SCATh_AnnexI_v5.4

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A a

B Part

B.1 Concept and objectives, progress beyond

state-of-the-art, S/T methodology and work plan.

Concept and project objectives

B.1.1.1 Objectives

The primary objective of SCATh is to enhance the safety, repeatability and precision of catheter-based interventional treatments. This will be achieved by bringing recent innovations in sensing and scanning technologies together with novel methods for data fusion, visualisation, surgical navigation and real-time modelling into a complete catheter system targeting four specific cardiovascular interventions.

Cardiovascular disease (CVD) refers to the class of diseases that involve the heart or blood vessels and is the single most common cause of death in the EU. In February 2008, the yearly European Cardiovascular Disease

statistics1 reported that CVD caused over 4.3 million deaths in Europe, which accounted for 42% of all mortality in the EU. The high incidence of CVD incurs a significant cost upon the European health care system with an estimated €192 billion invested in 2006, consisting of €110 billion in health care costs, €40 billion in productivity loss and €42 billion in informal care. Thus the occurrence of CVD has a major socio-economic impact in the EU and enhanced methods for delivering interventional treatment are of critical importance.

For the treatment of CVD, minimally invasive surgery (MIS) and catheter-based approaches are of particular importance as access trauma in the cardio-thoracic anatomy can significantly increase the risk of intra-operative and post-procedural complications. Catheter procedures are among the most common surgical interventions

used to treat CVD and they extend the range of patients able to safely receive interventional CVD treatment

even in age groups dominated by co-morbidity and unacceptable risks for open surgery (Mirabel 2008).

The downside lies at the increased complexity of the minimally invasive procedure, which is mainly caused by the loss of direct access to and sight upon the area of treatment. This results in:

• a lack of correspondence between pre-operatively formed models and the real interventional site caused by inaccuracies of the employed registration procedures, by the dynamic nature of the surgical site, or caused by insufficient knowledge of the local site at the catheter tip (lack of accurate real-time geometric, mechanical or physiological information);

• a heavy mental load to navigate the tool through an uncertain, complex and fragile environment. The interventionalist should also possess sufficient expertise to mentally map the one or two dimensional pictures into three dimensional models while performing the procedures, and should possess superior manual skills to manoeuvre the catheter to the desired location;

• few possibilities to detect and respond to unforeseen adverse situations (Kono 2005).

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All these factors lead to the fact that at this instant the chance of making medical errors in catheter-based

diagnosis or during intervention simply remains too high2,3. Above elements clearly indicate why training of skilled interventionalists is such a long and difficult process.

B.1.1.2 Concept

SCATh proposes, in line with the IST-2009.5.2 objective ICT for Patient Safety, a) ICT for safer surgery, the creation of an innovative ICT-platform for training, pre-operative planning and computer-aided surgical interventions. To realize maximal clinical impact, within the SCATh project, the focus will lie entirely upon catheter-based interventions and more specifically upon CVD-related catheter interventions.

The main objective of SCATh is the creation of an ICT platform that closes the existing gap between the reality of the catheter inside the cardiovascular system and the manner in which this reality is presented and made accessible to the interventionalist.

The risk related to medical errors can be attributed to 1) a deterministic component based on the patient’s risk factor, 2) a deterministic component based on the surgeon’s skill and the quality of procedure planning and procedure execution, and 3) a stochastic component caused due to unpredictable events. The SCATh ICT platform is a powerful and modular framework that allows the medical expert to reduce risk related to both components 2) and 3), by providing multiscale patient-specific data to the interventionalist (improved diagnosis, planning). These models will adapt in real-time to reproduce more faithfully the reality of the surgical theatre (improved response to unforeseen effects), relying on fusion of intra-operative data coming from tool-mounted and/or external sensors, with pre-operative patient-specific data. Safety-related indices will be computed to compress the vast amount of generated data in objective, easy-understandable indicators, allowing the surgeon to act swiftly when necessary. Furthermore, substantial efforts will be made to improve the controllability of the catheter by the interventionalist (improved procedure execution), allowing the latter to select his preferred modus

2_{The Institute of Medicine in Washington, D.C., published a report titled “To Err is Human”, according to which more people in the U.S. die} from medical errors every year than from traffic accidents. Figures vary between 50.000 and 100.000 fatalities.

3_{http://yourtotalhealth.ivillage.com/balloon-angioplasty.html?pageNum=5#5}_{explains that in 2-5% of the cases where balloon angioplasty} is performed an emergency bypass surgery is needed, also in 0.5% of the cases where stents are placed emergency bypass procedures are necessary.

Summary: Urgent investments are necessary to design and construct advanced ICT tools that can build

intrinsic safety into the catheter-procedures and as such allow the interventionalist to maintain a high standard for both quality and safety. The massive importance of CVD towards the European society and each single subject suffering from it, the need to constantly reinforce European leadership and medical innovation, the inherent complexity of current and future treatment procedures call for immediate and interdisciplinary action at a European level.

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of operandi. These facilities allow the interventionalist to manipulate patient models during short breaks or prior to the procedure (planning, diagnosis) to manipulate and control the catheter itself during the procedure (teleoperation) – to partly automate parts of the interventional procedure (shared autonomy) or manipulate the patient-specific models offline (training). Lastly, for medical errors related to the patient’s risk factor, SCATh refers to the readily available support tools such as EuroSCORE4 or similar.

The novel catheterization framework emphasizes the importance of real-time modelling through local sensing, by doing so it possesses the additional advantage of becoming less dependent on traditional techniques such as fluoroscopy, i.e. real-time X-ray imaging of catheter and blood vessels, injected with contrast agents, which are known for causing numerous complications including possible allergic reactions, thrombosis, embolization and bleeding, and dangers related to radiation exposure5. The alternative MR imaging methods are, apart from being bulky, restrictions for general use, and compatibility problems with certain instruments, also known for their high costs to the health care² system.

To achieve the ambitious sub goal of developing real-time multiscale cardiovascular models, SCATh opts for an approach along three distinctive but complementary research lines:

A. Top-down approach:

This approach investigates a series of methods that adapt and process global models of the cardiovascular

system (obtained by means of traditional pre-operative imaging) in order to represent the real-time and specific nature of the local environment of the catheter-tip within the patient lying on the operation table. For

anatomical models, this approach elaborates on previous experience obtained during participation to a Marie-Curie Training Network (ARIS*ER)6. The previous expertise (UPM, IVS, and K.U.Leuven) will be extended towards the development of parameterized models for online updating complementing for real-time sensory data (UPM) and automatic processing of safety-related indices. TUG, the expert in mechanical modelling of the endovascular system will hereto derive indices describing the danger of occurrence of tissue-damage due to mechanical loads during intervention.

