Devices for Endovascular Interventions - NIHR

Devices for Endovascular Interventions technical advances and translational challenges

List of Contributors

Foreword Cardiovascular disease is the major cause of deaths in the Western world, of which vascular disease is a main contributing factor. Current endovascular repair involves guiding special shaped catheters to a specific target in the aorta and auxiliary arterial vessels combined with different treatment options including stenting, embolization and ablation. For each of the treatment regimes, both clinical challenges and new technological advances are discussed. A major part of this report is focused on the development of new devices for endovascular interventions. These include devices that can provide intraoperative imaging and sensing, as well as implants that can be used for functional restoration and monitoring the efficacy of treatment processes.

This report also addresses the role of robotics for endovascular intervention and the current commercial state-of-the-art and emerging technologies. Steerable catheters incorporate flexible structures and special actuating modes are used to vary the shape and direction of intervention to provide consistent actuation, master-slave manipulation, with improved accuracy and safety. It is anticipated that there will be significant future developments in this area. In this report, the use of the endovascular approach for delivering new therapies including focused energy, drugs, or new gene and cell therapy is also discussed. It further outlines translational challenges with recommendations for technical developments, regulatory considerations,

Authors:

funding, market access and better collaboration between the clinical and engineering communities. I would like to thank all those involved in this report, particularly our expert panel for providing valuable advices and critical comments throughout the preparation of this report.

Professor Guang-Zhong Yang, CBE, FREng Imperial College London, UK

Gary Ansel

Ohio Health

USA

Michele Antonello

University of Padova

Italy

Zakaria Ayman

Hamad Medical Corporation, Doha

Qatar

Trevor Cleveland

Sheffield Vascular Institute

UK

Faye Cockram

Bolton Medical

UK

Michael Dake

Stanford University

USA

Saroj Das

Brunel Institute of Bioengineering

UK

Sebastian Debus

Universital Hospital Hamburg - Eppendorf

Germany

Matthew Eagleton

Cleveland Clinic

USA

Mohamad Hamady

St Mary's Hospital

UK

Henry Ip

Imperial College London

UK

Tudor Jovin

University of Pittsburgh Medical Centre

USA

Ehsan Kamrani

Harvard Medical School

USA

Mike Karim

Oxford Endovascular

UK

Thomas Kopf

Bolton Medical

UK

Donald Longmore

Coronary Artery Disease Research Association (CORDA)

UK

Tim Lueth

Technische Universität München

Germany

Chris McLeod


UK

Andreas Melzer

University of Dundee

UK

Bijan Modarai

Vascular Society of Great Britain and Ireland (Circulation Foundation) and King's College London

UK

Peter Mountney

Siemens

UK

Joanna Nicholls


UK

Madhava Pai


UK

Terry Peters

Robarts Research Institute

Canada

Peter Phillips

Lombard Medical

UK

Jim Reekers

Academisch Medisch Centrum

Netherlands

Robert Rhee

Maimonides Medical Center

USA

Graham Robinson

Hull Royal Infirmary

UK

Su-Lin Lee

The Hamlyn Centre

Mihaela Constantinescu


Jonathan Sobocinski

Aortic Centre, Hôpital Cardiologique, CHRU Lille, University of Lille

France

Wenqiang Bobby Chi

London, UK

Victoria Taylor

British Heart Foundation

UK

William Toff

University of Leicester

UK

Nicola Troisi

San Giovanni di Dio Hospital

Italy

Rami Tzafriri

CBSET: The Specialized and Integrated Preclinical Research Institute

USA

Raman Uberoi

John Radcliffe Hospital

UK

Pankaj Vadgama

Queen Mary's University London

UK

Naheed Visram

Hansen Medical

USA

Mark Whiteley

The Whiteley Clinic

USA

Guang-Zhong Yang


UK

Patricio Zaefferer

Instituto Argentino de Flebología

Argentina

Guang-Zhong Yang

EPSRC-NIHR HTC Partnership for Technology Network on Devices for Surgery and Rehabilitation

3

Table of contents

NIHR CRN White Paper on Endovascular Devices

2

List of Contributors

3

Table of Contents

5

Executive Summary

6

1. Endovascular Treatment 7 1.1. Stenting 7

1.1.1. Endovascular Aneurysm Repair 7 1.1.2. Coronary Artery Stenting 9 1.1.3. Peripheral Artery Stenting 9 1.1.4. Venous Stenting 9 1.1.5. Cerebral Stenting 9 1.1.6. Carotid Artery Stenting 9

1.2. Embolisation 9 1.2.1. Emboli 9 1.2.2. Clinical Applications of Endovascular Embolisation 11

1.3. Ablation 12 1.3.1. Cardiac Catheter Ablation 12 1.3.2. Endovascular Ablation of Hepatocellular Carcinoma 14 1.3.3. Treatment of Chronic Venous Insufficiency 14

2.2. Implants 18

2.2.1. Stents 18 2.2.2. Monitoring Devices 18 2.2.3. Valve Replacements 22 2.2.4. Electrodes 22

2.3. Robotics 27 2.3.1. Current Commercial Robotic Platforms 27 2.3.2. Research Platforms and Future Directions 29

2.4. Delivery of Therapies 32

2.4.1. Endovascular Catheterisation 32 2.4.2. Delivery of Cardiac Devices 38 2.4.3. Energy Delivery 38 2.4.4. Chemicals Delivery 42 2.4.5. Endovascular Gene and Cell Therapy 43

3. Translational Challenges and Considerations

44

4. Recommendations and Conclusions

48

References 50

2. Devices for Endovascular Interventions 16 2.1. Imaging 16 2.1.1. Preoperative Imaging 16 2.1.2. Intraoperative Imaging 16 2.1.3. Intravascular Imaginga 17 2.1.4. Sensing 17 2.1.5. Clinical Need 17

5

1. Endovascular Treatment 1.1. Stenting

Executive summary This report on Medical Devices for Endovascular Interventions was commissioned by The National Institute for Health Research (NIHR) Clinical Research Network (CRN) and supported by the EPSRC-NIHR HTC Partnership for Technology Network on Devices for Surgery and Rehabilitation to provide expert analyses to support and guide NIHR-CRN decision making. The aims of the report are: • To review the current and emerging developments for devices in endovascular interventions; • To collect expert views on technologies with the greatest potential impact on National Health Service (NHS) care;

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Devices for Endovascular Interventions

• To understand the challenges in device development, testing and clinical translation for endovascular devices; • To understand the clinical investigations required to support translation of these products into care use. This report is not a systematic review but includes a literature search and interviews with experts in endovascular procedures and device research from around the world. Case studies are also reported for the development of an endovascular devices from the academic perspective and a large UK clinical trial.

Endovascular intervention is a minimally invasive method for treating cardiovascular diseases via the vasculature. With this approach, the use of stenting is common. A stent is a small scaffold that can be implanted into the blood vessels in order to maintain the blood flow, as well as to reinforce the vessel wall. Most stents are made of biocompatible metals and those lined with fabric are called stent grafts. Stent grafts are widely used for treating aortic aneurysms. Once deployed, they form an inner lining of the aortic wall, restore the regular lumen geometry and prevent the vessel from rupture. Some stents are made with drug-eluting capabilities; they gradually and continuously release medicine to prevent restenosis. The performance of endovascular stenting is usually under the guidance of X-ray fluoroscopy to provide the visualisation of blood vessels and confirmation of successful deployments.

1.1.1. Endovascular Aneurysm Repair Although open surgery for aneurysm repair remains the standard of care, it is associated with lengthy procedure time, the need for general anaesthesia, and prolonged hospital stay and recovery. Endovascular Aneurysm Repair (EVAR) has now become a promising alternative. The goal of EVAR is to deploy made-to-measure stent grafts to restore vessel geometry and normal flow patterns, prevent further weakening of the vessel wall that can lead to aortic rupture. Successful implantation relies on careful pre-operative planning and ideally customised stent grafts that conforms to patient-specific vessel

geometry. Common imaging modalities used include CT angiography, magnetic resonance imaging (MRI)/MR angiography, and duplex ultrasonography (US). Clinically, contrast-enhanced CT is the most commonly used technique for pre-operative planning of EVAR (Erbel, Aboyans et al. 2014). A typical stent graft system consists of three components: 1) a delivery mechanism; 2) a self-expandable metallic mesh tube that supports the vascular attachment; and 3) a fabric coating on the mesh to exclude the aneurysm and conduct blood flow. The most common stent graft is built with a self-expanding nitinol scaffold supported with a polyester or polytetra-fluroethylene membrane. In practice, preoperative aneurysm morphology scoring is also important to define the difficulties of the procedures. The neck morphology of the aneurysm is a crucial factor for predicting long-term outcomes. The most common complications of EVAR are stroke and endoleaks. An endoleak is the perfusion of flow to the excluded aortic pathology and it can be classified according to the site of perfusion. A Type I endoleak happens when there is a continuous perfusion due to loose fixation at the proximal and distal attachment sites. A Type II endoleak occurs when there is a reverse blood flow through a branch vessel arising from the aneurysm sac, which is the most common type of endoleaks. Type III endoleaks are related to the defect of the device itself, such as the breakdown of the fabric coating, hence causing perfusion to the aneurysm sac. Type IV endoleaks happen when blood leaks from the fabric coating due to the porosity of the grafts. Finally, Type V endoleaks are usually caused by the expansion of stent grafts caused by increasing pressure inside (Erbel, Aboyans et al. 2014).

Patient preparation and intervention before the procedure is necessary to prevent Contrast medium–Induced Nephropathy (CIN) since iodine contrast agent is introduced during the catheter angiography. Intravenous sodium bicarbonate and preoperative hydration are useful to prevent CIN. EVAR is performed in a dedicated sterile operation room equipped with C-arm fluoroscopy or CT fluoroscopy. Considering the significant radiation involved, particularly for long procedures, the imaging modalities should also provide dose reduction technologies such as variable-rate pulsed fluoroscopy. Geometrical adjustment of the imaging view relative to the anatomy is important to the surgical outcomes. The use of the iodine contrast agent needs to be carefully regulated in order to prevent CIN (Walker, Kalva et al. 2010). The access of the endovascular instruments is achieved by percutaneous access at the femoral artery for EVAR. An angiography catheter is initially introduced to visualize the arteries. This is followed by endovascular catheterisation, which introduces a stiff guidewire by using a combination of elongated instruments such as a catheter and sheath. The next step is to insert the stent grafts delivery tool over the guidewire that has been previously introduced to the target regions. After the placement of the stent graft, endoleaks can be examined intraoperatively by carefully evaluating the images from the arteriogram. Type I and Type III endoleaks, if observed, should be immediately treated (Erbel, Aboyans et al. 2014). After an uncomplicated operation, the patient needs to stay in hospital overnight. Observation and monitoring methods include pain management, monitoring the access site and cardiopulmonary status.

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1.1.2. Coronary Artery Stenting

TYPE I Proximal or distal graft attachment site leaks.

TYPE II Retrograde flow into the aneurysm sac from aortic side-branches such as the lumbar or inferior mesenteric arteries.

TYPE III Caused by a defect in the graft either due to a fabric tear or disconnection of modualr overlap.

TYPE IV Graft wall porosity.

TYPE V Increase in maximum aneurysm diameter with no identifiable endoleaks.

Figure 1. The different types of endoleak. Adapted from: http://www.sciencedirect.com/science/article/pii/S0378603X17300700#f0005

For complex procedures, post-operative CT scans are often required. Lifelong imaging surveillance of patients after endovascular interventions is critical for monitoring implant status and detecting endoleaks. Renal function should also be monitored after EVAR. Contrast-enhanced CT remains the most common modality for postoperative imaging surveillance. However, for avoiding ionising radiation, this could be replaced by MR angiography and ultrasound. Implantable telemetric pressure sensor is another way of surveillance for monitoring the pressure inside the aneurysm sac, which has the advantage of being real time, continuous and low-cost (Walker, Kalva et al. 2010). In clinical practice, there are further complications other than endoleaks. Mechanical injury of the endothelial lining of the arterial wall may happen during navigation. This can initiate platelet aggregation, causing blood clots to form, and stimulate neointimal hyperplasia. In severe cases, this may lead to vessel perforation and dissection. Excessive pressure could rupture the blood vessel with dire consequences. Although stent graft infection occurs very rarely, but failure to detect infection can result in serious conditions. Antibiotics treatment is needed to mitigate the infection risk. Furthermore, to avoid ischemic complications and limb occlusion due to blockage of arteries by endovascular components, secondary interventions are required to treat these conditions. A Type II endoleak due to reverse blood flow through a branch vessel arising from the aneurysm sac is the most frequent reason for re-intervention. Selective catheterization, embolization,

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Devices for Endovascular Interventions

direct sac puncture and extra stenting are typical re-intervention techniques (Walker, Kalva et al. 2010). Thoracic Endovascular Aneurysm Repair Patients with thoracic aortic aneurysm are often asymptomatic. Clinical signs include chest pain and compression. Diagnosis can be achieved through imaging such as chest CT, X-ray and MRI. Access to aorta is achieved either by open surgery or by percutaneous intervention. From the contralateral femoral side access, a pigtail catheter is typically used for angiography. Then a stent graft is delivered over a stiff guide wire. A great proportion of thoracic aneurysm happens at the descending aorta, a slightly angulated tubular stent graft can be deployed to exclude the lesion from blood flow. In cases when important branches of the aortic arch is involved, branched or fenestrated stent grafts are used to maintain the blood flows through those branches. However, the branches should not be over-stented in order to prevent complications including stroke. Common complication associated with this procedure is endoleak. Type I and III endoleaks are regarded as treatment failure, while Type II is less serious and the solution tends to be conservative. For Type IV and V endoleaks, re-intervention and treatments is immediately required to prevent further expansion and tissue rupture (Erbel, Aboyans et al. 2014). Abdominal Aortic Aneurysm Repair For Abdominal Aortic Aneurysm (AAA), early diagnosis is difficult and aneurysm repair is often indicated when rupture actually happens or obvious symptoms such as back pain occurs. AAAs are classified according to their anatomic relationship to

the renal arteries. The aim of endovascular abdominal aortic aneurysm repair is to deploy a stent graft with image guidance, securing device fixation to the vascular wall covering the diseased aneurysmal sections, thus eliminating AAA sac pressurisation. Deploying stent grafts for AAA needs two access sites from both femoral arteries in order to delivering a single branched stent graft. The fixation of stent grafts may be divided into suprarenal and infrarenal fixation depending on the difficulties of the anatomy. The shape of the grafts can be customized based on patient specific anatomy, all FDA-approved stent grafts come with modular design that allows preprocedural configurations (Walker, Kalva et al. 2010).

Percutaneous Coronary Intervention (PCI) is the most common therapeutic procedure in cardiovascular intervention. Stand-alone coronary balloon angioplasty has been replaced by coronary stent implantation nowadays due to reduced chance of acute vessel closure and restenosis. The major difference of coronary stents compared to other stents is that they are deployed over a balloon at the lesion site (HowardAlpe, de Bono et al. 2007). There are two main categories of coronary stents, bare metal stents and drug-eluting stents. The traditional bare metal stents have relatively high rates of restenosis and 10%-20% of those cases need re-intervention. Drugeluting stents were first introduced in the 1990s. The idea is to gradually release antiproliferative agents to the vessel in order to slow down the process of neointimal hyperplasia, which causes restenosis (Stefanini and Holmes 2013).

