Medical device design within the ISO 13485 framework

The design and development of medical devices has become an increasing complex and regulated process. Little if any consideration is given to the regulatory requirements when developing medical devices in universities. This has resulted in an imposing barrier preventing academic innovation reaching clinical adoption. The scope of universities is not to become the legal manufacturer of medical devices. However, should the development of novel devices ever aim to benefit patient care and reach a clinical setting, design controls must be implemented throughout the project life cycle to demonstrate feasibility and safety. The aim of this thesis is to develop user-centred technologies which comply with industrial design control practices whilst helping to bolster and promote innovation within academia. Four projects relating to medical devices have been designed in response to well-defined and end-user-originated clinical needs. These devices can serve as the exemplar for the framework developed in this work with each reaching staggered phases of development within a controlled design process. Although unique, the devices have significant overlapping characteristics that lend the devices to parallel development, leveraging in-house know-how and ‘lessons learned’ into the process of innovation. This thesis focuses on the novelty and design of the aforementioned projects in a discrete structured approach and reflects on the development of each project within the context of a design control process which was developed as part of this work. It is the ultimate goal of this work to develop a flexible structured system compliant with the international requirements for product design and development which may be exported internationally. However, the full execution of this ambition was limited due physical, and financial limitations. This manuscript will describe the technical and commercial opportunity of devices and reflects on the success of developing same within a design control process developed as part of this work

Electropermanent magnetic anchoring for surgery and endoscopy

The use of magnets for anchoring of instrumentation in minimally invasive surgery and endoscopy has become of increased interest in recent years. Permanent magnets have significant advantages over electromagnets for these applications; larger anchoring and retraction force for comparable size and volume without the need for any external power supply. However, permanent magnets represent a potential hazard in the operating field where inadvertent attraction to surgical instrumentation is often undesirable. The current work proposes an interesting hybrid approach which marries the high forces of permanent magnets with the control of electromagnetic technology including the ability to turn the magnet OFF when necessary. This is achieved through the use of an electropermanent magnet, which is designed for surgical retraction across the abdominal and gastric walls. Our electropermanent magnet, which is hand-held and does not require continuous power, is designed with a center lumen which may be used for trocar or needle insertion. The device in this application has been demonstrated successfully in the porcine model where coupling between an intraluminal ring magnet and our electropermanent magnet facilitated guided insertion of an 18 Fr Tuohy needle for guidewire placement. Subsequent investigations have demonstrated the ability to control the coupling distance of the system alleviating shortcomings with current methods of magnetic coupling due to variation in transabdominal wall thicknesses. With further refinement, the magnet may find application in the anchoring of endoscopic and surgical instrumentation for minimally invasive interventions in the gastrointestinal tract

Loss of flexion during bronchoscopy: a physical experiment and case study of commercially available systems

During routine endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) procedures, especially with biopsy of lymph nodes in or around the left upper lobe, frequent reports have noted the loss of ultrasound image and needle angulation leading to an inability to biopsy nodes visualised by EBUS. The aim of this research was to investigate and compare this loss of angulation with commercially available scopes. Bench-top experiments and a clinical case study demonstrated the varying loss of scope angulation, flexibility and manoeuvrability with different scopes and biopsy instruments leading to procedural implications. Improvements in both the EBUS scope and needle characteristics are required to overcome this limitation which has implications in bronchoscope navigation and the diagnostic yield of EBUS-TBNA