B. Bottom-up approach:

This approach investigates the feasibility of building up a ‘global’ patient-specific, up-to-date model of the

cardiovascular system from local scans taken from the tip of the catheter while it advances within the

cardiovascular system. This is an entirely novel approach for catheterization, inspired by similar techniques for mobile robotic navigation, a so-called simultaneous localization and mapping (SLAM) method. Researchers from

ICL who worked on SLAM for other surgical applications will develop this new technique, which if successful could

cause a revolution in medical catheterization imaging techniques. K.U.Leuven will develop methods to compare results from both approaches and derive measures to quantify the quality of respective methods, and also derive safety-related indices extracted from them.

C. Pragmatic approach:

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http://www.euroscore.org/

5_{A study by the National Radiological Protection Board in the UK, one in every 1000 children will develop a tumour within}

five years after a catheterization.

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www.ariser.info.

The main advantages of the SCATh approach are:

• detailed real-time information of the catheter and its local environment; • reduced mental load on the interventionalist;

• improved manoeuvrability of the catheter and control by the interventionalist; • faster observation (2) of adverse events and better response (2,3) to such events; • reduced dependency on harmful and/or costly imaging techniques.

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A third, pragmatic approach will be taken in parallel to and benefiting from the information of approaches A and

B. The two SME’s belonging to this consortium (EndoS and AngioC) each introducing their unique and novel

sensing technology (catheter tip force sensing based on fiber bragg gratings, and infrared visualisation, respectively) will give support to employ these new sensor techniques for the benefit of approaches A and B. Simultaneously they will profit from the experience of the multidisciplinary consortium when investigating ways to fuse their sensory data with complementary data in order to develop real-time maps for a set of specific interventional procedures. The consortium will definitely benefit from the practical viewpoint from these SME’s. The developments made during this project will unlikely remain limited to theory.

The challenge to fuse the data from different research lines (A, B, C) will take place under coordination of ICL. Whereas K.U.Leuven together with UPM coordinates the activities aimed at presenting the assembled real-time information in an intuitive and easy to handle form to the interventionalist. The patient-specific multiscale data acquired during real experiments, and during real procedures in a later stage can serve as input for more realistic catheter simulations which can be used for training purposes.

The set of technological objectives put forward for SCATh are detailed in section 1.1.3. To steer the developments towards advancements that actually make their way through up into everyday’s interventional theatre, a set of interventional scenarios were carefully selected. These scenarios are described in section 1.1.4, together with their specific objectives. They will be used by SCATh to measure the achieved progress with respect to the state of the current medical practice.

B.1.1.3 Technological project objectives

Topic Project Objectives

Processing of pre-operative data Pre-operative

planning - automatic segmentation of the aorta and the left heart atrium’s wall and detection of diseased abnormalities,

- anatomical model parameterization for real-time adaptive registration, - automatic derivation of mechanical patient-specific models

- calculation of mechanical, geometrical and physiological based safety- indices to monitor during the surgery

Reduce dependency on intra-operative radiation-based imaging modalities ( to decrease radiation to less than 1 Gy):

- navigation in top-down approach

- the first fully bottom-up based navigation up to the heart

Select the most suitable technique/configuration for acquiring relevant data. Interest goes towards

Intra-operative imaging/sensing

- local environment scanning (based on novel techniques (InfraRed vision)) - position tracking

- intravascular force measurements - physiological parameters

Real-time anatomical modelling, based on parameterized anatomical model and real time adaptability.

Bottom-up real-time endovascular modelling Online model quality measurement

Intra-operative modelling

Safety-related indexes and thresholds

User interface Intuitive visualisation and interaction with multiscale models, resulting in a faster interpretation by the interventionalist

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manoeuvrability

- augmented manual control , - immersive teleoperation control,

- robust and safe full-autonomous control.

Experimentation Prototyping, validation and testing of the overall system on the selected catheter procedures

Table 1. SCATh technical objectives

B.1.1.4 Surgical scenarios and objectives

The SCATh focus lies on catheter-based interventions. Although many of the developed techniques will be generally applicable in this field, four catheter procedures were identified as case studies based upon which the main project goals have been set. They are discussed below.

Case Study 1: Positioning of endovascular grafts

A common treatment in the case of an abdominal aortic aneurysm (AAA) is a transfemoral intraluminal graft implantation (Parodi 1991). Once in position, this endograft effectively diverts the flow of blood away from the aneurysm wall, thus excluding the aneurysm from circulation. This procedure does not remove the aneurysm, but allows it to shrink over a period of time.

The positioning of the endograft in the aorta requires its careful attachment to a safe ‘landing zone’, where it does not obstruct side branches leading to vital organs. This is typically identified on pre-procedural CT or MRI images. During the procedure, the endograft’s position is monitored with intra-operative X-ray imaging, consequently applying high doses of contrast agent and radiation.

SCATh objectives:

• Provide intra-operative navigation and accurate positioning based on the fusion of pre-operative models and intravascular sensing information.

• Reduce (and, in the long term, even eliminate) the need for intra-operative X-ray imaging and the use of contrast agents.

• Provide a pre-operative check of the procedure, pinpointing the weak spots to enable the implementation of damage thresholds for the stent navigation and expansion.

• Reducing the occurrence paraplegia, due to spinal cord ischemia, from 32% (Bafort 2002) to less than 5%.

Case Study 2: Transcatheter aortic valve replacement

Figure 2. Medtronic Talent™ thoracic stent graft

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FP7-ICT-2009-4 6 Valve replacement is the definitive therapy for patients with

severe aortic stenosis. Transcatheter aortic valve replacement is a new experimental procedure that eliminates surgery by placing a stent-mounted bioprosthetic aortic valve (see figures), via a catheter (Vahanian 2008).

Such a procedure requires an initial balloon positioning and dilatation of the valve, followed by an accurate placement of the prosthetic device (Walther08a, Walther08b). It is of course essential that the device is placed correctly in all three planes, making the placement under two-dimensional fluoroscopy

with limited catheter control challenging and potentially dangerous, since the coronary ostia may be occluded (Davidson 2006).

• Provide intra-operative navigation and accurate positioning based on the fusion of pre-operative models and intravascular sensing information to allow easy and accurate placement in the frontal, saggital and transverse plane.

• Reduce (and, in the long term, even eliminate) the need for intra-operative X-ray imaging and the use of contrast agents.

• Develop accurate and safe model-based methods to automatically stabilize the implant’s position.

