Piezoresistor-Embedded Multifunctional Magnetic Microactuators for Implantable Self-Clearing Catheter

Indwelling catheters are used widely in medicine to treat various chronic medical conditions. However, chronic implantation of catheters often leads to a premature failure due to biofilm accumulation. Previously we reported on the development of a self-clearing catheter by integrating polymer-based microscale magnetic actuators. The microactuator provides an active anti-biofouling mechanism to disrupt and remove adsorbed biofilm on demand using an externally applied stimulus. During an in vivo evaluation of self-clearing catheter, we realized that it is important to periodically monitor the performance of implanted microactuators. Here we integrate gold-based piezoresistive strain-gauge on our magnetic microactuators to directly monitor the device deflection with good sensitivity (0.035%/Deg) and linear range (±30°). With the integrated strain-gauge, we demonstrate the multi-functional capabilities of our magnetic microactuators that enable device alignment, flow-rate measurement, and obstruction detection and removal towards the development of chronically implantable self-clearing smart catheter

Doctor of Philosophy

dissertationShunt catheter obstruction due to the foreign body host response is a serious problem in the treatment of hydrocephalus. Our goal was to reduce inflammatory cell adhesion on silicone catheters in an effort to limit shunt obstruction. We investigated chemical and mechanical cues that may influence macrophage and astrocyte adhesion, and using this knowledge, examined pertinent catheter modifications. A novel in vitro bioreactor, capable of measuring dependencies between macrophage and astrocyte adhesion, intracranial flow rate, pressure, pulsation frequency, and protein concentration, was developed and tested. Results demonstrated that a combination of chemical cues (particularly surface chemistry) and mechanical cues (particularly shear stress) influenced macrophage and astrocyte attachment to shunt catheters. The surface chemistry of the catheter was modified using long term coatings with anti-inflammatory capabilities including poly(ethylene) glycol and N-acetyl-L-cysteine, both of which significantly inhibited macrophage and astrocyte adhesion when tested in the bioreactor. Additionally, the shear stress through ventricular catheter drainage holes was manipulated by changing the diameter of these openings. Data generally suggested that macrophage and astrocyte adhesion decreases with increasing hole size. Two barriers were overcome in this research: (1) the development of an in vitro system capable of testing catheter constructs in a method superior to standard static in vitro culturing; (2) significant surface and architecture modifications that inhibit inflammatory cell adhesion which could be used in future studies to inhibit inflammatory-derived obstruction. Together, the implementation of this system and the modifications to current catheter design will help answer questions of how and why catheters fail

The Role of Transcranial Doppler Sonography in the Management of Pediatric Hydrocephalus

In the pathophysiology of pediatric hydrocephalus, a significant role is played by the negative influence of cerebral circulation with the emergence of cerebral hypoperfusion. Transcranial Doppler sonography is a noninvasive method that can be used for indirect measurement of intracranial pressure and decrease of intracranial compliance by assessment of changes of cerebral circulation. The goal of this work was to assess the cerebral circulation and intracranial dynamics in pediatric hydrocephalus. The work is also focused on evaluation of impact of various intracranial factors on Doppler parameters of cerebral circulation, especially in neonates with hydrocephalus. The ambition of this work is to improve indication and timing of drainage procedure in children with hydrocephalus by application of the scientific results and clinical experience

Development of an alternative ventricular catheter and an in vitro model of its obstruction

