Knowledge-Based Thrombectomy System

Abstract

Thrombectomy systems are disclosed that utilize a knowledge base comprising intra-procedural and inter-procedural (i.e., historical) measurement data that is correlated to deterministic events that predicate each measurement. Each thrombectomy procedure is thereby a compendium of cause and effect experimentation; experimental data are retained, in addition to being utilized intra-procedurally to determine future experimental configurations (deterministic events). Herein, experimental data comprise variable measurement data of intensive physical properties of the aspirate within the catheter (e.g., viscosity=10 cP, % thrombus=15%, thrombus load=25%, etc.). Knowledge-based thrombectomy systems engender procedure standardization across multiple thrombectomy systems, facilities and clinicians by standardizing the sequence of intra-procedural, deterministic events. Some embodiments feature a plurality of subsystems (experimental factors) such as Liquid Column Oscillator, Harmonic Oscillator, frequency, aspiration rate, infusion rate, mechanical or hydrodynamic lance, catheter position and/or configuration, etc.; these subsystems being operable at a plurality of setpoints (experimental levels). A knowledge base is compiled that identifies and exploits efficacious experimental configurations and abandons or modifies inefficacious experimental configurations.

Claims

1. An apparatus comprising: a first fluid conduit having a proximal end and a distal end, wherein, in use of the apparatus, the distal end of the first fluid conduit is fluidically coupled to a fluid reservoir, the fluid reservoir including a material attached to a wall thereof; and a reciprocating surface, wherein the reciprocating surface displaces fluid within the first fluid conduit, and wherein the reciprocating surface is operable to create an oscillating flow of a fluid within the first fluid conduit at a frequency less than 19,000 Hz, the oscillating flow within the first fluid conduit creating an oscillating motion of the material, thereby attriting the material.

2. The apparatus of claim 1 including: a transducer fluidically coupled to the fluid conduit; and a controller operable to receive input data from the transducer and vary the motion of the reciprocating surface.

3. The apparatus of claim 2 wherein varying the motion of the reciprocating surface comprises varying the speed of the motion of the reciprocating surface.

4. The apparatus of claim 2 wherein varying the motion comprises varying the distance of the motion.

5. The apparatus of claim 2 including a pump fluidically coupled to the first fluid conduit.

6. The apparatus of claim 5 including: a second fluid conduit; and a second pump fluidically coupled to the second fluid conduit.

7. The apparatus of claim 6 wherein: the second fluid conduit is at a first location with respect to the first fluid conduit at a first time; and the second fluid conduit is at a second location with respect to the first fluid conduit at a second time.

8. The apparatus of claim 2 wherein the distance between the proximal end of first fluid conduit and the distal end of the first fluid conduit is a first length at the first time; and the distance between the proximal end of first fluid conduit and the distal end of the first fluid conduit is a second length at a second time.

9. The apparatus of claim 1 wherein the reciprocating surface comprises a face of a piston.

10. The apparatus of claim 1 wherein the reciprocating surface comprises a diaphragm.

11. The apparatus of claim 1 wherein the reciprocating surface comprises a sonic transducer.

12. The apparatus of claim 2 wherein the transducer is operable to measure pressure.

13. The apparatus of claim 2 wherein the transducer is operable to measure frequency.

14. The apparatus of claim 2 wherein the controller is operable to measure a viscosity of the fluid within the fluid conduit.

15. An apparatus comprising a fluid conduit, the fluid conduit having a proximal end and a distal end, the fluid conduit comprising: a first lumen operable to transport a pressurized liquid from a proximal end thereof to a distal end thereof; wherein, in use of the apparatus, the distal end of the fluid conduit is fluidically coupled to a fluid reservoir, and at least a portion of the pressurized liquid is discharged into the fluid reservoir in a radial direction, thereby generating a reaction force exerted upon the fluid conduit in a direction opposite to the radial direction, the fluid conduit thereby being forced into contact with a wall of the fluid reservoir.

