Review of Recent Patents on Foldable Ventricular

0 downloads 0 Views 2MB Size Report
of valve development, it offeres accurate prediction on the expanding and crimping .... in-vitro and in-vivo tests of the RCP have been published. [13, 14].
Send Orders of Reprints at [email protected] 208

Recent Patents on Biomedical Engineering, 2012, 5, 208-222

Review of Recent Patents on Foldable Ventricular Assist Devices Po-Lin Hsu1*, Madeleine McIntyre1, Maximilian Kuetting1, Jack Parker2, Christina Egger1, Rüdiger Autschbach2, Thomas Schmitz-Rode1 and Ulrich Steinseifer1 1

Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University; and 2Department of Cardiothoracic and Vascular Surgery, University Hospital Aachen, Aachen, Germany Received: April 24, 2012

Revised: June 12, 2012

Accepted: June 20, 2012

Abstract: Congestive heart failure accounts for a high morbidity worldwide. The only effective treatment for end-stage patients is heart transplantation or, in light of the shortage of suitable donors, an artificial heart or ventricular assist device (VAD). The newer-generation continuous-flow rotary VADs allow for a significant reduction in size and an improvement in reliability. However, the invasive implantation still limits this technology from being offered to critically ill patients. To benefit more heart failure patients, there is a need to develop a long-term VAD which can be implanted via minimally invasive procedure. Recently, expandable/deployable devices have been investigated as a potential solution. Such a device can be inserted percutaneously via the peripheral vessels in its collapsed form and operate in its expanded form at the desired location. This paper reviews significant patents on foldable VADs using mechanical and/or material means. Mechanically folded structures adapt joints and links to facilitate the folding process whilst utilization of elastic materials allows the structure to be bent or twisted without permanent deformation. Current and future developments of foldable VADs are discussed. Foldable pumps could generate less blood damage and mechanical wear as compared to current miniature percutaneous VADs. Therefore, foldable VADs have the potential for longer-term application and minimally invasive insertion, providing a promising solution for heart failure patients.

Keywords: Blood pump, Heart failure, Collapse, Deployable, Expandable, Foldable, Minimally invasive, Ventricular assist device. INTRODUCTION The increasing global prevalence of congestive heart failure is a major healthcare concern, making up for 30% of global mortality [1]. In the most severe forms of this disease, the only effective treatment is heart transplantation, or in light of the shortage of suitable donors, a mechanical replacement heart or ventricular assist devices (VADs). Mechanical cardiac assistance in the form of ventricular assist devices (VADs) has become accepted as a therapeutic solution for end-stage patients when a donor heart is not available. The newer-generation VADs are inclusive rotary pumps generating continuous flow. These rotary VADs allow for a significant reduction in size and improvement in reliability and longevity. Despite advances made in modern VADs, the invasiveness of their implantation remains the major restriction limiting this technology from being offered as a last resort to critically ill patients. Therefore, the desire to develop minimally invasive and easily implantable devices has been stimulated in the last decade to enable earlier and wider VAD usage in heart failure patients. Several extracorporeal and implantable devices that can be inserted percutaneously via peripheral vessels or implanted *Address correspondence to this author at the Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University; Tel:/Fax: +49 241 80 - 89365 / - 82144; E-mails: [email protected]; or [email protected] 1874-7647/12 $100.00+.00

without major surgery have been developed. The extracorporeal devices have generally been used to unload the heart in the short term and allow time to recover its function or bridge the patient to other longer-term therapeutic options, such as the TandemHeart (CardiacAssist, Inc., Pittsburgh, PA, USA) and CentriMag systems (Levitronix LLC, Waltham, MA, USA). These devices have the advantage of reduced invasiveness during insertion and can potentially extend their application to less severe cases of heart failure; however, the cannulae are comparatively long elevating the risk of thromboembolism. In addition, infection and bleeding are the common complications associated with the insertion site. These systems restrict patient’s mobility and thus are mostly used as a bed-side support. Meanwhile, some miniature implantable blood pump systems have been developed; these systems can be divided into catheter-based devices or surgically-implanted devices. Impella (Abiomed, Inc, Danvers, MA, USA) is one example of catheter-based devices to provide acute support up to seven days; its axial-flow impeller is mounted on the distal end of the catheter and delivered via peripheral vessels [2]. Because of the percutaneous leads and catheter via femoral artery, patient’s mobility is also restricted. Circulite Synergy pump (CircuLite® Inc., Aachen, Germany) provides chronic partial support and is implanted into the pacemaker pocket via a less invasive left thoracotomy and the cannulation is established between the left atrium and subclavian artery [3]. These systems, in order to achieve the required hydraulic output, have to operate at a higher rotational speed (above 12,000 rpm) because of the reduced impeller size. This gives rise to increased wear at the © 2012 Bentham Science Publishers

Foldable Blood Pumps: Recent Patent Review

mechanical bearings, a significant shear stress, and a high local temperature resulting from increased speed which can induce hemodynamic complications, e.g. hemolysis. The safe operational period of the miniature pumps is thus still constrained. The intra-aortic balloon pump (IABP) is the only currently clinically approved foldable circulatory assist device. Developed in the late 1960s, the IABP uses counterpulsation (or diastolic augmentation) to marginally increase the cardiac output and coronary perfusion [4-6]. The IABP consists of a cylindrical balloon that is inserted via the femoral artery and sits in the aorta and counter-pulsates. It actively deflates in systole, increasing forward blood flow by reducing after load, and inflates in diastole thus increasing blood flow to the coronary arteries. To date, the IABP provides short-term circulatory support for conditions such as cardiogenic shock and post-cardiotomy. Whilst this device has successfully achieved a minimally invasive implantation, it does not actively augment the cardiac output and thus the hemodynamic improvements are significantly limited compared to a VAD. In order to realize minimally invasive VAD implantation, investigations have been focused on the concept of expandable/deployable devices allowing for percutaneous insertion. Such a device is inserted via the peripheral vessels in its collapsed form and expands to its original form at the desired location. Hydraulic demand can be achieved at a lower speed with a larger pump (original form) while the device can be introduced by a minimally invasive implantation (collapsed form), provided that the hydraulic efficiency is not compromised by the structural properties of the foldable impeller and housing. This design allows for percutaneous insertion without inducing complications, such as hemolysis, that result from the high rotational speed of a miniature pump. In particular, hemolysis is known to be associated with the shear rate, correlated to the tip clearance and velocity, and the blood residence time [7]. In addition, the negative effects of shear rate and residence time increase with temperature [8]. Therefore a reduction in rotational speed would allow for significantly reduced local temperature around the mechanical bearings and consequently a lower hemolysis rate. However, it must be noted, whilst reducing the rotational speed can allow for a reduction in shear, the increased impeller size and longer residence time can have the opposite effect. If a satisfactory balance between size and rotational speed will be achieved, it is expected that the reduction in operational speed will allow foldable VADs to achieve a longer support duration compared to existing minimally invasive devices while reducing relevant complications by avoiding major surgery. Over the course of the past decades, collapsible medical devices, such as stents and artificial heart valves, have repeatedly revolutionized surgical intervention. Since the first stent implantations in 1986 and subsequent randomized trials proved the superiority of stenting over balloon angioplasty, stenting has become an established form of therapy [9]. Initially, stents were manufactured from stainless steel and relied on balloon dilatation to reach their expanded form. This later changed when the benefits of shape memory alloys were discovered for this application and Nitinol became the