This thesis was previously held under moratorium from 5th November 2014 until 2nd June 2020.Intracranial pressure and volume varies considerably between hydrocephalic patients, and with age, health and haemodynamic status; if left untreated intracranial pressure rises and the ventricular system expands to accommodate the excess cerebrospinal fluid (CSF), with significant morbidity and mortality. Although considerable improvements in design have been made since their introduction all CSF shunts in use today have a high incidence of failure with shunt obstruction being the most serious. Conventional proximal shunt catheters are made from poly (di-methyl) siloxane (PDMS), the walls of which are perforated with holes for the CSF to pass through. The limited range of catheters, in terms of material selection and flow distribution, is responsible in large part for their poor performance.;The aim of the study is to design and fabricate an alternative design of proximal catheter with permeable walls, and to evaluate its performance in the presence of glial cells, which are responsible for blockage. Electrospun Poly-ether Urethane (EPU) samples were fabricated from solvent, by means of an electrospinning technique, to yield microfibrous polymer conduits. The hydrodynamic properties of EPU and conventional shunt were studied using a purpose-built shunt testing system.;The viability and growth of cells on candidate catheter materials such as PDMS and polyurethane in the form of cast films, microfibrous mats and porous sponges were studied in presence of proteins present in CSF after 48h and 96h in culture. The number of viable cells was significantly less on EPU samples compared to the other substrates, which suggests that the fibrous form of the material from which the catheter is made has a bearing on the cell growth. A cell culture model of shunt obstruction was developed in which the cells were subjected to flow during culture in vitro, and the degree of obstruction quantified in terms of hydraulic permeability post static and perfusion culture. The results indicate that a catheter made of EPU would be able to maintain CSF flow even with the presence of cells for the time period chosen for this study. These findings have implications for the design and deployment of micro porous shunt catheter systems for the treatment of hydrocephalus.Intracranial pressure and volume varies considerably between hydrocephalic patients, and with age, health and haemodynamic status; if left untreated intracranial pressure rises and the ventricular system expands to accommodate the excess cerebrospinal fluid (CSF), with significant morbidity and mortality. Although considerable improvements in design have been made since their introduction all CSF shunts in use today have a high incidence of failure with shunt obstruction being the most serious. Conventional proximal shunt catheters are made from poly (di-methyl) siloxane (PDMS), the walls of which are perforated with holes for the CSF to pass through. The limited range of catheters, in terms of material selection and flow distribution, is responsible in large part for their poor performance.;The aim of the study is to design and fabricate an alternative design of proximal catheter with permeable walls, and to evaluate its performance in the presence of glial cells, which are responsible for blockage. Electrospun Poly-ether Urethane (EPU) samples were fabricated from solvent, by means of an electrospinning technique, to yield microfibrous polymer conduits. The hydrodynamic properties of EPU and conventional shunt were studied using a purpose-built shunt testing system.;The viability and growth of cells on candidate catheter materials such as PDMS and polyurethane in the form of cast films, microfibrous mats and porous sponges were studied in presence of proteins present in CSF after 48h and 96h in culture. The number of viable cells was significantly less on EPU samples compared to the other substrates, which suggests that the fibrous form of the material from which the catheter is made has a bearing on the cell growth. A cell culture model of shunt obstruction was developed in which the cells were subjected to flow during culture in vitro, and the degree of obstruction quantified in terms of hydraulic permeability post static and perfusion culture. The results indicate that a catheter made of EPU would be able to maintain CSF flow even with the presence of cells for the time period chosen for this study. These findings have implications for the design and deployment of micro porous shunt catheter systems for the treatment of hydrocephalus

New Insight into Cerebrovascular Diseases

“Brain circulation is a true road map that consists of large extended navigation territories and a number of unimagined and undiscovered routes.” Dr. Patricia Bozzetto Ambrosi This book combines an update on the review of cerebrovascular diseases in the form of textbook chapters, which has been carefully reviewed by Dr. Patricia Bozzetto Ambrosi, Drs. Rufai Ahmad and Auwal Abdullahi and Dr. Amit Agrawal, high-performance academic editors with extensive experience in neurodisciplines, including neurology, neurosurgery, neuroscience, and neuroradiology, covering the best standards of neurological practice involving basic and clinical aspects of cerebrovascular diseases. Each topic was carefully revised and prepared using smooth, structured vocabulary, plus superb graphics and scientific illustrations. In emphasizing the most common aspects of cerebrovascular diseases: stroke burden, pathophysiology, hemodynamics, diagnosis, management, repair, and healing, the book is comprehensive but concise and should become the standard reference guide for this neurological approach

