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2 Table of Contents Directors report Page 1 About the Institute Page 2 Recent Highlights Page 4 Staff Page 5 Graduate Students Page 9 Physiome Project Page 10 Cell signalling & gene regulation Page 11 CellML Page 12 Tissue Structure Page 13 Cardiac Electrophysiology Page 15 Cardiac Mechanics Page 17 Cardiac Electromechanics Page 19 Cardiac Metabolism Page 21 Cardiovascular Magnetic Resonance Group Page 23 Lung and Respiratory System Page 25 Digestive system Page 27 Musculo-skeletal system Page 29 Orthopaedics Page 31 Skin Page 33 Immune / Lymphatic system Page 34 Breast Mechanics Page 35 Special sense organs Page 36 Emerging Projects Page 37 Kidney & urinary system Page 37 Brain & nervous system Page 37 Arti cial Muscles Page 38 Vocal system Page 38 Computational uid mechanics Page 39 Virtual Surgery Page 40 CMISS Software Development Page 41 Instrumentation Development Page 43 Telemetry Group Page 45 Graduate Life Page 46 Support Services Page 47 Publications Page 48

3 Directors Report The Bioengineering Institute We are now ve years old! The Bioengineering Institute began life in It brought together staff from Engineering and Medical and Health Sciences at the University of Auckland who shared a common interest in developing engineering approaches that would facilitate better understanding of biological function and provide the basis for new approaches to medical diagnosis and therapy. An important objective has been the development of anatomically and biophysically based mathematical models of aspects of human physiology, from genes to whole organs, together with the experimental techniques and the instrumentation required to measure cell and tissue properties and perform model validation experiments. Over the past ve years, the Institute has had to meet a number of challenges. We have attempted to create a new research culture and to strengthen our research infrastructure. It has been necessary to establish nancial and administrative structures to manage our activities. The Institute is wholly dependent on external funding and development of a broad portfolio of research grants and research contracts has been a critical imperative. We are particularly proud of the way in which Institute members have worked to achieve these goals while, at the same time, maintaining a strong sense of collegiality. Progress over the past two years, in particular, has been extremely pleasing. A number of independent, multi-disciplinary, Institute research groups working on heart, lungs, orthopaedics, musculo-skeletal and digestive systems have reached critical mass. We are making signi cant advances in the development of novel measurement technologies and with setting up mark-up languages, such as CellML, that will enable worldwide modelling resources to be shared through the internet. There has also been a steady increase in the numbers of staff and graduate students joining the Institute. This growth has been associated with a substantial increase in research outputs. The results of our research are being published with increased frequency in international journals of the highest quality and our record in attracting major research support has been very strong, with around $10M of new funding (spread over the next ve years) obtained in Two important features of modern medicine and biomedical science are the emergence of sophisticated new imaging methods and the development of computational techniques that will enable us to integrate function at the levels of gene, protein, cell, tissue, organ and organism. The Institute is playing a leading role in both areas. We have contributed to the establishment of state-of-the-art facilities for MR imaging, microct and advanced confocal microscopy at the University of Auckland and have substantial expertise with each of these modalities. We also lead the International Physiome initiative, which seeks to establish comprehensive web-accessible resources for modelling biological function from the gene to the organism. These activities have reinforced the Institute s international reputation and this is re ected by the extensive network of collaborations to which our investigators contribute. Our membership of the Centre for Molecular Biodiscovery (CMB), one of the seven government-funded Centres of Research Excellence (CoREs), has provided vital links to expertise in the School of Biological Sciences (SBS) and the School of Medical Sciences (SMS). Similarly, our involvement in the NZ Institute of Mathematics and its Applications (NZIMA) another CoRE has provided valuable contact with mathematicians. Finally, we need to look toward the future. The continued wellbeing of the Auckland Bioengineering Institute depends on the development of new research activities and new clinical and economic outcomes for our research. Our recent success in obtaining grants from international sources (Wellcome Trust, NIH, European Framework 6, EPSRC, Australian Research Council) is an indication of the level of international recognition the Institute s Principal Investigators have. There is ample evidence of such capacity within the Institute and we will work to foster it further. Professor Peter Hunter, Director Associate Professor Bruce Smaill, Deputy Director 1

