FIELD OF THE INVENTION

This invention relates to devices intended for removing acute blockages from blood vessels. Acute obstructions may include clot, misplaced devices, migrated devices, large emboli and the like. Thromboembolism occurs when part or all of a thrombus breaks away from the blood vessel wall. This clot (now called an embolus) is then carried in the direction of blood flow. An ischemic stroke may result if the clot lodges in the cerebral vasculature. A pulmonary embolism may result if the clot originates in the venous system or in the right side of the heart and lodges in a pulmonary artery or branch thereof. Clots may also develop and block vessels locally without being released in the form of an embolus—this mechanism is common in the formation of coronary blockages. The invention is particularly suited to removing clot from cerebral arteries in patients suffering acute ischemic stroke (AIS), from coronary native or graft vessels in patients suffering from myocardial infarction (MI), and from pulmonary arteries in patients suffering from pulmonary embolism (PE) and from other peripheral arterial and venous vessels in which clot is causing an occlusion.

BACKGROUND

Despite a wealth of information in the literature on the clotting cascade and on the biochemistry and etiology of thrombus in humans, remarkably little information is available on the physical and mechanical properties of this material. These properties are very pertinent to the interaction between thrombus and clot retrieval catheters and devices and the surrounding vasculature during mechanical thrombectomy of vessels occluded by thrombus material. Through extensive experimentation and research into thrombus material the inventors have discovered aspects of the properties and behaviour of certain clot/thrombus types that help to explain why these clot types can be particularly challenging to retrieve. Some of these findings are described in our WO2012/120490A, the entire contents of which are herein incorporated by reference.

Clot is essentially a living polymer, comprising a matrix of intertwined and cross linked fibrin strands within which are situated red and white blood cells, platelets and numerous other proteins and components. The inventors have discovered that the mechanical properties of a clot are strongly influenced by the relative percentages of fibrin and red blood cells, and that clots with a high (and highly organised) fibrin content and low red blood cell content tend to be much firmer and more cohesive than clots of a higher red cell content. Such clots have also been found to have a higher coefficient of friction, or in other words to be “stickier”. These firm and sticky clots can be very challenging to remove from a vessel.

Clots with a low fibrin content and high red cell content have been found to be less cohesive and more friable and to have a lower coefficient of friction than the more organised fibrin rich clots previously described. These properties mean that such clots may be easier to dislodge from the site of occlusion, but may tend to fragment during the retrieval process, with the consequent risk of loss of clot fragments into distal or new vascular territories.

Furthermore, the inventors have discovered that the fibrin matrix of the clot can result in the clot material exhibiting viscoelastic behaviour in certain circumstances. A series of experiments were carried out in which a range of clots of varying fibrin content were tested. The clot samples were held in a receptacle and an indentor was placed on the surface of the clot and subject to a fixed indenting force. The depth of penetration of the indentor into the clot was measured as a function of time for each clot type. Clots with a high fibrin content and low red blood cell content were found to exhibit the greatest viscoelastic effect, with the indentor effectively “creeping” into the clot over a period of several minutes, whereas with low fibrin content clots the indentor tended to almost fully penetrate the clots in a matter of seconds. greater levels of organisation (and clot maturity) of the fibrin structure resulted in firmer clots which were penetrated to a much lesser extent by the indentor.

This behaviour combined with the higher frictional properties of fibrin rich clots tend to make these clot types particularly challenging to retrieve by mechanical thrombectomy. Conventional stent-retrievers may find it difficult to penetrate and grip these firm clots, and the high level of friction they maintain with the vessel wall can result in a tendency for the clot to roll and compress.

Attempts to aspirate such clots into a catheter can also be very challenging as the clot must be deformed in order to fit into the catheter lumen, and the energy required to deform such clots is not easily attained by aspiration. The high frictional coefficient of these clot types adds further to the challenge of aspirating them into the distal mouth of a catheter. Even maintaining a suction grip on such clots so that they can be retracted to the safety of a more proximal guide or sheath is very difficult, as these firm clots do not tend to deform and reshape easily and thus do not readily conform to the shape of the catheter tip in order to effect a seal and consequent suction grip.

