MR-based navigation for robot-assisted endovascular procedures

There is increasing interests in robotic and computer technologies to accurately perform endovascular intervention. One major limitation of current endovascular intervention—either manual or robot-assisted is the surgical navigation which still relies on 2D fluoroscopy. Recent research efforts are towards MRI-guided interventions to reduce ionizing radiation exposure, and to improve diagnosis, planning, navigation, and execution of endovascular interventions. We propose an MR-based navigation framework for robot-assisted endovascular procedures. The framework allows the acquisition of real-time MR images; segmentation of the vasculature and tracking of vascular instruments; and generation of MR-based guidance, both visual and haptic. The instrument tracking accuracy—a key aspect of the navigation framework—was assessed via 4 dedicated experiments with different acquisition settings, framerate, and time. The experiments showed clinically acceptable tracking accuracy in the range of 1.30–3.80 mm RMSE. We believe that this work represents a valuable first step towards MR-guided robot-assisted intervention

Image-Based Force Estimation and Haptic Rendering For Robot-Assisted Cardiovascular Intervention

Clinical studies have indicated that the loss of haptic perception is the prime limitation of robot-assisted cardiovascular intervention technology, hindering its global adoption. It causes compromised situational awareness for the surgeon during the intervention and may lead to health risks for the patients. This doctoral research was aimed at developing technology for addressing the limitation of the robot-assisted intervention technology in the provision of haptic feedback. The literature review showed that sensor-free force estimation (haptic cue) on endovascular devices, intuitive surgeon interface design, and haptic rendering within the surgeon interface were the major knowledge gaps. For sensor-free force estimation, first, an image-based force estimation methods based on inverse finite-element methods (iFEM) was developed and validated. Next, to address the limitation of the iFEM method in real-time performance, an inverse Cosserat rod model (iCORD) with a computationally efficient solution for endovascular devices was developed and validated. Afterward, the iCORD was adopted for analytical tip force estimation on steerable catheters. The experimental studies confirmed the accuracy and real-time performance of the iCORD for sensor-free force estimation. Afterward, a wearable drift-free rotation measurement device (MiCarp) was developed to facilitate the design of an intuitive surgeon interface by decoupling the rotation measurement from the insertion measurement. The validation studies showed that MiCarp had a superior performance for spatial rotation measurement compared to other modalities. In the end, a novel haptic feedback system based on smart magnetoelastic elastomers was developed, analytically modeled, and experimentally validated. The proposed haptics-enabled surgeon module had an unbounded workspace for interventional tasks and provided an intuitive interface. Experimental validation, at component and system levels, confirmed the usability of the proposed methods for robot-assisted intervention systems

Placental mesenchymal stem cell sheets: motivation for bio-MEMS device to create patient matched myocardial patches

Congenital heart defects are the number one cause of birth defect-related deaths. Cardiovascular diseases are the most common cause of death worldwide. Layered cellular sheet constructs offer one very valuable option for cardiac patch implantation during surgical treatment of both pediatric and adult patients with cardiac defects or damage. A very exciting, relatively unexplored, autologous, available cell source for making patches are placenta-derived mesenchymal stem cells (pMSCs). In this study, pMSCs were assessed as a potential cell source for cardiac repair and regeneration by evaluating their differentiation capacity into cardiomyocytes, their effects on cardiac cell migration and proliferation, and their ability to be grown into cell sheets. It was found that pMSC cardiac protein content was enhanced by differentiation media treatment, but no beating cells were produced. Undifferentiated pMSCs improved migration and proliferation of a cardiac cell population and formed intact, aligned cell sheets. However, like many new cell sources for cardiac repair, pMSCs should still be functionally characterized to understand how compatible they will be with resident heart tissue. Implanting non-autologous, potentially pluripotent, non-myocyte (non-beating) cells presents concerns regarding electromechanical mismatch and implant rejection. The characterization of non-traditional cell sources such as pMSCs motivated the design of a bio-MEMS device that assesses contractile force and conduction velocity in response to electrical and mechanical stimulation of a cell source as it is grown and once it forms a cellular sheet. This ideally creates the ability for patient specific cell sheets to be cultured, characterized, and conditioned to be compatible with the patient’s cardiac environment in vitro, prior to implantation. In this work, the device was designed to achieve the following: cellular alignment, electrical stimulation, mechanical stimulation, conduction velocity readout, contraction force readout, and upon characterization, cell sheet release. The platform is based on a set of comb electrical contacts which are three dimensional wall contacts made of polydimethylsiloxane and coated with electrically conductive metals. Device fabrication and initial validation experiments were completed as part of this study; ultimately the device will allow for the complete functional characterization and conditioning of variable cell source cell sheet implants for myocardial implantation.2019-07-02T00:00:00

Interventional techniques in the management of persistent atrial fibrillation

Atrial fibrillation (AF) is a common cardiac rhythm problem experienced by patients and comprises an increasing demand on healthcare systems. AF is characterised by advanced neurohormonal remodelling in the atria resulting in dilation and variable degree of atrial fibrosis that can be measured by imaging techniques with difficulty in developing methods of identifying and quantifying left atrial (LA) fibrosis. LA fibrosis can be estimated by measuring LA scar using non-invasive imaging methods such as strain imaging in advanced echocardiography and in cardiac magnetic resonance (CMR) imaging. Achieving rhythm control strategy utilising catheter ablation (CA) has shown to be advantageous in improving quality of life (QOL) in patients with paroxysmal AF. The most effective method in management of AF has remained elusive in non-paroxysmal AF. Thoracoscopic surgical ablation (TSA) has been developed over the last decade by experienced surgeons with some promising early results but has not been investigated in long-standing persistent AF (LSPAF). I have attempted to answer some of the relevant questions that have remained in management of LSPAF by conducting a multicentre randomised control trial comparing efficacy between CA and TSA (CASA-AF RCT) and improvements in quality of life indices. In a sub-study, I measured LA volumes using echocardiography and CMR to determine reverse remodelling and LA function using tissue Doppler imaging and strain imaging to predict AF recurrence. In a CMR sub-study, a novel automatic LA segmentation algorithm was used to quantify LA fibrosis before and after ablation. I was able to quantify the response of the autonomic nervous system to targeted ganglionic plexi (GP) ablation as part of TSA compared to CA by measuring heart rate variability. I am hopeful that the knowledge gained from this thesis will help with an appropriate selection that will improve the management of patients with LSPAF.Open Acces