Automated catheter navigation with electromagnetic image guidance

This paper describes a novel method of controlling an endoscopic catheter by using an automated catheter tensioning system with the objective of providing clinicians with improved manipulation capabilities within the patient. Catheters are used in many clinical procedures to provide access to the cardiopulmonary system. Control of such catheters is performed manually by the clinicians using a handle, typically actuating a single or opposing set of pull wires. Such catheters are generally actuated in a single plane, requiring the clinician to rotate the catheter handle to navigate the system. The automation system described here allows closed-loop control of a custom bronchial catheter in tandem with an electromagnetic tracking of the catheter tip and image guidance by using a 3D Slicer. An electromechanical drive train applies tension to four pull wires to steer the catheter tip, with the applied force constantly monitored through force sensing load cells. The applied tension is controlled through a PC connected joystick. An electromagnetic sensor embedded in the catheter tip enables constant real-time position tracking, whereas a working channel provides a route for endoscopic instruments. The system is demonstrated and tested in both a breathing lung model and a preclinical animal study. Navigation to predefined targets in the subject's airways by using the joystick while using virtual image guidance and electromagnetic tracking was demonstrated. Average targeting times were 29 and 10 s, respectively, for the breathing lung and live animal studies. This paper presents the first reported remote controlled bronchial working channel catheter utilizing electromagnetic tracking and has many implications for future development in endoscopic and catheter-based procedures

Pre-clinical validation of virtual bronchoscopy using 3D Slicer

Lung cancer still represents the leading cause of cancer-related death, and the long-term survival rate remains low. Computed tomography (CT) is currently the most common imaging modality for lung diseases recognition. The purpose of this work was to develop a simple and easily accessible virtual bronchoscopy system to be coupled with a customized electromagnetic (EM) tracking system for navigation in the lung and which requires as little user interaction as possible, while maintaining high usability. The proposed method has been implemented as an extension to the open-source platform, 3D Slicer. It creates a virtual reconstruction of the airways starting from CT images for virtual navigation. It provides tools for pre-procedural planning and virtual navigation, and it has been optimized for use in combination with a of freedom EM tracking sensor. Performance of the algorithm has been evaluated in ex vivo and in vivo testing. During ex vivo testing, nine volunteer physicians tested the implemented algorithm to navigate three separate targets placed inside a breathing pig lung model. In general, the system proved easy to use and accurate in replicating the clinical setting and seemed to help choose the correct path without any previous experience or image analysis. Two separate animal studies confirmed technical feasibility and usability of the system. This work describes an easily accessible virtual bronchoscopy system for navigation in the lung. The system provides the user with a complete set of tools that facilitate navigation towards user-selected regions of interest. Results from ex vivo and in vivo studies showed that the system opens the way for potential future work with virtual navigation for safe and reliable airway disease diagnosis

Navigational bronchoscopy for early lung cancer: a road to therapy

Peripheral lung nodules remain challenging for accurate localization and diagnosis. Once identified, there are many strategies for diagnosis with heterogeneous risk benefit analysis. Traditional strategies such as conventional bronchoscopy have poor performance in locating and acquiring the required tissue. Similarly, while computerized-assisted transthoracic needle biopsy is currently the favored diagnostic procedure, it is associated with complications such as pneumothorax and hemorrhage. Video-assisted thoracoscopic and open surgical biopsies are invasive, require general anesthesia and are therefore not a first-line approach. New techniques such as ultrathin bronchoscopy and image-based guidance technologies are evolving to improve the diagnosis of peripheral lung lesions. Virtual bronchoscopy and electromagnetic navigation systems are novel technologies based on assisted-computerized tomography images that guide the bronchoscopist toward the target peripheral lesion. This article provides a comprehensive review of these emerging technologies

The proliferation of human mucosal-associated invariant T cells requires a MYC-SLC7A5-glycolysis metabolic axis

Mucosal-associated invariant T (MAIT) cells are an abundant population of innate T cells that recognize bacterial ligands and play a key role in host protection against bacterial and viral pathogens. Upon activation, MAIT cells undergo proliferative expansion and increase their production of effector molecules such as cytokines. In this study, we found that both mRNA and protein abundance of the key metabolism regulator and transcription factor MYC was increased in stimulated MAIT cells. Using quantitative mass spectrometry, we identified the activation of two MYC-controlled metabolic pathways, amino acid transport and glycolysis, both of which were necessary for MAIT cell proliferation. Last, we showed that MAIT cells isolated from people with obesity showed decreased MYC mRNA abundance upon activation, which was associated with defective MAIT cell proliferation and functional responses. Collectively, our data uncover the importance of MYC-regulated metabolism for MAIT cell proliferation and provide additional insight into the molecular basis for the functional defects of MAIT cells in obesity. </p