STATEMENTS OF THE INVENTION

This invention solves the challenge of aspirating fibrin rich clot material into a catheter by addressing the key challenges of 1) the friction between the clot and the catheter and 2) the energy/work required to deform these firm clots as they are aspirated into the catheter tip.

Conventional clot aspiration involves inserting a catheter (sometimes referred to as an intermediate catheter or aspiration catheter or distal access catheter) into the patient's vasculature and advancing the catheter up to the occlusive clot. A syringe or vacuum pump is then attached to the proximal end of the catheter and a vacuum applied to attempt to suck the clot into the catheter tip and out through the catheter. The level of the vacuum applied can be controlled to a very limited extent by the force applied to the syringe or by the pump setting, and typically a fairly constant pressure drop of 500 mmHg to 760 mmHg (or “full” vacuum) is applied. The difference in pressure between the blood vessel in which the clot is situated and the interior of the catheter creates a pressure gradient (which may exceed 760 mmHg as the patient's blood pressure is higher than atmospheric pressure) which urges the clot into the catheter mouth.

The diameter of the clot however is greater than the diameter of the catheter therefore for a clot to be aspirated into a catheter the clot must deform and elongate to fit into the catheter tip. The energy to deform the clot to fit into the catheter is effectively an extrusion energy as the catheter tip acts as a form of extrusion die for the clot. This extrusion energy is related to the fibrin content of the clot with higher fibrin clots requiring increased extrusion energy to aspirate the clot into the catheter. Current techniques to aspirate the clot involve applying a steady state vacuum to the tip of the catheter; however in many cases this does not provide sufficient energy to aspirate the clot fully into the catheter. Subsequent retrieval of the catheter either does not dislodge the clot or dislodges the partially retrieved clot and creates the risk of losing the partially exposed clot into a side branch or new vessel creating an ENT (Embolization in New Territory).

This invention improves the ability of a catheter to aspirate a clot fully, including clots which have higher fibrin content. As stated above, vacuum is applied to the catheter tip to create a pressure differential between the catheter and the blood vessel with the aim of aspirating or sucking the clot into the catheter and out of the vasculature. When the apparatus detailed in this invention is operating, the steady state vacuum normally applied at the tip of the catheter is modified to a pulsatile or wave configuration so that in one design configuration, the pressure differential between the catheter tip and the blood vessel plotted against time resembles a sine wave. The application of the aspiration force to the clot in a wave or pulsatile configuration applies an ‘impact load’ to the clot which can deform the clot and overcome the resistance or extrusion energy required to get the clot into the catheter more quickly and effectively than applying a continuous or steady aspiration force.

In addition, when clot occludes the distal tip of an aspiration catheter, part of the clot is inside the tip of the catheter. Testing has shown that compression and manipulation of thrombus increases the friction of the clot. Therefore compression of the clot at the tip of the catheter further increases the static friction between the clot and the inside surface of the catheter tip. The static friction between the clot and the catheter needs to be overcome to allow the clot to be aspirated fully into the catheter. The application of a pulsatile force to the clot can cause the clot to vibrate or move slightly proximally and distally, so that the interaction between the clot and the internal surface of the catheter changes from static friction to a dynamic friction interaction. Dynamic friction of clot has been shown in our testing to be lower than static friction therefore the total force to remove the clot is reduced when using the apparatus detailed in this invention.

The fibrin matrix of a thrombus is porous and red blood cells can migrate and flow within the matrix depending on pressure differentials and fibrin density. Applying a pulsatile energy or vacuum at the catheter tip can promote this movement of clot elements, allowing the red blood cells to be aspirated out of the fibrin matrix. The thrombus is then easier to aspirate as the red blood cell content of the clot decreases facilitating deformation of the fibrin matrix with reduced energy.