• Avoid injuries to the heart caused by the catheters; this includes a perforation of the muscle or damage to one of the valves within the heart

Case Study 3: Positioning and deployment of endoclamp balloon

Figure 3. SAPIEN transcatheter heart valve, Edwards Lifesciences, LLC

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FP7-ICT-2009-4 7 Cardiopulmonary bypass (CPB) is used to avoid the difficulty

of operating on a beating heart in cardiac procedures. To provide occlusion of blood flow from the surgical field and deviate it towards the CPB, in minimally invasive approaches, the aorta can be occluded by an endoclamp balloon (e.g. Heartport, see figure), instead of externally clamping it with a mechanical clamp (Gravlee 2007).

The initial positioning, the inflation of the balloon and the monitoring of the position during the procedure are very delicate and complex tasks that the surgeon has to perform. Monitoring the balloon is currently done using either fluoroscopy or Transesophageal Echography (TEE) and requires a very experienced surgical team. The control of the endoclamp balloon is not part of the actual cardiac procedure and should therefore not take up too much of the surgeon’s time.

• Develop a fully autonomous system for positioning the endoclamp balloon

• Autonomous control of the pressure in the balloon based on measurements and a physiological model of the compliance of the aorta.

• Provide a pre-operative check of the procedure, pinpointing the weak spots to enable the implementation of damage thresholds for the balloon navigation and inflation.

Figure 4. Heartport Endoartic Clamp, Redwood city, USA

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FP7-ICT-2009-4 8 Case Study 4: Percutaneous radiofrequency catheter ablation for atrial fibrillation treatment Radiofrequency catheter ablation is a procedure that is

performed to correct a disturbance in heart rhythm (arrhythmia) caused by abnormalities in electrical conduction of the heart. An ablation catheter is used to ablate cardiac tissue that may be the source or the conduction channel for the arrhythmia.

The main difficulty of this procedure lies in the localisation of the spot to be ablated. Therefore, a morphologic map of the chamber is being made by probing the catheter over the chamber and fitting a surface through the sequence of contact points. Apart from the risk of perforation, current mapping systems

are also subject to “tenting” (Knecht 2008). This effect is caused by the elasticity of wall of the chamber as it will tent when a force is applied on it by the catheter. This results in a map that is up to 40% larger in volume than the real organ, which compromises the treatment quality when using traditional (non force sensor mounted) catheters.

A second difficulty is the delivery of a well-dosed ablation. This depends on the interaction force with the cardiac wall. Too large interaction forces can result in a perforation while too little interaction forces (or no contact at all) will cause insufficient ablation. This means that the problematic conduction channels will not be destroyed.

• To speed up the generation of a morphologic map of the heart chamber based on intra-operative tracking of the catheter and force measurement.

• To use force measurements to control the interaction force during the ablation and therefore increase safety.

• To increase the current success rate of cardiac RF ablation from 50% ( Haegeli 2008) to 75%

Figure 5. Endosense TouchTM catheter during RF ablation in the atrium.

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B.1.2 Progress beyond the state-of-the-art

This section contains a compact description of the current practice and existing level of technology in the different domains covered by this project, as well as a description of the prevalent challenges. The focus lies on those technologies that are closely related to the methods employed and advanced during this project. At the end of each paragraph, an overview is given of the advances with respect to the state-of-the-art that will be achieved in the SCATh project.

B.1.2.1 Real-time sensing technologies for catheter guidance

a. Angiography for catheter guidance:

Angiography is the classical medical imaging technique used to visualize the lumen of blood vessels for diagnostic and interventional purposes. In the latter case it is also used to track the instruments used in the intervention. It is based on either X-ray fluoroscopy, computed tomography (CT) or magnetic resonance imaging (MRI) and often uses contrast agent7.

• X-ray Fluoroscopy:

Fluoroscopy is a technique to obtain real-time X-ray images of the internal structure of a living patient. When applied to arteries and veins, the technique is referred to as fluoroscopic angiography. Although fluoroscopy provides excellent visualization of bone structures, contrast agent is required to visualize tubular structures (Pfirrmann2001). Lead shutters and lead drapes are needed to minimize radiation exposure to patient and interventionalist, making the technique quite time-consuming for vascular interventional procedures.

The two major risks associated with fluoroscopy are radiation-induced injuries to the skin and underlying tissues (“burns”) and the possibility of developing a radiation-induced cancer in a later stage of life (Shope1996, Hall2008). Thus, radiation dose strongly limits the application of fluoroscopy in interventional procedures.

• Computed Tomography:

CT imaging uses X-rays in conjunction with computing algorithms to image the body. Combined with intravenous contrast it can allow 3D reconstructions of arteries and veins and is then referred to as CTA

(Computed Tomography Angiography). It is most commonly used as a pre-operative imaging tool, but has also proven to be an excellent tool in performing interventional procedures because of its good spatial resolution, especially in bone tissue (Gangi1997). CT-fluoroscopy enables real-time guidance in interventions and makes straight-forward and more complex procedures possible (Laufer 2001, Seibel 1997). The main drawback of CT-guidance is, as in X-ray fluoroscopy, the inherent radiation to which the operator and the patient are exposed.

• Magnetic Resonance Imaging:

Magnetic resonance imaging (MRI) is a well-known tool for non-invasive diagnosis based on the nuclear magnetization of (usually) hydrogen atoms. With the advent of novel fast imaging technologies and open magnets, MRA (Magnetic Resonance Angiography) is also becoming an imaging tool for guiding

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http://www.radiologyinfo.org/en/info.cfm?pg=angiocath

Figure 6. X-ray (with contrast medium) outlining the central arteries shows arterial disease at two spots (1,2)

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vascular interventional procedures (Saborowski2007). The main advantage of MRI over fluoroscopy is the elimination of ionizing radiation exposure. Moreover, MRI yields excellent soft tissue contrast and has the ability to visualize lesions in high resolution.

On the other hand, there are multiple technical challenges in guidance interventions under MRI, the most important being the need for MRI-compatible instruments that do not distort the image quality or induce local heating. Moreover, there are patients with absolute contraindications to MRI, such as patients with an implanted cardiac pacemaker or defibrillator, central nervous system aneurysm clips etc. (Buecker2006, Jacquier2007).

b. Alternative techniques for catheter guidance:

The three classical imaging techniques above have the common disadvantage of being bulky and sometimes even requiring adaptations to the building’s architecture, which is why other techniques are being explored for catheter tracking. Several other commercial technologies are currently available for tracking surgical instruments, which can also be applied (stand-alone or in combination) to the tracking of catheters: For visualization of the catheter, the tracking data is typically registered with pre-operative images.

• Acoustical tracking, based on ultrasound (Stoll2005), is a cheap, non-invasive and easy-to-use technique that provides 2D images, which are however of poor quality.