4 About the Bioengineering Institute About the Bioengineering Institute The Auckland Bioengineering Institute was established in 2001 as a cross-faculty research institute dealing with the application of engineering sciences to better understand emerging aspects of biological function and to develop new approaches to medical diagnosis and therapy. An important focus of our research is the development of anatomically and biophysically based mathematical models of human body function from genes to whole organs. Most of the projects undertaken by members of the Bioengineering Institute involve a combination of experimental measurement and mathematical modelling. Mathematical modelling requires a rm experimental foundation, while experimental biomedical research increasingly needs a mathematical framework with which to interpret complex results. The Institute therefore seeks to maintain a balance between software development on the one hand and instrumentation development and experimental biological or clinical studies on the other. Re ecting this, research in the Bioengineering Institute is typically carried out by multi-disciplinary teams whose members contribute skills across these areas. The different projects summarised in this brochure provide a detailed snapshot both the nature and the breadth of the activities being carried out by research groups in the Institute. The Institute consists of 80 people including 10 academics with joint appointments in undergraduate teaching departments the Engineering Science Department in the Faculty of Engineering and the Departments of Physiology, and Anatomy with Radiology in the Faculty of Medical and Health Sciences. We currently have 25 research scientists, 12 administrative, IT and software support staff and 8 technical laboratory and workshop staff in the Institute. The Institute also has around 30 graduate students with increasing numbers from Australia, Germany, Korea and the United States. The Institute is supported by external research grants primarily from the New Zealand Foundation for Research Science and Technology (FRST) and the Health Research Council of New Zealand (HRCNZ), together with the Marden Fund and Centres of Research Excellence scheme administered by the Royal Society of New Zealand (RSNZ). Institute members also hold international grants, in particular from the US National Institutes of Health (NIH), the Wellcome Trust, the European Framework 6 funding programme and the UK Engineering and Physical Sciences Research Council (EPSRC). Finally, the Institute has a signi cant stream of commercial funding from research contracts, consulting and sales of instrumentation and software licences. These activities are managed by the University s commercial arm, Auckland UniServices Ltd. The Bioengineering Institute occupies space on two sites at the University of Auckland. The majority of our staff and graduate students are located at UniServices House, 70 Symonds Street, close to the City campus of the University of Auckland. We also have staff, graduate students and laboratories at the Medical and Health Sciences Campus in Grafton, which is adjacent to Auckland Hospital, and a short walk from 70 Symonds Street. The Institute has its own supercomputer and has excellent facilities for instrumentation development, biomaterials testing and experimental physiology studies. In addition, we operate state of-the-art imaging facilities including an automated system for microscopic analysis of large tissue volumes, microct and functional uorescence imaging systems. We also have access to advanced clinical and high eld MR imaging facilities. The Institute has links with a wide range of disciplines and professions within the University and externally. We are members of two of the Centres of Research Excellence recently funded by the NZ Government: The Centre for Molecular Biodiscovery and the New Zealand Institute of Mathematics Applications. Institute staff who are members of the Engineering Science Department are responsible for the BE Biomedical Engineering degree programme, recently launched at the University of Auckland, while staff who are members of the Faculty of Medical and Health Sciences contribute to the BSc and BSc Honours Biomedical Science programmes, and to undergraduate medical teaching. Academically able students from each of these streams have entered our graduate programme. 2

5 About the Bioengineering Institute The Institute has close links with clinicians from the School of Medical and Health Sciences and the Auckland Hospital, and also with companies that market products and technologies for the Health Sector. Of particular importance are the strong research collaborations that we enjoy with international universities and research institutes. These include: Oxford University and Leeds University in the United Kingdom; the University of California, San Diego (UCSD), the University of Washington, Seattle, Vanderbilt University, Harvard University and the Massachusetts Institute of Technology (MIT) in the United States; and the National University of Singapore (NUS). Over the past decade, clinical medicine and biomedical science have been transformed by the emergence of revolutionary new technologies. Developments in imaging enable us to characterise structure and function in cells, tissues organs and the living body in exquisite detail. On the other hand, recent discoveries about protein-encoding sequences in the human genome and advances in molecular biology and biochemistry are enabling us to read the messages that control all aspects of biological function. To integrate this information we need to develop comprehensive models of human biology based on quantitative descriptions of anatomic structure and biophysical processes which reach down to the genetic level. The Physiome Project is an international initiative that seeks to develop mathematical models that link gene, protein, cell, tissue, organ and the whole body in one comprehensive framework. The Auckland Bioengineering Institute is playing a leading role in this initiative and also in the novel exploitation of imaging technologies. 3