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

209

material of choice for a new generation of self-expanding stents [10]. More recently, the drug eluting technology, biodegradable materials and the improvement of cell structure design leading to more flexibility and consideration of vascular biomechanics have been additional focuses of stent development. Software tools such as computer-aided design (CAD), computational fluid dynamics (CFD) and finite element method (FEM) are now state of the art in the design and development of medical devices. CAD software facilitates the design and construction of complex geometries. Simulation results using CFD provides valuable insights to optimization on blood flow pattern and even the interaction between blood and artificial surfaces. FEM give useful information on structural properties of the design; in the case of valve development, it offeres accurate prediction on the expanding and crimping mechanisms. These tools provide a cost effective development process and accelerate the optimization of stent cell geometries and their effect on the radial expansion force and crimpability. Lessons learnt from initial setbacks in the development of coronary stents helped expedite the development of other collapsible devices such as endovascular grafts, gastrointestinal stents, and most recently, transcatheter heart valves. An example is the development of complex delivery catheters which are increasingly incorporating functions like reposition ability and retrievability. Unlike stents and stent-grafts, transcatheter heart valves and foldable pumps are not only required to be stable but their crimping and unfolding processes must take the safety and efficacy of a functional element into consideration. This element can either be the valve leaflets, in the case of transcatheter valves, or a rotor and drive system, for foldable pumps. This poses new challenges, since the design of the stent frame must take more factors into account in order to achieve a certain functionality. Transcatheter heart valves demonstrate the possibility of capitalizing on an established technology and achieving a minimally invasive device by means of collapsing a structure to create a new form of therapy for previously untreatable patients. An analogous route can lead to the successful adoption of foldable pumps. This paper reviews a number of significant patents on foldable VADs. This review focuses on the novel design aspects, such as the folding mechanism and method of deployment, which improve upon the existing VAD devices. These innovative concepts aim to achieve a foldable pump by mechanical and/or material means. Mechanically folded structures normally adapt joints and links to facilitate the process while utilizing elastic materials allows the structure to be bent or twisted without permanent deformation. FOLDABLE VENTRICULAR ASSIST DEVICES Due to the current trend towards minimally invasive therapy, various designs for foldable circulatory support devices have been patented over the past decade. These devices have been identified, for the purpose of this review, as systems with an impeller having at least two distinct diameters; one for insertion and one during operation. The summarised patents outline devices that augment the cardiac output of patients suffering from heart failure or disease and that aim to provide appropriate physiological flow rates. The majority of systems consist of four basic compo-

210 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

nents: the folding impeller, an expandable housing, a flexible drive shaft, and a catheter system. The expandable housing is generally constructed from a shape memory mesh or frame covered by an elastic hose. It serves to house the impeller during rotation and provide a channel for the blood flow. The housing has two configurations, for deployment and operation, and is often used to constrain the impeller in its folded state, as shown in (Fig. 1A). The housing also protects the surrounding vessel wall during operation (Fig. 1B and C). A number of designs also include a fixation structure which centres the drive shaft and impeller within the housing. Similarly to existing miniature VADs, a flexible drive shaft connects the impeller to an external drive source and controller via the central lumen of the catheter system. The catheter system generally consists of an inner catheter and an outer sheath which can be axially displaced relative to each other. This motion can be utilized during pump deployment and retrieval to constrain the impeller and housing in the folded configuration. Descriptions of basic elements such as the catheter system, drive shaft and external drive source are omitted from this review unless they contribute significantly to the novelty of a specific foldable VAD concept. In addition to the apparatus, various patents describe a method for percutaneous deployment and removal of the system. Expansion and collapse of the impeller can be active and self-initiated or passive, requiring a force to initiate the process. This force can be derived from the axial displacement of the catheter system and drive shaft, the hydrodynamics of fluid flow or the centrifugal force due to rotation. The use of active or passive transformation of the structure determines the ‘natural’ or ‘force-free’ state of the impeller, which can exist at the folded or expanded position. The reviewed patents have been divided into three categories based on the type of folding mechanism employed. The classical approach incorporates structural components to facilitate folding whilst other designs utilize the material properties of the impeller to enable folding. A third category 



Hsu et al.

of ‘hybrid’ devices, which combine the use of structural features and material properties for folding, are also summarised below. STRUCTURAL FOLDING Patents outlining structurally foldable impellers have been classified as designs in which the primary mechanism for folding is a mechanical component such as a joint. Foldable devices have been created using joints or links for centuries and several designs draw inspiration from everyday expandable devices such as the umbrella, propeller, fan and balloon. Commonly used joints include the ball, hinge and pin joints. Expansion and collapse of these classical designs can be active or passive; however, a mechanism for activating the joint is usually required for at least one of these processes. In addition, a locking mechanism can be included to secure the impeller in the expanded configuration during operation. This locking mechanism must also be deactivated during device retrieval. Reitan, in US Patent 5749855 published in 1988, described a pump consisting of a foldable, two blade propeller attached to a drive shaft by a linking mechanism, such as a pin joint [11]. The pin allows the propeller to pivot between the stored configuration for insertion and deployed configuration for pump operation shown in (Fig. 2). The housing frame is composed of a protective cage of filaments. In US Patent Application 2011/0034874, Reitan & Epple disclosed further improvements on the aforementioned pump described in US5749855 and proposed a method for deployment of the propeller [12]. Sequential expansion of the cage and propeller is achieved using a two-step axial displacement of the sheath. The first stage causes expansion of the cage and the second stage provides the force to unfold the propeller. The propeller deployment is achieved using two actuator pins on the sheath which engage a cam surface on the propeller causing it to pivot to the open configuration.







Fig. (1). Examples of foldable pump housings; (A) housing to constrain the folded impeller [25] and (B) and (C) housing as protection for vessel wall [12, 26].

Foldable Blood Pumps: Recent Patent Review

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

211

The polyurethane (PU) pump housing has an annular bulge at the impeller position and is reinforced with elastic bars. The bulge funnels the radially directed outflow of the pump back along the axial direction of the housing. Relative axial motion is used for joint activation during folding, and expansion of the impeller is activated by the centrifugal force during operation. The invention has several possible placements for heart assistance, including inside the ventricle (intracardiac), and the ascending and descending aortas (intraaortic). Placement within the ascending aorta is shown in (Fig. 4C). One advantage of a radial pump design is that normally a lower rotational speed is needed for producing physiological flow rates compared to axial pumps. In addition, lower thrust force generated by a radial pump could avoid a complex fixation which would be a significant issue for axial pumps.



