Dundee Clinical Research Centre
The new Dundee Clinical Research Centre (CRC) is a joint activity of the College of Medicine and NHS Tayside Ninewells Hospital and Medical School – one of the largest teaching hospitals in Europe. It is designed for 3-Tesla magnetic resonance imaging (MRI) and positron emission tomography computed tomography (PET CT) facilities adjacent to an interventional suite, one of the first set-ups of this kind worldwide. Key joint projects are in the areas of early detection for cardiovascular disease, vulnerable plaque imaging, functional neuroimaging, cancer detection and staging and image-guided cancer diagnosis and treatment, including the target of integrated imageguided diagnosis and MRI-guided interventional procedures. The Universities of Dundee and St Andrews founded the Institute for Medical Science and Technology (IMSaT) to support clinical use of the Dundee CRC. IMSaT is adjacent to Ninewells Hospital and the new CRC. Ten thousand square feet of laboratory space is available for a fully equipped workshop incorporating computer-aided design and computer-aided manufacturing (CAD CAM), laser-cutting for manufacturing instruments and implants, a tissue laboratory, an imaging and photonics laboratory and an interventional MRI robotic laboratory adjacent to an interventional operating suite for pre-clinical trials. In addition to the development of devices according to ISO 13485 and good laboratory practices (GLPs), procedure workflow, process analysis, modulation and simulation for optimal systems integration and training courses will support the successful implementation of MRI-guided procedures and resonant implants (for more information, visit www.imsat.co.uk).
Magnetic Resonance Imaging-guided Robotic-assisted Interventions and Surgery
The robotic system INNOMOTION™ has been developed by the author in collaboration with Innomedic GMBH, Herxheim, Germany as the world’s first MRI- and CT-compatible robotic system with the CE mark. Current clinical studies on MRI-guided liver, prostate and bone biopsy and sciatic pain treatment reveal significant improvements using MRI-guided percutaneous interventions. INNOMOTION will be further developed at IMSaT for use in 1.5- and 3-Tesla MRI, with a specific focus on interventional oncology, neuro-interventional procedures and MRI-guided minimally invasive surgery.1 MRI-guided breast biopsy, tumour ablation, abscess drainage and heart valve implantation are further projects.
Magnetic Resonance Imaging-compatible Vascular Implants and Magnetic Resonance-guided Vascular Interventions
Vascular implants such as stents, vena cava filters (VCFs), cardioseptal occluders or prosthetic heart valves require post-interventional follow-up diagnostics, which are usually made using X-ray-based angiography or CT. MRI, with its superior soft-tissue contrast, arbitrary slice orientation and flow visualisation without the burden of ionising radiation and ionised contrast agents, would be the preferred imaging technique; however, most conventional vascular implants made of metal create significant image artifacts and shield the lumen due to the material itself, and also due to radiofrequency (RF) interference.2 Artifact-free visualisation of vascular implants is one of the conditions for a safe and reliable examination using MRI and MR-guided interventional techniques. Current research is looking to use this in order to improve stents, VCFs, prosthetic heart valves and other vascular implants through the integration of resonant circuits (Biophan Europe GmbH, Germany).
Magnetic Resonance Imaging – Background
In MRI, the object to be imaged is placed in a powerful uniform magnetic field. The rotations of the atomic nuclei (essentially, the hydrogen protons) within the tissue align along the main magnetic field (B0). The signal of these rotations is used for the imaging of this object. Two different imaging acquisition sequences are used in MRI: spin-echo (SE) and gradient-echo (GE).
Magnetic Resonance Artifacts
As discussed above, most conventional vascular implants are made of metal and, therefore, can cause significant image artifacts and shielding of the lumen due to the material itself and RF interference. The three main types of MR artifacts associated with metallic vascular implants are susceptibility artifacts, flow-related artifacts and RF artifacts. The RF artifacts of stents can be reduced by using non-magnetic metal, minimising the amount and surface area of the metal, increasing the size of stent cells, reducing the number of cells or cutting the cells open. These approaches are limited by the need for implants to provide adequate stability, i.e. the radial strength of stents. A possible way of reducing artifacts and improving the visibility of the implants is to modify them using resonant circuits tuned to the Larmor frequency of the MRI system (c. 42MHz at 1 Tesla).