6 Recent Highlights Grants Obtained A new 6 year NERF grant on Bioengineering Applications of Bioengineering Modelling was obtained by the musculo-skeletal group within the Institute. This extends an earlier NERF grant to a wider range of applications of our musculo-skeletal work. A two year Marsden grant was awarded to Martyn Nash for work on ventricular electromechanics and arrhythmias. Edmund Crampin and Merryn Tawhai both obtained grants from the Vice Chancellor s University Development Fund. An NIH grant was awarded to Nic Smith and Edmund Crampin for work with the Medical College Wisconsin on multiscale modeling of metabolism in the heart. An NIH project grant was obtained by Andrew Pullan for work with Vanderbilt University on modelling the digestive system. A Wellcome Trust grant was awarded to Peter Hunter to develop the Physiome project. This is a ve year joint project between Auckland and Oxford and is the rst time that the Wellcome Trust (the world s largest private medical funding agency) has awarded a major grant for a mathematical modelling project. A European Framework 6 grant for research on cerebral aneurysms was awarded to Peter Hunter to collaborate with European institutions. People Edmund Crampin was appointed to a joint teaching post in the Engineering Science Dept and research position in the Bioengineering Institute. Edmund did his undergraduate training in Physics at Imperial College in London and his PhD (DPhil in Applied Mathematics) at Oxford University where he also worked as a Postdoctoral Research Fellow (in Mathematical Biology). His current research interests in modelling gene regulation, signal transduction and metabolic pathways will help bridge the critical gap between the bioengineering world of computational physiology and the biomedical science world of genes and proteins. Edmund Crampin received an Early Career Research Excellence Award in 2005, from the University of Auckland, for his work on modelling gene regulation networks. Commercial Simon Malpas and David Budgett won the 2004 Spark Business competition and were successful in obtaining funding to establish a new company - now launched as Telemetry Research. We have appointed Dr John Cunningham under the Entrepreneur in Residence programme to spend one day a week in the Institute helping to identify and nurture new commercial initiatives. New Facilities Institute members have contributed to the establishment of the Centre for Advanced Magnetic Resonance Imaging (CMRI) at the Medical and Health Sciences Campus in Grafton. This includes a 1.5T clinical imaging system a high eld 4.7T system for experimental imaging and spectroscopic studies. Both are being used research groups from the Institute. A micro-ct system has been installed in the Institute and Professors Ian Reid and Jill Cornish from the Department of Medicine have contributed to this initiative. Using this instrument - the rst of its kind in New Zealand - it is possible to image the micro-structure of a 65mm 3 sample bone or lung tissue, for example, at 5 m resolution. 4

7 Staff Name Area Other Af liations Iain Anderson Orthopaedics, Arit cial Muscles, Engineering Science ME, PhD Musculo-Skeletal, Virtual Surgery Travis Austin PhD Cardiac Electrophysiology, CMISS Software Development John Baek Cardiovascular MRI Shane Blackett ME CMISS Software Development, CellML, Virtual Surgery Gib Bogle PhD Immune Lymphatic System David Budgett PhD Instrumentation Development, Telemetry Group David Bullivant PhD CMISS Software Development, Physiome Project Andrew Cantell IT Support Leo Cheng PhD Digestive System, Cardiac Electrophysiology, CMISS Software Development Edmund Crampin Cardiac Metabolism, Engineering Science DPhil Cell Signaling and Gene Regulation, Physiome Project Gareth de Walters IT Support Mark Donnelly Telemetry Maria Fung Administration Finance Matt Halstead PhD CellML Dane Gerneke Cardiac Electrophysiology, Tissue Structure Physiology Nirosha Herat Administration Sujeewa Hettiwatte PhD Cardiovascular MRI 5

8 Staff Name Area Other Af liations Darren Hooks Cardiac Electrophysiology Auckland District Health Board PhD, MBChB Peter Hunter ME, DPhil Professor Director Physiome Project, Cardiac Electrophysiology Cardiac Mechanics, Cardiac Electromechanics, Musculo-skeletal System Mark Jacobs Special Sense Organs Physiology PhD Shaun King Telemetry Group Juliana Kim PhD Musculo-skeletal System Robert Kirton PhD Cardiac Mechanics, Cardiac Metabolism Instrumentation Development Yme Kvistedal ME Lungs and Respiratory System Skin, Instrumentation Development Ian LeGrice Tissue Structure, Cardiac Electrophysiology Physiology MBChB, PhD Physiology, Cardiac Electrophysiology, Cardiac Mechanics, Instrumentation Development Tiong Lim IT Support Karen Lim Instrumentation Development Denis Loiselle Cardiac Metabolism, Cardiac Mechanics Physiology PhD Sharif Malak ME Orthopaedics, Arti cial Muscles Gordon Mallinson Computational Fluid Dynamics Mechanical Engineering PhD Professor HOD, Mech Eng Simon Malpas Telemetry Group, Kidney & Urinary System, Physiology PhD Instrumentation Development Associate Professor Andrew Miller CellML Fady Mishriki Telemetry Group Kumar Mithraratne PhD Musculo-skeletal System 6

