Realtime monitoring of thrombus formation in vivo using a self-reporting vascular access graft.

BACKGROUND: Chronic kidney disease (CKD) affects 10% of the global population costing over a hundred billion dollars per annum and leading to increased risk of cardiovascular disease. Many patients with CKD require regular haemodialyses. Synthetic arteriovenous grafts (AVG) are increasingly used to provide rapid vascular connection for dialysis. Initially, they have excellent patency rates but are critically limited by neointimal hyperplasia at the venous anastomosis, which drives subsequent thrombosis, graft failure and death. METHODS: Here, we describe a system in which electrical impedance spectroscopy sensors are incorporated circumferentially into the wall of a synthetic arteriovenous graft. This is combined with an implantable radiotelemetry system for data transmission outside the patient. The system was tested using monolayers of endothelial and smooth muscle cells as well as swine blood and clots with explanted human carotid artery plaques. Sensor testing was then performed in vitro and the device was implanted in vivo in female swine. RESULTS: The device can wirelessly report the accumulation of biological material, both cells and blood. Differences are also detected when comparing controls with pathological atheroma. In swine differences between blockage formation in a graft were remotely obtained and wireless reported. CONCLUSIONS: Combining electrical impedance spectroscopy and an implantable radiotelemetry system enables graft surveillance. This has the potential to be used for early detection of venous stenosis and blood clot formation in real-time in vivo. In principle, the concept could apply to other cardiovascular diseases and vascular implantable devices.

Chronic kidney disease is common throughout the world and required treatments are expensive. People with chronic kidney disease require frequent blood dialysis treatment to filter their blood and remove waste products and toxic substances circulating in the blood. For some patients, implantable tubular structures called AV grafts are used for providing access to dialysis. These grafts frequently block sometimes without warning leading to patients not being able to undergo dialysis. Through a series of laboratory experiments looking at cells that block the graft, fatty deposits and blood clots, we evaluated whether sensors could detect blockages in an AV graft. We also tested the device in an animal model. From these results we were able to show that our device could detect blockages within a graft. In the future we hope that introduction to the clinic of an optimized version of our device will reduce costs to healthcare systems and improve patient outcomes.

Detection of Blood Clots Using a Whole Stent as an Active Implantable Biosensor.

Many cardiovascular problems stem from blockages that form within the vasculature and often treatment includes fitting a stent through percutaneous coronary intervention. This offers a minimally invasive therapy but re-occlusion through restenosis or thrombosis formation often occurs post-deployment. Research is ongoing into the creation of smart stents that can detect the occurrence of further problems. In this study, it is shown that selectively metalizing a non-conductive stent can create a set of electrodes that are capable of detecting a build-up of material around the stent. The associated increase in electrical impedance across the electrodes is measured, testing the stent with blood clot to mimic thrombosis. It is shown that the device is capable of sensing different amounts of occlusion. The stent can reproducibly sense the presence of clot showing a 16% +/-3% increase in impedance which is sufficient to reliably detect the clot when surrounded by explanted aorta (one sample t-test, p = 0.009, n = 9). It is demonstrated that this approach can be extended beyond the 3D printed prototypes by showing that it can be applied to a commercially available stent and it is believed that it can be further utilized by other types of medical implants.

An Impedance Sensor for Pathologically Relevant Detection of In-Stent Restenosis In Vitro.

Cardiovascular disease (CVD) is the biggest cause of death globally. CVD is caused by atherosclerosis which is the accumulation of fatty deposits, often within the fine arteries of the heart or brain. These blockages reduce blood flow and lead to oxygen starvation (ischemia) which can lead to heart attacks and strokes. To treat blocked arteries an implantable device called a stent re-opens the artery to reinstate blood flow to the organ. The stent itself can become blocked over time by cell growth (intimal hyperplasia) which is characterised by excessive smooth muscle cell proliferation. Sensors based on electrical impedance spectroscopy (EIS) embedded in a stent could detect this re-blocking to allow for early intervention. Using platinum interdigitated electrodes on silicon sensor wafers we were able to co-culture different ratios of mouse smooth muscle cells and mouse endothelial cells on these sensors. This mimics the complex, multicellular environment which a stent is found in vivo when undergoing neo-intimal hyperplasia. Trends in the cell impedances were then characterised using the detection frequency and the gradient of change between populations over time which we termed 'Peak Cumulative Gradients (PCG). PCGs were calculated to successfully discriminate each cell type. This work moves towards a sensor that may help guide clinician's decision-making in a disease that is historically silent and difficult to detect. Clinical Relevance-This moves towards an early warning system for the detection of neo intimal hyperplasia ultimately leading to a reduction in stent complications.

Predicting Cardiovascular Stent Complications Using Self-Reporting Biosensors for Noninvasive Detection of Disease.

Self-reporting implantable medical devices are the future of cardiovascular healthcare. Cardiovascular complications such as blocked arteries that lead to the majority of heart attacks and strokes are frequently treated with inert metal stents that reopen affected vessels. Stents frequently re-block after deployment due to a wound response called in-stent restenosis (ISR). Herein, an implantable miniaturized sensor and telemetry system are developed that can detect this process, discern the different cell types associated with ISR, distinguish sub plaque components as demonstrated with ex vivo samples, and differentiate blood from blood clot, all on a silicon substrate making it suitable for integration onto a vascular stent. This work shows that microfabricated sensors can provide clinically relevant information in settings closer to physiological conditions than previous work with cultured cells.

