Needle-free Interstitial Fluid Acquisition Using a Lorentz-Force Actuated Jet Injector by Jean H. Chang S.B., Massachusetts Institute of Technology (2008) S.M., Massachusetts Institute of Technology (2010) Submitted to the Department of Mechanical Engineering in partial fulfillment of the requirements for the degree of MASSACHUSETTS INSTTtUTE OF TECHNOLOGY Doctor of Philosophy in Mechanical Engineering .~~~A^~~~ at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY February 2014 @ Massachusetts Institute of Technology 2014. All rights reserved. A uthor ..................... ................. .................. fGepartment of M" nical Engineering November 26, 2013 Certified by ......... Ian W. Hunter Hatsopoulos Professor of Mechanical Engineering Thesis Supervisor A ccepted by ....................... ......... David Hardt Chairman, Department Committee on Graduate Theses 2 Needle-free Interstitial Fluid Acquisition Using a Lorentz-Force Actuated Jet Injector by Jean H. Chang Submitted to the Department of Mechanical Engineering on November 26, 2013, in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Mechanical Engineering Abstract Interstitial fluid (ISF) provides information on a patient's health as it contains regu- latory molecules that are correlated with disease-related processes. However, current ISF acquisition techniques can be slow, resulting in patient discomfort and erroneous measurements. This thesis presents a fast (< 4 s), minimally-invasive, needle-free technique of extracting ISF samples using a Lorentz-force actuated jet injector. The jet injector is used to first inject a small volume of physiological saline to breach the skin, and the actuator is subsequently back-driven to create a vacuum in the ampoule and collect a sample that contains a mixture of ISF and injectate. The scope of this thesis is twofold: the first part aims to investigate the effect of jet injection on tissue, while the second part focuses on the development of the novel ISF acquisition method. A micro-CT imaging study identifies the magnitudes of injected jet speed that will influence injectate delivery to specific skin layers. A histology study highlights the differences in tissue damage between needle injections and jet injections. A new tool for quantifying the jet dynamics in tissue-a high-speed X-ray imaging system-is built and characterized. The system, which has a capture rate of up to 2,000 fps, is used to visualize jet injections into tissue in real-time, and for the first time measurements are made of the fluid speed in tissue. To develop the jet injector for ISF acquisition, a finite element model that describes the effect of different injection and extraction parameters on the ISF acquisition pro- cess is developed. The model is used to explain the trends seen in experimental work on post-mortem tissue, and the lessons learned from both the model and experimenta- tion are used to identify the parameters for a live animal study. The feasibility of the acquisition process is successfully demonstrated on live rats; the process is revealed to extract samples that have been diluted by a factor of 111-125. Thesis Supervisor: Ian W. Hunter Title: Hatsopoulos Professor of Mechanical Engineering 3 4 Acknowledgments First and foremost, I would like to thank my advisor, Professor Ian Hunter. I am extremely lucky to have worked in the BioInstrumentation Lab. Ian has always been incredibly supportive, making sure that his students had access to all the resources that we needed for our projects. I am lucky to have had an advisor who has encouraged me to explore the aspects of my project that I found interesting, and who has pushed me to constantly learn new skills. I have learned so much over the past six years. I would like to thank Sanofi-Aventis for the financial support for this thesis. I would also like to thank my committee members, Professor Linda Griffith and Professor Rohit Karnik. I appreciate the words of advice given to me during the course of this thesis. Dr. Cathy Hogan has taught me so much during my graduate career, both in the professional sense and in the personal sense. She has become a great friend, someone to joke around with, gossip with, and share my concerns. I will miss you. I would like to thank Professor Evelyn Wang, my mentor through Graduate Women at MIT. She has been such an amazing role model and has provided great advice as well as thoughtful words of encouragement to me for the last couple of years. I would also like to thank the other professors in the mechanical engineering department who have indirectly served as my mentors during my time at MIT. They have encouraged me to constantly challenge myself while at the same time making sure that I was enjoying it. Kate Melvin, thank you so much for all the work that you do in keeping the lab running. I could always count on her to have an amazingly positive attitude. Leslie Regan, Joan Kravit, and Una Sheehan also deserve a huge thank you for everything that they do to keep the department running smoothly. Throughout my graduate career I have had the pleasure of working with some of the brightest people I have ever met. Dr. Priam Pillai taught me so much when I first entered the lab, and mentored me until I felt confident enough to stand on my own. Dr. Brian Hemond, Dr. Bryan Ruddy, and Dr. Adam Wahab all provided 5 genius advice to me during my PhD. Ellen and Eli, I have always felt a special bond with you guys because we all started together. To the other BioInstrumentation lab members, Ashley Brown, Alison Cloutier, Nick Demas, Kerri Keng, Dr. Walker Inman, John Liu, Ashin Modak, Mike Nawrot, Geehoon Park, Miguel Saez, Span, and Jamie White, thank you so much for always being there to bounce ideas and chat when I needed a distraction. I was fortunate to have been given the opportunity to spend a few months working at our collaborator's lab in New Zealand. This