9 Staff Name Area Other Af liations Ayman Mourad PhD Cardiac Mechanics, Clinical Electrophysiology Martyn Nash Cardiac Mechanics, Cardiac Electromechanics, Engineering Science PhD Cardiac Electromechanics, Cardiac Electrophysiology, Breast Mechanics David Nickerson PhD Physiome Project, Cardiac Electromechanics, CellML, CMISS Software Development Poul Nielsen CellML, Instrumentation Development, Engineering Science PhD Breast Mechanics, Skin Karin Nielsen Heart Sock Development Wayne Pallas Telemetry Group Rocco Pitto Orthopaedics Surgery, Middlemore Hospital MBChB Associate Professor Stephen Poon IT Support Engineering Science Andrew Pullan Cardiac Electrophysiology, Digestive System Engineering Science PhD Digestive System, Musculo-skeletal System, Associate Professor Physiome Project Oliver Rohrle PhD Musculo-skeletal System Gregory Sands PhD Tissue Structure, Cardiac Electrophysiology, CMISS Software Development, Instrumentation Development Mohini Singh Administration Bruce Smaill Cardiac Electrophysiology,Tissue Structure, Physiology PhD Cardiovascular MRI, Associate Professor Instrumentation Development Deputy Director Nicolas Smith Cardiac Metabolism, Cardiac Electromechanics, Engineering Science PhD Cardiac Electromechanics, Cardiac Mechanics Musculo-skeletal System, Physiome Project Carey Stevens PhD CMISS Software Development, Cardiac Mechanics, CellML, Virtual Surgery Merryn Tawhai PhD Lung and Respiratory System, Physiome Project William Thorpe PhD Lungs and Respiratory System, Physiome Project, Vocal System 7

10 Staff Name Area Other Af liations Karl Tomlinson PhD CMISS Software Development Mark Trew PhD Cardiac Electrophysiology CMISS Software Development Peter Villiger CellML Lyn Vu Administration Assistant Susanna Yau Administration: Of ce Manager Alistair Young Cardiovascular MRI, Cardiac Mechanics, Anatomy with Radiology ME, PhD Tissue Structure Physiology Tingting Zhao Digestive System 8

11 Graduate Students Name Undergradute Enrolled Project Title Degrees in Phil Blyth BHB MBChB PhD Virtual reality simulation of hip surgery. Bryan Caldwell BSc (Hons) PhD Optical mapping of electrical activation in the heart. Jae-Hoon Chung BE (EngSci) PhD Modelling contact mechanics of the breast during mammography. Mike Cooling BCom (Hons), BSc,GDipSci PhD A quantitative model of IP3-calcineurin pathways. John Davidson BE (BME) PhD Electro-stimulation in biophysically-based models. Sarala Dissanayake BE (SoftEng) PhD Visualisation of CellML models. Tanusha Duffadar BE (BME) M.E. Patient-speci c model of whole leg for computer assisted surgery. Richard Faville BE (EngSci) PhD Biophysically-based computational model of the interstitial cells of Cajal Kerry Hedges BE (Mech), ME (Mech) PhD Modelling ventilation distribution in the lungs. Albert Ho BE (EngSci) M.E. Structure of bone in the knee. Jack Lee BE (EngSci) PhD Coronary circulation and autoregulation. Mathew Lim BE (BME) M.E. Neurological measurements with wireless sensor. Shane Lin MSc (CompSci) PhD Image processing of cardiac magnetic resonance images. Duane Malcolm BE(EngSci), ME (EngSci) PhD Modelling the structure and function of the mammalian lens. Tom McKay BE (BME) M.E. Arti cial muscles for augmenting human strength. Steve Niederer BE (EngSci) PhD Modelling ischemic regions in an electro mechanical coupled heart model. David Nordsletten BE PhD Ventricular uid mechanics and coupled uid-solids. Kieren O Brien BE (BME) PhD MRI imaging and ventricular mechanics. Jonathan Pearce BE (EngSci) PhD Ventricular uid mechanics. Adèle Pope BTech (BiomedSci) PhD Mechanics and remodelling in hypertensive cardiomyopathy. Vijay Rajagopal BE (EngSci) PhD 3D nite element model of breast deformation. Glenn Ramsey BE (Mech), ME (Mech) PhD Biomechanics of the equine hoof. Hayley Reynolds BE (EngSci) PhD Modelling Lymphatic ow. Sally Rutherford BSc (Hons) PhD Infarct border zone architecture and arrhythmias. Holger Schmid Dip Ing (Hons) PhD Constitutive Law Design for Myocardium. Vickie Shim BE (Elect) PhD Modelling patient bone density in the femur. Ping Si BE (Elect) PhD Wireless power for biomedical applications. Kenneth Tran BE (BME) Hons PhD Multi-scale computational modelling of cardiac oxygen delivery. Dean Tai BTech (Opto-electronics) PhD Intramural mapping of electrical activation in the heart. Jonna Terkildsen BSc (Hons) M.E. Modelling cellular volume and ionic effects In cardiac ischaemia. Shane Windsor BE Hons (Mech) PhD Hydrodynamic trail following in predatory sh. Nina Van Essen BE (EngSci) PhD Modelling the human mastication process. Rita Yassi BE (EngSci), (Bioeng) ME PhD Modeling of the gastro-oesophageal junction. 9 8