• Inertial tracking (e.g. Intersense Inertiacube2+, USA) uses accelerometers and gyrosensors to provide 3D position information. However, the sensors are prone to a non-negligible amount of drift, which is why inertial tracking should be combined with other modalities.

• Electrical tracking (LocaLisa, Medtronic and Ensite NavX, St. JudeTM) is based on the tracking of electrodes mounted on the catheter tip and provides the relative 3D position of the tracked instrument in an uncalibrated volume.

• Electromagnetic tracking (e.g. AuroraTM NDI, Flock of BirdsTM, AscensionTM) can reach a good level of accuracy (Aurora NDI position accuracy RMS=0.9 mm and Ascension microBird accuracy RMS=1.4mm), in an acceptable volume (average working volume 0,125 m3). The main problem with EM systems used in a clinical setting is that they introduce ferromagnetic metals or conductive material into the imaging system, which can reduce the accuracy of imaging systems considerably (Hummel 2005). Research is ongoing to describe protocols and techniques to assess and improve the accuracy of such systems (Risholm 2007, Nafis 2006, Frantz 2003, Kindratenko).

c. Scanning of the catheter environment:

The process of imaging the local environment surrounding the catheter is provided by a number of scanning technologies:

• Systems that incorporate an ultrasound imaging transducer within the catheter tip have made intravascular ultrasound (IVUS) applications practical for human subjects. In the case of the VOLCANOTM system and Ultra ICE TM catheter, the scanning takes place in radial direction, perpendicular to the axis of the catheter (Onorato 2007). Another approach is taken by the AcuNavTM system whereby a longitudinal image plane is scanned that contains the axis of the catheter (Ren 2002). The AcuNavTM system is already integrated with the CartoTM navigation system (Biosense). For peripheral and intracardiac applications the probe can be larger than the one used in Figure 7. MRI of a normal aorta (with contrast medium)

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coronary arteries for which resolution will be significantly reduced. The larger sized probes may however limit their use in smaller patients and their disposal after each single use incurs high cost. • Alternatively, an external US probe applied to the patient surface can be used for real-time 3D

visualization of the catheter and its environment (Hung 2007). Such a probe has been successfully applied for catheter guidance (McKendrick 2005). Unlike transesophageal echocardiography, which involves endotracheal intubation, transthoracic echocardiography does not require the patient to be under general anaesthesia.

• Most optical techniques require temporary blood replacement with an optically clear liquid. However, recently the use of an infrared (IR) camera is proposed to overcome this requirement (Honda 2008). Blood becomes sufficiently transparent in the near IR region around 1.7 µm as well as around 2.2 µm. The visibility in blood is about 6-10 mm at a wavelength of 2.1µm. Angiocam develops and sells a system based on this principle for vision through blood. Their technology is currently being integrated into an intra-cardiac catheter in order to give a real-time view of the inside of the beating heart and the major blood vessels.

• Intravascular optical coherence tomography (OCT) can achieve a resolution of 10-20 µm which is about 10 times better than IVUS (Kubo 2007) with the trade-off being poorer penetration through blood and tissue. It is capable of resolving microstructure of atherosclerotic plaque and intracoronary thrombus. The delay-scanning interferometry approach of OCT is improved by varying the frequency of emitted light over a set range, an approach termed optical frequency domain imaging (OFDI) which can realise higher detection sensitivity and hence faster imaging speeds (Yun 2006).

• Intravascular MRI (IV MRI), e.g. from TopSpin Medical, overcomes the difficulty of imaging deeper coronary arteries using traditional MRI scanners by use of miniature IV MRI probe fitted over a guidewire. Aortic imaging resolution of 156µm in-plane was achieved in animal studies (Worthley 2003) and a resolution of 312µm in-plane was achieved in human studies with SNR far superior to that achievable using external antenna (Larose 2005). IV MRI devices that also incorporate the magnetic field and RF generation functions don’t require an external MRI scanner for normal operation. Local static magnetic field gradients are generated at the site of measurement however instead of imaging the actual morphology, a simplified spatial representation of the lipid-rich component or the arterial walls is provided as a colour-coded diagram for each sector. A depth range of 250µm can be achieved when assessing lipid-content or arterial plaques (Wilensky 2007).

Advances with respect to the state-of-the-art

• A major objective of SCATh is to reduce and eventually omit the need for classical (harmful or bulky) imaging technology during catheterization procedures.

• This will be achieved by a novel methodology based on SLAM (simultaneous localisation and mapping). The input for the SLAM-approach will be one or a combination of the alternative tracking systems described above together with one of the above scanning techniques.

• Algorithms for real-time processing of the scanning data will be developed.

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d. Force Sensing:

Despite the common understanding that force information is of great use to improve the controllability of catheter procedures (Yokoyama 2008), catheter force sensing is still a very young technology. E.g. force information can be useful for controlling the cardiac radiofrequency ablation process and to avoid applying too much force to the heart wall, which can lead to perforation (Endosense 2008a).

One can distinguish between two categories of sensors. Proximal force sensors are sensor systems that are mounted at the proximal

side of the catheter (near the handle). They estimate the force applied on the tip of the catheter by measuring the force at the insertion point (Jayender 2008). However, this approach is highly sensitive to friction little sensitive to forces perpendicular to the tip axis. Recently, distal force sensors have been developed to overcome these limitations and to allow precise tri-axial measurement of the force vector. Such miniature force sensors require careful fabrication and are integrated into a particular type of catheter.

Endosense has developed an open irrigated, radiofrequency ablation catheter equipped with a tri-axial force sensor positioned at the distal tip (figure 3). This catheter can measure the contact force between the heart wall and the catheter tip. This information can be used to increase safety and effectiveness of radiofrequency catheter ablation procedures (case study 4) for the treatment of supraventricular arrhythmias.

B.1.2.2 Geometrical modelling of aorta and atrium

No interventional catheter procedure takes place before the patient undergoes a preprocedural scan through means of MRI or CT. The interventionalist will analyse the patient-specific scan in order to plan the interventional procedure and she/he will typically rely on the preprocedural data during the procedure. To reduce the mental workload, the obtained patient data can be pre-processed by a computer program and a set of geometrical models can be computed automatically. Generation of these models requires segmentation and model reconstruction. This paragraph gives a non-exhaustive overview of the current state-of-the-art in processing techniques employed to derive geometrical models of the cardiovascular system, more specifically the aorta and the atrium.

a. Aorta segmentation:

Segmentation of the arterial lumen is a mature research field. It has been extensively investigated and computer tomography angiography (CTA) is the gold standard imaging modality for the preoperative sizing of endograft diameters.