Resonators with a resonance frequency equal to the Larmor frequency produce local signal intensity enhancement by increasing the flip angle (FA) of GE. The frequency of the resonator is defined by the capacity of the condenser and the inductivity of the coil.3 Active MRI markers can be attached to the medical instruments in a similar way to X-ray markers, for example using solenoid, meander, surface, saddle and other designs.4
Active Magnetic Resonance Imaging Resonant Stents
Stents require post-interventional follow-up to detect intraluminal changes such as thrombus or intimal hyperplasia. MRI examination would be the favoured non-invasive imaging technique, but conventional metal stents shield the lumen because of the metal itself and RF interference (Faraday gauge). The use of a resonant circuit tuned to the Larmor frequency and placed around the stent should improve visualisation of the stent lumen. Active MRI resonant stents provide non-invasive visualisation of instant thrombosis and restenosis without the need for gadolinium contrast agents.
Material and Methods
Self-expanding commercially available Nitinol stents have been equipped with a solenoid coil resonator in order to develop fully biocompatible balloon-expandable stents, combine self-expanding stents with an integrated microcoil resonator and evaluate MRI of the stent lumen. The resonator was also applied as a supplement sheath (covered stent type) and directly mounted onto the stents. The lumen of the stent was partially filled with a thrombus of porcine blood and a section of a porcine aorta wall to simulate intimal hyperplasia; this was tested in 1- and 1.5-Tesla MRI scanners.
The resonator stimulates all substrates inside the stents and enhances the signals from the Nitinol stent lumen. Fresh porcine aortic wall was rolled into the stent to simulate intimal hyperplasia, and fresh human blood thrombus was placed in the stent to simulate instant thrombosis. Artificial stenosis and the thrombus were visualised in a 0.9% saline water container (Philips 1.5-Tesla fast field echo (FFE), repetition time (TR) 50ms, echo time (TE) 6ms, FA 20º).
Balloon-expanding stents have been tested in an animal trial in chinchilla rabbits5 and in 45–60kg domestic pigs approved by the animal board of the University of Essen. Under general anaesthesia, a carotid artery port was implanted and the stents delivered to the left and right iliac arteries under fluoroscopy. Subsequent MRI examination was performed at 1.5 Tesla. In the first animal, a signal void was discovered in the left iliac stent that proved to be a thrombus clot on post mortem explantation of the stent (see Figure 1a). Eccentric 50% restenosis was detected after 34 days of survival (see Figure 1b). Further results will be published elsewhere.
Active Magnetic Resonance Imaging Self-expanding Prosthetic Heart Valves
Heart valve prostheses cause significant artifacts in MRI images, compromising MRI diagnostics of the valve function. Percutaneously implantable heart valves are made of balloon-expanding stainless steel stents or self-expanding Nitinol stents; only the latter are suitable for integration of resonant circuits.
Material and Methods
Resonant circuits have been designed and integrated into Nitinol stent-based heart valve prostheses.6 Porcine pulmonary and aortic heart valves were excised from a fresh porcine heart of a six-month old pig and sutured with 6-0 Prolene (Ethicon Inc.) into the Nitinol stent (Memotherm, Bard Angiomed, Ø=18mm). A 50cm-long delivery system has been custom-made using viton tube – a modified 12mm laparoscopic disposable trocar (Tyco). The valve has been implanted under MRI into a fresh porcine heart through a transapical approach (see Figure 2).
The heart valve could be visualised in the MRI by a low FA (15°). The signal difference between the valve and the test liquid was significant and the shielding of the Nitinol stent could be overcome. The heart valve could be successfully implanted in a porcine animal model approved by the Animal Care and Use Committee of the National Institutes of Health (NIH) in 80–85kg female minipigs under general anaesthesia through a minimally invasive transapical approach.7
The resonant circuit overcomes the shielding of the Nitinol heart valve frame, increases signal and signal to noise ratio (S/N) and provides high contrast without the need for contrast agents. Diagnostic and MRI-guided implantation of stents and stent-based heart valves can be facilitated with the INNOMOTION robotic system, as the delivery system is kept stable and aligned to the image orientation.