12 Physiome Project Group leader Peter Hunter Group Members David Bullivant Edmund Crampin Martyn Nash David Nickerson Poul Nielsen Andrew Pullan Nic Smith Carey Stevens Merryn Tawhai The objective of the Physiome Project of the International Union of Physiological Sciences is to provided a comprehensive framework for modelling the human body using computational methods that can incorporate the biochemistry, biophysics and anatomy of cells, tissues and organs. To support that goal, the project is developing XML markup languages (CellML, FieldML) and software tools for creating, executing and visualising the output of computer models at the cell, tissue, organ and organ systems levels. It is also establishing web-accessible databases to provide the physiological information necessary to support these models. Major developments in science and medicine are the recent explosions of information in genomics and proteomics, which are providing a plethora of information relating to the regulation of cell function. On the other hand, recent developments in imaging (using MRI, CT, PET, ultrasound and electrical mapping for instance) are providing detailed information on function at organ and organ systems. The challenge of the Physiome project is to set up a modelbased computational framework which spans this information gap. We see this as an important step toward the development of a patient-speci c paradigm for diagnosis and treatment in the medicine of the future. Recent Publications Hunter P.J. and Nielsen P.M.F. A strategy for integrative computational Physiology. Physiology. 20: , Hunter P.J., Smith N., Fernandez J. and Tawhai M. Integration from proteins to organs: The IUPS physiome project. Mechs. Age.Develop., Vol 126(1): , Crampin E.J., Halstead M., Hunter P., Nielsen P., Noble D., Smith N. and Tawhai M. Computational physiology and the physiome project. Eur. J. Physiol., 89(1):1-26, Hunter P.J. The IUPS physiome project: a framework for computational physiology. Prog. Biophys. Mol. Biol., 85(2-3): , Hunter P. J. and Borg T. Integration from proteins to organs. The Physiome Project. Nature Rev., 4(3): , Hunter P.J., Robbins P. and Noble D. The IUPS Human Physiome Project. Eur. Journal of Physiol., 445(1):1-9, Physiome Project Funding Sources FoRST Wellcome Trust NIH Collaborations Jim Bassingthwaighte University of Washington, Seattle Denis Noble Oxford University David Paterson Oxford University Peter Kohl, Oxford University Andrew McCulloch UCSD and many other groups in the US, Europe, and Asia 10 8

13 Cell Signalling & Gene Regulation Group leader Edmund Crampin Cell Signalling & Gene Regulation Associates Peter Hunter Cristin Print Peter Shepherd Graduate Students Mike Cooling Daniel Hurley Biological systems are characterised by regulatory and adaptive properties, ranging from homeostatic mechanisms to switching between alternative substrates or pathways. We are developing models and tools for the analysis of biological signalling networks, in particular focusing on the cardiac myocyte. Current projects include modelling the cell signalling networks in the heart; in particular the IP3/PKC pathway, and the signal transduction pathways and gene targets involved in cardiac hypertrophy. Making sense of functional genomics data sets is the huge challenge for systems biology, following from the successes of genome sequencing projects. Large data sets on protein-protein interactions and gene expression pro les are becoming available as high-throughput measurement technologies are established. We are developing mathematical and computational approaches to identify topological and kinetic properties of complex biochemical networks from analysis of these data sets, in particular for the networks of regulatory interactions underlying gene expression. Recent Publications Wildenhain J. and Crampin E.J. Reverse engineering scale-free regulatory networks using gene perturbation data. IEE Systems Biology (in press 2006). Crampin E.J., Schnell S. and Mcsharry P.E. Mathematical and computational techniques to deduce complex biochemical reaction mechanisms. Prog. Biophys. and Mol. Biol., 86 (1): Crampin E.J., Mcsharry P.E. and Schnell S. Extracting biochemical reaction kinetics from time series data. Lect. Notes AI., 3214: , 2004 Crampin E.J. & Schnell S New approaches to modelling and analysis of biochemical reactions, pathways and networks (Editorial). Prog. in Biophysics & Mol. Biol., 86 (1): Funding Sources CMB CoRE Centre for Molecular Biodiscovery UARC Collaborations Bio-Informatics Institute Dept. of Engineering Science, University of Oxford Biocomplexity Institute, Indiana University