Fig. (2). Reitan Catheter Pump in stored configuration with cage omitted (top) and deployed configuration (bottom) [12].

This design has been developed into the Reitan Catheter Pump (RCP) (CardioBridge GmbH, Hechingen, Germany) to be implanted in the descending aorta of patients suffering from compromised left ventricular function to reduce the ventricular after load and increase peripheral perfusion. The in-vitro and in-vivo tests of the RCP have been published [13, 14]. The first-in-man study of the RCP was reported in 2009, this study described the application in high-risk patients undergoing percutaneous coronary intervention, and preventing compromise in whom developed ischemia; the maximum support duration of the device was approximately five and half hours [15]. In US Patent 6981942 published in 2006, Khaw & Li disclosed a pump with an inflatable impeller consisting of a hub and inflatable blades made preferably of polyethylene terephthalate (PET) [16]. The impeller housing is composed of an inflatable stator constructed from an elastic material that expands to fit the surrounding vessel wall when inflated. The inner surface of the stator is less elastic and is supported by a wire frame connected to the impeller via hinges (Fig. 3 B). Deployment and retrieval is easily achieved by inflating or deflating the blades and stator with a biocompatible fluid such as saline solution. The pump can be positioned across the aortic (Fig. 3A) or pulmonary valves in the case of left or right ventricular dysfunction, respectively. The system is designed to produce physiological aortic and pulmonary arterial flow rates running at approximately 2,000 rpm for short-term (3-7 days) ventricular unloading. In contrast to the axial pump designs, Siess, in US Patent Application 2008/0103591, disclosed a foldable centrifugal pump consisting of flexible radial vanes stretched between two supporting walls [17]. The walls have radial spokes covered by a polymer skin and are attached to the impeller hub via hinges (Fig. 4A). In the stored configuration the walls and vanes are folded against the shaft as shown in (Fig. 4B).



Fig. (3). (A) Khaw & Li valvo-pump and (B) the inflatable impeller and wire frame (housing omitted) [16].

In International Patent Application 2011/076439, Röhn described a radially compressible impeller consisting of a series of fan-like blades. Each blade is constructed from a plurality of struts, connected to the hub at a single hinge, with a membrane stretched in-between, as shown in (Fig. 5) [18]. A hub indentation and receptor apparatus are proposed to house and lock the terminal struts of the blade within the hub to prevent blood passing between the hub and blade during operation. A hub cut-out is also proposed to house the

212 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3



Hsu et al.





Fig. (4). (A) Centrifugal Impeller of US2008/0103591 and (B) the impeller in stored configuration (bottom) and during operation (top). (C) Intra-aortic placement of the pump [17].

folded struts during insertion. Different blade geometries can be achieved using a combination of struts with various lengths and angulations (Fig. 5). The blades are passively expanded and collapsed using axial push and pull elements. The pump system is designed for intra-cardiac use to augment the cardiac output.

Elastic materials, such as PU, with a low elastic modulus allow for folding and unfolding without permanent deformation using the stored strain energy. However an elastic material is generally insufficient for withstanding the hydrodynamic loads during operation of the impeller and therefore must be reinforced in some manner. Materials with non-linear properties have a stress-strain relationship dependent on various parameters such as the direction or magnitude of the applied load, the temperature, or the pH. For example, a non-linear material can exhibit a high, linear elastic modulus at small operational loads and a lower elastic modulus at high stress such that large, recoverable strains can be achieved during folding. Nonlinear materials commonly employed in medical applications include shape memory alloys (SMA) and shape memory polymers (SMP). Nitinol, possessing thermal shape memory effects and superelasticity, is the most commonly used SMA in medical applications due to its biocompatibility and corrosion resistance and is employed in a wide variety of applications [19-22].

Fig.(5). Fan-like impeller design for a curved blade geometry [18].

MATERIAL FOLDING Several designs utilize the inherent material properties of the blade structure to achieve a foldable impeller in which the blades need to exhibit two distinct states, one allowing elastic deformation into the stored position and the other that can resist the hydrodynamic forces during operation.

Nitinol has two distinct solid phases, austenite and martensite; stable at high and low temperatures, respectively [19]. The shape memory effect of Nitinol occurs when the austenite to martensite transformation is induced by a temperature change. At low temperatures, the soft martensite phase is easily plastically deformed into new shapes whilst the original structure can be recovered by increasing the temperature. Superelasticity occurs when the austenite to martensite transformation is induced by an applied stress causing large strains with only small changes in the applied stress.

Foldable Blood Pumps: Recent Patent Review

The shape change occurs due to the phase transformation; however, due to the instability of martensite at high temperatures, removal of the applied stress causes the reverse transformation and the original shape is recovered [23]. This property is largely exploited in expandable stent technology where the stent is crimped and constrained for percutaneous insertion by applying a stress and then self-expanded to its original shape by removing the constraining stress. In the case of an expandable stent, the force to collapse the stent is relatively large in comparison to the force it exerts on the vessel wall, thus the stent causes minimal damage to the surrounding tissue whilst effectively resisting collapse. Superelasticity allows for recovery of up to 8% strain for Nitinol in comparison to around 0.5% recoverable strain in stainless steel and other metal alloys. This provides clear benefits for the design of foldable impeller blades and self-expanding pump housing. SMPs present a promising material for medical applications. Most commonly PU based thermoplastics, SMP exhibit large, reversible, temperature dependent variations in elastic modulus [24]. The normally rigid polymer exhibits a rubbery elastic state when heated above the glass transition temperature (Tg) such that deformation is readily achieved. A rigid structure is compressed by rolling, folding or deforming above Tg and then cooling below Tg where the folded state is self-maintained without a constraining force. Elastic recovery occurs when the structure is reheated above Tg and the expanded structure becomes rigid when cooled. The range of possible Tg values is wide and can be selected by proper manufacturing procedure. Recently, the ‘cold hibernated elastic memory’ (CHEM) foam structure has been developed as self-deployable material and holds the advantages of lower mass, faster deployment, and higher full/stowed volume ratio compared to solid SMPs. SMPs are light weight and can recover up to 400% strain; however, the lower recovery stress has limited their use to applications which do not need to withstand a significant load. In addition, anisotropic properties, where the stiffness of the material depends on the direction of the applied force, can be exploited when the folding force can be applied in a different direction to the operational load. This can be achieved using the geometry of the structure or the material composition. The inherent material composition such as crystal, fibre or pore alignment can be influenced by manufacturing and processing methods whilst additional structures, such as a web or fibres, can be used to strengthen an elastic material and aligned to give anisotropic behaviour. This anisotropic property ensures the rigidity of the blade in one direction while maintaining flexibility in the direction of folding. In the design of foldable structures for the medical environment it is very common to combine the benefits of shape memory materials with those of elastic materials. This is demonstrated by the largely exploited combination of a shape memory frame, to provide strength and self-expansion properties, with an elastic polymer covering or membrane to increase flexibility. Several of the summarised patents employ this concept for the impeller design, foldable by material means, and for the expandable housing design in the structural and material based systems.