Active Magnetic Resonance Imaging Vena Cava Filter
Implantation of VCFs is performed under X-ray fluoroscopy and application of nephrotoxic X-ray contrast media. Commercially available VCFs consist of metals that produce artifacts in MRI and shield the filter lumen from RF. To solve these problems, we have developed two MRI active VCFs (cone and basket shapes) for visualisation in MRI-guided delivery and non-invasive detection of captured thrombi.8
Material and Methods
New VCFs were cut from Nitinol tubes coated with gold and polymer, which function like a resonant circuit (resonator). The capacitor is thereby replaced by the parasitic capacity of the filter and adjusted by the coating. All filters were tuned using a frequency analyser to the Larmor frequency of 1.0 Tesla (42MHz) and 1.5 Tesla (64MHz).
Basket-type VCFs have been evaluated in acute animal trials in the Department of Radiology RWTH Aachen and approved by the IRB. In the first pilot in 16kg female domestic pigs, MRI-guided implantation and thrombosis delivery though a 16F femoral access and subsequent retrieval was successful. The filter was re-implanted and a 5ml thrombus formed in a syringe injected through the femoral access sheath. Imaging of the thrombus was performed and the filter subsequently explanted after termination of the animal. Further results will be published elsewhere.
These results demonstrate that active VCFs with resonance structure improve thrombus detection, while the signal enhancement facilitates delivery and retrieval of the VCF under MRI guidance without the use of gadolinium-based contrast agents. The resonant function of VCFs is based on design and coating without any additional capacitor, and will be suitable for human use. Resonant VCFs provide MRI-guided placement visualisation of captured thrombi and retrieval without the need of gadolinium contrast agents.
Active Magnetic Resonance Imaging Occluder for Cardioseptal Defects
Percutaneous closure of cardioseptal defects – patent foramen ovales (PFOs), atrioseptal defects (ASDs) and ventricular septal defects (VSDs) – is increasingly performed under X-ray, which brings the disadvantages of ionising radiation and lack of soft-tissue contrast. To overcome these problems, MRI should be used. Closure of such defects under MRI has been proved in animals,9 but is hampered by image artifacts produced by the materials of the closure devices and the use of fast sequences for cardiac imaging.10 Therefore, an exact differentiation of the implant and heart tissue, and cardiac MRI in general, are compromised (see Figure 3a).
Material and Methods
For better visualisation we developed a new occluder for the closure of PFOs and ASDs that functions as a resonant circuit. The occluder was implanted into fresh porcine hearts placed in a water-filled plastic container inside the MRI scanner.
Precise differentiation between the occluder and tissue were obtainable (see Figure 4b). Based on these tests, an occluder made of Nitinol was produced. A laser-cut Nitinol version that functions in a similar way to VCFs is under development (NDC, Fremont, CA, US).
With occluders designed in the form of a resonator tuned to the corresponding Larmor frequency of 1.0-Tesla/1.5-Tesla MRI, local signal enhancement is possible. This concept provides improved contrast and can therefore facilitate MRI-guided delivery; follow-up diagnosis thus becomes possible without the need for gadolinium contrast agents.
The projects have been financially supported by Biophan Inc., Rochester, NY, US. The following co-workers and collaboration partners are mentioned with gratitude for their excellent support and work: E Immel,1,2,3 S Michitsch,2,3 S Konak2,3 and P Bremer.3 Clinical partners: G Lorenz,4 H Quick,5 C Naber,5 J Spillner6 and E Spuentrupp.6 1. Institute of Medical Science and Technology (IMSaT), Universities of Dundee and St Andrews, UK; 2. Biophan Europe GmbH, Castrop, Rauxel; 3. INSITE med. and Dept of Physical Engineering, University of Applied Sciences, Gelsenkirchen; 4. Sankt Marien-Hospital, Gelsenkirchen-Buer; 5. Depts of Radiology and Cardiology, University of Essen; 6. Depts of Radiology and Cardiac Surgery, RWTH Aachen.
The resonant stent animal trial was a 50% BMBF-funded project in co-operation with the Depts of Cardiology (C Naber) and Radiology (H Quick), University of Essen, Germany, 2005–2006.
International patents have been issued for stents and VCFs and are pending for the heart valve and the septal occluder.