamine APS ammonium persulfate FDA Federal Drug Administration NIH National Institutes of Health IACUC Institutional Animal Care and Use Committee C drug concentration D dimensional T tesla Gd-DTPA gadolinium- diethylenetriaminepentacetate SPIO Super Paramagnetic Iron Oxide MION Monocrystalline Iron Oxide Nanocompounds GFP Green fluorescent protein x BPLPs Biodegradable photoluminescent polymers MSCs Mesenchymal stem cells TDT Tissue Doppler Tracking CDI Color Doppler Imaging ROI Region of interest ANOVA Analysis of Variance HSD Honestly significant difference MW Molecular weight NMP N-methyl pyrrolidinone PBS