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

213

An expandable pump was disclosed by McBride et al. in US Patent 7927068 published in 2011, whereby the impeller consists of a hub and a plurality of flexible blades which can be radially compressed to achieve a stored configuration, as shown in (Fig. 6) [25]. The blades are ideally made from a non-linear material. The proposed design includes a winglet structure on the distal blade to act as a hydraulic bearing and a hub indentation to reduce internal mechanical stresses during folding.

Fig. (6). McBride impeller in stored (top) and deployed (bottom) configuration [25].

Campbell et al., in US Patent Application 2011/0004046, expanded on the cannula design in the aforementioned US7927068 [26]. The housing is incorporated into the catheter, which has a fixed-diameter proximal segment and an expandable distal segment. A stationary vane assembly, consisting of a vane hub and a plurality of vanes, is positioned within the housing distal to the impeller to act as a centering mechanism. The vane assembly has a stored and a deployed configuration and moves axially with the impeller. Active expansion is achieved using the stored energy in the folded blades and superelastic effects of the housing matrix. With the help of guidance tools, passive collapse of the housing is achieved by axial sliding of the catheter sheath thereby causing compression of the impeller for device removal. The device is intended for positioning across the pulmonary or aortic valve for augmentation of right or left ventricular output. Schmitz-Rode & Günther, in US Patent 6533716, published in 2003, proposed a radially collapsible impeller consisting of a Nitinol helix frame and elastic, cross-woven membrane (Fig. 7) [27]. The impeller is compressed by full extension of an elastic band which connects the two ends of the frame. Passive expansion or collapse occurs with release or stretching of the elastic band. The expandable catheter pump (ECP) can be positioned across the aortic (Fig. 7) or pulmonary valves to augment ventricular output of the left or right heart as a short term solution for cardiogenic shock patients. The prototype ECP has been reported to have an expanded diameter of 6.5 mm and can be delivered via a 9 French sheath [28]. The ECP is capable of delivering 4 L/min at 32,000 rpm with 60 mmHg pressure difference in the bench test. In the animal trials it was placed inside the

214 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

left ventricle and the minimum flow rate was 2.5 L/min. The maximum duration of pump operation was six hours.



Hsu et al.

In International Patent Application 2010/127871, Liebing gave a general description of a foldable pump system with a rotor consisting of blades constructed from a shape memory frame with a polymer membrane and an expandable housing [30]. The pump and housing are able to be displaced axially for greater compression. A distal bearing is disclosed having radially extending struts which stabilize the hub within the housing and can be folded inwards for insertion (Fig. 9).





Fig. (9). Liebing pump System [30].

Fig. (7). Cross-valve placement of the Schmitz-Rode & Günther pump (left) and the radially compressible impeller (right), US6533716 [27].

In US Patent Application 2009/0093764, Pfeffer, Schmitz-Rode & Günther described a two-blade impeller composed of a comb-shaped Nitinol frame covered by a PU skin [29]. The radial struts of the frame are connected to the drive shaft via small rings (Fig. 8) and the relative angle and distance between adjacent struts allows for highly adaptable rotor geometry. The housing is incorporated in the catheter as an expandable, Nitinol mesh with a PU cover. Expansion is active using the stored energy of the blades and superelasticity of the housing. Similarly to the above design, this device is able to augment right or left ventricular output in cardiogenic shock patients using a transvalvular positioning of the pump.

In International Patent Application 2011/035929, Schumacher, Scheckel & Schlicht disclosed a unique design with a rotor that can be converted from a low density material, in the expanded state, to a high density material for insertion [31]. The rotor is constructed from a material, such as PU foam or sponge, with deformable cavities that can be filled with a fluid (Fig. 10). An open or closed pore configuration can be used. In an open pore material an applied pressure expels the fluid in the pores allowing for compression. Alternatively, if a closed pore configuration is chosen, or the open pore material is covered by a membrane, then the fluid inside the pores can be compressed by the applied external pressure and will expand automatically on removal of the force. A semi-permeable membrane can also be used to facilitate osmotic compression and expansion such that when placed in contact with blood the rotor swells. The geometry of the cavities can be designed to give anisotropic properties to the blade, allowing radial compression whilst retaining stiffness during operation. The foam rotor can be cut from a flat sheet and rotates to form a helical geometry. The rotor is enclosed in a compressible foam housing. HYBRID FOLDING MECHANISM In International Patent Application 2009/073037, Shifflette disclosed an expandable pump and housing to address the drawbacks of the structurally folding patents by Reitan and Khaw & Li [32]. The ellipsoidal pump housing consists of a cage of Nitinol ribs surrounded by an elastic membrane and is biased to the open position. Therefore, no axial force on the drive cable is required to actuate and maintain expansion. Two concepts for achieving a foldable impeller were described. The first outlined a simple pin joint, similar to US5749855, allowing the rigid blades to fold into a recess in the hub for insertion. An alternative folding mechanism consists of a series of blades each connected to the impeller hub via a spring loaded hinge joint. In both instances the impeller blades are biased to the deployed state such that active expansion occurs.

Fig. (8). Comb-like Impeller with adjustable geometry [29].

In US Patent 7942804, granted in 2011, Khaw described a surgically implanted intra-cardiac VAD that can be folded to

Foldable Blood Pumps: Recent Patent Review

facilitate less invasive insertion and positioning of the pump in the ventricle [33]. The impeller blades and housing each consist of structural supporting elements, such as inflatable tubes or Nitinol wires, and a surrounding membrane. The blades and housing are foldable by inflation or by use of a flexible material. The motor unit base is sutured to the external heart wall and serves to connect the intra-ventricular pump to the motor unit via a drive shaft (Fig. 11).

Fig. (10). PU foam impeller and housing [31].

Fig. (11). (A) Pump system positioned in the ventricle driven by the shaft-connected extra-cardiac motor unit; (B) blade and pump housing showing the structural supporting elements [33].

