During the design and validation phase, medical devices undergo rigorous and extensive testing to establish both the biocompatibility and mechanical stability of the device before obtaining regulatory approval and being implanted into patients as treatments for disease and injury. However, the human body is highly adaptive and cells and tissues can change their composition, structure and function in response to biophysical stimuli – in particular, those imposed by these medical devices when they are implanted into the body. Indeed, it is well known that muscles get bigger and stronger when we exercise, but it is less widely understood that many other cells and tissues of the body, such as skin, vessels, bones, cartilage and heart tissue, also respond to changes in the mechanical forces they experience. For example, when astronauts return from a long spaceflight, their bones are as weak as those of older people with osteoporosis. This is because of the weightlessness arising in space, which triggers the cells to think that the bone is not needed anymore and they then begin to eat away at it. The success of medical devices is also dictated by such responses. For example, cardiovascular stents impose mechanical forces on the arterial wall when they are scaffolding open an atherosclerotic plaque. However, the mechanical stresses induced by the stent on the vessel wall actually stimulate biological responses in the cells, which activate the cells to start making new tissue (in an attempt to reduce the stress in their environment) but this ultimately leads to a re-blockage, known as restenosis. Hip and knee replacements also activate unwanted responses in bone cells, due the fact that the metallic implant bears most of the applied stress and leaves the surrounding bone unloaded, which activates the cells to remove bone and leads to implant loosening (a process known clinically as stress-shielding) and the requirement for a revision surgery. Although such responses are critical for the long-term performance of medical devices, they remain poorly understood and so the ability to control such reactions has not yet been fully harnessed. Our research in the Mechanobiology and Medical Device Research Group (MMDRG) at NUI Galway seeks to understand such responses so that they can ultimately be accounted for during the design of medical devices.

Mechanobiology at NUI Galway

Mechanobiology is an emerging field, which integrates engineering mechanics with cell biology, molecular biology and genetics to investigate how biological cells can sense and respond to changes in their local mechanical environment. My research group is trying to understand how exactly biological cells know what forces are applied to them, and how they are able to change the design of tissues when we change our activity. We do this using a combination of engineering and biology: for example, we study the design of the bones, heart valves and cells by treating them like engineering structures and apply physics, maths and computer models to compare the forces at the cell level during different activities. This is comparable to methods a civil engineer compares the design concepts for two bridges by using computational models to test how they perform under different stresses. However, a particular challenge in the field of mechanobiology lies in understanding the mechanical environment at the cell level. Cells and tissues of the body are highly elastic and deformable materials that interact with body fluids, and this behaviour represents a challenging multi-physics problem. Although computational models are already widely used to predict medical device performance during the design phase and for regulatory purposes, these models largely neglect this complex multi-physics environment. Latest advances in computational modelling have now provided tools that can simulate interactions between deformable structures and adjacent fluid flows. These can now be applied to model the complex behaviour of organs, tissues and cells of the body, and also to predict the in-vivo performance of medical devices. Fluid-structure interaction approaches can model the fluid, cells and tissues, and account for the large deformation at cell membranes under physiological fluid flows and mechanical forces. Using such approaches, computational modelling of prosthetic heart valves can be applied to model the interaction between blood flow and deformation of the valve leaflets. These models can provide an insight into how valve design regulates blood flow and can also predict whether cellular responses to the forces imposed by the valve cause ‘valve calcification’, a common complication of prosthetic heart valves. Our research also strives to develop both multiscale modelling platforms that incorporates the hierarchical structure of biological tissues at multiple size-scales (organ, tissue and cellular level). These models need to accurately represent the native anatomy and replicate the in-vivo physical environment, and so models are generated using high resolution medical imaging (CT, MRI) and advanced microscopy data. Material properties can be calibrated to cellular and tissue properties derived through experimental testing of biological cells and tissues.