1.1.3. Peripheral Artery Stenting For high-risk patients, long-term systemic atherosclerosis could lead to peripheral artery diseases in lower limbs and upper limbs. For Superficial Femoral Artery (SFA) diseases, stenting shows lower rate of restenosis, leading to significant improvement in functionality of the lower limbs compared to standard treatment such as Percutaneous Transluminal Angioplasty (PTA). However, there is a high risk of stent fracture in peripheral artery stenting. The choice of stents therefore highly depends on the location of the specific peripheral artery in order to prevent fracture. For example, coiled stent is favoured in Common Femoral Artery (CFA) as it is more resistant to bending compared to a mesh tube stent. Studies involving translating technologies from coronary artery interventions have shown promise. For example, drug-eluting stents for coronary artery can be used in tibial artery, with preliminary results showing reduced chance of restenosis (White and Gray 2007).

1.1.4. Venous Stenting

Figure 2. A Cook Medical (Bloomington, IN, USA) Zenith stent graft (reprinted from (Cayne, Adelman et al. 2009), ©2009 with permission from Elsevier).

Venoplasty/angioplasty and venous stenting is commonly applied to chronically thrombosed veins. Venous angioplasty initially opens the blockage of the vessel, then stents are required for maintaining the blood flow because of the low intravascular blood pressure of the venous system. Swelling is a common syndrome of obstructed venous system including Inferior

Vena Cava (IVC), Superior Vena Cava (SVC), Internal Jugular Vein’s (IJV), Innominate Veins (INV), iliac veins and subclavian veins. Self-expanding stents are the best for interventions in the venous system. Balloon expandable stents are poor choices since deformation may cause server restenosis. For typical IVC/SVC stenting, long-term patency rate can be as high as 95%. The complications associated with venous stenting are rare. The examination and visualization of the procedure can be done by Intravascular Ultrasound (IVUS), CT and MRI (Bjarnason 2010).

stroke. Progression of plaque at the carotid bifurcation leads to luminal narrowing and ulceration. Carotid stents are used to enlarge and support the vessel from stenosis (Wyse, Hospital et al. 2010). There are two major categories of carotid stents with open or closed stent architectures. The open-cell stents are used for more difficult and angulated lesions. Drug-eluting stents are used in the carotid circulation for reducing the chance of restenosis. Bleeding and carotid restenosis are rare complications that happen during the operation (Saw 2007).

1.1.5. Cerebral Stenting

1.2. Embolisation

Atherosclerotic intracranial arterial stenosis is one of the most common causes of stroke. There are two major treatments available: aggressive medication and Percutaneous Transluminal Angioplasty and Stenting (PTAS). PTAS is a relatively new strategy for treating ischemic stroke, the procedure is operated by neurointerventionists by deploying self-expanding stents to intracranial arteries (Novitzke 2009). Intracranial angioplasty may be introduced before the deployment in order to open the stenosis. However, PTAS does not show superior outcomes compared to medical therapy. It has a higher rate of periprocedural stroke, death and restenosis (Chimowitz, Lynn et al. 2011).

Catheter embolisation is a minimally invasive treatment whereby embolic agents are delivered via a catheter into a blood vessel to block blood flow. The procedure is performed under X-ray fluoroscopy guidance. Access to the site is via guidewires and catheter and successful deployment of the emboli is confirmed through digital subtraction angiography.

Stent retriever technology is a recent method that shows significant improved results for acute ischemic stroke treatments (Gascou, Lobotesis et al. 2014). A stent retriever device is a non-permanent stenting system that removes the plaque in cerebral arteries. The procedure starts with introducing a microcatheter and a steerable microwire to the occluded site. Then the stent retriever delivery system is introduced over the microcatheter and deployed over the thrombus. After the stent retriever is fully expanded, angiography is performed to to examine the temporary recanalisation. Then stent retriever will be recovered and pulled back with the guiding catheter. A CT scan is typically performed at the end of the procedure to screen for haemorrhagic transformation, which is a major complication after the procedure. Further image examinations are performed for the same purpose.

1.2.1. Emboli A range of embolic agents can be delivered via catheter embolisation (Leyon, Littlehales et al. 2014). These range from liquids to particles that have varying degrees of cost, availability and possible side effects. All these agents are designed to deliberately cause ischaemia and necrosis. Mechanical occlusive devices include balloons and coils. Particulate agents can be classified as spherical or nonspherical, also available in various sizes. Liquid agents are designed to solidify once in place. Sclerosing agents induce tissue necrosis directly. A summary of the different types of embolization agents available is presented in Table 1.

1.1.6. Carotid Artery Stenting Carotid Artery Stenting (CAS) is a minimally invasive approach to prevent ischemic stroke, which is a leading cause of cardiovascular related death. Carotid atherosclerosis is a major risk factor for

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Type

Description

Application

Balloons

No longer in common use. Can be used as a temporary occlusion device.

Large vessel embolization.

Coils

Permanent occlusion. Firmer coils used for anchoring while softer coils for packing. Detachable or non-detachable systems. Available in a wide range of sizes of delivery catheter. Easily available and relatively low cost.

Any microcatheter: neurointervention, haemorrhage, peripheral vascular embolization.

Amplatzer Vascular Plug

Based on the amplatzer device used in interventional cardiology. Highly effective and safe. Good control over positioning and can be repositioned. More expensive than coils. Risk of device migration if incorrectly sized.

Many applications in peripheral vasculature.

Provided as a powder to be reconstituted with contrast agent and saline to allow for delivery through a catheter. Permanent occlusion. Particle clumping and blockage of catheters can occur due to differing particle sizes. Difficult to predict level of embolisation.

Uterine fibroids, lower gastrointestinal bleeding, hepatic neoplasms, devascularisation of hypervascular tumours

Very precisely sized and smooth. Low inflammatory reaction. More predictable level of embolization. Risk of nontarget embolization.

Uterine artery embolisation, devascularising hypervascularized tumors.

Autologous Clot

Used where the clot can break down to restore circulation within hours. Rarely used today.

High flow priapism, chemoembolization, epidural blood patching.

Gelatin

Foam or powder forms. Low cost and relatively temporary. Possible reflux and nontarget embolization.

Large and medium vessel embolization.

Mechanical Occlusive

Figure 3. A Solitaire FR revascularization device employing stent retriever technology (reprinted from (Machi, Costalat et al. 2012), ©2012 with permission from BMJ Publishing Group Ltd.)

Particulate Polyvinyl Alcohol

Microspheres

Liquid Adhesive

Cyanoacrylates solidify on contact with ionic fluid such as blood or saline. Low cost. Prior training required.

Any.

Onyx

Nonadhesive and solidifies from outside to inside. Overcomes some of the difficulties with adhesives. Expensive.

Mainly in neurointervention.

Low cost but side effects are common. Can cause pain and thus may require general anaesthetic.

Peripheral AVMS.

Foam. Provides sonographic and fluoroscopic contrast. Low cost. Low risk of transient visual and neurologic symptoms.

Varicosities, varicoceles, gastric bleeding, peripheral venous malformations.

Sclerosing Absolute Alcohol

Sodium Tetradecyl Sulfate

Table 1: A summary of the different embolization agents currently available.

10 Devices for Endovascular Interventions

1.2.2. Clinical Applications of Endovascular Embolisation Clinical applications of embolization can be categorised as vascular, bleeding, oncology, women’s health, men’s health, and obesity. While the examples described below are non-exhaustive, they provides an overview of the many possible uses of endovascularly deployed emboli (Golzarian, Sapoval et al. 2010).

Vascular Cerebral Arteriovenous Malformations (AVMs) The first embolisation of a Cranial Arteriovenous Malformation (AVM) is credited to Alfred J Luessenhop (Maiti, Bir et al. 2016). Cerebral AVMs are complex networks of abnormal arteries and veins within the brain that lacks an intervening capillary bed. This results in high flow that can result in haemorrhage and thus neurological injury (Ellis and Lavine 2014). Treatment options include microsurgical resection, stereotactic radiosurgery, and endovascular embolization; a combination of these approaches is usually used. Embolisation is typically performed premicrosurgery or pre-radiosurgery and less usually delivered alone. Liquid agents, particulate agents, and coils are normally used in these procedures. The risks of this procedure can be substantial – with rates of 5%-15% reported in the literature. Cerebral Aneurysms The gold standard for the treatment of cerebral aneurysms is currently

microsurgery (Rosenwasser, Chalouhi et al. 2014) although endovascular techniques have evolved considerably, with coils, stents and flow diverters now available for placement. Endovascular treatment is also suitable for ruptured aneurysms. While endovascular coiling appears to have a lower complication rate than microsurgical clipping. The rate of reintervention is higher, indicating a lower long-term durability. Whether endovascular treatment should be attempted in the first place will depend on the location of the aneurysm, its clinical grade and configuration, as well as medical comorbidities.

Bleeding Epistaxis (Nose Bleeds) Epistaxis is the acute haemorrhage from the nostril, nasal cavity, or nasopharynx and spontaneous epistaxis that requires embolization is idiopathic in nature (Krajina and Chrobok 2014). Causes can include a tumour blush, telangiectasia, aneurysm, and/or extravasation. Embolisation using a microcatheter and microparticles decreases the flow to the bleeding nasal mucosa while avoiding damage to the nasal skin and palate mucosa. Coils are not recommended. The success rate of embolization for epistaxis is 71-94%. Recurrent Hemoptysis Hemoptysis is the coughing up of blood or blood-stained mucous from the respiratory tract and causes can include bronchiectasis, chronic obstructive pulmonary disease, tuberculosis, and malignancy (Ramírez Mejía, Méndez Montero et al. 2016). Bronchial artery embolisation, introduced in 1974, is the main endovascular therapy

for hemoptysis although it does not deal with the underlying cause; recurrence is therefore frequent. Embolic agents used include polyvinyl alcohol (PVA), microspheres, cyanoacrylate and gelfoam. Coils are avoided as they preclude further embolization if necessary. Gastrointestinal Bleeding In major nonvariceal upper gastrointestinal bleeding, the use of embolization has increased over open surgery. A recent literature review on existing studies comparing the two showed that while there was no difference in the mortality rates after both procedures, embolization appeared to show an increased risk of rebleeding (Beggs, Dilworth et al. 2014). Further studies are required to confirm this finding. Endoleak Management The most common endovascular complication after endovascular abdominal aortic aneurysm repair (EVAR) is type II endoleak, whereby the sac refills via a branch vessel. Preoperative embolization of patent aortic side branches is performed in some centres, with the aim of preventing a type II endoleak. For post-EVAR embolization, the feeding artery and/or the aneurysm sac may be embolised. However, a review of studies looking at prevention of endoleaks via embolisation has shown variable success rates and identified a number of disadvantages to embolisation (Brown, Saggu et al. 2016). Likewise, with treatment of post-EVAR endoleaks, there exist relatively high reintervention rates that necessitate a careful risk versus benefit review.

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Figure 4. The Stereotaxis Niobe magnetically navigated catheter robot for interventional electrophysiology procedures (reprinted from (Armacost, Adair et al. 2017) ©2006, with permission from John Wiley and Sons).

Trauma Haemorrhage Whilst there are no clear guidelines for the treatment of traumatic pelvic injuries, one possible procedural intervention is angiographic embolisation (Mauffrey, Cuellar III et al. 2014). Studies have shown a success rate of 85-100% in the use of interventional angiographic embolisation for the treatment of unstable pelvic fractures. However, while success of the procedure is high, the mortality rate remains high, making the use and role of embolization in cases of pelvic fracture controversial. The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma recommends that patients with on-going haemodynamic instability undergo treatments including angiographic embolisation (Rossaint, Bouillon et al. 2016). Oncology Embolisation can be used for the delivery of regional therapies for the treatment of cancers – these include chemoembolisation and radioembolisation. One key area of embolisation for oncology is in the treatment of liver masses (Molvar and Lewandowski 2015). Randomised control trials have shown a survival benefit of conventional transarterial chemoembolisation in patients with hepatocellular carcinoma. Retrospective data and noncontrolled prospective studies have shown that both chemoembolisation and radioembolisation are safe and effective for the treatment of primary and metastatic liver disease and benign liver lesions.


Women’s Health Uterine fibroid embolisation is a wellestablished treatment for symptomatic uterine fibroids and is performed by the embolisation of the uterine artery (Lopera, Suri et al. 2013). Particulate agents are used; PVA used to be the standard but this is now Embospheres (Biosphere Medical, Rockland, MA). The technical success rate is 84-100% while the clinical success rate is 90% - the fibroid will shrink as well the uterus. Postpartum haemorrhage is the main cause of pregnancy-related maternal death worldwide and may also be treated with uterine artery embolization, similar to the treatment of fibroids. Bleeding can be control to the order of 80-90% and the uterus can be preserved. In this case the embolic agents used are particulate or adhesives, with coils occasionally used. Pelvic Congestion Syndrome (PCS) causes chronic pelvic pain in women. Its causes are varied but can be associated with the presence of ovarian and pelvic varicose veins. It can be treated by transcatheter pelvic variceal embolization, with a technical success rate of over 95% and with 68-100% of patients reporting a relief in symptoms. Sclerosing or liquid embolic material is chosen for this procedure; coils are avoided due to their potential to migrate. Men’s Health Prostate artery embolization is becoming more commonly used for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.

While large, randomised studies are required to establish the efficacy of the technique, current evidence suggests that it is a promising method, especially if pharmacotherapy is not fully successful (Jones, Rai et al. 2015). Obesity With the increase in obesity around the world, there have been growing interests in catheter driven treatments, including bariatric left gastric artery embolization (Anton, Rahman et al. 2015). Initial evidence suggests the promise of this technique for weight management though the first animal studies showed a possible risk of post-embolisation gastric ulcer formation. Further trials are required to elucidate the role of embolization for obesity.

1.3. Ablation 1.3.1. Cardiac Catheter Ablation Ablative therapy in the heart is used for the treatment of complex arrhythmias unresponsive to medication and lifethreatening to the patient. The most common method of choice is the delivery of radiofrequency (RF) energy waves from the tip of a flexible catheter at precise myocardial positions in order to cause irreversible lesions in the arrhythmic tissue. Nowadays, a myriad of conditions are treated by these means, including atrial and ventricular tachycardias (Klein, Shih et al. 1992, Stevenson, Khan et al.