This invention is suitable for the aspiration of clots with varying fibrin content from 0% to 100%, and is particularly suited to the aspiration of clot or thrombus which has fibrin content greater than 30%. The invention relates to the removal of a blood clot from the human vascular system. In particular it more specifically relates to the removal of a blood clot from the neurovasculature including the anterior and posterior circulation. Techniques and means of removing blood clots, or clotted blood particles in the form of emboli are already well known and established in use. When the presence of a clot is identified in the body it may be treated by best medical treatment (BMT) in the form of medication or by surgical intervention. Surgical intervention can involve the use of mechanical means to dislodge and remove the clot. Blood clots may also be identified and referred to as emboli. Surgical intervention may be in the form of minimally invasive endovascular intervention where by the clot or embolism is accessed within the blood vessel by the distal end of a catheter that has been introduced within the arterial system at a remote location such as the Common Iliac artery. This is well known and relevant to the background of this invention.

Referring to an endovascular intervention described herein one of the means used to effect the removal of a clot through surgical endovascular intervention, is to use what is commonly referred to as ‘aspiration’ of the clot mass through a catheter. Aspiration is a technique whereby negative pressure or suction can be applied to the clot mass within the blood vessel through the distal end of a catheter, the catheter being connected at the proximal end to a vacuum source.

It is well known that there are clots which cannot be moved or removed even with the maximum intensity of vacuum or aspiration being applied to them. The present invention relates to but is not limited to this situation and to the removal of these types of arduous blood clots. This invention presents and describes a method of removing blood clots by applying a pulsatile energy comprising of a sequence of alternating forces through the distal tip of a catheter which is adjacent to or abutting the blood clot wherein this sequence of pulsatile forces applied to the clot and having the effect of deforming the clot in addition to aspirating the clot back through the catheter. The pulsatile force may also be described as being in the form of a sequence of pulses applied to the clot over a period of time, commonly referred do as frequency. Each pulse comprises of a sequential positive and negative volumetric displacement of fluid at the catheter distal tip. This cyclical positive and forward projecting pressure followed by negative pressure can be described mathematically in general but not limited to a sinusoidal function.

It is known that the aspiration function applies a negative force in the form of negative pressure of approximately 500-760 millimetres of mercury (mm Hg) at the tip of the catheter creating a flow from the distal to the proximal end of the catheter and recovering the content of this flow in a container which is part of the circuit and located close to the vacuum source. This pulsatile sequence of positive and negative pressures are applied through the catheter in conjunction with the aspirated negative pressure. The source of the pulsatile force is separate and independent of the source of the aspirated suction.

Waveforms which represent the sequence of pulsatile positive and negative pressures constitute inventive steps.

It is well known that there are clots which cannot be moved or removed by the level of aspiration being applied to them. The present invention relates to the removal of these types of clots. The invention describes in method of applying pulsatile force through a catheter at the distal tip to the clot which has the effect of aspirating the clot in one or more pieces and retrieving it into the catheter. The pulsatile force is in the form of a sequence of pulses applied to the clot over a period of time. Each pulse comprises of a sequential positive and negative volumetric displacement of fluid at the catheter distal tip or varying negative volumetric displacements.

This period cycle of varying negative pressure can be described mathematically in general but not limited to a sinusoidal function. The pulsatile sequence of pressures are applied in conjunction with the application of a steady state negative pressure/suction force. It has also been observed as a further inventive step that the blood clot can be recovered by applying the pulse without any aspiration.

With regard to the sinusoidal profile of the pressure emitted at the tip of the catheter then the pressure profile may vary about a pure sine wave in the following ways. A sine wave can be described for this purpose as having four components to it which are equal in frequency and amplitude but may be positive or negative. If the first part of the wave is an increasing pressure induced by the forward motion of a piston then the second part will be a negative pressure caused by a reverse motion of the piston. The piston is driven by a shaft or connecting rod that is rotated in a cycle along the length of the shaft and thus directing the piston in a forward and reverse motion. In terms of the since wave describing this motion the first part of the curve indicating the increasing pressure is referred to as the rise time. The next part of the curve which represents a reverse motion of the piston and results in negative pressure at the catheter tip, this is referred to as the fall time or the decay time. The curve has one positive peak and one negative peak in each cycle. In a sequence of cycles constituting a sequence of pulses, the time from peak to peak is the same in a sine wave. The peak of a sine wave can be said to have no duration as the intensity or amplitude of the wave is changing continuously even as it transitions from positive to negative.