Challenges to the Development of the Next Generation of Self-Reporting Cardiovascular Implantable Medical Devices.

Cardiovascular disease (CVD) is a group of heart and vasculature conditions which are the leading form of mortality worldwide. Blood vessels can become narrowed, restricting blood flow, and drive the majority of hearts attacks and strokes. Reactive surgical interventions are frequently required; including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Despite successful opening of vessels and restoration of blood flow, often in-stent restenosis (ISR) and graft failure can still occur, resulting in subsequent patient morbidity and mortality. A new generation of cardiovascular implants that have sensors and real-time monitoring capabilities are being developed to combat ISR and graft failure. Self-reporting stent/graft technology could enable precision medicine-based and predictive healthcare by detecting the earliest features of disease, even before symptoms occur. Bringing an implantable medical device with wireless electronic sensing capabilities to market is complex and often obstructive undertaking. This critical review analyses the obstacles that need to be overcome for self-reporting stents/grafts to be developed and provide a precision-medicine based healthcare for cardiovascular patients. Here we assess the latest research and technological advancement in the field, the current devices; including smart cardiovascular implantable biosensors and associated wireless data and power transfer solutions. We include an evaluation of devices that have reached clinical trials and the market potential for their end-user implementation.

Impedimetric Detection and Electromediated Apoptosis of Vascular Smooth Muscle Using Microfabricated Biosensors for Diagnosis and Therapeutic Intervention in Cardiovascular Diseases.

Cardiovascular diseases remain a significant global burden with 1-in-3 of all deaths attributable to the consequences of the disease. The main cause is blocked arteries which often remain undetected. Implantable medical devices (IMDs) such as stents and grafts are often used to reopen vessels but over time these too will re-block. A vascular biosensor is developed that can report on cellularity and is amenable to being mounted on a stent or graft for remote reporting. Moreover, the device is designed to also receive currents that can induce a controlled form of cell death, apoptosis. A combined diagnostic and therapeutic biosensor would be transformational for the treatment of vascular diseases such as atherosclerosis and central line access. In this work, a cell sensing and cell apoptosing system based on the same interdigitated electrodes (IDEs) is developed. It is shown that the device is scalable and that by miniaturizing the IDEs, the detection sensitivity is increased. Apoptosis of vascular smooth muscle cells is monitored using continuous impedance measurements at a frequency of 10 kHz and rates of cell death are tracked using fluorescent dyes and live cell imaging.

The Future of Cardiovascular Stents: Bioresorbable and Integrated Biosensor Technology.

Cardiovascular disease is the greatest cause of death worldwide. Atherosclerosis is the underlying pathology responsible for two thirds of these deaths. It is the age-dependent process of "furring of the arteries." In many scenarios the disease is caused by poor diet, high blood pressure, and genetic risk factors, and is exacerbated by obesity, diabetes, and sedentary lifestyle. Current pharmacological anti-atherosclerotic modalities still fail to control the disease and improvements in clinical interventions are urgently required. Blocked atherosclerotic arteries are routinely treated in hospitals with an expandable metal stent. However, stented vessels are often silently re-blocked by developing "in-stent restenosis," a wound response, in which the vessel's lumen renarrows by excess proliferation of vascular smooth muscle cells, termed hyperplasia. Herein, the current stent technology and the future of biosensing devices to overcome in-stent restenosis are reviewed. Second, with advances in nanofabrication, new sensing methods and how researchers are investigating ways to integrate biosensors within stents are highlighted. The future of implantable medical devices in the context of the emerging "Internet of Things" and how this will significantly influence future biosensor technology for future generations are also discussed.

TBT causes regime shift in shallow lakes.

Tributyltin (TBT) is an organotin compound used since the early 1960s as a biocide in boat antifouling paints. Its use has been linked to a host of negative effects in marine ecosystems including malformations and imposex in Mollusca and acute toxicity in many other aquatic animals. Yet, the consequences of TBT use in freshwaters are largely unknown. Here, for the first time we reveal that TBT may have caused hitherto unsuspected damage to freshwater ecosystems. Through an analysis of dated sediment cores collected from a system of recreationally boated, shallow lakes, we show that first evidence of TBT is associated with a dramatic loss of submerged vegetation and associated diverse animal communities. Cause and effect are difficult to unravel in our study. However, we hypothesize that TBT, through reducing populations of grazing organisms in lakes already affected by eutrophication, promoted the replacement of macrophytes by phytoplankton, ultimately leading to a regime shift in the ecosystem. Our findings may have parallels in freshwater ecosystems all over the world.

Association patterns and shoal fidelity in the three-spined stickleback.

We investigated pairwise association patterns and shoal fidelity in free-ranging, individual three-spine sticklebacks (Gasterosteus aculeatus) by capturing entire shoals of sticklebacks and tagging each shoal member with a unique individual mark before releasing the shoal at the point of capture. We recaptured tagged fishes in the study area on five subsequent days, noting their identity, their location and the individuals with which they were associated. Stable partner associations between fishes were observed which might provide the basis for shoal fidelity via social networks. These results suggest the potential for the kinds of inter-individual association patterns assumed by models of predator inspection and 'tit-for-tat' behaviours in free-ranging fishes.