1993, Tracy, Swartz et al. 1993, Kalman, VanHare et al. 1996, Poty, Saoudi et al. 1996, Sacher, Roberts-Thomson et al. 2010), Wolff-Parkinson-White syndrome (Calkins, Sousa et al. 1991, Jackman, Wang et al. 1991, Calkins, Langberg et al. 1992), and more recently atrial fibrillation (Jaïs, Haïssaguerre et al. 1997, Nademanee, McKenzie et al. 2004, Pappone, Vicedomini et al. 2006). In addition to RF energy, there has been extensive interests in using laser ablation for cardiac application. Laser energy has already been used in destroying cancerous tissue, such as liver carcinoma (Gough-Palmer and Gedroyc 2008). Its benefit compared to RF energy is that lesions are potentially not influenced by the quality of the contact between the tissue and catheter tip (Anton, Rahman et al. 2015). Previous studies (Anton, Rahman et al. 2015) looked into ablation bovine myocardium with an irrigated laser catheter (RytmoLas, LasCor GmbH, Taufkirchen, Germany) with promising results for dynamic procedures such as cardiac arrhythmias. Khurram et al (Khurram, Catanzaro et al. 2015) discovered no statistical difference between postablation scar in RF, laser, and cryoablation, as shown in late gadolinium enhancement MRI. Another alternative is the use of microwave energy. Potential benefits include controlled heating of large volumes and reduced charring, one of the main issues with traditional RF catheters (Chiappini, Di Bartolomeo et al. 2003). Moreover, the ablation lesion is deeper for the same tissue surface temperature;

lesions not deep enough are a common issue, as they do not contribute to arrhythmia suppression. Despite some of the advantages, microwave ablation has a limited use for the current cardiology practice. Qian et al (Qian, Barry et al. 2015) described a first attempt at designing and using a microwave catheter for pulmonary vein isolation in vitro. They reported good results and emphasised the need for an in-vivo contactless ablation technique with results that are less susceptible to cardiorespiratory motion. Additionally to RF, laser and microwave ablation, cryoablation has been described as therapeutic means for curing heart rhythm disorders (Heart Rhythm Society 2017). Similarly to laser catheters, the delivery devices have a balloon at the tip containing refrigerant. The balloon technique is used for single ablation of each of the pulmonary veins in atrial fibrillation management. By inflation, the balloon comes in contact with the root of the pulmonary veins and freezes them. The result is a scar, just as in the other thermal techniques. However, other local or reentrant tachycardias need to be treated with traditional point-by-point ablation catheters. An advantage of cryoablation compared to the other types of energy is the possibility of temporary reversible alteration of the tissue as opposed to permanent damage. This is in particular useful for confirmation of the intended ablation site (Beggs, Dilworth et al. 2014, Brown, Saggu et al. 2016). While it can be argued that

electroanatomical mapping is already used for establishing the target, shortterm cryoablation can be a secondary source of information and can be used in conjunction with electrical mapping to simulate the effect of permanent ablation. This is not available yet in any of the electroanatomical mapping software versions on the market. However, because of the possibility of reversible ablation, there have been several cases of tachycardia circuit recovery and need for redo procedure (Heart Racing 2017). Further investigations showed that the catheter thickness is positively correlated with the efficiency of the procedure. Secondly, it was reported that cryoablation causes less intraprocedural complications than RF energy (Heart Racing 2017). Among these advantages are less charring, blood clots (common complication in atrial RF ablation) and in general better outcome even in regions with reduced blood flow. In the general context of robotically assisted cardiovascular procedures, electromagnetic navigation has facilitated access and manipulation at anatomically difficult sites. For cardiac ablation in particular, the technology was implemented in the Niobe system (Stereotaxis, St. Louis, MO, USA) which uses two permanent magnets to generate a field in which the magnetic tip and flexible shaft of the catheter can move to any position (Figure 4).

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Habib VesOpen Catheter

Endovascular RF catheter for vascular remodelling and dilatation of vascular stenosis Interventional radiologist inserts catheter for benign and malignant cases of vascular stenosis and occlusion. Dr Madhava Pai (Department of Surgery, Hammersmith Hospital, Imperial College London, UK) reported on its use for treating hepatocellular carcinoma with portal vein thrombus (PVT).

Habib VesCoag

Precise vascular occlusion, RF endovascular ablation for primary and secondary liver cancers, thus cutting out the blood supply to the tumour. It also stops local endoluminal or endovascular haemorrhage and can be used as a chemical delivery system, e.g. for arteriovenous fistulae or varicocele.

Habib EndoHPB

Endoscopic bipolar RF probe for tissue ablation in the gastro-intestinal tract, for tumour ablation in the bile duct and head of the pancreas Preparation of tissue for stent insertion in order to delay clotting on the metal lace.

Habib Endoblate

Endoscopic bipolar RF probe for tissue ablation in the gastro-intestinal tract, for tumour ablation in the bile duct and head of the pancreas Preparation of tissue for stent insertion in order to delay clotting on the metal lace.

Figure 5. The Aeon Phocus – an advanced magnetically controlled catheter robot for interventional electrophysiology procedures (reprinted with permission from Aeon Scientific, Zurich, Switzerland).

One of the newest developments in magnetic navigation for cardiac ablation procedures is Aeon Phocus (Aeon Scientific, Zurich, Switzerland). The navigation system makes use of the company’s patented electromagnetic steering to provide easy access to any of the four cardiac chambers. In a review of remote magnetic navigation outcomes for cardiac ablation, it was established that such devices were most often used in atrio-ventricular re-entrant tachycardias (Oxley, Opie et al. 2016). Acute and intermediate success rates were as high as 95% and 93%, respectively. However, these figures can be achieved in the manual procedures as well. Looking into areas which can potentially benefit from the magnetic system’s catheter softness and higher stability, (Oxley, Opie et al. 2016) showed that for ventricular tachycardia, the manual success rate of 79% was improved to 97% by using a robotic catheter. Moreover, it was deemed that such a magnetic navigation system could be highly suitable for enclosed space applications such as epicardial ablation. Transcatheter Aortic Valve Implantation and Atrial Fibrillation In the context of heart rhythm disorders, it is important to note that atrial fibrillation is a common complication of Transcatheter Aortic Valve Implantation (TAVI) (Saeed, Hetts et al. 2012, Rossaint, Bouillon et al. 2016). The incidence can be as high as 53%. It was reported that both preoperative and TAVI-induced atrial fibrillation impact negatively the clinical outcomes of the valve replacement procedure, contributing to a higher mortality rate.


The first analysis was performed at 30 days and 1 year after discharge, with higher rehospitalisation and mortality rates in patients who were in sinus rhythm before the procedure and then converted to atrial fibrillation. There is no conclusive study to our knowledge to investigate a possibly decreased mortality rate if the incurred atrial fibrillation is treated (Rossaint, Bouillon et al. 2016). In the second study, (Saeed, Hetts et al. 2012) proposed the presence of atrial fibrillation before TAVI as a predictor of the post-procedural mortality rate at 1 month. They also concluded that atrial fibrillation is more likely to be induced if the TAVI procedure is performed transapically. Their study showed that 30% of the patients with no previous episodes of atrial fibrillation experienced supraventricular rhythm disorders after the intervention.

1.3.2. Endovascular Ablation of Hepatocellular Carcinoma In a broader sense, ablation is employed as therapy for several types of cancer (hepatocellular carcinomas, benign thyroid nodules, colorectal metastases to the liver, other liver, kidney, and bone tumours), with percutaneous access in most cases. While there is great potential in microwave and cryoablation for these particular applications, the lack of medical devices with endovascular access restricts the possibilities of therapy to RF, which is less effective in less conductive lung or

Table 2: EMcision devices for endovascular ablation of the hepatic vascular system

bone tissue (Brace 2009). However, there has been an increase in these alternative treatments, with focus on standardised energy delivery for each application and organ. One of the few endovascular systems based on microwave ablation is produced by EMcision (Department of Surgery, Hammersmith Hospital, London, UK (2017)). The company has been marketing several types of catheters, primarily for endovascular ablation of hepatic vein and other hepatocellular or gastrointestinal carcinoma. In Table 2, an overview of their most important and clinically approved devices is given. The bipolar RF catheters are shaped according to their intended application, but all of them are meant for a minimally invasive endovascular insertion to the targeted site.

1.3.3. Treatment of Chronic Venous Insufficiency Chronic venous insufficiency is the result of reflux from the saphenous veins into venous segments which hamper the normal blood flow. Very often, the reflux is caused by the failure of the saphenofemoral junction valves (Weiss and Weiss 2017). Traditionally treated surgically, this condition has been managed with laser ablation of the saphenous vein junction and subsequent elimination of the abnormal segments. Both laser and RF ablation are in use (Khilnani and Winokur 2017). Additionally to ablation, recurrent cases are also treated

with stenting of the iliac arteries (Eberhardt and Raffetto 2005). One of the most popular endovenous laser treatment systems is VenaCureEVLT (Angiodynamics, Queensbury, NY, USA), whose principle is presented in Figure 6. The procedure is guided by intraoperative ultrasound. It has been reported that despite very good outcome of ablative treatment for chronic venous insufficiency, there is a significant learning curve associated with the limited intraoperative visualisation (Hissink, Bruins et al. 2010). Cannulation is difficult with only real-time ultrasound information. A possible addition to the system is preoperative image overlay for better orientation and for pre-planning the procedure. For RF ablation, Covidien (Dublin, Ireland) patented the Venefit procedure, which seals varicose veins using an in-house developed catheter-energy generator-stylet triplet. Tzilinis et al (Tzilinis, Salles-Cunha et al. 2005) reported the use of one of their earlier RF ablation technologies in treating great saphenous vein incompetence in what was one of the first minimally invasive procedures to treat chronic venous inefficiency. A randomised controlled trial has been conducted to compare outcome in laser and RF ablation using the two systems described above (Gale, Lee et al. 2010). They concluded that endovascular laser use caused more bruising, but yielded better long-term results than RF ablation. Currently, there is a comparative clinical

study running until 2028 to further investigate the difference in short and long-term effects of laser vs. RF ablation of varicose veins (Clinical Trials 2017). More recently, endovascular foam sclerotherapy was developed for minimally invasive treatment of varicose veins. A sclerosant solution is injected into the veins in order to cause clots and block the damaged veins. These unfunctioning veins will be resorbed in the body with time. The injection is performed under ultrasound guidance. This being a novel therapy, there has been little follow-up on the effects of foam injection. However, several complications (Circulation Foundation 2017) are expected: thrombophlebitis due to hardening of the foam in the superficial veins, thrombosis in the bigger veins, and stroke from excess foam (Bundy 2014). The NIHR is currently funding a clinical trial to further compare the different endovascular therapies for chronic vein insufficiency (Ellis and Lavine 2014).

1. Catheter advanced to treatment area

2. Vein closes as catheter is withdrawn

Figure 6. The principle of the VenaCureEVLT (Angiodynamics, Queensbury, NY, USA) endovenous laser treatment system (2017) with adaptation from http://venacure-evlt.com/ varicose-veins/treatments/RF-ablation/

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Better use of the latest imaging modalities in endovascular guidance would contribute to shorter procedural time and more effective procedures.

2. Devices for Endovascular Interventions 2.1. Imaging While strictly speaking not a medical device, the imaging used in guidance and deployment of endovascular devices does play a major role in their design and effectiveness in vivo. We cover below the current clinically available imaging modalities as well as the stateof-the-art modalities, methods and new sensing technologies that are relevant to endovascular devices.

2.1.1. Preoperative Imaging Preoperative imaging for endovascular planning typically involves MRI or contrast-enhanced CT in the form of a CT angiogram. Segmentation of the vessels allows for a complete 3D understanding of the shape and underlying complexity of the patient-specific anatomy. The use of 3D printing for planning and visualisation for particularly complex cases has also received interest. While the cost of 3D printing is steadily reducing, the recent increased attention given to virtual reality may see this technology replaced. Haemodynamic quantification is possible using imaging methods such as phasecontrast MRI or Doppler ultrasound. However, when such methods are unavailable, the use of computational fluid dynamics to perform simulations within the


3D reconstruction has shown promise for the prediction of the impact of intervention on haemodynamics.

2.1.2. Intraoperative Imaging The majority of endovascular procedures are guided via X-ray fluoroscopy with the use of iodine-based contrast agent to highlight vessel locations. For intraoperative 3D reconstruction, the same machine can provide cone-beam CT scans. While this imaging modality is affordable, the radiation dosage to the patient and the practitioner is significant. The contrast agent used is also nephrotoxic. Reduction of the x-ray exposure and the use of contrast agent is therefore important. There has been much research into the use of MRI for guiding endovascular procedures (Saeed, Hetts et al. 2012). By integrating micro-coils into medical devices, their 3D position can be shown with respect to the anatomy. MRI is a safe imaging modality although it is currently loud, expensive, and requires special, MR compatible tools. However, MRI is a versatile technique, providing not only anatomical information but also functional data including quantitative measures such as shear stress, elasticity, perfusion and velocity. The incorporation of this information would aid in intervention decision making and device placement in vivo. For intracardiac use,

imaging to determine tissue temperature or ablation depth would aid in treatment of arrhythmias with MRI. Similarly, for thermal ablation, functional imaging could assess the effectiveness of energy delivery. Ultrasound imaging has been used to guide mitral valve repair and transcatheter aortic valve replacement (Bundy 2014) but there is scope for more effective use of the imaging technology. It has been shown that ultrasound can be used for targeting instruments and anatomy with sufficient accuracy and with this, safety of the procedure has been improved. Ultrasound imaging augmented with preoperative images can replace X-ray fluoroscopy and improve guidance in valve replacement procedures (Li, Rajchl et al. 2015).

2.1.3. Intravascular Imaging For intravascular imaging, current techniques include ultrasound and Optical Coherence Tomography (OCT). Intravascular Ultrasound (IVUS) is a radial ultrasound transducer at the tip of a catheter and is already in clinical use for classification of arterial tissues. OCT is another biomedical tissue-imaging technique that provides high-resolution optical images of the vessel but only allows for limited imaging depth. While IVUS offers greater imaging depth than OCT, both imaging modalities are still less commonly available in UK hospitals

compared to those in North America. A forward facing intracardiac ultrasound probe is currently being developed by VytronUS, Inc (Sunnyvale, CA, USA); this probe is based on low-intensity collimated ultrasound and the system allows both 3D reconstruction of the endocardial walls and ablation of tissue, both through blood and without tissue contact. Pre-clinical studies have demonstrated the safety and efficacy of the system when performing ablation to isolate the pulmonary veins (Koruth, Schneider et al. 2015). An increased interest in photoacoustic imaging methods has also raised the possibility of incorporating this imaging modality onto intravascular catheters and guidewires.

2.1.4. Sensing Apart from imaging, the 3D position and orientation of devices in vivo can be achieved through electromagnetic (EM) tracking and navigation. It is anticipated that this technology, already in use in cardiac electrophysiology for the 3D position tracking of the distal end of mapping and ablation catheters, will be gaining more applications in endovascular interventions (Manstad-Hulaas, Tangen et al. 2012). Other tracking technologies are currently incorporated into existing commercial systems, particularly for cardiac catheter ablation. These include the Biosense-Webster CARTO system and Boston Scientific Rhythmia system,

both based on magnetic fields, and the St Jude EnSite system, based on impedance mapping. Companies such as Sensuron (Sensuron 2016) have also started looking into the provision of fibre-optic based shape sensors that can be incorporated into guidewires and catheters. Whilst EM sensors can only provide the 3D position of a discrete set of points, fibre-optics sensors have the potential to determine the entire 3D shape of medical devices in vivo. New research has looked at the use of shape sensing for improved navigation for endovascular procedures (Mandal, Parent et al. 2016).

2.1.5. Clinical Need More effective use of the current available image modalities in endovascular guidance would contribute to shorter procedural time and more effective procedures. This would aid in the reduction of radiation without requiring an outlay of capital for new imaging equipment. However, the future of endovascular interventions would be in newer, safer, faster imaging modalities but these are still at the development stage. There is promise in the use of other similar technologies, such as electromagnetic tracking, which is already in use in cardiac electrophysiology mapping and in percutaneous procedures.

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Intracranial aneuryms may be treated via the insertion of flow diverters, allowing the diversion of flow and endoluminal vessel reconstruction.