Therapeutic DNA: Delivery and as a delivery vehicle

A review of gene delivery methods and gene editing methods, as well as original research utilizing DNA as a delivery vehicle is presented in the following thesis. Thousands of diseases have been linked to genes. Gene therapy, either delivering therapeutic genes or editing DNA bases, has arisen as a treatment option with the potential to cure diseases, rather than just ease symptoms. Genes and editing tools need to be delivered to cells for these therapies to be effective and many techniques have been developed to address the issue of delivery. Nonviral and viral methods have been used to deliver nucleic acids and several different protein systems have been employed to edit genes. Gene therapy will continue to evolve as delivery are improved. Along with being delivered as a therapeutic molecule, DNA has been investigated as a carrier itself. DNA origami, have been utilized to deliver chemotherapies to breast cancer. Globally, millions of women are affected by breast cancer each year. DNA origami was analyzed as a carrier for the chemotherapy Doxorubicin (DOX) in two triple negative breast cancer (TNBC) cell lines, a type of breast cancer with few treatments. The killing efficiency and uptake of DOX loaded into a model DNA origami triangle (DOX-DNA-T) were elucidated. Inhibition of various pathways revealed DOX-DNA-T was internalization by multiple energy-dependent pathways. DOX-DNA-T altered the subcellular localization of DOX and increased the concentration of DOX inside cells. A delayed killing was observed with DOX-DNA-T compared to free DOX, but the carrier was able to modulate the toxicity between cell lines. Overall, DNA delivery is able to treat various disease conditions and DNA origami is an interesting carrier for therapeutics --Abstract, page iv

A Platform for Robot-Assisted Intracardiac Catheter Navigation

Steerable catheters are routinely deployed in the treatment of cardiac arrhythmias. During invasive electrophysiology studies, the catheter handle is manipulated by an interventionalist to guide the catheter's distal section toward endocardium for pacing and ablation. Catheter manipulation requires dexterity and experience, and exposes the interventionalist to ionizing radiation. Through the course of this research, a platform was developed to assist and enhance the navigation of the catheter inside the cardiac chambers. This robotic platform replaces the interventionalist's hand in catheter manipulation and provides the option to force the catheter tip in arbitrary directions using a 3D input device or to automatically navigate the catheter to desired positions within a cardiac chamber by commanding the software to do so. To accomplish catheter navigation, the catheter was modeled as a continuum manipulator, and utilizing robot kinematics, catheter tip position control was designed and implemented. An electromagnetic tracking system was utilized to measure the position and orientation of two key points in catheter model, for position feedback to the control system. A software platform was developed to implement the navigation and control strategies and to interface with the robot, the 3D input device and the tracking system. The catheter modeling was validated through in-vitro experiments with a static phantom, and in-vivo experiments on three live swines. The feasibility of automatic navigation was also veri ed by navigating to three landmarks in the beating heart of swine subjects, and comparing their performance with that of an experienced interventionalist using quasi biplane fluoroscopy. The platform realizes automatic, assisted, and motorized navigation under the interventionalist's control, thus reducing the dependence of successful navigation on the dexterity and manipulation skills of the interventionalist, and providing a means to reduce the exposure to X-ray radiation. Upon further development, the platform could be adopted for human deployment

Virtual and Augmented Reality Techniques for Minimally Invasive Cardiac Interventions: Concept, Design, Evaluation and Pre-clinical Implementation

While less invasive techniques have been employed for some procedures, most intracardiac interventions are still performed under cardiopulmonary bypass, on the drained, arrested heart. The progress toward off-pump intracardiac interventions has been hampered by the lack of adequate visualization inside the beating heart. This thesis describes the development, assessment, and pre-clinical implementation of a mixed reality environment that integrates pre-operative imaging and modeling with surgical tracking technologies and real-time ultrasound imaging. The intra-operative echo images are augmented with pre-operative representations of the cardiac anatomy and virtual models of the delivery instruments tracked in real time using magnetic tracking technologies. As a result, the otherwise context-less images can now be interpreted within the anatomical context provided by the anatomical models. The virtual models assist the user with the tool-to-target navigation, while real-time ultrasound ensures accurate positioning of the tool on target, providing the surgeon with sufficient information to ``see\u27\u27 and manipulate instruments in absence of direct vision. Several pre-clinical acute evaluation studies have been conducted in vivo on swine models to assess the feasibility of the proposed environment in a clinical context. Following direct access inside the beating heart using the UCI, the proposed mixed reality environment was used to provide the necessary visualization and navigation to position a prosthetic mitral valve on the the native annulus, or to place a repair patch on a created septal defect in vivo in porcine models. Following further development and seamless integration into the clinical workflow, we hope that the proposed mixed reality guidance environment may become a significant milestone toward enabling minimally invasive therapy on the beating heart