• The interaction force in combination with tracking/scanning information will be used to construct a reliable morphologic map of the atrium prior to RF ablation.

• For damage prevention, a layer of supervisory control will be implemented in order to restrict interaction forces, which will significantly improve safety during navigation.

• SCATh will investigate how the force measurements can be used to provide haptic feedback taking into account the highly nonlinear aspects of the catheter system.

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One of the main applications of the analysis of aortic anatomy is the diagnosis and planning of the positioning of endovascular grafts for abdominal aortic aneurysm treatment (Subasic 2005), one of our clinical target applications (see WP1). The other main application field is the diagnosis of aortic dissections, which can be accurately diagnosed in both CTA and 3D contrast material-enhanced MRI (Liu2007).

Nevertheless, the accuracy of the static imaging (CTA) of a dynamic process is uncertain. The aortic configuration and diameter may change during the cardiac cycle, and dynamic MRA demonstrated that pulsatile aortic distension is not equal in all axes, but rather occurs as an asymmetrical expansion and contraction (vanHerwaarden 2006). A recent, more detailed study revealed that aortic pulsatile distention in young healthy volunteers is asymmetric, with up to 41% radius change in the descending aorta (vanPrehn 2009).

For treatment planning of aortic dissection the reliable identification of the true and false lumen is crucial. However, a fully automatic computer aided diagnosis system capable of displaying the different lumens in a user-friendly manner is still not available. Contributions have been done towards the identification of the true and false lumens (Kovacs 2006, Lee 2008).

Some works specifically address the segmentation of the endovascular grafts for the follow-up of the patient (deBruijne 2003). This is needed to detect and prevent complications such as the process of aneurysm shrinkage, ongoing aneurysmal disease, and damage or fatigue of graft material.

b. Atrium segmentation:

Segmentation of the blood pool in the atrium to model the heart chamber is dealt with in most commercial navigation systems, such as EnSite NavX (St. Jude), Carto (Biosense Webster), LocaLisa (Medtronic).

The main clinical need for atrium segmentation is the better guidance of interventional cardiac electrophysiology (EP) procedures. Electroanatomical mapping (EAM) for deriving 3-D structural information during these procedures has been demonstrated to improve the efficacy of catheter ablation (Pappone 2001). EAM has been further enhanced by the use of segmented surface models representing the left atrium and pulmonary veins (LAPV) imaged with volumetric techniques (MR/CT). Algorithms for LAPV segmentation have been presented for CT (Nollo 2004, vonBerg 2005), CTA (John 2005) and MRA (John 2005, Karim 2008).

The pre-procedural anatomy derived from these models can be quite different from that at the time of intervention. Recently, a method for intra-procedural LAPV imaging has been developed based on contrast-enhanced 3D rotational X-ray angiography (3D RA) (Thiagalingam 2008). And rapid and automated methods for the extraction of the LAPV geometry for catheter guidance have been proposed (Meyer 2008).

• SCATh will focus on making the segmentation methods more robust and accurate in the varying image conditions also taking into account the dynamic model variations due to the beating of the heart.

• The feasibility of segmentation of multiple wall layers (media and adventitia) in CT and MR images will be investigated in SCATh.

• SCATh will produce a relevant set of geometrical parameters that parameterize the physical space of the lumen as well as algorithms for the calculation of these parameters. The parameterized geometrical model will serve as an input for the intra-operative navigation tools.

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FP7-ICT-2009-4 14 order to detect high-risk regions (e.g. aneurysms).

B.1.2.3 Mechanical modelling of the cardiovascular system

Mechanical modelling of biological soft tissue is an active research topic throughout the world, an important applications being surgical simulation with reliable deformation and haptic feedback. Mechanical models can be subdivided into heuristic models, continuum-mechanical models and hybrid models, the latter being a combination of the first two. Heuristic models are most commonly used in current commercial surgical simulators and have the advantage of relatively fast computation but lack realism (Meier 2005). Therefore, more realistic continuum-mechanics based models (using finite element and sometimes on boundary element methods) are entering the scene. Continuum mechanics-based Finite Element Modelling (FEM) of the cardiovascular system has progressed dramatically in the last ten years. A lot of effort is put to the definition of constitutive models

that capture the complex nonlinear behaviour of cardiovascular tissue and soft tissue in general (Famaey 2008). The current state-of-the-art includes, but is not limited to a layer separated, fibre-reinforced constitutive model for the arterial wall with experimentally determined material properties (Holzapfel 2000; Holzapfel 2002; Sommer 2005, Holzapfel 2005a Holzapfel 2008). The artery is treated as a two-layer fibre-reinforced thick-walled tube, the two two-layers representing the media and the adventitia. These are the main (solid) mechanically relevant components in healthy arteries. Thus, a third layer (the intima) is disregarded because it has a negligible effect on the mechanical response. The mechanical contribution of the collagen fibres may also include a measure of fibre dispersion (which has been demonstrated experimentally) (Holzapfel 2005a, Holzapfel 2005b, Gasser06).

An important factor for model realism is patient specificity. The state-of-the-art allows image-based, patient-specific model geometries which provide clinically relevant information (Holzapfel 2002). One important lacking feature so far, is the availability of reliable patient-specific constitutive model parameters.

Mechanical modelling allows the calculation of local tissue stresses and deformations due to instrument manipulations in a procedure. These stress and deformation levels can be related to a certain level of tissue damage. Kiousis et al. (Kiousis IP) has developed a numerical and computational framework to quantify soft tissue damage based on FEM.

Figure 9. Model of the major components of a healthy elastic artery (Holzapfel 2000)

• To enhance patient-specificity, SCATh will perform extensive uniaxial and biaxial soft tissue experiments, to correlate patient factors (e.g. age, gender, pathology,…) with material behaviour. This will result in a ‘material property factor’ indexed database of human mechanical properties to facilitate accurate and clinically relevant FEM.

• Post-operative analysis of the position- and force-data recorded during surgical procedures, will be used to continuously update and improve this database.

• To enhance procedural safety, SCATh will make advances with respect to damage prevention through mechanical modelling. Damage indices will be calibrated and validated based on a

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B.1.2.4 Physiological sensing and models

There is an abundance of miniaturized sensors on the market that can be mounted on a catheter in order to measure local physiological parameters such as temperature, pressure, haemoglobin concentration, pCO2, pO2 and O2-saturation. The parameters have great potential to enlarge efficiency and safety of catheter procedures (Li 2008). Therefore, the development and integration of miniaturized sensors in catheters is an active research field (Tanase 2002, Haga 2004). Several studies in literature describe methods relying on physiological parameters and models to monitor the progress and outcome of a surgical intervention. In (Fullerton 2008) the venous O2-saturation is used as a beneficial aid in the early, or even late, diagnosis of cardiac tamponade. Cardiactamponade is a clinical syndrome caused by the accumulation of fluid in the pericardial space.It is a medical emergency, which can occur during catheter RF ablation, i.e. during case study 4 (Hsu 2005, O’neill 2008). In (Denninghoff 2003) a link is demonstrated between retinal venous O2-saturation and cardiac output. Another example is the use of the lowest perioperative mean arterial pressure as a reliable index to assess spinal cord ischemia (Chiesa 2005).