14 CellML Group Leader Poul Nielsen Research Staff Matt Halstead Shane Blackett Carey Stevens David Nickerson Peter Villiger Andrew Miller Graduate Students Sarala Dissanayake Associates Edmund Crampin Peter Hunter CellML is an XML-based language designed to specify, store, and exchange models of biological systems. It is used to describe the components, and the mathematical relationships between components, of biological models. CellML enables model builders to share models, construct models as a hierarchy of existing models, facilitating the process of model building, testing, publication, and curation. The language, based upon a relatively small number of concepts, is general enough to describe models of a wide variety of biological processes. A repository of models is publicly available on the CellML web site www. cellml.org. Tools to facilitate the use of CellML include visual editors, simulation software, validators, and application programming interfaces for a variety of computer languages. Current work includes linking CellML models to a variety of biological ontologies and databases. CellML Recent Publications Le Novere N., Finney A. and Hucka M. Minimum information requested in the annotation of biological models (MIRIAM). Nat. Biotechnol., 23(12): , Lloyd C., Halstead M. and Nielsen P. CellML: Its future, present and past. Prog. Biophys. Mol. Biol. 85(2-3): , Cuellar A., Lloyd C., Nielsen P., Halstead M., Bullivant D., Nickerson D. and Hunter P. An overview of CellML 1.1, a biological model description language. Trans. Soc. Model Sim. Int., 79(12): , Hedley W., Nelson M.R., Bullivant D. and Nielsen P. A short introduction to CellML. Phil. Trans. R. Soc. Lond. A,359(1783): , Funding Sources SBS CoRE NEDO (Japan) Collaborations University of NSW SBML BioPax University of Washington 12

15 Tissue Structure Group Leader Ian LeGrice Group Members Dane Gerneke Greg Sands Bruce Smaill Graduate Students Adèle Pope Bryan Caldwell Jack Lee Holger Schmid Associates Colin Green Peter Hunter Yme Kvistedal Denis Loiselle Poul Nielsen Alistair Young Martyn Nash Tissue Structure Our work originated from the detailed measurement of cardiac structure in which we characterised myocyte arrangement throughout the ventricular wall in dog and pig hearts. These data have been incorporated into detailed nite element models of cardiac anatomy that have been used by ourselves and others to study the electrical and mechanical function of the heart. In order to visualize myocyte and connective tissue organization at appropriate resolution we have developed an automated imaging system that enables extended-volume images to be acquired rapidly. A high precision three-axis translation stage and digital camera are coupled with a confocal microscope and histological ultramill under the control of a central computer. With this system it is feasible to rapidly capture extended 3D images of tissue and acquire morphological data in systematic serial studies of structure and function for any soft biological tissue. Use of the system is expanding to cover a wide range of tissues including: myocardium from hypertensive rats, infarct border zone, coronary vasculature, pig atrium, rat kidney, gastro-oesophageal junction, lymph nodes, cochlea, and neural tissue. The structural information collected will typically be used in computer modeling studies investigating the relationship between organ structure and function. Recent Publications Sands G., Gerneke D., Hooks D., Green C., Smaill B. and LeGrice I. Automated imaging microscopy. Microsc. Res. Tech., 67: , LeGrice I., Sands G., Hooks D., Gerneke D. and Smaill B. Microscopic imaging of extended tissue volumes. Clin. Exp. Pharm. Physiol., 31(12):902-5, Le Grice I.J., Pope A. and Smaill B. The architecture of the heart: myocyte organization and the cardiac extracellular matrix. In: Interstitial brosis in heart failure. Villareal F.J. (Ed), New York, Kluwer Academic Press. pp3-21, Le Grice I.J., Smaill B.H., Young A.A., Blackett S. and Christie G. Two images in Microscopy II: Image Analysis & 3D Reconstruction. Purdue University Cytometry Laboratories. Multimedia Knowledge, Inc. ISBN: , Young A.A., LeGrice I.J., Young M.A. and Smaill B.H. Extended confocal microscopy of myocardial laminae and collagen network. J. Microsc., 192: , Le Grice I.J., Smaill B.H., Chai L.Z., Edgar S.G., Hunter P.J. and Gavin J.B. Laminar structure of the heart: Cellular organisation and connective tissue architecture in ventricular myocardium. Am. J. Physiol., 269:H571-H582, Funding Sources Wellcome Trust NERF 13