Doctor of Philosophy

dissertationNeural recording devices are a therapeutic and diagnostic option for central nervous system (CNS) diseases and a vital component of neuroscience research. However, poor functional longevity is a major hurdle facing this broad class of devices. Decreases in functionality are associated, in part, with the foreign body response (FBR) surrounding chronically implanted recording devices; which includes chronic inflammation, astrogliosis, blood-brain barrier (BBB) leakiness, and neuronal cell death. Two potential areas for intervention were explored including the initial hemorrhage that results from device insertion and the neuroinflammatory sequela. Researchers have shown that cellular interactions with extracellular matrix (ECM) are able to affect both of these aspects of the FBR. The central hypothesis driving this work is that ECM coatings which target the initial hemorrhage, should decrease the FBR. This was investigated by coating silicon microelectrode arrays (MEAs) with ECM and implanting them into motor cortex of rats. Two ECM coatings were investigated, including the xenogeneic clinically-used Avitene Microfibrillar Collagen Hemostat and allogeneic astrocyte-derived ECM. Results show that the allogeneic astrocyte-derived ECM decreased astrogliosis within the recording zone at the 8-week time point. This decrease in astrogliosis may improve device functionality, as indicated by previous studies that correlated recording metrics to histology. Interestingly, the xenogeneic Avitene coating increased IgG within the recording zone at the 8-week time point. Collectively, these results show that ECM coatings with different genetic backgrounds and compositions are able to differentially affect specific aspects of the FBR. To broaden the knowledge on the FBR to neural recording devices, the FBR of headstage components used to anchor CNS devices to the skull was analyzed. Results showed that the FBR to fixation screws and fixation anchoring adhesive illicit a chronic FBR that has all of the hallmarks described for MEAs implanted in brain tissue. Moreover, results show evidence of persistent neuroinflammation below a variety of fixation screws including chronic macrophage activation, demyelination, and neural tissue loss. Understanding the FBR of fixation techniques, which is common to a wide variety of CNS devices, may improve the biocompatibility of existing devices and provide a reference for future biologically-informed device designs

Volume 22, issue 5

The mission of CJS is to contribute to the effective continuing medical education of Canadian surgical specialists, using innovative techniques when feasible, and to provide surgeons with an effective vehicle for the dissemination of observations in the areas of clinical and basic science research. Visit the journal website at http://canjsurg.ca/ for more.https://ir.lib.uwo.ca/cjs/1163/thumbnail.jp

Biomarkers in patients with idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a condition affecting a small percentage of the elderly population; however it is the only known treatable cause of dementia. Surgical cerebrospinal fluid (CSF) diversion is the only known treatment for the condition today. However, such a procedure is not to be offered lightly and any expected benefit has to balance the associated surgical risks. The prognosis of a favourable surgical outcome has been problematic since the conception of the syndrome. None of current prognostic tests reaches 100% sensitivity or specificity and it is felt that there might be a need for a combination of tests, rather than a single one to maximize the chances of selecting the right patients to offer a surgical CSF diversion procedure. Biomarkers are biological substances that may act as surrogate markers of response to a treatment or to characterise a disease’s progression over time. The aim of this study was to identify CSF markers of favourable surgical outcome in patients with iNPH undergoing the insertion of a ventriculoperitoneal shunt (VPS). We first describe the effects of external lumbar drainage (ELD) on the CSF biochemistry of these patients. Correlations are made with imaging data obtained from volumetric analysis and neuropsychological tests in order to obtain a complete profile of these patients. The rostrocaudal gradients of the CSF markers examined are reported showcasing the need to understand that commonly reported values from lumbar CSF do not necessarily reflect pathological changes occurring at cerebral level. Finally, we report on the individual as well as combined prognostic value of 7 CSF markers on surgical outcomes at 6 months. The pathophysiological significance of these markers is discussed individually. It is concluded that the combined power of total tau and Aβ 1-42 may be useful in predicting favourable surgical outcomes at 6 months; further studies applying the findings in a larger cohort and correlating findings with longer outcomes are warranted to enhance the clinical application. The biochemical profile of patients with iNPH appears unique and different than patients with Alzheimer’s dementia or control subjects