16. The apparatus of claim 15 wherein the conduit comprises a second lumen, wherein the distal end of the first lumen is a distance, d, from a distal end of the second lumen, wherein in use of the apparatus, the distance, d, has a first value at a first time and a second value at a second time.

17. An apparatus comprising: a) a fluid conduit having a proximal end and a distal end, wherein, in use of the apparatus, the distal end of the fluid conduit is fluidically coupled to a fluid reservoir, the fluid reservoir containing a fluid and including a material attached to a wall thereof, the material having different physical properties from the fluid; b) a pumping system operable to generate a differential pressure between the proximal end and the distal end of the conduit, the pumping system having a setpoint and operable to create a flow of the fluid within the conduit; c) means for attriting the material, the means having a setpoint; d) a transducer operable to measure an amount of the material contained within the conduit; e) a system controller, wherein the system controller: (i) is operable to cause the means to attrite the material, receive measurement data from the transducer, adjust the setpoint of the pumping system, and adjust the setpoint of the means; (ii) executes a first experiment comprising a combination of a first setpoint of the pumping system and a first setpoint of the means; (iii) receives a first value of the measurement data based on the first experiment; (iv) correlates, using the first value of the measurement data, the first experiment to the first measurement of the amount of the material contained within the catheter.

18. A method comprising: (i) performing a first thrombectomy procedure using a thrombectomy apparatus, wherein the thrombectomy apparatus includes setpoint-controlled means to attrite thrombus, setpoint-controlled means to aspirate a fluid within a catheter, and means to measure thrombus within the catheter, wherein the first thrombectomy procedure comprises operating the thrombectomy apparatus at successive setpoints, wherein for each successive set point, an amount of thrombus within the catheter is measured and correlated to the respective setpoint, and wherein some of the setpoints positively correlate to the amount of thrombus within the catheter; and (ii) performing a second thrombectomy procedure using the thrombectomy apparatus, wherein at least some of the setpoints that positively correlate to the amount of thrombus within the catheter are used to as setpoints for the setpoint-controlled means to attrite thrombus and the setpoint-controlled means to aspirate a fluid within a catheter.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0146] FIG. 1A depicts a Liquid Column Oscillator (LCO)/Harmonic Oscillator (HO) catheter combination positioned within a blood vessel. The piston is to the right, and the thrombus shown pushed to the right. The acoustic tube is shorter and there is a higher frequency standing wave emanating from the catheter.

[0147] FIG. 1B depicts an LCO/HO catheter combination with the piston to the left, and the thrombus shown pulled to the left. The acoustic tube is longer and there is a lower frequency standing wave emanating from the catheter.

[0148] FIG. 1C depicts pressure limiter 10 in exploded view.

[0149] FIG. 1D depicts pressure limiter 10 in assembled view under pressure.

[0150] FIG. 1E depicts pressure limiter 10 under atmospheric pressure or vacuum/suction.

[0151] FIG. 1F depicts pressure limiter 10 under pressure and venting to exhaust port/tube.

[0152] FIG. 1G depicts impulse mechanism 90 is the cocked state.

[0153] FIG. 1H depicts impulse mechanism 90 in the uncocked state.

[0154] FIG. 2A depicts a thrombus in a neutral configuration within a blood vessel.

[0155] FIG. 2B depicts a thrombus in a distal/extended configuration within a blood vessel.

[0156] FIG. 2C depicts a thrombus in a neutral configuration within a blood vessel.

[0157] FIG. 2D depicts a thrombus in a proximal/retracted configuration within a blood vessel.

[0158] FIG. 2E depicts an oscillating vessel wall; the vessel wall is shown distended in a first vibrational mode.

[0159] FIG. 2F depicts the vessel wall in a first undulating vibrational mode.

[0160] FIG. 2G depicts the vessel wall in a second undulating vibrational mode.