The present invention describes wave profiles applied at the catheter tip which can be at variance to a pure sine wave in the following manner. One is that the rise time may not be equal to the decay time. The rise time may be longer or shorter duration that the fall time duration. Secondly the peak of the wave may have a duration or a dwell time. The purpose of the dwell time is to allow fluid or blood some time to fill into the space in the piston chamber or time to pass through the orifice at the end of the chamber.

The nature of the pulse applied to dislodge and retrieve the blood clot can be defined by the following variables or control aspects:ReciprocationFrequencyAmplitudeRise timeDwell timeDecay/Fall time

While the application of the reciprocal motion of both positive and negative displacement in sequence is not well known, there are a number of methods available that are well known for reciprocal motion as described.

One is a purely mechanical cyclical drive system whereby the moving piston within the chamber is connected to crank shaft or the outer radius of a disk which is rotated so as to drive the piston to and fro. This to and fro distance is known as the stroke length. It is well known to use this method in positive displacement pumps but not positive and negative displacement in sequence.

Another well known method of generating reciprocal motion is by electromechanical means using electromagnetic induction whereby a magnetic field is induced in a coil of wire or alternately in two coils of wire for more control over different forces in each direction to create the forces necessary to move the piston to and fro in the chamber

The source of the power can be an alternating current and voltage or a direct current whereby the positive and negative cycles are achieved by switching mode control circuit.

As mentioned heretofore the cyclical motion which results in a symmetrical sinusoidal wave form of positive and negative pressure is the simplest. It may be desirable to alter the shape of the wave form so that the negative pressure is greater than the positive pressure or so that the rate of increase in pressure is greater of less than the rate of decline in pressure. It is recognised herein that there may be an advantage in having no or less positive pressure than negative pressure so that vibration of the clot mass is reduced. It is recognised and presented as an inventive step that the introduction of dwell time on the peak and the trough of the wave form allows time for the fluid displacement to take place on both the positive and negative parts of each cycle. This is more relevant and important as the frequency of the cycles increases.

According to the invention there is provided a system for removing occlusive clot from a blood vessel comprising a vacuum source and collection chamber, a catheter to communicate the negative pressure to the location of the clot, and an apparatus to modify a steady state vacuum provided by a vacuum source to a series of pulses or a waveform configuration. In one iteration this apparatus contains a mechanical drive system whereby a moving piston within a fluid chamber is connected to crank shaft or the outer radius of a disk which is rotated so as to drive the piston to and fro creating a positive and negative fluid displacement in sequence. This variable fluid displacement is combined with the steady state vacuum or negative displacement provided by the vacuum pump to produce a waveform pressure differential between the catheter and the blood pressure at the tip of the catheter adjacent to the clot in the vasculature.

In one iteration the reciprocal motion to create the positive and negative fluid displacement is generated by electromechanical means using electromagnetic induction whereby a magnetic field is induced in a coil of wire or alternately in two coils of wire for more control over different forces in each direction to create the forces necessary to move a piston to and fro in the fluid chamber.

In another iteration the fluid displacement is generated by moving the piston using other electromechanical means such as the piezoelectric effect.

In another iteration the fluid displacement is generated using other mechanical means such as a pneumatic drive.

In one configuration of the invention, the apparatus to create the pulsatile or waveform pressure differential is separate to the vacuum pump and chamber and is connected through tubing and connectors. In another iteration the apparatus of the invention and the vacuum pump are integrated in a single unit.