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

215

In US Patent 8079948, granted in 2011, Shifflette disclosed a novel impeller design for the intra-cardiac pump system outlined in WO2009073037 [34]. The impeller consisting of one or more blades; each divided into a plurality of bladelets, and covered by a flexible membrane. Each bladelet has a concave pressure face and a convex suction face to create one-way rigidity (Fig. 12A). This anisotropy allows the concave side to be easily folded down to the impeller hub but gives the bladelet a rigid structure when a force is applied against the concave face. The bladelets are narrower and have a smaller radius of curvature at the base and overlap or abut adjacent bladelets at the distal end. The bladelets can be made from Nitinol, stainless steel or a polymer and the flexible membrane from silicon, latex, PU or bovine pericardium. The blades can be actively expanded by stored energy or passively ‘spun out’ using the operational fluid forces. A particularly similar impeller design for use as an intra-cardiac pump, as shown in (Fig. 12B), was disclosed in the International Patent Application 2010/149393 by Töllner [35]. A series of lamellae, similar to the aforementioned bladelet, are pivoted to a hub element so that the lamellae can fold towards the rotational axis. The hub element can be produced in different modular lengths. By assembling the hub elements, a variable-pitched helix can be economically made and thus a hydraulic optimised impeller/rotor. In International Patent Application 2011/089022, Töllner disclosed a pump, collapsible by a combination of stretching and radial compression [36]. The impeller consists of a hub and a series of blades both constructed from an elastically compressible material, such as an elastomer or foam. Axial lengthening of the hub causes consequent stretching and radial compression of the blades. In addition, the foldability of the blades is increased via two mechanisms. First, the blades have a concave shape in the unstretched position, providing rigidity during operation, which is partially or totally eliminated during stretching, as shown in (Fig. 13). Second, the blades may exhibit an internal support structure, to stiffen the blade, which is flattened during stretching (right column of Fig. 13) to make the blade more easily folded. Complete collapse of the blades is facilitated by longitudinal stretching and radial compression of the housing. Passive deployment of the system utilizes opposing axial displacement of the catheter components to stretch and radially compress each element. The pump system is designed to be implanted across either of the semilunar valves to augment ventricular output. Töllner and Scheckel later disclosed another compressible impeller concept utilizing pivotable stiffening struts embedded within an elastically deformable blade in International Patent Application 2012/007140 [37]. The proposed impeller can have a hub or be hubless. The blade has three distinct states; the force-free state where the struts extend radially as well as folded and operational states where the struts are deformed in opposing directions. The stiffening struts can be made from a stiff plastic or metal, such as Nitinol, and can be designed to have anisotropic properties allowing deformation in the folding direction but guaranteed rigidity in the operational state (Fig. 14). Tensile elements, containing glass or polycarbonate fibres, can be added to stabilize the struts and/or impeller in the operational state. These elements have an unstretched configuration during the

216 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

(A)

(B)

proximal

Hsu et al.

Suction Face

Pressure Face

Rotational Axis

distal

Convex Face

Fig. (12). (A) Bladelet structure of Shifflette pump in the expanded (top) and folded (bottom) configuration [34]; (B) lamellae structure of the Töllner impeller pivoted to the hub elements [35].

Fig. (13). Unstretched configuration during operation (top row) and stretched configuration (bottom row) for folding, depicting the radial compression (left), curved geometry (center), and strengthening structure (right) of the impeller [36].

force-free and folded states and become fully extended at the operational position to prevent further deformation of the blade during operation. 



Fig. (14). (A) Combined tensile element and stiffening strut in one part; (B) recesses on the stiffening strut to enable anisotropic compressibility [37].

Schumacher & Röhn, in International Patent Application 2011/035926, described a more detailed rotor concept for the general pump system outlined in WO2010127871 [38]. The blade is a neckless rotor with a network of webs spanning between two outer frames and is covered by a film to provide a smooth blade surface. Ideally a SMA is used for the frame and web structure which can be laser cut from a flat sheet and twisted into a helical rotor. Several designs for the web geometry are outlined to give the blade anisotropic properties as shown in (Fig. 15). In contrast to aforementioned patents, the rotor is rigidly fixed to the housing such that both components rotate together. Schumacher & Scheckel disclosed an alternative rotor design for the aforementioned system in International Patent Application 2012/007141 using a composite-style material to achieve compressibility [39]. The rotor has a series of blades which are constructed from an elastic base material reinforced by radially expanding fibres to provide mechanical support and anisotropic properties. The base material can be a solid or foam PU, thermoplastic elastomer, rubber or superelastic polymer and the fibres can be glass, carbon, plastic or natural fibres. The rotor has three configurations: the compressed state, the unfolded force-free state, and the operational state where the blades are deformed under loading.

Foldable Blood Pumps: Recent Patent Review

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

217

Fig. (15). Various web designs for the radially compressible impeller (top row) and their graphical projections (bottom row) [38].

In US Patent Application 2011/0257462, Rodefeld & Frankel described an expandable, mixed flow pump to augment cavopulmonary flow in patients with a univentricular Fontan circulation [40]. A novel impeller geometry was disclosed consisting of a plurality of filaments encased in a flexible PU membrane. When compressed axially the filaments bulge outwards forming a biconical disc-shaped impeller as shown in (Fig. 16). The filaments of the impeller frame can be made from Nitinol to exploit shape memory affects for active deployment. Several variations of the above impeller design are discussed such as including a helical twist in the frame filaments and utilizing a pressure gradient to control the membrane deformation between adjacent filaments (Fig. 16B). The use of anisotropic filaments, that are more flexible in the central region, is suggested to facilitate the formation of the deployed bulging geometry.

augment the cardiac output and thus have the potential to offer full ventricular support in contrast to the IABP. (A)

DISCUSSION The aforementioned inventions aim to reduce surgical risks and complications by achieving foldability for rotatry blood pump systems. The systems described in this review are categorised according to their folding mechanisms. The materials, structural features, and expanding/compressing mechanisms of the granted patents and patent applications of substantial difference are summarized in Table 1. The IABP is the only foldable cardiac assist system in clinical use due to the advantages over other mechanical assist devices in terms of ease of insertion and removal. Nevertheless, it does not have the capability to provide the level of support of a VAD. The bulky console required to synchronize with the cardiac cycle and the pneumatic drive of the IABP restrict the mobility of the patient and prevent it from being fully implantable. In comparison, the foldable VADs operate in a continuous manner thus do not require a complex synchronization. Furthermore, these VADs actively

(B)

Fig. (16). (A) Positioning of the impeller in the modified Fontan vessels of the heart; (B) the impeller showing a helical filament frame with troughs formed by the membrane deformation [40].

218 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

Table 1.

Hsu et al.

Categorization of Foldable VAD Concepts According to Configurations Impeller Structural Feature

Housing

Hub

Blades

Y

2 blade propeller

Y

Inflatable

Y

Plurality blades

Y

Centrifugal vanes + supporting walls

Y

Struts with membrane

Y

Plurality blades

N.A.

PU, foam, metal

N

Single helix

Frame + membrane

NiTi + elastic material

System Compression

Ext Drive +Shaft

Features

Materials

Style

Materials

Expansion

N.A.

Filament cage

N.A.

Passive – Passive – Axial Axial Y displacement displacement

In vitro & in vivo tested; 2 actuator pins engage cam surface on impeller to pivot the blade

PET

Elastic – Inflatable more on stator + outer layer Wire frame than inner

Passive – Inflation

Passive – Deflation

Inflated with saline, air, any biocompatible fluid

Locking mechanism: N.A.