• Physiological parameters and models will be integrated systematically in the control of the SCATh platform, in order to improve the monitoring of the progress and outcome of the procedure. Some examples are given below:

• The pressure in the EndoClamp balloon (see case study 3) is typically estimated based on a pressure measurement at the proximal end of the catheter. Integrating a model of the aortic compliance (Guyton 2005) will increase the accuracy of the estimate.

• SCATh will investigate how O2-saturation can be used to monitor initial damage and prevent further damage caused by tamponade. Especially for case study 4, this will result in improved safety and prediction of the surgical outcome.

B.1.2.5 Real-time modelling

Folllowing the top-down approach described in the introduction, the geometrical model of the cardiovascular system is registered to the real-time tracking data. Several studies on the quantitative evaluation of a rigid registration approach are described in literature. In (Fhamy 2007) an accuracy of landmark registration of 5.6 +- 3.2 mm was reported, shifted to 9.2+- 2.1 when integrated with surface registration. In (Zhong 2007) the error between planned path of ablation and the real path of ablation is over 10 mm. In (Decarret 2007) the catheter positioning in 18 patients was subject to spatial errors in the order of 0.5-1 cm relative to intracardiac echo imaging. These studies suggest that the approach of

synergistic experimental and computational approach.

• SCATh will investigate how pre-operative calculations (using a patient-specific mechanical model) on critical scenario’s in the procedure can be used for online damage prevention.

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rigid registration, applied in commercial products like the Carto System8 and the EnSite NavX9, result is inaccurate localization of catheter within its environment.

Following the bottom-up approach, the scanning technology deployed at the catheter tip will be used to construct a model of the surrounding structures in real-time and use this information to augment the existing parameterized patient specific model. The main approach for this will be to use simultaneous localisation and mapping (SLAM) to recover the intravascular and intracardiac geometry while concurrently determining the catheter’s position within the anatomy.

The SLAM concept has received significant interest from the autonomous robotics community as a method for recovering a sensor’s egomotion as it navigates through an unknown environment (Newman 2007). For SLAM input data is typically provided by laser range scanners, which infer rich geometric information within man made environments especially when the system is grounded (Nieto 2006). For airborne applications radar has been used (Langelaan 2005) and for on or in water applications both radar and sonar have been deployed (Benjamin 2006). Scanning methods more pertinent to SCATh have also been deployed in mobile robotics, for example ultrasound and more recently white-light cameras in visual SLAM systems (Niera 2008, Davison 2007).

One of the fundamental assumptions in SLAM systems is that the environment is static and rigid. Recently, some approaches have been reported to deal with moving object within the rigid environment (Wangsiripitak 2009). For minimally invasive surgery (MIS) the feasibility of SLAM within a deformable environment has also been demonstrated by using a stereo-laparoscope (Mountney 2006).

• With the top-down approach, the accuracy is expected to raise from 5 to 3mm by using a non-rigid registration approach.

• The use of SLAM in SCATh offers the unique opportunity to safely navigate through the patient’s anatomy without prolonged expose to X-Ray radiation. Dealing with a deformable environment, however, is a major technical challenge, which will be addressed by using a the pre-operatively generated geometric model.

• The scanning technologies available within a catheter system will also shape the SLAM approach developed for SCATh. In particular, feature selection and subsequent temporal matching will be investigated to accommodate tissue deformation and blood flow in the scanning field-of-view.

B.1.2.6 Visualisation of interventional procedures

The aim of visualisation technology is to provide an intuitive representation of the catheter location within its environment. Fluoroscopy, providing a real-time visualization has been the gold standard for years, although its application was restricted as radiation exposure has to be minimized. Therefore, a major step in catheter procedures has been the development of nonfluoroscopic 3D navigation and mapping systems (Thornton 2007, Oral 2008). On the market, there are several systems such as the Carto System and the EnSite NavX, providing good 3D visualization of the catheter in the pre-operatively

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acquired geometric model, which facilitates the accuracy and efficacy of catheter procedures (Wong 2004). EnSite NavX e.g. provides different visual representations throughout the workflow of the operation. Figure 10 shows the registration of the catheter space to the preoperative segmented anatomy of the heart.

In the framework of the Marie Curie Actions project ARISER, KUL and IVS worked together on the real-time visualization of the catheter in the aorta. A simplified 3D model of the catheter was registered with the patient's anatomy and visualized through two 2D views and one customizable 3D view of the whole scene. Figure 11 shows the visualisation system, indicating the key concepts and tools. This visualisation platform is based on Studierstube (Schmalstieg 2002), an open source framework for developing augmented reality applications that uses the 3D modelling library Coin10 and opentracker (Reitmayr 2001).

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www.coin3d.org

Advances with respect to the State-of-the-art

As the efficacy of catheter procedure strongly depends on the visualization of the procedure, this project puts a considerable amount of effort in the design of the graphical user interface (GUI). However, the objective is not to go beyond the state-of-the-art. In this project, a GUI architecture will be defined, allowing to visualize in a well-organized way the relevant information of the sensing modalities and models developed models.

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FP7-ICT-2009-4 18 Figure 11. Catheter visualisation platform developed in ARISER

B.1.2.7 Automation or semi-automation for catheterization

Inspired by the success of the Da Vinci surgical system11 for laparoscopy and motivated by attempts to reduce X-ray exposure for both patient and surgeon, robotic tools for catheterization have recently appeared on the market. Both the electromechanical Sensei Robotic Catheter System12 (Hansen Medical Inc.) (figure 12) and the magnetic navigation system Niobe13 (Stereotaxis Inc.) allow navigation of conventional catheters from a distance. Initial experience with these systems shows the feasibility of a teleoperation approach (Saliba 2008a and Pappone 2005). However, these products lack a full integration of the control with the available knowledge. As research on the use of robotic tools for catheterization started only recently, there is no consensus yet on which is the most suitable control approach: autonomous control, teleoperation control, shared control or a combination of one of these (Romano 2007).