16 Extended-volume images of left ventricular myocardium. Rat hearts are perfused with Bouin s xative and picrosirius red which labels connective tissue. Transmural samples are embedded in resin and extended-volume confocal microscopy is performed to assemble large 3D images that provide detailed structural information, for example on the organisation of myocardial laminae, blood vessels and connective tissue. The adjacent gure was obtained from a tissue block of dimension 4.25 x 0.9 x 1.1 mm. The upper image highlights the laminar structure of ventricular myocardium, while the lower image has been thresholded to extract collagen organisation. Surface imaging microscopy is also used when specimens are very large or where non- uorescent histological stains are most appropriate. Specimens are embedded in wax or resin. The upper surface is etched so that a thin layer can be exposed to a rapidacting histological stain, such as toluidine blue. The surface is imaged using a digital camera, then planed in the ultramill and the complete process is repeated. The gure at the right is a montage of 4 contiguous images of the endocardial surface of a segment of pig right atrial appendage. The terminal crest can be seen on the lower left boundary and the complex network of pectinate muscles is also evident. (A photo micro lens (1:1) was used and the largest dimension is 52 mm.) The gure at the left is a single image of a rat right ventricular trabeculum. This cross-sectional view shows the organisation of myocytes, capillaries and elastic tissue. (Acquired through a microscope using a 20 x 0.7NA objective; largest dimension 80 m). Tissue Structure Extended-volume image of the rat kidney. The kidney is perfusion- xed and the vascular endothelium is stained with TRITC conjugated to wheat germ agglutinin. Segments of kidney are embedded in resin and extended-volume confocal microscopy is performed to assemble 3D images over the whole cross-section of the organ. The adjacent gure shows a longitudinal section of the kidney (composed of 228 montaged confocal microscope images), which highlights glomerular distribution (bright spots) in the renal cortex. 14

17 Cardiac Electrophysiology Group leaders Bruce Smaill Andrew Pullan Cardiac Electrophysiology Group Members Travis Austin Leo Cheng Darren Hooks Peter Hunter Ian LeGrice Ayman Mourad Martyn Nash Greg Sands Mark Trew Graduate Students Bryan Caldwell Dean Tai Sally Rutherford Associates Dane Gerneke John Harvey David Nickerson Steve Niederer Nic Smith This interdisciplinary research group which involves bioengineers physiologists and cardiologists is employing function-based computer models of the heart and novel measurement techniques to visualise and study electrical activity of the heart, with particular emphasis on the mechanisms that underlie arrhythmia, brillation and de brillation. The spread of electrical activity through the heart chambers is being mapped experimentally using multichannel optical and electrical probes. Computer models that include detailed information about the structure and electrical properties of the cardiac chambers are being used to generate and study virtual arrhythmias. Accurate computational techniques that enable the 3D spread of cardiac electrical activation to be reconstructed from electrical potentials measured on the body surface are also being re ned and validated. Clinical studies are being carried out to evaluate the utility of this technique. Recent Publications Trew M., LeGrice I., Smaill B. and Pullan A.J. A nite volume method for modeling discontinuous electrical activation in cardiac tissue. Ann. Biomed. Eng., 33: , 2005 Nash M.P. and Pullan A.A. Challenges facing validation of noninvasive electrical imaging of the heart. Ann. Noninvasive Electrocardiol., 10:73-82, Caldwell B.J., LeGrice I.J., Tai D., Hooks D.A., Pullan A.J. and Smaill B.H. Intramural measurement of transmembrane potential in the isolated pig heart: Validation of a novel technique. J. Cardiovasc. Electrophysiol., 16: , Sands G., Trew M., Hooks D., LeGrice I., Pullan A. and Smaill B. Constructing a tissue-speci c model of ventricular microstructure Proc. 26th Annual IEEE EMBS Conference, , Funding Sources Collaborations Clinical Links HRCNZ David Paterson, Oxford Warren Smith, Auckland RSNZ Richard Clayton, Shef eld Peter Taggart, London Wellcome Trust (UK) UARC