SS or polymer

Cage + membrane

NiTi + PU, Si, Latex, elastomeric polymer

Active – Stored energy

Passive – Axial Y displacement

Joint: hinge

Polymer skin (supporting walls)

Frame + sheath

Elastic material + PU

N.A.

N.A.

N.A.

Passive – Passive –Axial Axial displacement displacement

Mesh + membrane

NiTi + polymer

Active – Stored energy

Passive – Axial Y displacement

Hub indentation

Mesh + membrane

N.A.

Active – Stored energy

Passive – Stretching

In vitro and in vivo tested

Mesh + membrane

SMM + PU,PP,PE, Si

Active – Stored energy, temperature

Passive – Axial Y displacement

Structural Reitan Device US5749855, 1998 US20110034874

US6981942, 2006 Khaw & Li

WO2009073037 Shifflette

US2008/0103591 Siess

Joint: pin joint Locking mechanism: N.A. Joint: none Locking mechanism: N.A. Joint: pin or hinge

Locking mechanism: N.A.

Y

Passive – Passive – Axial Centrifugal Y force & axial displacement displacement

N.A.

Bulge in housing funnels radially directed fluid in axial direction

Joint: single hinge WO2011/076439 Röhn

Locking mechanism: Receptor in hub for terminal struts

Y

Cut-out in hub to house folded struts

Material US7927068, 2011 McBride et al. US6533716, 2003 Schmitz-Rode & Gunther US2009/0093764 Pfeffer, SchmitzRode & Gunther

WO2010/127871 Liebing

Y

N.A.

Single helix

Plurality blades

Non-linear

Frame + membrane

Frame + membrane

NiTi + highly elastic PU

SMM + polymer

Mesh + membrane

Winglet

Y

Active – Stored energy

Passive – Axial SMA, displacement Y plastic + PU Passive – Axial displacement

Third operational state

Very flexible geometry Body cap for smooth contact with vessel wall

Folding star-shaped fixation device

Open/closed pores WO2011/035929 Schumacher, Scheckel & Schlicht

Y compressible

Plurality blades

Anisotropic: Aligned pores

PU foam

N.A.

Foam

Active – Osmosis, fluid expansion, diffusion

Passive – Applied pressure

Gas expelled/ compressed Y

Semi-permeable membrane for osmotic swelling Cut from flat sheet

Hybrid

US7942804, 2011 Khaw

US8079948, 2008 Schifflette

Y

Single blade

Structural element + membrane

NiTi + elastic material

Bladelets + membrane Anisotropic: Concave (pressure), convex (suction)

NiTi, SS, polymer +

Y

Plurality blades

Structural element + membrane

N.A. Si, PU, latex, bovine pericardium

NiTi + elastic material

Active – Stored energy

N.A.

Active – Stored energy Passive – Centrifugal

N N.A

Passive - Force on convex side

Implanted motor unit

Y

Requires surgical implantation. Inflatable tubes can replace NiTi wire as structural element

N.A.

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

Foldable Blood Pumps: Recent Patent Review

219

(Table 1) contd…. Impeller Hub

Blades

Y

Plurality blades

N

Single blade

Structural Feature

Housing Materials

System Ext Drive +Shaft

Features

Passive – Passive –Axial Axial displacement displacement

Y

N.A.

Active – Stored energy

Passive

Y

Housing and rotor rigidly fixed and rotate together

Active – Stored energy

Passive – Axial Y displacement

Third operational state

Passive – Screw actuator

Mixed flow pump to augment Fontan circulation

Style

Materials

Expansion

N.A.

N.A.

SMM + plastic

Compression

Hybrid WO2011/089022 Töllner WO2011/035926 Schumacher & Röhn

Y

Plurality blades

N

Single impeller surface

US2011/0257462 Rodefeld & Frankel

Frame + membrane Anisotropic: Webs

WO2012/007141 Shumacher & Sheckel

Compressible elastomer, Stiffening structure foam Curved blade

Blade + Fibres Anistropic: Radial fibres

SMA + flexible Mesh + film membrane Solid/foam PU, thermoplastic, elastomer, Mesh + rubber, SMP + membrane Glass, carbon, plastic, natural

Frame + memSS, NiTi, brane Anisotropic: polymer + Si based PU filaments

Cage + membrane

N.A.

Nitinol + Flexible elastomer

Active – Stored energy Passive – Screw actuator

Cut from sheet

Y

Polyethylene terepthalate (PET), Stainless steel (SS), Ntinol (NiTi), Polyurethane (PU), Silicon (Si), Polypropylene (PP), Polyethylene (PE), Shape memory material (SMM), Shape memory alloy (SMA), Shape memory polymer (SMP).

The dimensions of a foldable pump are constrained by patient anatomy. When minimally invasive insertion is desired, in particular via peripheral vessels, the size for delivery is significantly limited. Since patient anatomies vary, the device can be applied to more patients if the folded size is sufficiently small. Using structural means of folding can result in small folded volumes, such as the Reitan catheter pump (RCP), outlined in US5749855. The folded pump is delivered via the femoral artery using a 30 cm, 14 French sheath introducer; the delivery size can be further decreased to 10 French for the insertion in patients with narrow, diseased or tortuous femoral or iliac vessels. Additional features, such as the hub recess illustrated in Patent Application WO2011/076439 by Röhn, can further reduce the insertion diameter. Although the structural folding is straightforward and easy to apply, more sophisticated structural features are needed if a complex geometry is required, e.g. a hydraulically optimised impeller, such as the bladelet feature in US8079948 and the variable-length strut design in WO2011/076439. One of the apparent risks when using a blood-immersed mechanical joint to fold a blood pump is thromboembolism, which often occurs in areas of discontinuous geometry where blood circulates or stagnates. On the other hand, using material properties to fold or unfold a device reduces or eliminates the use of joints, such as in the ECP. In addition, the impeller is generally in the natural force-free state during operation; therefore, a locking mechanism to hold the blade in the deployed state is no longer a critical design parameter. One obvious challenge in these material based inventions is the high stress level at the regions of greatest deformation. For example, significant stress at the connection between the frame and hub tends to cause permanent deformation of the material. More flexible materials could be used, but the blades will not withstand as

high loading as more rigid materials do, and thus are prone to bending. A compromised hydraulic efficiency was reported using flexible impellers completely made of PU materials [41]. Additionally, due to the intrinsic properties, the foldable impellers are less strong than non-foldable ones and unwanted deformation and vibration may occur during operation. It has been the main challenge addressed in the majority of the inventions to ensure the rigidity at the expanded state while keeping flexibility during folding. The design of hybrid devices aims to combine the advantages of both structural and material folding methods. In some inventions, anisotropic properties were proposed to strengthen the blades by adapting structural features such as WO2011/089022 and/or material combinations, such as WO2011/035926. In particular, these designs allow for complex blade geometry such as US8079948 and WO2010/149393. These folding designs, which accommodate various blade geometries, have two main advantages: the impeller can preserve optimal hydraulic efficiency and can be adapted for different hemodynamic requirements without redesigning the folding mechanism. The key feature of foldable devices is that they will be expanded and compressed inside the body. After being delivered to the desired location, either in the vessel or in the heart chamber, the device is deployed in situ. Most structural folding devices are expanded passively while the material folding devices utilize the stored potential energy to restore the geometry once the constraining force, such as a cover sheath or housing, is removed. At the end of the therapy, the device has to be compressed again to enable its withdrawal. Current inventions exclusively use passive means to fold the device. This requires a specially designed tool, e.g. a withdrawal catheter, to facilitate the device re-compression and