2.2. Implants Drug Eluting Stents The first balloon angioplasty for the treatment of coronary heart disease was performed in 1977, while the first coronary stent implantation was in 1984. Since then, percutaneous, catheter-based interventions for coronary heart disease have evolved and significant advances have been made (Katz, Harchandani et al. 2015). However, the use of angioplasty and bare metal stents tended to result in restenosis, and this eventually led to the development of drug eluting stents which could locally deliver antiproliferative drugs to reduce neointimal hyperplasia, the primary cause of restenosis. The use of drug eluting stents over bare metal stents in the treatment of extracranial vertebral artery disease has been investigated, with results showing that the use of drug eluting stents reduces restenosis, recurrent symptoms and target vessel revascularisation (Tank, Ghosh et al. 2015). However, there is some evidence to suggest that the use of some drug eluting stents is linked to a high incidence of thrombosis (Palmerini, Biondi-Zoccai et al. 2012).

2.2.1. Stents


Bioabsorbable Stents While drug eluting stents are now mainstream in the treatment of coronary artery disease, they still carry some risks, including thrombosis, local inflammatory reaction, and restriction of vasomotion (Brie, Penson et al. 2016). Bioabsorbable stents, such as the ABSORB BVS (Abbott Vascular, Santa Clara, USA), the first fully bioresorbable vascular scaffold, have shown to provide both vessel support and drug delivery without the need for the

traditional metal structures. However, further studies are still required to show results comparing bioabsorbable stents to drug eluting stents or bare metal stents and these need to focus on the long term, after full absorption (Wayangankar and Ellis 2015). Limitations to current bioabsorbable stents include their bulk, the risk of stent fracture, and the challenges of visibility under X-ray guidance. Stent Grafts Stent grafts are tubes of fabric reinforced with metal stents and are widely used for the endovascular treatment of aneurysms, typically deployed via catheters. The main challenges are their use in the treatment of aneurysms located near branching vessels (Crawford, Sanford et al. 2016). The use of fenestrated stent grafts in FEVAR (fenestrated endovascular aneurysm repair) have been shown to be effective in the short and median term (Georgiadis, van Herwaarden et al. 2016), with most clinical issues similar to those experienced in EVAR (endovascular aneurysm repair). The use of in-situ fenestrations in stent grafts (Malina and Sonesson 2015) or physician modified stent grafts may help catheter-based treatment of more complex aneurysms. The main limitations are the time and costs required to manufacture patient-specific fenestrated stent grafts as they are currently all handmade. The ability to automate some or all of the planning and manufacturing steps will help reduce costs and ensure that patients are able to be treated as soon as possible.

the insertion of flow diverters, allowing, as their name suggests, the diversion of flow and endoluminal vessel reconstruction (Rosenwasser, Chalouhi et al. 2014). The use of devices such as the PipelineTM Embolization Device (PED) (Covidien, Irvine, CA, USA) has been shown to be more cost effective and time efficient, with higher occlusion rates within large, unruptured aneurysms. Like most other implantable devices, however, longer follow up studies are required to determine the rate of complete occlusion within patients (Briganti, Leone et al. 2015).

2.2.2. Monitoring Devices Monitoring devices such as the CardioMEMs, the first and only FDA-approved heart failure (HF) monitor, have been shown to improve quality-of-life in patients and reduce hospital admissions. CardioMEMS (St Jude Medical, St. Paul, MN, USA) is a permanent implant delivered via catheter to the pulmonary artery, where arterial blood pressure is measured. The CHAMPION randomised control trial showed that the use of the CardioMEMS device was linked to a reduction of hospital readmissions in NYHA class III heart failure patients (Abraham, Adamson et al. 2011).

Figure 7. A NEVO drug eluting stent that is also bioabsorbable; its use of multiple reservoirs allows for the release of different drugs (reprinted from (Räber 2011), ©2010 with permission from John Wiley and Sons).

Flow Diverters Intracranial aneuryms may be treated via

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CASE STUDY: From Concept to Clinical Translation - Endovascular delivery of permanent PA pressure sensor – Dr Chris McLeod , Imperial College

We have been developing a permanent implantable pulmonary artery (PA) pressure sensor and is currently working at clinical translation of the device. This was developed with funding from the Wellcome Trust and the Department of Health under the Health Innovation Challenge Fund.

Hypothesis 1. Heart Failure (HF) is a progressive disease whose progression can be retarded by avoiding destabilisation episodes and re-hospitalisation. 2. HF is composed of multiple pathologies for which different treatments are required. The pathologies result in detectable biochemical and physical signals and in clinical symptoms. 3. Of the physical signals, monitoring filling pressure will give the earliest warning of potential destabilisation (Adamson 2009). 4. Device-less telemonitoring of self-reported symptoms has failed to improve patient outcomes (Tele-HF and TIM-HF trials in USA and Europe respectively). 5. Pulmonary Artery Pressure (PAP) is safer than Left Atrial Pressure (LAP) in the first instance –until thromboembolism has been excluded from the risks. 6. Continuous, ambulatory monitoring offers the full picture – resting levels, responses to exercise, variability on circadian, sleep, autonomic, respiratory cycle timescales. 7. Titration of pharmaceutical therapy based on objective PAP data will enable better control of PAP while minimising pharma side-effects.


Data Supporting the Hypothesis The CHAMPION trial using CardioMems’ permanentlyimplanted PAP sensor has shown a very significant decrease (38%) in its primary endpoint – reduction in rehospitalisation. The data was one daily PAP trace of about 20 seconds recorded while the patient lay supine on a bed over the recording equipment.

Development Roadmap A new technology, derived from one implementation of a real-time automotive tyre pressure monitoring system, can be used with a portable, wireless monitoring system to provide PAP data from patients during the full range of daily activities. This will generate a more complete picture of patients’ natural responses to rest, exercise and sleep. The sensor is excited, and read, wirelessly at a high radio frequency (RF). HF is categorised into preserved-ejection-fraction (HEFPEF) and reduced-ejection-fraction (HEFREF), largely coinciding with diastolic HF and systolic HF respectively. PAP during exercise has been shown to be a very potent prognostic indicator for HEFPEF patients (Dorfs, Zeh et al. 2014). A new RF PAP sensor should be implanted by endovascular access. The patient will wear a reader which will supply power to the sensor and read its signal. The reader will store the data and be able to stream it in real-time to a remote server.

Funding An initial fund of about £100k was raised in 2007 from Imperial College and Imperial Innovation to employ a postdoctoral research assistant for one year to manufacture test samples of a sensor working at physiological pressures.

The data generated enabled a successful grant application to the Wellcome Trust technology transfer section for a 3-year development programme (2008-2011) including an appropriately-sized sensor and a reader. The results enabled a successful larger grant application to the Health Innovation Challenge Fund for working sensors and retaining stent for the PA, a delivery and deployment catheter and a portable reader suitable for patient use. The programme (2011-2015) included the technical developments necessary for a repeatable production process for all the components, a pre-clinical trial in an animal model, application to the Medicines and Healthcare products Regulatory Agency (MHRA), ethics committee(s) and research regulatory committee(s) for a Phase 1 (firstin-man, safety) study, and the completion of this study. Initially, the scope of the clinical trial could not be predicted and the funders have subsequently generously added an extension to cover the time and cost of the trial.

Collaborations and Sub-contracts While the fundamental system design and the detailed design of the components has been carried out within Imperial College, all the manufacturing has been subcontracted to companies already proficient within their specialist areas. For some companies this has been their first medical device development. We have, within the College team, Professor Sir Magdi Yacoub as Clinical Lead and Dr Iqbal Malik, head of the catheterisation lab at the Hammersmith Hospital, as a very experienced interventionist. These two have advised all clinical aspects of sensor position – allowing for the limited penetration of RF into and out of the body – and its anchoring within the PA. They have also set specifications

for the delivery catheter (femoral vein to PA) and control during deployment. They have participated in the early animal trials and specified any modifications necessary for improving the system.

Current Position We have successfully deployed devices in the PA of 80kg swine and measured PAP acutely. The designs of the components have been altered slightly and frozen. Production-equivalent devices are now being made for testing in chronic animal recordings.

Next Steps The data from the chronic animal studies will be presented along with the design files in an application to the MHRA for a Phase 1 clinical trial. The same data and files will be prepared for eventual submission, along with the results from the clinical trial, to a Notified Body when we apply for a CE mark for the system. By this time a commercial entity will be needed to hold the CE mark. If these steps are all successful, a Phase 2 (efficacy) trial should follow. This will necessarily be a much more expensive undertaking than the Phase 1 trial and will need significant commercial funding.

Conclusion Although there is no conclusion yet, we hope that the above description will illustrate some of the processes in translating an idea into an endovascular device and the timescale required if the system is complex.

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2.2.3. Valve Replacements The four main valves of the heart are the two atrioventricular valves: the mitral valve and the tricuspid valve, and the two semilunar valves: the aortic valve and the pulmonary valve. Transcatheter valve technology today has enabled the replacement of these valves via minimally invasive means (Figulla, Webb et al. 2016). The first transcatheter heart valve implantation was performed in the pulmonary position in 2000 and in the aortic position in 2002 (Testa, Latib et al. 2016); since then, thousands of patients have been treated in this way. Another minimally invasive alternative to surgical approaches is to perform valve replacement transapically. Percutaneous pulmonary valve implantation is a less invasive means of treating right ventricular to pulmonary artery stenosis or pulmonary regurgitation (Ansari, Cardoso et al. 2015). Patients with adult congenital disease are most likely to benefit as they require repeated surgical intervention due to right ventricle outflow tract dysfunction. Transcatheter Aortic Valve Implantation (TAVI) or Transcatheter Aortic Valve Replacement (TAVR) is now an established method for patients with aortic stenosis, who are unable to tolerate the conventional surgical aortic valve replacement. Since the first case in 2002, over 200,000 procedures have been performed worldwide (Vahl, Kodali et al. 2016). Important issues to be considered in the future for TAVI include device


durability and expansion of clinical indications; concerns about the former are the main reason why TAVI has not been expanded to lower-risk patients. Recent trials (PARTNER-1, CoreValve, and NOTION) comparing TAVR to surgical aortic valve replacement (SAVR) have shown the benefits of TAVR for high-risk patients but further trials are required for lower-risk patients (Carvajal, Villablanca-Spinetto et al. 2016). The field is rapidly evolving and it is likely that these large trials will help define future directions. The use of TAVI or other catheter based procedures for patients with aortic regurgitation, however, is still not established due to the presence of valvular calcification and distortion of aortic root anatomy (Bonow, Leon et al. 2016). Unlike the aortic valve, transcatheter mitral valve implantation is a less commonly performed procedure (Testa, Latib et al. 2016). The procedure is more difficult than TAVI, with less direct valve delivery, heterogeneity of mitral valve disease and the need for better imaging and navigation during the procedure (Nishimura, Vahanian et al. 2016). While a number of devices already exist, there is a lack of studies showing clinical proof of safety and efficacy. Thus far, there is a strong association between severe tricuspid regurgitation (TR) and mortality. For effective treatment of the former, new devices for transcatheter treatment have become available (RodésCabau, Hahn et al. 2016). However, this area is generally understood to be the least represented in terms of clinical device

availability with major challenges due to large tricuspid valve annulus dimensions, a lack of valve calcification, close proximity to the right coronary artery, and fragility of the tricuspid valve annulus tissue. Appropriate prospective trials are required to determine the effectiveness of transcatheter approaches over traditional surgical methods.

Valve Replacement

Manufacturer

Device

Pulmonary Valve

Medtronic

Melody transcatheter pulmonary valve

Edwards Lifesciences

Sapien Pulmonic transcatheter heart valve


Sapien 3 Valve

Medtronic

CoreValve Evolut R

Symetis

Large and medium vessel embolization.

JVT Research & Development Corporation

JenaValve

St Jude Medical

Portico Valve

Direct Flow Medical

Direct Flow Medical Valve

Medtronic

Engager Valve

Boston Scientific

Lotus Valve

Abbot Vascular

MitraClip

Cardiac Dimensions

Carillon Mitral Contour System

Mitralign

Mitralign Percutaneous Annuloplasty System (MPAS)

Valtech

Cardioband

P&F Products & Features Vertriebs GmbH

Tric Valve

Edwards

SAPIEN Valve


FORMA

Mitralign

Mitralign

4Tech Cardio

TriCinch

Aortic Valve

In the future, new technologies such as tissue engineered valves and issues with device durability are expected to see an increase in use of these minimally invasive procedures.

2.2.4. Electrodes Recently, it has been shown that it is possible to record brain activity from within a vein using a passive stentelectrode recording array (Oxley, Opie et al. 2016). Traditionally, high-fidelity intracranial electrode arrays require direct implantation into the brain and this endovascular approach, thus making this approach safer. Current limitations are the durability of the delivery wire but the approach is very promising for reliable chronic neural recordings.

Mitral Valve

Tricuspid Valve

Table 3: A summary of commercially available transcatheter valve devices.

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CASE STUDY: The UK TAVI Trial

UK TAVI Registry http://sbhci.org.br/wp-content/uploads/2010/11/SLIDES-DEAPRESENTA%C3%87%C3%83O55.pdf

Purpose The UK TAVI registry was primarily organised as a support platform for introducing the TAVI procedure in the UK. The focus was on collecting and analysing high quality data from these procedures via the Central Cardiac Audit Database (CCAD). The data was encrypted before it was collected centrally in the CCAD.

Collaborations The UK TAVI registry is the result of collaborative work between professional societies, i.e., the British Cardiovascular Intervention Society (BCIS) and the Society for Cardiothoracic Surgery (SCTS), the Department of Health and specialist commissioners, and health technology assessment organisations and regulators, i.e., the National Institute for Health and Care Excellence (NICE).

Data The dataset comprised information from cases before 31 December 2009. This amounts to 872 patients from 26 centres. There were 67 subjects from 2007, 272 from 2008, and 533 from 2009. Out of the 872 cases, 10 were unsuccessful valve implants.

Analysis The documented valves were of two types: 460 CoreValve (Medtronic, Minneapolis, MN, USA) and 402 SAPIEN (Edwards, Irvine, CA, USA). The analysis on the registry showed that the two types were preferred in conjunction with different access and implantation techniques. The statistical analysis also covered the mortality and morbidity outcome depending on the vascular access. Finally, the results of a 2-year follow-up were published. The survival rate was higher for patients whose valves were implanted transfemorally compared to other methods


UK TAVI trial (statistical significance value of the test p = 0.017). The two curves are shown in the second figure. The study also included an analysis of the learning curve, as the trial was conducted in order to support the uptake of TAVI in the clinical praxis. The 2-year survival rate in the first 20 cases was compared to the survival rate in the rest, with the outcome of the subsequent cases being only marginally better than that of the first ones. In a more recent analysis of the same dataset, at a 6-year follow-up of the same cohort, it was observed that the clinical profiles of TAVI patients did not change, but they were discharged sooner after the procedure than in the early years. Moreover, their long-term outcomes improved over the 6 years of TAVI experience. The study also helped in defining risk and outcome predictors: periprocedural stroke, nonfemoral access, and postprocedural aortic regurgitation (Leyon, Littlehales et al. 2014). Another study based on the dataset in the UK TAVI registry investigated the dependency of procedure outcome on the access route (transfemoral, transapical, or subclavian) and the valve type (SAPIEN vs. CoreValve). It was discovered that the transapical heart puncture and valve implantation correlated with higher mortality than in a transfemoral access and delivery (Li, Rajchl et al. 2015).