was made possible by of course my generous advisor Ian, and also by Dr. Peter Hunter and Dr. Andrew Taberner. The members of the Auckland Bioengineering Institute were incredibly welcoming to me when I arrived. Dr. Jessica Jor and Adam Reeve spent time training me on new equipment, and Rhys Williams spent a good amount of time helping me set up my jet injector. Alex Anderson, Ming Cheuk, Mark Finch, Nikini Gamage, Prasad Babarenda Gamage, Callum Johnston, Tom Lintern, Matt Parker, and Paul Roberts also made me feel so welcome and made sure that I was enjoying my visit to New Zealand. I would also like to thank the MISTI Global Seed Fund for the financial support to travel to New Zealand. I can confidently say that my friends played a major role in me finishing my PhD. They have always been a wonderful distraction from the rigors of graduate school. I am lucky to have such amazing friends. When I look back at my time in graduate school, I know that I will remember most the incredible times I had with my friends. Finally, I would like to thank my family who has given me so much love and has been so supportive of me in everything that I have done. My parents know exactly how much to push me, and at the end of the day they just want me to be happy. Their number one piece of advice that they gave me while I was growing up was that I should always make sure that I was happy doing what I was doing. I am lucky to have such a great relationship with my sister. Even though we have quite different personalities, we still manage to have that "sister thing," where we can read each other's minds. And I am proud of my little brother, who I have watched become an adult these past few years. 6 Contents 1 Introduction 21 1.1 M otivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.2 Prior A rt . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.3 Fluid Sample Acquisition using a Needle-free Jet Injector . . 23 1.4 Chapter Descriptions . . . . . . . . . . . . . . . . . . . . . . 26 2 Device Development 27 2.1 Device description . . . . . . . . . . . . . . . . . . . . . . . . 27 2.1.1 Control System Hardware . . . . . . . . . . . . . . . 29 2.1.2 Control System Software . . . . . . . . . . . . . . . . 29 2.2 Sum m ary . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3 Injection Studies 37 3.1 Background: Skin Layers . . . . . . . . . . . . . . . . . . . . . . . . 39 3.1.1 Microstructure . . . . . . . . . . . . . . . . . . . . . . . . . 40 3.2 Effect of Injection Parameters on Injection Depth . . . . . . . . . . 44 3.2.1 Optimal Delivery Target: the Dermis . . . . . . . . . . . . . 44 3.2.2 Importance of contact force . . . . . . . . . . . . . . . . . . 45 3.2.3 Experimental Methods . . . . . . . . . . . . . . . . . . . . . 46 3.2.4 Results and Conclusions . . . . . . . . . . . . . . . . . . . . 46 3.3 X-ray Microtomography Studies of Jet Injections . . . . . . . . . . 49 3.3.1 Experimental Methods . . . . . . . . . . . . . . . . . . . . . 49 3.3.2 Results . . . . . . . . . . . . . . . . . ... - .... . . . .. 50 7 3.4 Histological examination of tissue damage due to jet injections . . . . 58 3.4.1 Experimental Methods . . . . . . . . . . . . . . . . . . . . . . 58 3.4.2 R esults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 4 High-speed X-ray imaging studies 63 4.1 Device development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 4.1.1 Prior A rt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 4.1.2 Functional requirements . . . . . . . . . . . . . . . . . . . . . 65 4.1.3 Component selection . . . . . . . . . . . . . . . . . . . . . . . 66 4.1.4 Characterization . . . . . . . . . . . . . . . . . . . . . . . . . 68 4.1.5 Future improvements . . . . . . . . . . . . . . . . . . . . . . . 70 4.2 X-ray imaging of needle injections . . . . . . . . . . . . . . . . . . . . 71 4.3 High speed X-ray imaging of jet injections . . . . . . . . . . . . . . . 73 4.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 5 Modeling of Interstitial Fluid Acquisition Method 79 5.1 Model setup and assumptions . . . . . . . . . . . . . . . . . . . . . . 79 5.1.1 Darcy's Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 5.1.2 Resistance to Dermal Interstitial Flow . . . . . . . . . . . . . 81 5.1.3 Change in Tissue Permeability due to Swelling . . . . . . . . . 86 5.1.4 Dermis model . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 5.2 Modeling of Vacuum Acquisition Methods . . . . . . . . . . . . . . . 92 5.2.1 Model setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 5.2.2 R esults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 5.3 Modeling of JI ISF Acquisition Method . . . . . . . . . . . . . . . . . 95 5.3.1 Modeling Injection . . . . . . . . . . . . . . . . . . . . . . . . 96 5.3.2 Simulations of the Effect of Injection Parameters . . . . . . . 98 5.3.3 Simulations of the Effect of Extraction Parameters . . . . . . 101 5.4 D iscussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 8 6 Extraction studies 111 6.1 Experiments on Post-Mortem Tissue: Porcine . . . . . . . . . . . . .111 6.1.1 Experimental Methods . . . . . . . . . . . . . . . . . . . . . .111 6.1.2 Dependence on Injection Parameters . . . . . . . . . . . . . . 112 6.1.3 Dependence on Extraction Parameters . . . . . . . . . . . . . 116 6.2 Lessons learned from modeling and experimentation . . . . . . . . . . 120 6.2.1 Experiments with benchtop device on post-mortem rat skin . 120 6.2.2 Experiments with Handheld Device . . . . . . . . . . . . . . . 121 6.3 Live animal studies: rat . . . . . . . . . . . . . . . . . . . . . . . . . 123 6.4 Sum m ary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 7 Conclusions 127 7.1 Suggestions for Future Work . . . . . . . . . . . . . . . . . . . . . . . 128 7.1.1 Effect of jet injection on tissue . . . . . . . . . . . . . . . . . . 128 7.1.2 ISF acqusition . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 9 10