220 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

removal. However, this kind of tool will have to be customised for individual devices to fit the unique geometry and folding mechanism. It would be difficult to develop a “universal” tool for foldable VAD removal. Special pre-operative care must be taken, such as patient selection and monitoring to offer sufficient data to guarantee the anatomical fitting. This type of therapy may not be used in patients with vessel disease, e.g. vascular sclerosis. During operation, elimination of potential damage on the surrounding tissues is of vital importance. Some inventions described a supplementary housing which serves as a protection/fixation and/or assists device expansion. Tissue ingrowths and adhesion towards the housing are potential risks and thus cause complications especially at device withdrawal; however, these will be less severe in short-term applications than in longer-term assistance. A distinct advantage of these foldable devices is the minimally invasiveness compared to existing surgically implantable VADs. In comparison to existing miniature percutaneous VADs, these devices have a potential advantage of being able to run at lower rotational speeds if a comparable hydraulic efficiency is maintained and therefore have relatively less mechanical wear and can potentially reduce hemolysis. This however presents the difficult task of designing an impeller that can be folded without compromising the hydraulic efficiency. Besides a hydraulically optimized impeller geometry, the blood contacting surfaces have to be designed to avoid thrombus formation and tissue ingrowths. CFD will provide a powerful tool to optimize the flow pattern to ensure minimal occurrence of hemolysis and thromboembolism. In addition, all the supplementary components, such as its housing and fixation, have to be simultaneously functional and foldable, presenting an extra design challenge.

Hsu et al.

devices continues due to the fundamental requirement of foldability. In addition to the insufficient design of supplementary components, the foldable impeller designs have not been developed to a computational or experimental testing phase, with the exception of the RCP and ECP devices. Therefore, analysis of the efficiency and reliability of each design is not possible at this stage. As mentioned in the discussion, current foldable pump concepts have the clear advantage of reducing invasiveness arising from major surgery required for implantable VADs. A lower operating speed compared to the miniature percutaneous VADs is possible, allowing for a reduction in complications and mechanical wear. Developing a foldable pump which is implantable and capable of longer-term support will considerably extend the benefits of a foldable pump to wider patient population, such as for those undergo bridge to recovery where prolonged support duration is needed. From the experience learnt from IABP and published results of foldable VADs, which has been restricted for short-term support, longer support duration of the foldable VADs can be realized only if several critical issues are addressed in current inventions: No Percutaneous Moving Components Current inventions are exclusively coupled by a flexible shaft with an external drive motor. This sufficiently restricts the support duration because of mechanical wear and difficulties in stabilising the flexible rotating shaft. Development of a miniature electric motor directly coupled with the impeller can avoid the use of flexible shaft and eventually facilitate an implantable device. Easy and Sustainable Expansion

CURRENT & FUTURE DEVELOPMENTS The patents outlined generally give a well-developed and thorough description of the possible folding mechanism of the impeller. They are, however, distinctly lacking in further development of the overall system including details regarding the supplementary components. The impellers with structural features generally failed to propose a locking mechanism which is necessary to guarantee a safe and efficient operation. Several inventions have proposed a foldable frame covered by a flexible membrane; however, very few addressed the method of connecting the hub and the flexible blade surface. Blood will pass through the gap between the hub and blade that would harm the hydraulic efficiency and generate unwanted hemodynamic effects. One simple solution was offered in WO2011/076439 whereby the terminal blade struts were embedded within a hub recess; however, this introduces a new geometric discontinuity and area for blood stagnation. In conventional pump design, a stationary flow straightener (inducer) and diffuser are implemented to promote pressure generation; but in the majority of pump concepts, the design of such components was not included. It is clear that the presence of these extra components will pose additional design challenges as the development of these

Some inventions appear to require constantly connection to an external device to maintain their deployed state. For example, the inflatable impeller in US6981942 would need an air/fluid supply to keep the inflated state for operation; otherwise, a one-way valve with a seal would be necessary to prevent air/fluid discharge if no external supply will be provided. This implies the disadvantages of a large external pressure or fluid source for inflation, in addition to a potentially more complex actuation procedure. Another example, demonstrated by the RCP, is a catheter initiated locking mechanism making it necessary to keep the percutaneous catheter throughout the operation. This effectively limits the support duration and the patient’s mobility. Independent Fixation The majority of current inventions illustrates a catheterbased blood pump. This, however, relies on a constantlyconnected catheter and/or surrounding tissues (e.g. valve leaflets) to stabilize the impeller in the vessel or ventricle. A robust fixation without the need of such a percutaneous connection will reduce the impact on the tissues caused by system vibration, as well as the complications induced by the presence of a catheter at the insertion site. Although there

Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3

Foldable Blood Pumps: Recent Patent Review

may still be percutaneous power leads, similar to the clinical VADs and other artificial organs, such existing technology is expected to be easily transferable and present less technical challenges which prevent foldable pumps from long-term uptake. Additionally, in case of severe complications or pump failure, removability should be considered in order to facilitate device withdrawal without complications. This means that, depending on design of the foldable pump and its supplementary components, the activation mechanism of folding has to be reconnected and the fixation needs to be detached to remove intracorporeal elements. Therefore, appropriate tools for device withdrawal, or manipulation, will very likely require a sophisticated catheter system customized for individual folding mechanism. Current devices, such as the IABP, extracorporeal circulatory assist devices and miniature blood pumps, have several limitations preventing their use in longer-term applications. The IABP lacks active flow augmentation and incorporates several large external components. Similarly, extracorporeal devices severely limit patient mobility. Catheterbased miniature pumps could progress to percutaneously implantable devices with the development of miniature drive sources but will still face complications associated with a high rotational speed. Thus the foldable VAD presents a promising design for achieving minimally invasive, mid- to long-term circulatory support. A vast research is still needed to develop the next generation of novel foldable VADs in terms of system design, reliability and efficiency. Its successful implementation would allow the augmentation of cardiovascular performance and offer a new generation of minimally invasive devices. The capability of providing more flexible therapy for a wider range of patients will allow potential cardiac recovery and offer a significant boost in quality of life. CONFLICT OF INTEREST Thomas Schmitz-Rode is shareholder of Aachen Innovative Solutions AIS GmbH.