The dynamic behaviour of the catheter, while navigating the catheter in a constrained environment, is highly nonlinear and is affected by the frictional forces acting along the length of the catheter, the flexibility of the catheter, the insertion force and the shape and size of the catheter and the environment (Jayender 2008a). Navigating the catheter is therefore a real challenge, which can be addressed by an autonomous control based on real-time tracking of the catheter in the environment (Villagran 2007 and Jayender 2008b) or by teleoperation control, which is closely related to teleoperation control of nonholonomic systems, such as wheeled mobile robots, i.e. when the input degrees of freedom (DOF) are not kinematically similar to the motion DOF (Mut 2002). While doing teleoperation control, the catheter can be under position control or rate control (Romano 2007). Both navigation approaches, i.e. autonomous and teleoperation, depend on the use of a ‘robot’ to steer the catheter from outside the body of the patient. An overview of robots for catheter steering is presented in (Da 2008 and Saliba 2008b).

11 www.intuitivesurgical.com/products/davinci_surgicalsystem 12 www.hansenmedical.com/products/sensei.aspx 13 eu.stereotaxis.com/products-technology/magnetic-navigation

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Figure 12. The Sensei Robotic Catheter system of Hansen Medical for catheter control via a teleoperation approach Several studies mention the lack of perception of the interaction force as an important drawback of the Sensei Robotic Catheter System (Da 2008 and Kanagaratnam 2008). Accurate control of the interaction force is useful during catheter ablation (see scenario 2 in WP1) and it can help to avoid damage or perforation of cardiac and vascular structures (Kanagaratnam 2008, Marcelli 2008 and Da 2008). Next to local force control at the catheter tip (Jayender 2008c), haptic feedback is often proposed to restore the kinesthetic perception of the surgeon. So far, only very little research is done on bilateral control teleoperation control of a catheter, although the interest in training simulators for catheterization with haptic feedback demonstrates the importance of haptic feedback (Gobbetti 2000, Barnes 2005, Ma 2007). Next to autonomous and teleoperation control, shared control has been proposed in order to enhance safety for the patient (Bertocchi 2006). In this work, not only the position of the instruments is controlled, but also the physiological pressure in the explored space, as even small variations in pressure can have serious consequences.

In the framework of the Marie Curie Actions project ARISER, an autonomous control approach for positioning the endoclamp balloon (see case study 3) was developed by K.U.Leuven and IVS. A purpose-built robot is used to steer the catheter. The control is based on a successful integration of tracking data, sensor input, pre-operative images and online registration (Furtado 2008).

• SCATh will investigate the feasibility of autonomous control of the catheter by making use of the location of the catheter with respect to its environment. Integrating knowledge on the catheter’s environment, through the SLAM-approach will result in more accurate and reliable positioning.

• As several previous works mention the lack of haptic feedback, bilateral teleoperation control of the catheter will be investigated. The haptic feedback will be based on force and position measurement and the real-time model of the environment.

• Both autonomous control and bilateral teleoperation control will be extended with a layer of supervisory control. In order to guarantee safe navigation and manipulation the interaction forces, physiological parameters and the occurrence of critical scenarios are continuously monitored through a shared control approach.

• Next to position and orientation of the catheter, SCATh will investigate how other things can be controlled. The balloon inflation e.g. (see case study 3) will be controlled based on a physiological model of the aorta’s compliance.

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B.1.3 S/T methodology and associated work plan

B.1.3.1 Overall strategy

The framework for ICT-enhanced catheterization is explained by the figure below, detailing the interaction between the different work packages of the project.

Figure 13. Block diagram of the SCATh project

A series of techniques to acquire accurate and relevant real-time information will be investigated (WP2). Techniques to derive geometrical (WP3) and mechanical models (WP4) for the endovascular system will be refined, and methods will be derived to allow for the incorporation of real-time data in these models (WP5). This will include the development of SLAM-based algorithms for catheterization. A powerful user interface (WP6) will be designed that allows a) intuitive interpretation of the real-time multiscale model and b) intuitive control of the diagnostic or interventional catheter through the use of advanced control algorithms (WP7). The new concepts for tracking, sensing, modelling and manipulation of the surgical environment will be integrated in a common platform with existing technological state of the art (WP8) in close cooperation with clinical experts both in design and evaluation phase (WP1). Training scenario’s can easily be implemented by emulating real-time sensor data and making use of previously obtained patient models.

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B.1.3.2 Timing of the different WP's

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FP7-ICT-2009-4 22 Table 2. Project GANTT chart

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FP7-ICT-2009-4 23 Interdependency of tasks: PERT diagram

Figure 14. SCATh PERT diagram.

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B.2 Implementation

B.2.1 Management structure and procedures

B.2.1.1 Organisational structure

All planning and control of the project, as well as the overall responsibility, lies with the coordinating partner (K.U.Leuven). This entails the following duties:

• to monitor that all partners comply with their obligations under the EC Grant Agreement and the Consortium Agreement;

• to receive the financial contribution from the EC and to distribute it in accordance with the EC Grant Agreement and the Consortium Agreement;

• to keep the records and financial accounts of the Community financial contribution and to inform the Commission of its distribution thereof;

• to be the intermediary for efficient and correct communication between the partners and the Commission on the progress of the project;

• administration, preparation of minutes and provision of the chairperson of the Project Management Board, and follow-up of its decisions;

• reviewing the reports to the Commission to verify consistency with the project tasks before transmitting them to the Commission.

To support the project coordination, the management structure is composed by two different entities: • The Project Management Board (PMB)

• The Technical Management Board (TMB)

The project will also be supported by an External Advisory Board.

Further details for the management structure will be fixed in a Consortium Agreement (CA) to be finalised before the grant agreement is signed.

Project Management Board (PMB)

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The Project management board (Fig. 15, Tab.7) is composed by the project coordinator (or his representative) and by the person in charge of each partner (or his/her representative). The decision making procedures and voting follows the rules described in the Consortium Agreement.

The main objective of this board is the overall coordination of the project. The PMB is the ultimate decision making body of the project. It is chaired by the Project Manager and will contain representatives from every project partner. The PMB will meet regularly during the course of the project to review progress and discuss any issues which might have come up regarding the coordination as well as the interaction between the partners. These meetings should take place at least every twelve months.

The responsibilities of the PMB include the following:

• High-level progress monitoring of the project activities, with final validation of the related deliverables and milestones, and of the exploitation and dissemination of project results;

• Follow-up of different other issues: financial, administrative, reporting, planning, consortium and cooperation between partners, etc;

• Intellectual property management;

• Decision making on any needed modifications of the general project approach and project restructuring if necessary;

• Amendments to the consortium agreement. • Deciding on conflicts of interest.

• Liaison with the European Commission in ensured through regular communication by the Project coordinator and, where necessary, invitation of the Project officer to PMB meetings.