Conclusion The UK TAVI registry was a successful UK-wide data collection project, with subsequent analysis of several key indicators, including mortality and morbidity as function of endovascular access method, but also including steepness of the procedure learning curve. Keeping in mind that the analysis was performed in the early days of TAVI (2007-2009), the in-hospital mortality of 6.2% and the 1-year mortality of 19.7% were deemed as encouraging results, which actually improved to the current day.

http://www.nets.nihr.ac.uk/projects/hta/095563

Hypothesis

Start date: February 2013

TAVI is non-inferior to surgical repair at one year and each year up to 5 years.

Collaborations: interventional cardiologists, cardiac surgeons, patient representatives, experts in research design, clinical trials, medical statistics, health economics, cardiac imaging, geriatric medicine. Additionally, institutions are also involved in the trial: Department of Health Heart Team, the National Specialised Commissioning groups, NICE, and the national societies for interventional cardiology and cardiac surgery.

Purpose 1. A ssessment of clinical effectiveness and cost utility of TAVI vs. open surgical repair of aortic valve, as well as development of morbidity and mortality predictors to guide the patient-specific decision between the two procedures. Only immediate effectiveness of TAVI has been documented so far; the trial will investigate the long-term outcomes (5-year follow-up) and compare them to the well-established conventional procedure. http://www.nets. nihr.ac.uk/__data/assets/pdf_file/0007/113947/PRO-09-5563.pdf 2. Mortality at 30 days, 1, 2, 3, 4, and 5 years Even with a very low mortality rate of 5.8% in surgical aortic valve replacement, one third of the elderly patients are still considered at high risk for this procedure (Lopera, Suri et al. 2013). Ten years after this publication, the UK TAVI Trial defined it as one of its objectives to assess TAVI effectiveness, develop performance indicators, and make recommendations for the treatment of the high-risk patients with transcatheter procedures.

Data 808 patients with aortic stenosis and at medium or high risk for open surgery for which procedure-related outcomes such as stroke, symptom relief, quality of life, occurrence of aortic regurgitation, and valve-durability during follow-up are known. Any CE-marked device and any approach in clinical use are allowed for this study. There are 3 valves meeting the European standards: Medtronic self-expanding CoreValve, Edwards balloon-expandable SAPIEN and SAPIEN XT.

Dissemination 1. B ased on the results of this study, the NHS will enforce a policy for the uptake of TAVI as routine clinical practice and as potential individually tailored treatment for patients with aortic stenosis. 2. T here will be an economic analysis attached to the study and this will include device, staff, consumables, complications, and hospital stay costs and will also compare these figures for transarterial and transapical procedures.

25

2.3. Robotics Current endovascular approaches are limited by excessive exposure to radiation, a lack of 3D mapping, as well as lost haptic feedbacks. In the last two decades, there is a growing interest in robotic steerable catheter technology which brought benefits such as improved precision and stability, reduced radiation doses, improved comfort and access to difficult and tortuous anatomy (Di Biase, Wang et al. 2009). However, these commercial platforms tend to alter the natural bedside manipulation skills of the operator, hence manually acquired experience and dexterity are not well utilised. Improved 3D navigation, integrated force feedback and improved ergonomics are unmet clinical needs in the development of robotic endovascular intervention.

2.3.1. Current Commercial Robotic Platforms Robotic Systems for Electrophysiology Therapies Sensei X2 by Hansen Medical (Mountain View, CA, USA, now part of Auris Medical) and Niobe magnetic navigation system (Stereotaxis, St. Louis, MO) are two major commercial robotic platforms for cardiac electrophysiology (EP) therapies. The Sensei X2 system has been successfully used in cardiac mapping and ablation (Saliba, Reddy et al. 2008, Di Biase, Wang et al. 2009). It can be used with the Artisan® or the narrower Magellan steerable catheters. These robotic catheters consist of an inner (leader) catheter within an outer sheath and the deflection of each component is controlled via tendon-driven actuation. Both systems are arranged in a masterslave setup, with which the operator uses either a 3D joystick or navigation buttons on the remote workstation. The CoHesion


visualization module in Sensei X2 allows the integration of a commercial 3D electroanatomical mapping system (EnSite, St. Jude Medical, MN, USA). It can also incorporate a distal tip force measurement system (IntelliSense), which provides visualization of the forces and tactile feedback. The Niobe system, on the other hand, uses two permanent magnets to generate a magnetic field for controlling the tip deflection of the catheters. The deflection angle and direction are controlled by changing the orientation of the outer magnets using a mouse and/or a joystick at the workstation, while a distal motor drives the translational movement of the catheters. This system has been successfully used for mapping and ablation, as well as treatment of coronary and peripheral arterial disease (Ernst, Ouyang et al. 2004, Di Biase, Fahmy et al. 2007). 3D mapping and navigation are provided by the 3D electroanatomical CARTO mapping system (Biosense Webster, Brussels, Belgium). Magnetic navigation brings benefits such as lower stiffness of the magnetic catheters compared to the tendon driven instruments, with reduced risk of tissue perforation and damage. Recently, the Vdrive of the Niobe system was cleared by FDA, which allows Niobe to control third party diagnostic catheters and ablation devices. Other magnetically steered robotic catheter systems for EP application include the CGCI (Catheter Guidance Control and Imaging) by Magnetecs Inc. (CA, USA) and the Aeon Phocus by Aeon Scientific (Zurich, Switzerland). The CGCI system uses eight electromagnets in a semi-spherical pattern to generate dynamic magnetic field and steering of the magnetized catheters is achieved by changing the electrical current

through each magnet (Gang, Nguyen et al. 2011). The Aeon Phocus also uses eight electromagnets to enhance the field strength and contract forces between the catheter and the tissue. Moreover, Amigo (Catheter Robotics Inc. NJ, USA) is a mechanically driven remote system which allows manipulation of standard commercial mapping catheters in 3 degrees-of-freedom to control respectively insertion, retraction and deflection of the catheter tip. It is equipped with an intuitive remote controller that replicates the natural skills of manipulating standard EP catheter. Robotic Systems for Endovascular Interventions The development of steerable robotic catheter technology also facilitates its clinical application in more general vascular surgeries. The Magellan system by Hansen Medical, for example, works with standard 2D fluoroscopy images and force sensing is not incorporated. The Magellan system is equipped with narrower steerable catheters compared to the Sensei system, it also consists of a guidewire driving system that allows the synchronization control of its robotic catheter and a conventional guidewire, which is useful for accessing narrow anatomy. The Magellan robotic eKit was FDA approved, allowing manipulating third party micro-catheters through its robotic catheter. This facilitates access to more tortuous vessels. The CorPath GRX System (Corindus Vascular Robotics, MA, USA) is another robotic system to mechanically drive standard instruments specifically in percutaneous coronary interventions. The bedside robotic driver allows retraction/insertion and rotation of guidewire and stent/balloon catheter separately. The operator can

27

Figure 9. Magellan Robotic System from Hansen Medical (Reprinted from (Burgner-Kahrs, Rucker et al. 2015) ©2015, with permission from IEEE).

Application: EP or Vascular (V)

Steerable Catheter

Force Feedback

Intuitive Human/ robot Interface

Sensei X2

EP

Yes

Yes

Training Required

operator. The only platform that considered such ergonomics is the Amigo system in that the remote controller replicates the use of standard handle of the steerable catheter. Furthermore, most platforms target on EP procedures. Thus far, force sensing and haptic feedbacks are also lost in current systems since miniaturising the force sensors for these catheters is challenging.

Description

Robotic Platforms

A trend for these commercial systems for general endovascular intervention is to integrate third party standard catheters. A recent start-up company, Robocath released their R-one™ robotic assistance platform, allowing robotic manipulation of conventional catheters and guidewires for interventional cardiology. Mechanically driving catheters eliminate hand tremors

of the operator, which potentially improves stability and precision of the catheterization. Remote-controlled system can also significantly reduce the radiation risks of the operator during the procedure. Furthermore, operator comfort is added since he/she can sit at the workstation and does not need to wear the heavy protection suits. As for the limitations of the current commercial robotic platforms, the controlling of the robot in most platforms is based on directional buttons, joysticks or haptic devices. It therefore changes the natural bedside manipulation skills of the

3D navigation

also manipulate the instruments outside the operation room to avoid radiation exposure. The system has been approved by FDA after clinical practices since 2011 (Granada, Delgado et al. 2011).

Yes

Steerable catheter actuated by pull-wire; remotely controlled by buttons and a joystick

Magellan

V

Yes

No

Training Required

No

Steerable catheter actuated by pull-wire; remotely controlled by buttons and a joystick:

Niobe

EP

Yes

No

Training Required

Yes

Steerable catheter actuated by permanent magnetics; joystick/mouse controller; Third party diagnostic/interventional catheters

Amigo

EP

Yes

No

Easy

No

Conventional steerable catheter; Hand-held ergonomic controller replicated natural skills

CorPath 200

V

No

No

Training Required

No

Conventional catheters and guidewire only for percutaneous coronary interventionprocedure; joystick controller

CGCI

EP

Yes

No

Training Required

Yes

Magnetic steerable catheter, joystick controller

Aeon Phocus

EP

Yes

No

Training Required

Yes

Magnetic steerable catheter, joystick controller

Robocath R-one

V

No

NA

Training Required

NA

Conventional catheters and guidewires; joystick controller

Allows manipulation of third party micro catheters

2.3.2. Research Platforms and Future Directions Research Platforms in Robotic Catheterization In parallel to commercial developments, there are also many research platforms that are being developed in academic research institutions. Most groups focus on building compact and light systems while integrating force feedbacks. The System for Endovascular Teleoperated Access (SETA) is a robotic catheterization platform that can manipulate the catheter and the guidewire simultaneously (Srimathveeravalli, Kesavadas et al. 2010). It is constructed by friction drive wheels and a translatable pulley stage that allows translational and rotational movements of the instruments. Force-torque sensors are embedded at the wrist of the robot for proximal force sensing and force feedback to the user is through the master interface. Another characteristic friction drive wheel-based system is the dual-finger robotic hand (DRH) for Percutaneous Coronary Intervention (PCI) (Bian, Xie et al. 2013), it has an active wheel driver paired with an idle driver. The rollers can insert and retract a conventional catheter or guidewire, while twisting the elongated instruments can be achieved by moving the rollers up and down. It is a bioinspired design that replicates the motions of the forefinger and the thumb when naturally manipulating the catheter. Researchers have also proposed linear stepping and clutch-based design for inserting and rotating the catheter (Arai, Fujimura et al. 2002, Guo, Wang et al. 2013). Instead of using roller-based driving mechanisms, the catheter was actuated by rotation and linear translation of the stage, with a secondary stage controlling

the tip deflections (Marcelli, Cercenelli et al. 2008, Fu, Gao et al. 2011, Tavallaei, Gelman et al. 2015). A steerable catheter with Shape Memory Alloy (SMA) actuation has also been presented, with the advantage of producing large and plastic tip bending (Jayender and Patel 2008). Recent developments of those platforms focused on integrating more commercial endovascular instruments, thus facilitating clinical implementation of the robotic system, such as allowing manipulation of conventional catheters and guidewires, as well as Y-connectors for contrast agent injection (Cha, Yoon et al. 2016). In endovascular procedures, there is a general loss of haptic feedback during manipulation. Carefully managed force control can lower the risk of complications in intracardiac procedures and endovascular interventions. Many research platforms embedded distal force sensors at the tip of the catheter that allows force feedback through their haptic interfaces such as Phantom Omni (Sensable Technologies) and Novint Falcon (Novint Technologies) (Guo, Kondo et al. 2007, Wang, Zhang et al. 2010), as well as customised haptic device that utilises natural skills of the operator in catheter manipulation (Payne, Rafii-Tari et al. 2012). Other platforms for catheter manipulation provide force feedback to the operator according to proximal force measurements at the slave side, through a gimbal-based master joystick or an ergonomic catheter handle which replicates conventional manipulations (Park, Choi et al. 2010, Guo, Wang et al. 2013). Another group incorporates force sensors into the friction drive system to allow haptic feedback (Fu, Gao et al. 2011). Shape based analysis of the catheter can also provide tip contact

force and direction estimation through real-time images (Back, Manwell et al. 2015). Kesner and Howe also proposed a new control method based on visual servoing that uses intraoperative US images of the beating heart to regulate the catheter tip forces and compensate fast tissue movements (Kesner and Howe 2011). There are also extensive interests in computer-assisted navigation. These systems typically use electromagnetic sensors at the tip of the steerable catheter to provide semi-autonomous navigation (Ganji, Janabi-Sharifi et al. 2009). Other approaches also incorporate virtual fixtures to construct a virtual environment to regulate catheter motions. These include using real-time 2D images to track distance between the catheter tip and the vessel centreline, hence providing haptic feedback to prevent collision and endothelial damage (Park, Choi et al. 2011, Ghembaza and Amirat 2004). For improved ergonomics, Thakur et al. (Thakur, Bax et al. 2009) proposed a design of recording translational and rotation motions when operator is manipulating a “master” catheter, and then replicates those motions on a “slave” catheter. Customised joysticks with force feedbacks were also proposed by various group (Tanimoto, Arai et al. 2000, Guo, Guo et al. 2015). Another design is to integrate handle of a conventional steerable catheter on the master manipulator for controlling the tip deflection (Tavallaei, Gelman et al. 2015). To reduce the cognitive load of the operator during manipulation, methods based on learning from demonstration for human-robot shared-control have been proposed (Rafii-Tari, Liu et al. 2013).

Table 4. Current commercial robotic platforms for endovascular procedures 28 Devices for Endovascular Interventions

29

Intuitive Human/ robot Interface

3D navigation

MRI Compatible

Description

Figure 10. The compact telerobotic catheter navigation system proposed by (Tavallaei, Gelman et al. 2015) ( ©2015 with permission from John Wiley and Sons)

Force Feedback

As mentioned earlier, most robotic catheterization platforms did not consider the natural manipulation skills of the instruments, and high costs of proprietary instruments limit the wide application of those platforms. Future directions include designing ergonomic master interface that simplifies training, preferably using low-cost conventional instruments while enhancing the stability and precision of catheterization.

Steerable Catheter

imaging can be achieved, especially with the continuing improvement of fluoroscopic imaging devices.

Application: EP or Vascular (V)

Incorporating miniaturised force and motions sensors into small instruments such as catheters and guidewires is practically

difficult. One of the solutions for force sensing is to embed sensors at the proximal site, but the friction between elongated instruments and the sheath may attenuate the forces from the distal site. Vision based forces sensing through catheter shape analysis has been introduced, but problems such as limited image quality and lateral force measurements in torturous anatomy remain to be solved. Most instrument tracking methods can only track the tip positions of the instruments. However, tracking the body of the instruments is also important for peripheral endovascular interventions. Robust tracking of both catheters and guidewires under X-ray

Research Robotic Platforms

Future Research Challenges Currently, navigation of endovascular intervention still relies heavily on 2D X-ray images and static digital subtraction angiography (DSA). 3D anatomy and depth information are lost so operators need to register the live 2D images based on the memory of 3D anatomy. MRI-guided intervention is an emerging topic that can potentially provide dynamic 3D images in endovascular intervention. However, the development of fully MRI compatible robots remains challenging.

Srimathveeravalli et al.