In one embodiment of the invention the piston to generate the pressure differential at the catheter tip is located within the catheter body which acts as the fluid chamber. The piston is moved proximally and distally in the catheter through a linear connection to a drive system located at the proximal end of the catheter. Alternatively the piston is moved in the catheter through electronic means positioned within the catheter.

In one configuration of the invention, the apparatus to create the fluid displacement to produce a waveform pressure differential contains a single piston in a fluid chamber which is moved forward and back using a mechanical or electromechanical drive. In a different configuration of the apparatus multiple fluid chambers with pistons are connected to facilitate complex waveforms. The displacement output of the apparatus can then be a summation of the displacements of each piston which can be programmed to operate independently.

In one iteration of the device the piston used to create the fluid displacement is similar to a syringe with a moving seal between the piston and the fluid chamber. In another iteration other known hydraulic cylinder configurations are used to produce different waveform configurations.

In another iteration of the invention the tip of the catheter is vibrated by electromechanical means to reduce the friction between the catheter and the clot and help overcome the extrusion or deformation energy required to aspirate the clot. The catheter tip vibration can be combined with a large aspiration lumen with a cross sectional area greater or equivalent to a 0.030″ diameter lumen and in the preferred embodiment has a cross sectional area greater or equivalent to a 0.040″ diameter lumen. The catheter with the vibrating tip may be used with a steady state aspiration vacuum or with the waveform pressure differential as described elsewhere in the patent. The frequency of the tip vibration may range from 5 Hz to ultrasonic frequencies of greater than 20,000 Hz.

Also according to the invention there is provided a method of removing occlusive clot from a blood vessel comprising the steps of:—

providing a guide catheter or sheath and an intermediate catheter, the intermediate catheter having a distal mouth and being configured such that it is advancable within the lumen of the guide catheter;

inserting the guide catheter into a first vessel proximal of an occlusion;

connecting the proximal end of the intermediate catheter to an aspiration source which consists of a vacuum pump, a collection chamber and the apparatus of the invention;

advancing the intermediate catheter through the lumen of the guide catheter until the tip of the intermediate catheter extends distal of the guide catheter into a vessel adjacent to the occlusion;

applying steady state aspiration to the proximal end of the intermediate catheter;

the intermediate catheter being configured to direct said aspiration through the distal lumen of the intermediate catheter to aspirate the clot into the mouth of said intermediate catheter.

If the clot is not aspirated switch on the apparatus of the invention to provide a waveform pressure differential between the catheter and the blood pressure surrounding the clot. The waveform pressure differential overcomes the extrusion energy of the clot and reduces friction between the clot and the catheter so that the clot can be aspirated through the intermediate catheter into the collection chamber and out of the vasculature.

In one embodiment of the invention, this waveform resembles a sine wave with a fixed frequency and amplitude, and equal rise and decay times.

In another embodiment of the invention, the frequency or time between peaks of the waveform may vary and increase or decrease with time. A repeating frequency pattern may also be utilised such as multiple high frequency pulses followed by a number of low frequency pulses.

Similarly in another embodiment the amplitude of the waveform may vary with time and consist of increasing or decreasing amplitudes or a combination of different amplitude pulses.

In another embodiment the rise and decay times of the waveform may vary such that the decay time is shorter than the rise time or vice versa, or a combination of different rise and decay times may be beneficial in aspirating the clot, for example, a saw tooth waveform.

Another wave pattern utilised in an embodiment of the invention is a truncated or square wave pattern where a dwell time is incorporated into the wave cycle at the peak or trough of the wave or at both times. A dwell time may also be incorporated into a wave pattern at any point in the cycle, for example, producing a step wave pattern.

In another embodiment of the device the amplitude of the pressure differential is such that positive pressure may be applied to the clot for a fraction of the time of the wave cycle to increase the impact load applied to the clot.

In one embodiment of the invention the waveform is a combination of a number of the waveforms or features described elsewhere in this patent. In another embodiment, the invention may be programmable to apply specific pressure differential waveforms to the catheter tip which may be optimised for different clot types, for example, a pre-programmed optimized waveform may be applied for a fibrin rich clot which would be different to the waveform optimized for an erythrocyte rich clot.