[0161] FIG. 3A depicts an LCO 100 with catheter tip a distance away from a thrombus.

[0162] FIG. 3B depicts a catheter tip in close proximity to a thrombus.

[0163] FIG. 3C depicts a catheter tip penetrating a thrombus.

[0164] FIG. 3D depicts a catheter tip and thrombus bolus; the catheter tip has been withdrawn from the thrombus.

[0165] FIG. 4A depicts oscillating flow pressure vs time waveforms for three combinations of LF oscillator frequency and stroke.

[0166] FIG. 4B depicts a decaying oscillating flow pressure waveform vs distance for three combinations of LF oscillator frequency and stroke.

[0167] FIG. 4C depicts an effect of viscosity on the oscillating pressure waveform.

[0168] FIG. 4D depicts a velocity waveform of oscillating flow with superposition of aspiration. With aspiration, the net flow out of the catheter may be positive, negative or zero.

[0169] FIG. 4E depicts a pressure vs time waveform for a pressure-limited LF oscillator.

[0170] FIG. 4F depicts a pressure vs time waveform for a time-varying piston stroke cycle.

[0171] FIG. 5A depicts an LCO thrombectomy system with viscometric aspiration and infusion 400.

[0172] FIG. 5B depicts an LCO thrombectomy system with viscometric aspiration and infusion 400 featuring mechanized positioning of infusion tube within the catheter.

[0173] FIG. 5C depicts the distal ends of catheter and infusion tube showing axial and radial nozzles.

[0174] FIG. 5D depicts the distal end of infusion tube proximal to a thrombus.

[0175] FIG. 5E depicts the distal end of infusion tube extended to hydrodynamically interact with the thrombus.

[0176] FIG. 6 depicts measured aspirate viscosity vs. time during (a portion of) a representative thrombectomy procedure. Phases of thrombus aspiration are enumerated and distinguished from blood.

[0177] FIG. 7 depicts seven representative thrombectomy system process variables (factors) which may be setpoint/level-controlled. The units, range, increment, number of increments and loop termination index are also shown.

[0178] FIG. 8 depicts a representative system controller and the interfaces to input data and output system control.

[0179] FIG. 9A depicts a representative thrombectomy control flowchart.

[0180] FIG. 9B depicts a representative effect subroutine to evaluate current data with respect to previously determined values and execute control actions based upon the evaluations.

[0181] FIG. 9C depicts a representative distance subroutine that measures the distance between a catheter tip and a thrombus, and to execute control actions based upon the measurement.

[0182] FIG. 9D depicts a representative clog detect/avert subroutine that operates proactive measures to prevent clogging of a catheter.

[0183] FIG. 10 depicts a representative two-factor response surface, wherein frequency and stroke are independent variables and aspirate viscosity is the dependent variable.

[0184] FIG. 11 depicts a representative three-factor response surface wherein factor (1), factor (2) and factor (3) are independent variables; aspirate viscosity is the dependent variable. Four types of thrombus (anatomical/thrombus morphological) are shown as response surfaces/volumes.

[0185] FIG. 12 depicts a plurality of knowledge-based thrombectomy systems, each performing a plurality of thrombectomy procedures; a plurality of log data files are shown within a system and distributed throughout a network of systems.

[0186] FIG. 13A depicts page 1 of a representative thrombectomy data log file.

[0187] FIG. 13B depicts page 2 of the representative thrombectomy data log file.

[0188] FIG. 13C depicts page 3 of the representative thrombectomy data log file.

[0189] FIG. 14 depicts a block diagram depicting a physical relationship between a thrombectomy system, the patient vascular system, the surgical suite and remote database/compiler.

[0190] FIG. 15 depicts a representative architecture and communication pathways between a system controller and a database/compiler.