V

No

Yes

Training Required

No

No

Friction drive mechanism, both standard guidewire and catheter manipulation

Guo et al.

V

No

Yes

Easy

No

No

Ergonomic master interface, Linear Stepping driving. Standard catheter

Wang et al.

V

No

Yes

Training Required

Yes

No

Standard catheter, haptic interface

Jayender et al.

V

Yes

Yes

Training Required

No

No

SMA actuated catheter

Fu et al.

V

Yes

Yes

Training Required

Yes

No

Steerable pull-wire catheter with EM sensors, haptic controller

Thakur et al.

V

No

No

Easy

No

No

Standard catheter, master replicating natural motion

Tanimoto et al.

V

No

Yes

Easy

No

No


Payne et al.

V

No

Yes

Easy

No

No


Tavallaei et al.

V

Yes

No

Easy

No

Yes

Standard catheter, master replicating natural motion and catheter handle

Bian et al.

V

No

No

Easy

No

No


Cercenelli et al.

EP

Yes

No

Training required

No

No

Standard steerable EP catheter, joystick controller

Park et al.

EP

Yes

Yes

Easy

No

No

Standard steerable EP catheter, controller replicating catheter handle

Ganji et al.

EP

Yes

Yes

Training required

No

No

Standard steerable EP catheter with EM sensor, haptic controller

Table 5. Current research robotic platform for endovascular procedures


31

2.4. Delivery of Therapies 2.4.1. Endovascular Catheterisation Imager II Angiographic Catheter http://www.bostonscientific.com/en-US/ products/catheters--diagnostic/imager-iiangiographic-catheter.html

Pulmonary arteriovenous embolization (Jones, Rai et al. 2015), catheterisation of intercostal and lumbar arteries (Koruth, Schneider et al. 2015), renal artery pseudoaneurysm treatment (Krajina and Chrobok 2014)

Table 6. Boston Scientific (Marlborough, MA, USA) diagnostic catheters

AngioJet Ultra Coronary Thrombectomy System

http://www.bostonscientific.com/en-US/products/thrombectomy-systems/angiojet-ultracoronary-thrombectomy-system.html large thrombus removal system. According to the manufacturer, this is the only FDA-approved device for use in coronary arteries.

AngioJet Peripheral Thrombectomy System

http://www.bostonscientific.com/en-US/products/thrombectomy-systems/angiojetthrombectomy-system.html

atherosclerotic plaque and the therapy is therefore similar to the management of coronary vessel atherectomy and angioplasty. The purpose of atherectomy in this case is (complete) leg salvage by revascularisation (Golzarian, Sapoval et al. 2010). The authors gave a summary of the endovascular strategies and possible access sites depending on the constricted section of the vessel. This is shown in Table 8. Chronic Total Occlusion (CTO) About 20-40% of the critical limb ischemia and peripheral arterial disease patients suffer from additional chronic total occlusions which obstruct the advancement of catheters in the vessels during endovascular procedures (Maiti, Bir et al. 2016).

Relating to cardiac disease, 15% of all coronary angiography result in a diagnostic of chronic total occlusion (Ramírez Mejía, Méndez Montero et al. 2016). These patients used to be considered only for coronary bypass surgery, but nowadays endovascular revascularisation techniques can be used. It was even showed that successful opening procedures can increase patients’ survival chances in case of future cardiac events (Rosenwasser, Chalouhi et al. 2014). While angioplasty and stenting are viable options for these patients, a new technology combining forward imaging and atherectomy has emerged. Examples of this are the Ocelot, Ocelot PIXL, and Ocelot MVRX catheters (Avinger, Redwood

City, CA, USA), which incorporate optical coherence tomography for real-time crosssectional visualisation of the vessel wall and a spiral tip for protruding through the occlusion. While there is a significant overlap in the technologies used for critical limb ischemia and peripheral arterial disease, chronic total occlusion also requires refined devices that can protrude through the blockage, a step prior to either angioplasty or atherectomy. Alongside the Ocelot catheters stand the Crosser CTO Recanalization Catheter (Bard, Tempe, AZ, USA) and the FRONTRUNNER XP CTO Catheter (Cordis, Bridgewater, NJ, USA). While the FRONTRUNNER deploys a simple pair of hinged jaws to

pharmacomechanical device for peripheral use. active aspiration. 89% limb salvage for acute limb ischemia patients. AngioJet ZelanteDVT Thrombectomy Catheter

http://www.bostonscientific.com/en-US/products/thrombectomy-systems/angiojetzelantedvt-thrombectomy-catheter.html

Vessel section

Strategy

Access

Aortoiliac artery

Self-expandable stent, e.g. Xpert Pro, Absolute Pro and Absolute Pro LL Self-Expanding Stent Systems (Abbott Vascular, Santa Clara, CA, USA)

Common femoral artery

http://www.abbottvascular.com/int/products/peripheral-intervention/ xpert-pro.html & http://www.abbottvascular.com/int/products/ peripheral-intervention/absolute-pro.html

deep vein thrombosis in peripheral veins Table 7. Boston Scientific (Marlborough, MA, USA) thrombectomy systems Mitral Valve

Peripheral Artery Disease and Critical Limb Ischemia As in many other revascularisation application, the endovascular approach has become the first choice for patients suffering from peripheral artery disease, with surgical by-pass only as a backup option (Mandal, Parent et al. 2016). These include: • Percutaneous transluminal angioplasty, with possible stent implantation in order to keep the vessel dilated. The balloons come in different lengths, facilitating quick therapy even for long lesions (Golzarian, Sapoval et al. 2010),


• Subintimal angioplasty, for which a guidewire creates access by piercing the vessel lining to bypass the occlusion and then enter back the true lumen. This procedure is performed for total occlusions of the vessels and can avoid blockages even longer than 15 cm. One example of these devices enhanced with visualising technology is the Pioneer Plus catheter (Volcano, San Diego, CA, USA) which incorporates IVUS for crosssectional imaging of the artery.

• Excimer laser-assisted angioplasty.

• Simple nitinol, covered, drug-eluting, and bioabsorbable stents.

Untreated peripheral artery disease and advanced thickening of the vessel wall lining can lead to critical limb ischemia, which shows as rest pain, ulcers, and even gangrene. The constriction is caused by

• Cryoplasty, during which the vessel walls are frozen in the vessel’s expanded state.

Several state-of-the-art endovascular atherectomy devices are presented in Table 8. Many of them have slightly adapted versions for coronary vessel plaque removal, a very similar procedure to the endovascular therapy for peripheral artery disease.

MitraClip

http://www.abbottvascular.com/int/products/peripheral-intervention/ omnilink-elite.html

• Excisional atherectomy. • Cutting balloon angioplasty.

Balloon-expandable stent, e.g. Omnilink Elite Peripheral Stent System (Abbott Vascular, Santa Clara, CA, USA)


Femoropopliteal artery

Covered stent

Upper brachial/radial extremity

Angioplasty


Atherectomy


Atherectomy


Self-expandable stent


Table 8. Endovascular strategies for treating critical limb ischemia (Golzarian, Sapoval et al. 2010)

33

http://emea.cordis.com/emea/endovascular/lower-extremity-solutions/access/diagnosticcatheters/tempo-aqua-hydrophilic-coated-angiographic-catheter.html

tactile and torque control due to braided shaft. However, the distal tip is non-braided and boasts increase flexibility. This prevents damage by piercing the vessel wall. tungsten-filled tip tracking for less use of contrast agent. http://emea.cordis.com/emea/endovascular/lower-extremity-solutions/access/diagnosticcatheters/tempo-angiographic-catheter.html braided nylon body tungsten-filled tip for easier tracking

NYLEX Angiographic Catheter

comes in one piece, for better stability and rigidity in the high flow rate environments

SUPERTORQUE Angiographic Catheter

Chronic Total Occlusion (CTO) System & CrossBoss CTO crossing catheter

http://emea.cordis.com/emea/endovascular/lower-extremity-solutions/access/diagnosticcatheters/supertorque-angiographic-catheter.html braided polyurethane body

non-braided pig-tail tip with side holes for flushing. braided body. Table 9. Examples of Cordis (Bridgewater, NJ, USA) diagnostic catheters used with CTO recanalization systems.


Orbital atherectomy

http://emea.cordis.com/emea/endovascular/lower-extremity-solutions/access/diagnosticcatheters/supertorque-mb-angiographic-catheter.html

Peripheral arterial disease

Angulated tip for carving plaque as the device advances. The angle is adjustable. Debris is collected in a cone at the catheter tip (Dominguez, Bahadorani et al. 2015). Disadvantage: distal embolization 7.3% (Akkus, Abdulbaki et al. 2015) calls for additional embolic protection device.

Atherectomy catheter

Crossing catheter to act as guidewire

http://www.bostonscientific.com/en-US/ products/cto-systems/coronary-chronictotal-occlusion-system.html

http://www.bostonscientific.com/en-US/ products/cto-systems/crossboss-ctocatheter.html

Chronic total occlusion, re-entry in the true lumen

Atherectomy catheter

Crossing catheter to act as guidewire

http://www.bostonscientific.com/enUS/products/cto-systems/stingray-ctoballoon-catheter-and-guidewire.html

http://www.bostonscientific.com/en-US/ products/cto-systems/offroad-reentrycatheter.html

Rotablator (Boston Scientific, Marlborough, MA, USA)

Calcified coronaries, prepare calcified regions for stenting

Disadvantages: myocardial infarction 9.7%, due to plaque pieces in the blood stream.

TruePath (Boston Scientific, Marlborough, MA, USA)

Chronic total occlusion

http://www.bostonscientific.com/en-US/products/cto-systems/truepath-cto-device. html

Jetstream (Boston Scientific, Marlborough, MA, USA)


Only device to include continuous active aspiration.

CVX-300 Excimer Laser and Turbo-Power/ Elite/Tandem (Spectranetics, Colorado Springs, CO, USA)

Coronary and peripheral arterial disease

CDiamondback 360 (CSI360, St. Paul, MN, USA)


(Boston Scientific, Marlborough, MA, USA)

able to withstand high flow rates

SUPERTORQUE MB Angiographic Catheter

Device description

Chronic total occlusion

Stingray LP & OffRoad re-entry catheter systems

http://emea.cordis.com/emea/endovascular/lower-extremity-solutions/access/diagnosticcatheters/nylex-angiographic-catheter.html non-braided nylon body for high flow rates.

Application

http://www.ev3.net/peripheral/us/plaque-excision

(Boston Scientific, Marlborough, MA, USA)

hydrophilic coating for easy navigation in the vessel wall, between the lining and the true lumen.

TEMPO Angiographic Catheter

SilverHawk and TurboHawk (ev3, Plymouth, MN, USA

Directional atherectomy

(Maiti, Bir et al. 2016) concluded their review of endovascular treatments for limb ischemia by suggesting future trials to test the superiority of atherectomy compared to the less-embolic stenting. In the same review, it was reported that brachytherapy (gamma radiation) has been used to suppress the cell proliferation in the vessel wall, but more research and comparison with the gold standard is needed to validate the therapy. Finally, cryoplasty of the abnormally growing tissue has been under investigation, but the results have been inconsistent and more in-depth research is needed.

Method Devices

Rotational atherectomy (Rotoablation)

TEMPO AQUA Catheter

Rotoablation is actually a mechanical removal of arterial calcium and cholesterol plaque with a drilling catheter inserted via the endovascular route. The most affected vessels are coronary arteries and veins, but the technique is also used for treating peripheral arterial disease (Akkus, Abdulbaki et al. 2015). Atherectomy, as the more general term for this procedure, involves shaving or vaporising plaque. (Akkus, Abdulbaki et al. 2015) gave a review

of the available and approved atherectomy technologies in 2015, which are summarised in Table 10.

Best revarscularisation rates compared to the other methods (Akkus et al.)

Some of the diagnostic catheters used in conjunction with the CTO recanalization systems are enumerated in Table 9. The chosen examples are manufactured by Cordis (http://emea.cordis.com/emea/ endovascular/lower-extremity-solutions/ access/diagnostic-catheters.html).

Rotoablation and Atherectomy Mechanically similar to thrombectomy but used for a different application is the so-called rotoablation or rotational atherectomy. While it does not involve energy delivery per se, as in the case of RF or laser ablation, it does cause destruction of unwanted tissue.

Laser atherectomy

cut through the occlusion, the Crosser CTO is actuated with AC current which brings piezoelectric crystals in the catheter tip to high-frequency mechanical vibrations, thus breaking through the blockage. The catheters usually require additional diagnostic catheters. This is a safety measure which stemmed from early experience and failure with the non-surgical treatment of chronic total occlusions in both peripheral and coronary vessels (Rosenwasser, Chalouhi et al. 2014, Molvar and Lewandowski 2015).

http://www.bostonscientific.com/en-US/products/plaque-modification/rotablatorrotational-atherectomy-system.html

Disadvantage: high embolisation rate, need for additional embolisation protection. ttp://www.bostonscientific.com/en-US/products/atherectomy-systems/jetstreamh atherectomy-system.html Fibre-optic catheters to vaporise the plaque. High revascularisation rate with small distal embolization risk, comparable to angioplasty. http://www.spectranetics.com/solutions/ The technology can also be used in chronic total occlusion, where it has the advantage that no guidewire is needed to pass through the blockage before the therapy can be delivered (Lumsden, Davies et al. 2009). Increased diameter of the ablated lumen with orbital rotation speed thanks to the eccentric arrangement of the cutting crown (Dominguez, Bahadorani et al. 2015). Disadvantage: risk of cutting through the vascular wall (dissection) 11.3% http://csi360.com/products/diamondback-360-peripheral-orbital-atherectomy-system/

Table 10. Atherectomy devices in clinical use

35

Balloon Angioplasty This is a non-corrosive alternative to atherectomy. It does not involve carving, cutting, or ablating through plaque, but rather widening the vessel with a waterinflated balloon. In order to keep the vessel expanded, a metallic stent is sometimes implanted. According to (Mauffrey, Cuellar III et al. 2014, Maiti, Bir et al. 2016), the 5-year limb salvage rate can be as high as

NC TREK Coronary Dilation Catheter

Abbott Vascular (Santa Clara, CA, USA)

for the traditional surgical revascularisation, i.e., 89%. While atherectomy remains a niche therapy, possibly due to its less investigated safety, balloon angioplasty and stenting are the methods of choice for most patients with peripheral artery disease (Marcus, Payne et al. 2016). While some of the angioplasty and atherectomy devices for peripheral

artery disease have been discussed in the previous section, we will now give examples of balloon angioplasty systems for coronary occlusion, without excluding their adaptability and application to the peripheral vessels. Some available designs for peripheral artery disease are included.

http://www.abbottvascular.com/int/products/coronary-intervention/nc-trek. html?augd80fucqml6snstt9

flexible tip with tungsten markers for tracking. controlled force and pressure for predictable inflation.