Accelerate product development and regulatory approval

[caption id="attachment_39594" align="alignright" width="300"] CLICK TO ENLARGE Mechanobiology process for medical-device design[/caption] Our computational modelling tools are applied in collaborative projects with medical devices companies, to provide them with an advanced understanding of the underlying changes in the mechanical environment that occur with particular medical devices or surgical procedures. Thus, we aim to accelerate product development and regulatory approval of medical devices by providing computational test platforms to predict cell level mechanical stimulation under loading imposed by medical devices. But these techniques are just emerging and have not yet been applied in a widespread fashion to model the complex behaviour of organs and tissues of the body to predict the long-term performance of medical devices. Although abundant research has been dedicated to understanding cell and tissue properties during normal physiology and disease, it remains that the physical behaviour of a vast majority of cells, tissues and organs of the body have not yet been characterised. Such properties are essential to inform the design of medical devices that can perform adequately in the complex in-vivo physical environment. Our research seeks to address this gap in knowledge by developing mechanical test methods appropriate for cells and tissues, but also uses biology to identify tiny force sensors in the body, similar to strain gauges and flowmeters, which are made of proteins. When mechanically stretched, these proteins start a cascade of internal processes within the cell, which produce biochemicals that act as signals to activate other cells when the mechanical environment is not favourable. We also design experiments to drive fluid over the cells, and in that way put forces on them and study changes in the biology. Indeed, one of the most exciting things that we do is to design bioreactors, which are devices that can recreate the forces cells experience in the body, such as pressure and fluid flow from the pumping of the heart and in our bones, due to everyday activities like walking. We use these experimental methods and bioreactors to uncover changes in the biology that occur after medical device implantation. Pre-clinical testing of medical devices involves extensive bench testing to verify safety, in particular the likelihood of mechanical failure and biological rejection. But these bench tests do not fully recreate the environment within the human body, because they cannot account for the physical interaction of the devices with the native tissue/organ (e.g. mechanical, thermal, chemical) or biological interactions with the device. Our ongoing research seeks to develop laboratory models (ex-vivo) that can recreate cell and tissue responses to the biophysical stimuli, which will ultimately provide an understanding of the biological responses that occur to stress imposed by medical devices. It is our goal that this research will promote informed experimentation and analysis on medical devices, particularly informing device design and reducing the burden of animal testing. Our research has been funded through the European Research Council, which funds ‘blue sky’ research, but also by Science Foundation Ireland (SFI) and the European Regional Development fund through the SFI Investigators program, the Irish Research Council and industry funding from Medtronic, Stryker and Boston Scientific, and CÚRAM, the SFI-funded National Centre for Research in Medical Devices. Laoise-mcnamaraAuthor: Prof Laoise McNamara is a personal professor in biomedical engineering at the College of Engineering and Informatics, National University of Ireland, Galway. She established the Mechanobiology and Medical Device Research Group (MMDRG) at NUI Galway in 2009 and was awarded an ERC Starting Independent Researcher Award to conduct frontier research in Mechanobiology in 2011. The MMDRG uses multidisciplinary approaches to derive understanding of mechanobiology and how this process contributes to development, disease and medical device outcomes. They develop in-vitro tissue regeneration strategies that exploit mechanobiological responses. Prof McNamara was awarded a Science Foundation Ireland (SFI) Investigators Grant to identify mechanobiology-based therapeutic approaches for treatment of osteoporosis. She has also been awarded various other Health Research Board, SFI and Irish Research Council funding. Her research group have been awarded numerous presentation prizes and travel awards (American Society for Mechanical Engineering, American Society for Bone and Mineral Research, Orthopaedic Research Society, European Society for Biomechanics, MIMICS Innovation Award, Engineers Ireland, Bioengineering in Ireland, Fulbright, NUI and SFI travelling scholarships). Prof McNamara collaborates with Stryker, Boston Scientific and Medtronic, applying her expertise in computational and experimental mechanobiology to the pre-clinical assessment of surgical and minimally invasive medical devices.