Also provided are additional variants of this method, including:

A method as described above in which the waveform pressure differential is applied to the intermediate catheter as it approaches the occlusion for the first time.

An additional variant of this method is to apply the waveform pressure differential to the guide catheter or sheath if an intermediate catheter is not being used in the procedure. Alternatively the waveform pressure differential can be applied to both the intermediate catheter and the guide catheter at the same time.

The waveform or pulsatile pressure differential applied to the intermediate catheter described in this patent can also be used when the intermediate catheter is used in conjunction with a stentriever device. The waveform pressure differential reduces the friction between the clot and the catheter and helps to deform the clot. This gives additional benefits of reducing the shear forces acting on the clot as it is retrieved into the intermediate catheter by the stentriever device.

According to the invention there is provided a system for removing occlusive clot from a blood vessel comprising:—a catheter; andan apparatus for generating a pulsatile vacuum force to pulse the pressure gradient at a distal end of the catheter.

In one case the apparatus comprise a vacuum pump and a pulse generator.

In one embodiment the pulse generator is integral with the vacuum pump.

In another embodiment the pulse generator is separate from the vacuum pump.

The pulse generator in one case may be located between the vacuum pump and the proximal end of the catheter.

There may be a flexible tubing between the vacuum pump and the proximal end of the catheter.

In one embodiment the pulse generator is applied to the flexible tubing.

The pulse generator in one case comprises a reciprocating plunger.

The pulse generator in another case comprises a rotatable cam.

The cam may comprise an outer bearing to minimise drag on the tubing. The outer bearing may comprise a sliding outer layer.

In one case the flexible tubing is uniform cross section along the length thereof.

In one embodiment the flexible tubing is of variable cross section along the length thereof.

The system may comprise a controller for controlling the apparatus for generating a pulsatile vacuum source. The controller may be adapted or configured to vary the pressure over time in a waveform.

In one case the waveform has a fixed frequency and amplitude, and equal rise and decay times.

In another case the waveform has a varying frequency with time.

The waveform may have varying amplitude with time.

The waveform may have a different rise and decay time.

In one case the waveform rise and decay times change with time.

In some cases the waveform is a truncated or square waveform incorporating a dwell time at the peak and trough of each wave.

The waveform may incorporate one or more dwell times within each wave producing a stepped wave configuration.

The invention also provides a method for removing occlusive clot from a blood vessel comprising the steps of:—delivering a catheter to a location adjacent to an occlusive clot; andapplying a pulsatile vacuum to the clot using the catheter.

The method in some cases comprises the step of varying the pressure over time in a waveform.

The waveform may have a fixed frequency and amplitude, and equal rise and decay times.

The waveform may have a varying frequency with time.

The waveform may have varying amplitude with time.

The waveform may have a different rise and decay time.

The waveform rise and decay times may change with time.

The waveform may be a truncated or square waveform incorporating a dwell time at the peak and trough of each wave.

The waveform may incorporate one or more dwell times within each wave producing a stepped wave configuration.

In one embodiment the system comprises a canister which is configured to receive aspirated blood or material.

In one case the system comprises a vacuum pump which is connected to the canister. The vacuum may be drawn through the canister.

In one embodiment the system comprises a first vacuum pulse generator. In one case the system comprises a second vacuum pulse generator. The vacuum pulse generators may be configured to operate separately, at the same time, or at different times to vary the vacuum pulse generated.

In one case the first pulse generator comprises a valve having a housing and an element which is rotatable and/or oscillatable in the housing.

In one case the second pulse generator is adapted to engage a flexible tube. The second vacuum pulse generator may comprise a rotatable cam.

In another case the first vacuum pulse generator comprises a pump. The system may further comprise non-return valves located on both sides of the pump.

In a further case the system comprises a canister configured to receive aspirated blood or material and the first pulse generator comprises an obturator which is movable through the canister.