Threader MicroDilatation Catheter

Boston Scientific (Marlborough, MA, USA)

http://www.bostonscientific.com/en-US/products/dilatation/threader-micro-dilatationcatheter.html

Despite being a better option than surgery, angioplasty can have certain risks. These include embolization, where the displaced plaque enters the blood stream, vessel rupture due to over-inflating of the balloon, access site inflammation, and radiation exposure. While there used to be concern over re-stenosis and reversibility of angioplasty in its early years (Gralnek 2014), it seems that more consistent studies have overruled this assumption. An alternative to the common inflating balloon angioplasty is the cutting balloon angioplasty. While this is a more invasive procedure, it mediates the risk of restenosis and vessel expansion (Marcus, Payne et al. 2016). It is also suggested that this is a technology superior to atherectomy and rotoablation thanks to the soft balloon which supports the microblades and thus allows for

a more controlled remodelling of the lumen. It was concluded from pre- and postoperative imaging that cutting balloon angioplasty achieved its success by acting on the plaque itself and not on the vessel wall, as with inflating balloon angioplasty (Maiti, Bir et al. 2016). Two manufacturers currently offer cutting balloon catheters: Boston Scientific (Marlborough, MA, USA) with their Flextome Cutting Balloon Dilatation Device (Scientific 2017) and the Spectranetics (Colorado Springs, CO, USA) AngioSculpt PTA Scoring Balloon Catheter (Spectranetics 2017). In addition to angioplasty for revascularisation of limbs and heart, new devices have emerged for other nontraditional uses. The technology in inflating or cutting balloon angioplasty has been used for revascularisation and re-opening of other vessels, such as the ones involved

in dialysis. Boston Scientific has been commercialising one of these devices, the Peripheral Cutting Balloon, a Microsurgical Dilatation Device for Haemodialysis Access Management (Boston Scientific 2017), but BARD Peripheral Vascular (Tempe, AZ, USA) have a whole range of endovascular drug delivery products. Despite positive experience with cutting balloon angioplasty, there used to be some concern about the size of the bladed balloons and the devices causing pressure and vessel perforations (Mauffrey, Cuellar III et al. 2014). While these might have been issues in the early days of this technology, newer generation cutting balloons, such as the ones previously listed, have systems for controlling inside pressure and balloon inflation sizes and thus avoiding injuries.

strength and power to dilate small and tight lesions. dilation of stenotic coronary vessels. guidewire support for resistance against kinking.

ATLAS GOLD PTA Dilatation Catheters

BARD Peripheral Vascular (Tempe, AZ, USA)

http://www.bardpv.com/?portfolio=atlasgold BARD Peripheral Vascular claim this catheter to be the most non-compliant large diameter balloon on the market. better fit of the balloon in the vessel, thus minimising the lumen straightening which occurs if a too long balloon is used. large diameter vessels.

Table 11. Examples of balloon angioplasty systems currently available

Figure 11. Balloon angiography – here the balloon is inflated with a stent. (By BruceBlaus - Own work, CC BY-SA 4.0 (22 February 2016)


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Concrete evidence of improving outcomes is the major hurdle for translating new technologies to clinical use. To demonstrate the effectiveness of new technologies, extensive clinical studies need to be conducted with due consideration of efficacy, cost-effectiveness and user acceptance.

2.4.2. Delivery of Cardiac Devices TAVI The key to a successful TAVI procedure is accurate placement of the replacement valve. This in turn can be achieved with precise tracking of the end effector, whether it is an instrument that grasps and saws a chord onto a mitral valve leaflet, an expandable stent for valve replacement, or an ablation catheter. In mitral valve replacement, a difference was noted between the navigation and the positioning phase. Navigating safely to the target is clearly important. If the navigation takes too long or is impaired, the procedure itself on the target cannot take place. The technology for each of the navigation and positioning phases should be treated differently. While accurate positioning is important down to the submillimetre range, the guidance, i.e., preoperative and intraoperative image registration, for the navigation step itself does not need to be this accurate. As a matter of fact, since online registration is a computationally expensive process, the continuous update of a very accurate registration algorithm could cause longer navigation times. The challenges enumerated in this section are shared by all major procedures: TAVI, AAA or other stent placement interventions. These include migration, kinking or fracture of stents. One of the main reasons of the intraprocedural damage is the lack of personalised implants, i.e., of patient-specific grafts, but more importantly of implants suitable for each part of the anatomy. The kinking

of stents during implantation has already been addressed by medical companies in their newest products. Bolton Medical (change to Sunrise, FL, USA) has introduced a braided layer in the outer sheath of their delivery system in order to prevent the destruction of the stent-graft during insertion (Bolton Medical 2017).

2.4.3. Energy Delivery It is estimated that a new range of endovascular platforms will emerge in the near future, enabling the delivery of drugs in situ in order to accelerate arterial wall healing. The safety of ablation catheters need to be proven in order to be accepted as means of energy delivery. The reasons are the dangers of energy delivery itself, but also of contact with dynamic soft tissue under minimal visualisation. The intraprocedural guidance is provided by limited fluoroscopy sequences, lowresolution ultrasound, and sometimes by more expensive electroanatomical mapping systems and auxiliary electromagnetic sensors attached at the tip of the catheter. The state-of-the-art tools all try to address these navigation and safety issues. For cardiac ablation, the purpose is transmural scar to block abnormal conduction; in chronic vein insufficiency, this is complete vessel sealing, while for cancer treatment it is full destruction of tumour. The American Foundation for Women's Health and StopAfib provided a review of the types of (StopAfib 2017) catheter in use for cardiac ablation. They are summarised in Table 12.

done to correlate tissue parameters for monitoring the effect of each energy impulse. The question concerns both aspects of the energy delivery – efficiency (was it enough to change the substrate?) and safety (was it enough not to create damage to neighbouring tissue?). This can potentially open new research in the field of online tissue characterisation, but so far there has been only limited progress on enabling real-time intraoperative use of this method. One of the means employed so far is the measurement of contact force, which is correlated to the result of the ablation. While its amplitude or direction relative to the cardiac wall are not visualised per se intraoperatively, state-of-the-art electroanatomical mapping systems such as CARTO (Biosense Webster, Diamond Bar, CA, USA) or RHYTHMIA (Boston Scientific, Marlborough, MA, USA) display the raw information from the catheter tip. Table 12 shows some example catheters for therapeutics, ultrasound, ablation and intraoperative electroanatomical guidance. It has been suggested that a viable alternative to the real lesion depth measurement is the combined monitoring of tissue temperature, catheter tip contact force and cooling. For tachycardia interruption procedures or pulmonary vein isolation, intraoperative imaging showing the continuity of the lesion line should be added.

Catheter type

Description

Therapeutic catheter

NAVISTAR DS

Ultrasound catheter

SOUNDSTAR

Enhance lesion formation monitoring and safety in atrial fibrillation and ventricular tachycardia procedures by combining intracardiac echo and electroanatomical mapping for better anatomy visualisation.

Diagnostic catheter

Dynamic Tip Diagnostic Catheter

Very steerable tip with a handle-controlled lock mechanism.

LASSO

Reference location information in atria.

Diagnostic catheter

Multiple electrode catheter with deflectable tip. Temperature measurement at two different sites, and thus less error also in approximation of lesion formation.

placement in the coronary sinus.

Deflectable catheter with electrode pairs equally spaced along the curvature.

Ablation catheter

Chilli II Cooled Ablation Catheter

Patented Closed-loop Cooling System so that no fluid enters the bloodstream. This also reduces the risk of air emboli and cools the catheter regardless of tissue contact angle. Catheter cooling prevents coagulum formation and enables the use of higher RF power. 25,000 cases in the US.

Mapping catheter

Constellation Full Contact Mapping Catheter

focal arrhythmia mapping in real time. whole electroanatomical map in one heartbeat from 64 electrodes. pacing capabilities. super-elastic alloy as material for a spline-shaped catheter. basket conforms to atrial anatomy

In the application of cardiac ablation, a considerable amount of work has been Table 12: Examples of catheters produced by Biosense Webster (Diamond Bar, CA, USA)


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Catheter type

Description

Single point RF catheters

Only the catheter tip can deliver energy and ablation can only be performed in a pointby-point fashion, keeping each ablation point close to the previous in order to produce a continuous lesion. The single-point technology allows only for unipolar energy delivery.

Multielectrode RF catheters

The catheter has several electrodes with energy delivery capabilities. The catheters can work in bipolar mode, reducing thermal injuries to adjacent tissue. However, there is little clinical experience with these catheters.

RF catheters with contact force sensing

There is a force sensor integrated in the catheter tip to assess contact force and quality of lesion formation.

Balloon catheters

Laser and cryoablation balloon catheters, used most often for atrial fibrillation treatment by pulmonary vein isolation. The catheter is advanced into the left atrium and the balloon at the tip is inflated. The energy delivery from the balloon to the pulmonary vein ostia occurs at the same time and continuous along the whole contact perimeter.

Table 13. Catheter types used in cardiac ablation procedures (StopAfib 2017)

Figure 12: Left: visually guided laser balloon. The white spot is the aiming and ablation spot. Right: endoscopic view from the balloon in the left superior pulmonary vein. The arrow points out the ablation spot (Dukkipati, Cuoco et al. 2015).

Arctic Front Advance CryoAblation Catheter

EvenCool Technology for better coolant delivery 2-3 applications per vein to isolate

Merchant et al (Merchant, Levy et al. 2016) completed a review on the usefulness of the myriad of available ablation catheters to conclude that the tools’ application is dependent on the patient-specific anatomy. They analysed the case of circular catheters in pulmonary vein isolation, showing that the one-size-fits-all circular catheter couldn’t be used in more than 10% of their patients. More recently, visually guided laser balloons have been proposed to replace ablation catheters in pulmonary vein isolation (Dukkipati, Cuoco et al. 2015) (Figure 13). The aim of this technology is to create a continuous isolation line around the pulmonary veins, which is currently imperfect when created point-by-point with RF ablation catheters. First results from the study were that the two techniques are equivalent. However, the operators had not had previous experience with the visually guided laser balloon. This raises hopes for even better results in the future. It was reported that patients remained free of atrial fibrillation in 90% of the cases compared to 20% using point-by-point RF ablation, according to follow-up at three months (Segal 2017).

The balloon technology has the advantage that it does not necessitate extensive anatomical mapping. Once the pulmonary vein ostium is located, the inflated balloon will adhere to each side forming a complete circle. The ablation result is also less prone to cardiorespiratory motion. The technology offers benefits only in atrial fibrillation treatment through pulmonary vein isolation. It does not offer any advantages in linear or local ablations such as for atrial and ventricular tachycardia. Table 13 shows a range of products working with the EvenCool Technology of Medtronic (Minneapolis, MN, USA) designed to work together as a CryoAblation system. Table 15 illustrates some of the example ablation devices for other arrhythmias, including RF and cryoablation catheters, diagnostic catheters, and sheaths used for insertion and stabilisation of these catheters (http://www.medtronic.com/ us-en/healthcare-professionals/products/ cardiac-rhythm/ablation-arrhythmias.html).

Complications: stenosis can occur if balloon is inflated in the vein instead of the atrium and then advanced to the pulmonary vein ostia http://www.medtronic.com/us-en/healthcare-professionals/products/cardiac-rhythm/ ablation-atrial-fibrillation/arctic-front.html Achieve Mapping Catheter Catheter

8 electrodes on a circular loop, similar to Biosense Webster’s Lasso catheter. http://www.medtronic.com/us-en/healthcare-professionals/products/cardiac-rhythm/ ablation-atrial-fibrillation/achieve.html

Freezor MAX Cardiac CryoAblation Catheter Used in conjunction with Arctic Front Advance CryoAblation Catheter, to complete possible gaps in the encirclement of the pulmonary veins. It can therefore be used in focal and linear ablations as well. http://www.medtronic.com/us-en/healthcare-professionals/products/cardiac-rhythm/ ablation-atrial-fibrillation/freezormax.html Table 14. The Medtronic (Minneapolis, MN, USA) Cardiac CryoAblation system, for atrial fibrillation treatment, i.e., pulmonary vein isolation

Ablation catheter

4/5 mm RF Conductr (Multi-Curve) Series Ablation Catheters

http://www.medtronic.com/us-en/healthcare-professionals/ products/cardiac-rhythm/ablation-arrhythmias.html Bi-directional steering Variable curve-sizes with one catheter

Cryoablation catheter

Freezor Cardiac CryoAblation Catheter

Focal ablation of reentrant tachycardias occurring at the atrioventricular node. Mapping mode also available with the same catheter in order to test the potential ablation site. The reversibility of short-term cryoablation is used here to allow the recovery of the AV node in case of accidental ablation (http:// www.eplabdigest.com/articles/Mechanisms-and-ApplicationCardiac-Cryoablation). This would not be possible in the other thermal procedures, where the heat effect is irreversible.

Figure 15. Examples of ablation and cryoablation catheters by Medtronic (Minneapolis, MN, USA)


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alternative, although not suitable for any anatomy, are drug-eluting stents. These are easiest ways for implanting in large enough vessels, which are less prone to bending or kinking. Abbott Vascular (Santa Clara, CA, USA) has a range of drug-eluting stents as listed in Table 17. While most of them are for coronary disease, there are also solutions for peripheral use available.

2.4.4. Chemicals Delivery Apart from vessel expansion, another application of inflating balloons, which actually required an extension and additional development, is drug delivery. While the inflation or cutting produces a physical effect on the vessel at macroscale, modern technology addresses and targets tissue at smaller scale, by chemical treatment, cell, or gene infusion. Boston Scientific and BART Peripheral Vascular (Tempe, AZ, USA) already produce balloons catheter for targeted drug delivery (Table 16).

In a review of endovascular intervention for various types of peripheral artery disease, Thukkani and Kinlay (Marcus, Payne et al. 2016) concluded that total occlusions, critical limb ischemia and other peripheral artery lesions can be treated more successfully with drug-eluting stents, even in high risk patients, such as those suffering from diabetes mellitus. Comparing results at 6 months in patients

Endovascular drug therapy by coated inflating balloon provides only short-term delivery, which may not be sufficient to treat the target region. A longer-term

Boston Scientific (Marlborough, MA, USA)

Quantum Maverick Balloon Catheters

BART Peripheral Vascular (Tempe, AZ, USA)

LUTONIX 035 Drug Coated Balloon PTA Catheter

with bare-metal stents, it was discovered that the drug-eluting devices reduced the restenosis rate from 55% to 4% (Molvar and Lewandowski 2015). These figures were similar in peripheral and coronary artery disease. The closely related drug-coated balloons, while having the disadvantage of temporary treatment and vessel occlusion, can potentially extend the range of anatomy for which drug-eluting technologies can work. While stents are prone to thrombosis and fracture, the balloon can advance higher, beyond the knee which currently limits the height of stent implantation (Marcus, Payne et al. 2016).

2.4.5. Endovascular Gene and Cell Therapy

impact of the study was a spur for future work into making gene therapy more efficient.

One of the most recent research directions is therapy at small scale, i.e., cell and gene therapy. There is a myriad of publication on possible applications and preliminary results. Some of the endovascular approaches emerged in recent years are highlighted here.

Gene therapy and cell transplantation were also thought to be an alternative for patients who cannot be considered for standard revascularisation procedures in peripheral arterial disease (Crawford, Sanford et al. 2016). The authors reviewed some of the delivery catheters, most of them modified balloons similar to the ones for chemicals delivery. They classified them into passive diffusion catheters, pressuredriven balloon catheters, and mechanicallyassisted injection catheters. Furthermore, they described angiogenesis, i.e., artificial growth of endothelial cells for vessel wall lining, which are to be implanted endovascularly after development.