Technical Management Board (TMB)

The TMB (Fig.16) is the driving force for all the RTD activities; it is composed by three different entities: • The Work Package Leaders (WPL) (Table 10)

• The Ethical Task Force (EthTF) (Table 9) • The Exploitation Task Force (ExTF) (Table 8)

Figure 16 Technical Management Board

The Work Package Leaders (WPL) have the responsibility of assuring that milestones and deliverables, related to the led WP, are delivered respecting the deadlines defined in the Grant Agreement. The WPL

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will also assure the deliverable’s quality by evaluating them against the means of verification described in the Deliverable list. As much as possible external reviewers will be solicited to present feedback on delivered results. The meetings of the TMB will follow the project’s necessities; at least every six months an exhaustive report of progress will be made by all the TMB members, this reporting will be either oral, during meeting be it physical or by teleconferencing, or written.

The main purpose of the Ethical Task Force (EthTF) is to guarantee medical and ethical integrity during execution of all experiments. Among their duties there will be:

• evaluation of the state of progress of the project to decide if it is medically authorized to perform a certain experiment;

• providing advice on the content and protocol of the experiments;

• acquiring approval of the content and protocol of the planned experiments by an external ethical committee;

• steering the project towards clinically realistic solutions.

An essential part of the TMB is the Exploitation Task Force (ExTF). The main objective of this task force is to steer the project towards scientifically and economically valuable results. The main duties of this task force are:

• supervising the dissemination and exploitation; • solving possible intellectual property issues;

• devising plans for the exploitation of project’s outcomes.

Depending on the issues at hand an appropriate voting procedure will be agreed upon by the relevant partners.

The people that represent the partners in the PMB are shown in Table 3.

Partner Person in charge

K.U.Leuven Jos Vander Sloten

UPM Enrique Gomez

ZHAW Thomas Järmann

IVS Ole Jakob Ellle

ICL Guang-Zhong Yang

TUG Gerhard A. Holzapfel

EndoS Giovanni Leo

AngioC Ingo Krisch

Table 3. Members of the PMB

The people forming the ExTF are listed in Table 4.

ZHAW Thomas Järmann

K.U.Leuven Mauro Sette

EndoS Giovanni Leo

AngioC Ingo Krisch

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FP7-ICT-2009-4 27 The people forming the EthTF are shown in Table 5.

IVS Eric Fosse

K.U.Leuven Paul Herijgers

Table 5. People forming the EthTF The work package leaders are listed in Table 10.

Work Package

Work Package Leader Person in charge

WP9 K.U.Leuven Mauro Sette

WP1 IVS Ole Jakob Elle

WP2 IVS Ole Jakob Elle

WP3 UPM Enrique Gomez, Borja Rodriguez Vila

WP4 TUG David Pierce

WP5 ICL Danail Stoyanov

WP6 UPM Patricia Sanchez, Maria Elena Hernando

WP7 K.U.Leuven Emmanuel Vander Poorten

WP8 ZHAW Thomas Järmann

Table 6 Work Package Leaders

External Advisory Board (EAB)

To increase the quality of the research results stemming from the assembled conducted research, this project will make use of an external advisory board that is not bounded by the tight constraints, nor is involved in the decision process. At all times, partners can invite members of the EAB to discuss progress and problems or to receive a critical review on the current evolution by a third party who is not involved in the decision process.

An initial set of potential members of the EAB will be presented by the PMB in the negotiation phase of the contract (at this instant eSaturnus14, experts in visualisation of medical procedures, and Mentice AB15, with unique expertise in catheter procedure simulation, have already given their consent to join the EAB). During these contract negotiations every partner will have the right to veto any member of the EAB. If conflict of interest arises during the run of the project, vetoing external advisors must go through the PMB. Only after a full consensus is reached, in favour of a decision to keep the external advisor, the latter can keep belonging to the EAB. After the negotiation phase it is only possible to introduce new EAB members after receiving of a full consensus at a partner meeting of the PMB. A limited budget is foreseen as travel cost to pay expenses of EAB members that participate to official meetings of the consortium and bring in their expertise and knowledge. Requests for expenses should be directed at the PMB.

The PMB will decide over the need to sign a confidentiality agreement by the members of the EAB and the partners of the consortium. Members that would like to invite people from the EAB to an official

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project meeting should formulate their request towards the PMB (project coordinator) with reasonable time in advance. The latter is responsible to report this request to all partners. Upon objection by any single partner, the invitation of members of the EAB will be redrawn.

B.2.1.2 Management Procedures

Decision making

Throughout the project the goals and interests of all partners need to be respected and therefore a consensus in decision-making between all parties is desirable. The PMB is responsible for solving any issues between partners with respect to this decision-making process. Issues will be resolved by voting, where each project partner has one vote. The Project Manager’s vote is decisive in case of equality. When necessary, temporary working groups on specific issues important to the project progress can be set up, with clearly defined objective and identified decision power.

The responsibilities are divided as follows:

• operational decisions are dealt with by WP Leaders.

• everyday management is handled by Task Leaders, who report to the relevant WP Leader. • administrative issues are taken care of by the Project Manager.

Communication flow

To enhance information flow between partners the co-ordinating partner will create a mailing list for the overall project and for each work package. A proper document numbering and registration system will be established. An FTP server will be used to host shared documents and developments among partners. Additionally a shared workspace system such as BSCW will be installed in order to allow easy collaboration. Contributions to the biyearly project report are required by each partner and it will be compiled by the Coordinating Partner and delivered to the EC. This report will contain:

• progress report

• planning for the next period

• disseminations at meetings/conferences/events • administrative or contractual issues

The Coordinating partner will produce the financial reports on an annual basis, according to usual EC guidelines.

IP management

a. LRD

The Technology Transfer Department at K.U.Leuven R&D offers active support with respect to all aspects related to intellectual property and the protection and commercialisation thereof via a staff consisting of 4 technology transfer officers, two of whom have been involved extensively in technology transfer aspects related to stem cells, and one IPR officer. Support is offered with respect to: Providing information on Intellectual Property Rights (IPR); Assessing the feasibility, patentability and market potential of an invention; Determining a protection strategy; Drafting and filing a patent application (in close interaction with an external patent attorney); Follow-up of patent procedures & costs; Negotiating and drafting Non-Disclosure Agreements (NDA), Material Transfer Agreements (MTA) and Consortium Agreements; Negotiating and drafting of license agreements; and finding industrial partners.

Representatives from K.U.Leuven R&D will monitor the dissemination of results, the management of knowledge, and the exploitation of the results. They will set-up follow-up activities when the project