18 A bidomain model of heart tissue that incorporates microscopic information about the organization of heart muscle cells chambers of the heart is used to predict the spread of electrical activation across a segment of heart wall from a midwall stimulus. Isochronal activation surfaces are presented in the top image while tracellular potentials are presented in the lower image 10ms after activation. Optical probes have been developed that enable cell membrane potential to be recorded at up to 7 sites across the heart wall. The heart is stained with a membrane bound dye for which uorescent emission is affected by changes in cell membrane potential. A bre optic bundle is used deliver excitation light from a laser to sites in the heart wall and to collect the uorescence emission adjacent to these sites. Typical optical potentials are shown in panel at right. Clinical characterisation of cardiac electrical activity in patients. Spatial organization of maximum restitution slope (left) and range of diastolic intervals for which restitution slope is greater than unity (right) in two patients, illustrating the regional heterogeneity within patients and between patients. (AVD: aortic valve disease; CAD: coronary artery disease). Collaborative study involving Dr Peter Taggart (University College Hospital London), Dr Martyn Nash (Auckland), Dr Richard Clayton (Shef eld), and Prof David Paterson (Oxford). Cardiac Electrophysiology 16

19 Cardiac Mechanics Group leaders Martyn Nash Alistair Young Group Members Brett Cowan Peter Hunter Ian LeGrice Poul Nielsen Carey Stevens Rob Kirton Nic Smith Graduate Students Kevin Augenstein Holger Schmid Cardiac Mechanics Associates Rob Doughty Dane Gerneke Rob Kirton Chris Occleshaw Espen Remme Nic Smith Ralph Stewart The mechanical function of the heart is governed by the contractile properties of the cells, the mechanical stiffness of the muscle and connective tissue, and the pressure and volume loading conditions on the organ. We have shown that heart muscle has a complex layered, brous 3D architecture that has a profound effect on its mechanical behaviour. Accurate Finite Element models of heart shape, tissue architecture and mechanical properties have been developed to realistically predict normal and pathological mechanical processes. Tissue testing devices have also been developed to characterise the mechanical properties of heart muscle during extension, compression and shear. One area of active research is the development of better material laws that can be used to interpret in-vitro and in-vivo tissue behaviour. Sophisticated analysis methods are being developed for the understanding of diastolic and systolic mechanisms of dysfunction. These techniques will allow improved diagnosis of patients and evaluation of treatment. Recent Publications Augenstein K., Cowan B., LeGrice I.J., Nielsen P.M.F. and Young A.A. Method and apparatus for soft tissue material parameter estimation using tissue tagged magnetic resonance imaging. J. Biomech. Engr., 127: , LeGrice I.J., Pope A. and Smaill B. The architecture of the heart: Myocyte organization and cardiac extracellular matrix. In Interstitial brosis in heart failure. F Villareal Ed., Springer, Academic Press. pp3-21, Remme E.W., Young A.A., Augenstein K.F., Cowan B. and Hunter P.J. Extraction and quanti cation of left ventricular deformation modes. IEEE Trans. Biomed Eng., 51(11): , Remme E.W., Hunter P.J., Smiseth O., Stevens C., Rabben S.I., Skulstad H. and Angelsen B.B. Development of an in-vivo method for determining material properties of passive myocardium. J.Biomech., 37(5):769-78, Stevens C., Remme E., LeGrice I. and Hunter P. Ventricular mechanics in diastole: material parameter sensitivity. J. Biomech.,. 36(5):737-48, Nash M.P. and Hunter P.J. Computational mechanics of the heart: from tissue structure to ventricular function. J. Elast., 61(1/3): , Funding Sources Collaborations Clinical Links Industry Links HRCNZ UCSD Chris Occleshaw, Auckland Siemens NHF Oxford University Ralph Stewart, Auckland Varian Wellcome Trust (UK) 17 13

20 Heart muscle bre and connective tissue organisation gives rise to mechanical behaviour that varies depending on the loading orientation. This is known as mechanical orthotropy of cardiac tissue. Recordings of tissue stretch versus load (mechanical stress) registered against the bre-sheet microstructural directions provide the necessary information to characterise the mechanical properties of heart muscle and the construction of microstructurally-based material laws. An anatomically accurate computational model of the left and right ventricles, including quantitative descriptions of the muscle architecture, allows application of realistic boundary conditions (pressure, volume) and orthotropic mechanical properties. Cardiac Mechanics Heart cycle simulations validated against clinical and experimental recordings of organ deformation (from MRI, ultrasound, etc) provide regional estimates of ventricular wall stress. Increased wall stress is known to be correlated with oxygen demand and used as a marker for disease. 18

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