Early work was conducted by (Sensuron 2016) and studied the enhancement of gene delivery to the arterial wall by ultrasound impulses. The clinical background was given by the high restenosis rate after angioplasty. Gene therapy was believed to be able to heal the vessel wall before restenosis initiated. The

Similarly to the peripheral arterial disease, gene therapy found application in endovascular treatment of intracranial aneurysms (Georgiadis, van Herwaarden et al. 2016). The purpose was the development of natural occlusion of aneurysms, in order to avoid surgical clipping or mitigate incomplete coil embolisation. One more promising application in recent years was gene therapy for the brainaffecting Hurler disease (Briganti, Leone et al. 2015). The genes would be delivered endovascularly or intraventricularly, much like in intra-arterial chemotherapy for brain tumours. While the delivery route did not seem to pose a problem, the issue was the consensus about which genes would be the most effective.

http://www.bostonscientific.com/en-US/products/catheters--balloon/quantum-maverickballoon-catheters.html Drug-eluting balloon for interventional cardiology http://www.bardpv.com/?portfolio=lutonix-035 Drug-coated balloon catheter for prevention of arterial restenosis, with delivery in a single inflation

Table 16. Balloon catheters for targeted drug delivery

XIENCE Alpine Everolimus Eluting Coronary Stent System

http://www.abbottvascular.com/int/products/coronary-intervention/xience-alpine.html

XIENCE Xpedition Everolimus Eluting Coronary Stent System

http://www.abbottvascular.com/int/products/coronary-intervention/xience-xpedition.html

Stent is placed by balloon inflation.

According to the company, it achieves low thrombosis rate. The results are based on 18 million implants to date. Flexibility for tortuous anatomy.

XIENCE PRIME Everolimus Eluting Coronary Stent System

http://www.abbottvascular.com/int/products/coronary-intervention/xience-prime.html

XIENCE V Everolimus Eluting Coronary Stent System

http://www.abbottvascular.com/int/products/coronary-intervention/xience-v.html

XIENCE Prime BTK Everolimus Eluting Peripheral Stent System

http://www.abbottvascular.com/int/products/peripheral-intervention/xience-prime-btk.html

9 million stents implanted worldwide

Metallic stent with controlled drug release.

BTK stands for below-the-knee. This confirms the previous statements that drug-eluting stents are preferentially implanted in regions not prone to kinking. Primary stenting of focal lesions with controlled drug release. 98.7% limb salvage at 1 year.

Table 17. Abbott Vascular (Santa Clara, CA, USA) drug eluting stents


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3. Translational Challenges and Considerations Concrete evidence of improving outcomes is the major hurdle for translating new technologies to clinical use. A recent study has examined the regulatory clearance and/or approval of new medical devices (Marcus et al. 2016). While not solely focused on endovascular devices, their cross-sectional study showed in decreasing order of likelihood for a device to obtain regulatory approval if it was 1) developed by industry alone, 2) developed jointly by industry and academia, and 3) developed by academia alone. However, the results were not statistically significant and there was no clear explanation as to why this was the case. The authors suggest that industrial interests are the main drivers for regulatory approval for specific devices. It may highlight the need for greater collaboration between academia and industry to ensure the clinical applicability and translation of medical devices developed. This has also led to the observation that most medical device innovations are currently driven by industry. During the development of new medical devices, effective communication between the technical and clinical parties is essential. The key is not for engineers just to ask what clinicians would like


but what is required at each stage of the operation. While clinicians may initially have certain ideas about what the device should look like and what it should do, technical barriers can prevent an exact implementation. Continuous clinical input and feedback is essential during this developmental process. Another major challenge is the testing of new devices in patients. In addition to stringent regulatory requirements for in vivo testing, it can be difficult to find clinicians who are supportive of testing new technologies in patients particularly for engineering prototypes; this may be circumvented by including clinicians from the very beginning of product development. While testing may start on phantoms or animals, patient evidence is critical for any device to achieve clinical uptake. To demonstrate the effectiveness of new technologies, extensive research and clinical studies have to be conducted with due consideration of ethics, data privacy, ergonomics and user acceptance. More importantly, they also need to consider cost-effectiveness and evidence of improving outcomes and competition by different solutions. Typical clinical studies may take years to perform and the

outcome of improvement may not always be clear. As such, the cost of studies often discourages many commercial companies from investing in healthcare technologies, but to focus only on fast growing consumer markets. Coupled with the complex procurement processes, adopting new technologies in clinical practice is often challenging. There are however a number of organisations in the UK that provide support to companies developing medical technologies and conducting healthcare research that can provide support across this pathway. Translational Support from NIHR - The access to larger patient cohorts is a clear benefit of multi-centre collaborations for clinical trials and for assessing the efficacy of new devices for endovascular interventions. The NIHR has thus far established a number of Healthcare Technology Co-operatives (HTCs) with different clinical focuses (https://www. nihr.ac.uk). These centres of expertise work closely with industry and act as a catalyst for NHS 'pull' for the development of new medical device concepts, healthcare technologies and technologydependent interventions. A primary focus is on clinical areas of high morbidity and have high potential to improve treatments

and quality of life for NHS patients, as well as the effectiveness of healthcare services that support them. The HTCs work closely with patient groups, charities, industry and academics. Closely related to endovascular intervention is the NIHR Cardiovascular HTC (http://www. guysandstthomasbrc.nihr.ac.uk/nihr-htc/), which is tasked to identify, encourage and facilitate the development of new medical devices and technology driven solutions that will improve the diagnosis, treatment and well-being of patients with cardiovascular disease. To coincide with the publication of the Life Science Industrial Strategy of the UK government, NIHR has recently announced 11 Medtech and In Vitro Diagnostic Co-operatives (MICs, https://www.nihr.ac.uk/fundingand-support/funding-to-provide-nihrfacilities/medtech-and-in-vitro-diagnosticco-operatives.htm). These NIHR MICs are to build expertise and capacity in the NHS to develop new medical technologies and provide evidence on commerciallysupplied in vitro diagnostic test and to bring together patients, clinicians, researchers, commissioners and industry. These NIHR MICs will replace the existing NIHR HTCs as well as the NIHR Diagnostic Evidence Co-operatives by incorporating and retaining their remits.

Adoption and NHS procurement - The NHS in the UK is the “largest single healthcare delivery organisation in the world” (NHS National Innovation Centre 2012). Medical devices may be procured at national, regional and local levels, usually depending on the value, size and complexity requirements of a device and the NHS will consider the clinical and cost effectiveness of medical devices before they will be procured. From a medtech industry perspective, the NHS represents a major opportunity for medical devices, but in the same time a significant challenge in navigating the system’s structures and requirements. The Accelerated Access Review, which aims to speed up access to innovative drugs, technologies and diagnostics for NHS patients included the publication of an innovation pathway covering the entire development lifecycle from product idea to adoption and uptake by the NHS, which is a useful aid for those navigating the pathway and includes details of a number of key organisations, including the NIHR, which can provide support along this pathway. It has been noted that less attention is often given to ‘how-to’ compared with ‘principles’ knowledge at the early stages of the product development process and that this has contributed to incomplete

implementations or discontinuations after initial adoption (Kyratsis, Ahmad et al. 2012). Organisations such as Academic Health Science Networks (AHSNs) and the NIHR, can help to bridge the gap between developers and the NHS to enable due consideration of how product functionality aligns with clinical needs and care pathway considerations. Clinical evaluation and CE marking of medical devices - In the case of devices to be placed on the market in Europe, manufacturers need to determine whether their product is a ‘medical device’ as defined by the Commission Directives [https://ec.europa.eu/growth/sectors/ medical-devices/regulatory-framework_ en]. Products falling within the scope of these directives, will need to demonstrate compliance with the applicable essential requirements as part of the CE-marking process before they can be placed on the market. As part of the process of ‘clinical evaluation’ required by the Directives, that is the assessment of clinical data relating to the device to demonstrate its safety and performance, a specific clinical study or ‘clinical investigation’ may be required. Where this is the case, manufacturers must notify the relevant competent authority in advance. For studies taking

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place in the UK, this will be the MHRA (https://www.gov.uk/guidance/notifymhra-about-a-clinical-investigation-fora-medical-device). Further guidance is available at https://www.gov.uk/ topic/medicines-medical-devices-blood/ medical-devices-regulation-safety. For novel products particularly those that that challenge the current regulatory framework, the MHRA Innovation Office, provides a single point of access to free expert regulatory advice and guidance which is available to all types and sizes of organisation. It is worth noting that what clinical trials cannot answer either is what the true clinical durability of the tested devices are; they are designed to test safety but provide no long-term clinical proof of usefulness. With many vascular regions undergoing great movement or high blood flow, the mechanical longterm stability of the devices implanted are unknown. By the time such knowledge is available, it is likely that the devices are supplanted by newer iterations. Such a flood of devices prevents the establishment of a standardised procedure and corresponding standardised devices. Approval and set-up of research in the NHS - For manufacturers wishing to conduct device related research in the


NHS in England, including both clinical investigations for CE-marking purposes as well as other clinical research studies of devices, they will need to apply for Health Research Authority (HRA) Approval before they can begin. The HRA is one of a number of organisations that work together in the UK to regulate and approve different aspects of health and social care research. HRA Approval brings together an assessment of governance and legal compliance, with the independent REC opinion provided through the UK Health Departments’ Research Ethics Service and replaces the need for local checks of legal compliance and related matters by each participating organisation in England. Participating NHS organisations now focus their resources on assessing, arranging and confirming their capacity and capability to deliver the study. Through its Study Support Service, the NIHR CRN can help researchers and the life sciences industry to plan, set up and deliver high quality research in the NHS in England, this includes early feasibility advice and help to identify appropriate study sites as well as provide support with performance oversight to support successful delivery of the study to its recruitment targets.

Data ownership and privacy - In the fastgrowing data driven wearables sector there are important considerations for supporting the appropriate sharing of information whilst ensuring personal data is adequately protected. With reform of the EU’s data protection framework underway, including the introduction of the new General Data Protection Regulation (Regulation (EU) 2016/679) in 2016 which will apply from May 2018, device manufacturers will need to give due consideration to the principles of data protection by design and by default throughout the product development lifecycle. In addition, the recent publication of the proposal for a Regulation on Privacy and Electronic Communications, intended to update and replace the existing Directive (2002/58/ EC), means that manufacturers need to stay up-to-date with developments in this area. Whilst some data sharing between patients and healthcare workers is already in place, it is likely this will grow further. Therefore, there are important considerations for the future on the development of such data sharing, and access to clear guidance and standards, particularly for supporting small and medium enterprises, will be key.

Environmental concerns – With increasing awareness of the environmental impacts from electronics and devices, new products and devices have to adopt an eco-design approach. From electronic components, circuit design, package design, and materials, to manufacturing processes, transportation, recycling, and product end-of-life, ‘green’ approaches can be implemented across the whole product cycle. There are life-cycle assessment (LCA) tools, which support the design and production of ‘green electronics’ (Griese, Schischke et al. 2003, Mueller, Griese et al. 2004, Stevels 2007) and further advice on environmental management systems is available from the Institute of Environmental Management and Assessment. Although very few regulations apply for using only ‘green’ approaches, (e.g. RoHS Directive 2002/95/EC and WEEE Directive 2002/96/EC, REACH No. 1907/2006) any changes to requirements in this area could have significant impacts on the cost of production and manufacturing processes.

Following an open competition, leading NHS organisations have been awarded funding to host NIHR Medtech and In vitro diagnostic Co-operatives (MICs). • NIHR London In Vitro Diagnostics Co-operative (NIHR London IVD Co-operative) • NIHR Leeds In Vitro Diagnostics Co-operative (NIHR Leeds IVD Co-operative) • NIHR Newcastle In Vitro Diagnostics Co-operative (NIHR Newcastle IVD Co-operative) • NIHR Surgical MedTech Co-operative • NIHR Brain Injury MedTech Co-operative • NIHR Cardiovascular MedTech Co-operative • NIHR Devices for Dignity MedTech Co-operative (NIHR D4D MedTech Co-operative) • NIHR Mental Health MedTech Co-operative (NIHR MindTech MedTech Co-operative) • NIHR Trauma Management MedTech Co-operative (NIHR Trauma MedTech Co-operative) • NIHR Children and Young People MedTech Co-operative (NIHR CYP MedTech Co-operative) • NIHR Community Healthcare MedTech and In Vitro Diagnostics Co-operative (NIHR Community Healthcare MedTech and IVD Co-operative) The NIHR MICs will build expertise and capacity in the NHS to develop new medical technologies and provide evidence on commercially-supplied in vitro diagnostic (IVD) tests. Funding is provided over five years for leading NHS organisations to act as centres of expertise; bringing together patients, clinicians, researchers, commissioners and industry.

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4. Recommendations and Conclusions Endovascular intervention is playing an increasingly important role clinically, not only for treating cardiovascular diseases, but also for oncological interventions. Innovative device design, integrated with sensing and therapeutic delivery would encourage further clinical uptake of the technologies. This report assesses the current state-of-the-art in endovascular devices and emerging technologies for addressing some of the unmet clinical needs. With the range of new devices being developed, it is important to direct more funding to systematic clinical trials. There are few studies on the long-term durability of endovascularly implanted devices, partially due to the novelty of these devices. However, such long-term studies are required to prove clinical benefit to the patient. Funders of clinical research should help facilitate and encourage these studies. It is also imperative that the development of medical devices, particularly within academia, involves clinicians who have direct experience in the use of these devices. There is a risk in academia for research to be performed without complete understanding of the unmet clinical needs. Future research projects should ensure that clinical collaborators


are part of the team. Furthermore, improved reporting on patient outcomes are required to ensure that the current diagnosis and treatment policies in place are working. This includes improved monitoring of patients after treatment and the possible monitoring of patients in their own homes.

resonance imaging or ultrasound, and improved navigation technologies, such as the use of electromagnetic tracking in other endovascular applications apart from cardiology, are required to ensure the correct placement of devices, reducing complications, reoperation, and ionising radiation.

Recent advances in Robotics have demonstrated their role in the deployment of endovascular devices and the current commercially available systems have been shown to simplify catheter manoeuvrability with improved stability and safety. However, current systems are expensive, occupy a large footprint in theatre, and in many cases, significant training is required to teach clinicians a new system of catheter manipulation that is vastly different from manual catheterisation. New systems that are smaller, smarter and more affordable, while being more intuitive to use, are required.

There are currently limited opportunities to treat diseases in the ascending aorta and aortic arch (thoracic region) due to the limitations in fenestrated stent grafts for this particularly complex region. Improvements to fenestrated stent grafts are required and these are likely to need personalisation of the devices on a patient specific level.

The current state-of-the-art in intraoperative guidance is via X-ray fluoroscopy. As discussed previously, while this imaging modality provides real-time guidance, visualisation of soft tissues is limited and exposure to ionising radiation is a significant problem. Novel use of safer imaging methods, such as magnetic

haemorrhage, and arterial spasm. In this regard, it is necessary to research into new passive catheter design, including research into biomaterials for catheter shafts which cause less reaction. An alternative is the development of active catheter design, including sensors for better control, feedback, and guidance integrated with robotic navigation.

By creating lower profile devices, the proportion of patients suitable for EVAR is likely to increase. Lower profiles have already been achieved in stent grafts, for example, through newer modular designs, improved stent designs, and adoption of new stent metals and graft fabrics. Current research has shown that the most common source of peri- and postprocedural damage occurred because of the catheter shaft exerting pressure at undesired places in the vessel lumen, leading to complications such as trauma,

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