Individuals with obesity who survive SARS‐CoV‐2 infection have preserved antigen‐specific T cell frequencies

Objective: Obesity is a major risk factor for severe disease in COVID-19, with increased hospitalization, intensive care unit admission, and mortality. This increased impact of COVID-19 in people with obesity (PWO) is likely driven, in part, by the well-described obesity-induced immune dysregulation. Obesity has also been associated with impaired immune memory in many settings, including weakened responses to hepatitis B, tetanus, rabies, and influenza vaccination. Recently, it was reported that PWO who have COVID-19 have reduced IgG antibody titers with defective neutralizing capabilities. However, it remains unknown whether PWO generate durable T cell immunity to SARS-CoV-2. Methods: This study investigated SARS-CoV-2-specific T cell responses in a cohort of 40 patients (n = 20 PWO and n = 20 matched control individuals) who had recovered from COVID-19. T cell (CD4+, CD8+) cytokine responses (IFNγ, TNFα) to SARS-CoV-2 peptide pools (spike, membrane) were determined using multicolor flow cytometry. Results: Circulating T cells specific for SARS-CoV-2 were readily detected in the total cohort. PWO displayed comparable levels of SARS-CoV-2 spike- and membrane-specific T cells, with both T cell subsets responding. Conclusions: These data indicate that PWO who survive COVID-19 generate robust and durable SARS-CoV-2-specific T cell immunity that is equivalent to that seen in those without obesity

Randomized placebo controlled trial evaluating the safety and efficacy of single low dose intracoronary insulin like growth factor following percutaneous coronary intervention in acute myocardial infarction (RESUS-AMI)

Background: Residual and significant post-infarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), remains an important clinical issue. In preclinical models low dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodelling effects. We studied the safety and efficacy of immediate post PCI low dose intracoronary IGF1 infusion in STEMI patients. Methods: Using a double-blind, placebo controlled, multi-dose study design, we randomized 47 STEMI patients with significantly reduced (≤ 40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n=15), 1.5ng IGF1 (n=16) or 15ng IGF1 (n=16). All received optimal medical therapy. Safety endpoints were freedom from hypoglycaemia, hypotension or significant arrhythmias within 1 hour of therapy. The primary efficacy endpoint was LVEF and secondary endpoints were LV volumes, mass, stroke volume, and infarct size at 2 months follow up, all assessed by MRI. Treatment effects were estimated by analysis of covariance adjusted for baseline (24hrs) outcome. Results: No significant differences in safety endpoints occurred between treatment groups out to 30 days (chi squared test, p-value = 0.77).There were no statistically significant differences in baseline (24 hrs post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5ng IGF1, treatment with 15ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (p=0.018), LV mass (p=0.004) and stroke volume (p=0.016). Late gadolinium enhancement (±SD) at 2 months was lower in 15ng IGF1 (34.5±29.6g) compared to placebo (49.1±19.3g) or 1.5ng IGF1 (47.4±22.4g) treated patients, though the result was not statistically significant (p = 0.095). Conclusion: In this pilot trial, low dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose dependent benefit on post MI remodeling that may warrant further study. Despite timely reperfusion by primary PCI (PPCI) a significant cohort of patients develop adverse left ventricular remodelling with clinical sequelae such as arrhythmia and heart failure[1].Therapeutic approaches to avert such remodeling, including a variety of cell therapy and ischemia- reperfusion-injury mitigation trials have achieved modest success 2.;3. Thus, there remains a significant opportunity for novel therapies in this field