[6] [7] [8]

[9] [10] [11] [12] [13] [14] [15]

[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

ACKNOWLEDGEMENTS

[27]

This work was supported by START funding from the University Hospital Aachen, RWTH-Aachen University.

[28]

REFERENCES [1] [2] [3] [4]

[5]

Cardiovascular diseases (CVDs) Fact Sheet No. 317. World Health Organisation. [Online] September 2011. http://www.who.int/ mediacentre/factsheets/fs317/en/index.html. Raess D, Weber D. Impella 2.5. J Cardiovasc Transl Res 2009;2(2):168-72. Krishnamani R, DeNofrio D, Konstam MA. Emerging ventricular assist devices for long-term cardiac support. Nat Rev Cardiol 2010; 7:71-6. A. Kantrowitz, S. Tjonneland, P. S. Freed, S. J. Phillips, A. N. Butner, and J. Sherman, Jacques L., “Initial clinical experience with intraaortic balloon pumping in cardiogenic shock,” JAMA, vol. 203, no. 2, pp. 113–118, 1968. S. K. Moulopoulos, R. Stephen, and S. Topez, “Extracorporeal assistance to the circulation and intreaortic balloon pumping,” Trans Am Soc Artif Intern Organs, vol. 7, pp. 85–90, 1962.

[29] [30] [31] [32] [33] [34] [35] [36]

221

S. K. Moulopoulos, S. Topez, and W. J. Kolff, “Diastolic balloon pumping (with carbon dioxide) in the aorta-a mechanical assistance to the failing circulation,” Am Heart J, vol. 63, pp. 669–675, 1962. Paul R, Apel J, Klaus S, Schügner F, Schwindke P, Reul H. Shear Stress Related Blood Damage in Laminar Couette Flow. Artificial Organs. 2003;27:517-29. Lepock JR, Frey HE, Bayne H, Markus J. Relationship of hyperthermia-induced hemolysis of human erythrocytes to the thermal denaturation of membrane proteins. Biochim Biophys Acta 1989;980:191–201. Grech ED. Percutaneous coronary intervention. I: History and development. BMJ. 2003;326:1080-2. Stoeckel D, Pelton A, Duerig T. Self-expanding nitinol stents: material and design considerations. European Radiology. 2004;14:292-301. Reitan Ö. Catheter Pump. US5749855, 1998. Reitan Ö, Epple K. Catheter Pump for Circulatory Support. US20110034874, 2011. Reitan Ö, Steen S, Ohlin H. Hemodynamic Effects of a New Percutaneous Circulatory Support Device in a Left Ventricular Failure Model. ASAIO J 2003;49:731-6. Reitan Ö, Sternby J, Öhlin H. Hydrodynamic Properties of a New Percutaneous Intra-aortic Axial Flow Pump. ASAIO J 2000; 46(3): 323-9. Smith EJ, Reitan Ö, Keeble T, Dixon K, Rothman MTA. First-InMan Study of the Reitan Catheter Pump for Circulatory Support in Patients Undergoing High-Risk Percutaneous Coronary Intervention. Catheter Cardiovasc Interv 2009;73(7):859-65. Khaw K, Li J. Temporary Blood Circulation Assist Device. US6981942, 2006. Siess T. Foldable Intravascularly Inserted Blood Pump. US20080103591, 2008. Röhn D. Radially Compressible and Expandable Rotor for a Fluid Pump. WO2011076439, 2011. Barras CDJ, Myers KA. Nitinol-Its Use in Vascular Surgery and Other Applications. Eur J Vasc Endovasc Surg 2000;19:564-9. Petrini L, Migliavacca F. Biomedical Applications of Shape Memory Alloys. Journal of Metallurgy 2011. Duerig T, Pelton A, Stockel D. An Overview of Nitinol Medical Applications. Mat Sci Eng 1999:149-160. Morgan NB. Medical shape memory alloy applications - the market and its products. Mat Sci Eng 2004;378:16-23. Biscarini A, Mazzolai G, Tuissi A. Enhanced Nitinol Properties for Biomedical Applications. Recent Patents on Biomedical Engineering 2008;1(3):180-96. Sokolowski W, Metcalfe A, Hayashi S, Yahia L, Raymond J. Medical Applications of Shape Memory Polymers. Biomed Mater 2007;2(1):S23-S27. McBride MW, Mallison TM, Dillon GP, Campbell RL, Boger DA, Hambrie, SA, et al. Expandable Impeller Pump. US7927068, 2011. Campbell RL, Walsh JM, Metrey D, Kunz RF, Mallison TM, Boone E, et al. Blood Pump with Expandable Cannula. US20110004046, 2011. Schmitz-Rode T, Günther, RW. Self-deploying Axial-Flow Pump Introduced Intravascularly for Temporary Cardiac Support. US6533716, 2003. Schmitz-Rode T, Graf J, Pfeffer JG, Buss F, Brücker C, Günther RW. An Expandable Percutaneous Catheter Pump for Left Ventricular Support: Proof of Concept. J Am Coll Cardiol 2005; 45(11): 1856-61. Pfeffer JG, Schmitz-Rode T, Günther RW. Catheter Device. US20090093764, 2009. Liebing R. A Fluid Pump Changeable in Diameter in Particular for Medical Application. WO2010127871, 2010. Schumacher J, Scheckel M, Schlicht H. Compressible Rotor for a Fluid Pump. WO2011035929, 2011. Shifflette M. Medical Device. WO2009073037, 2009. Khaw K. Replaceable Expandable Transmyocardial Ventricular Assist Device. US7942804, 2011. Shifflette M. Article Comprising an Impeller. US8079948, 2011. Töllner T. Compressible and Expandable Blade for a Fluid Pump. WO2010149393, 2010. Töllner T. Fluid Pump having a Radially Compressible Rotor. WO2011089022, 2011.

222 Recent Patents on Biomedical Engineering, 2012, Vol. 5, No. 3 [37] [38] [39]

Töllner T, Scheckel M. Radially Compressible Rotor for A Pump Having An Impeller Blade. 2012. Schumacher J, Röhn D. Rotor for an Axial Converying a Fluid. WO2011035926, 2011. Schumacher J, Scheckel M. Rotor for a Pump, First Elastic Material. WO2012007141, 2012.

and Expandable WO2012007140,

Hsu et al. [40] [41]

Flow Pump for Produced with a

Rodefeld M, Frankel S. Active or Passive Assistance in the Circulatory System. US20110257462, 2011. Throckmorton A, Kapadia J, Carr J, Powell C, Tate R, Traynham D. Flexible Impeller Blades in an Axial Flow Pump for Intravascular Cavopulmonary Assistance of the Fontan Physiology. Cardiovasc Eng Technol 2010; 1(4):244-55.