DETAILED DESCRIPTION OF THE DRAWINGS

[0191] Liquid Column Oscillator 100. FIGS. 1A and 1B depict liquid column oscillator (LCO) 100 fluidically coupled to a portion of a patient's vascular system containing thrombus 240. LCO 100 includes two independently operating oscillator systems. Namely, (i) lower-frequency (LF) oscillator 102 including piston 120, cylinder 200, and associated actuation elements, and (ii) higher-frequency, or harmonic (HO) oscillator 104, including sonic transducer 110, acoustic tube 130, and slide 150. The two oscillator systems are fluidically coupled to catheter 220, which, in use, is inserted into a portion of the vasculature shown as vascular access 225. Vascular Access 225 is typically gained by means of a medical device such as an introducer sheath (not shown). LCO 100 (and subsequently presented embodiments) is representative of an apparatus that features multiple subsystems that are setpoint controlled. As previously discussed, a thrombectomy featuring a plurality of subsystems (factors), each having a plurality of setpoints (levels), may give rise to a large number of combinations thereof.

[0192] Among objectives of some embodiments (such as LCO 100) is to conduct a sequence of experiments. Some experiments enable a correlation of cause and effect (or stimulus-response) phenomena of a system (e.g., a biological system such as: vascular system, lymph system, gastric system, etc.) to deterministic events (e.g., causes, stimuli, etc.). During these experiments, the apparatus may be termed in operation or operated, when systems of the apparatus (e.g., motors, oscillators, pumps, etc.) are in operation (e.g., rotating, oscillating, pumping, etc.). A typical sequence of events comprising an experiment is presented as an example. Step1: the apparatus setpoint(s) is/are assigned. Step 2: the apparatus is operated with the setpoints assigned in step 1. Step 3: a property of the aspirate is measured. This concludes the experiment; step 4 may be optionally conducted concomitantly with, or subsequent to, the experiment. Step 4: the assigned apparatus setpoint(s) are correlated to the measured property of the aspirate. Embodiments of the invention provide a way to correlate measurement data (e.g., viscosity, relative/absolute flow rate, % thrombus, thrombus load, flow characteristic, state of flow, etc.) to deterministic events (e.g., setpoints, apparatus operation, manipulation, repositioning, etc.); the measurement data being predicated upon the deterministic events. Some depicted embodiments illustrate a means, apparatus or structure that enables cause and effect or stimulus-response phenomena to be measured, documented and/or analyzed.

[0193] In operation, LCO 100 generates oscillatory motion and/or pressure fluctuations of the contents of catheter 220 (e.g., blood, saline, thrombus, etc.) and that of tissue proximate to the end of the catheter. Among any other functionality, the oscillatory flow and/or pressure generated by LCO 100 dislodges, disintegrates, or partially attrites thrombus 240/attachments 260 that are proximate to the distal end of the catheter in the vasculature. In operation, LCO 100 generates oscillatory motion and/or pressure fluctuations of the contents of catheter 220 (e.g., blood, saline, thrombus, etc.) and that of tissue proximate to the end of the catheter. Among any other functionality, the oscillatory flow and/or pressure generated by LCO 100 dislodges, disintegrates, or partially attrites thrombus 240/attachments 260 that are proximate to the distal end of the catheter in the vasculature. In operation, LCO 100 generates oscillatory motion and/or pressure fluctuations of the contents of catheter 220 (e.g., blood, saline, thrombus, etc.) and that of tissue proximate to the end of the catheter. Among any other functionality, the oscillatory flow and/or pressure generated by LCO 100 dislodges, disintegrates, or partially attrites thrombus 240/attachments 260 that are proximate to the distal end of the catheter in the vasculature. Thrombus 240 is shown connected to vessel wall 280 by attachments 260. Attachments 260 may be fibers, tissue, thrombotic or other material; they are depicted to represent the physical connections between thrombus 240 and vessel wall 280. As discussed further below, the two oscillator systems (LF oscillator 102 and harmonic oscillator (HO) 104) are independently controlled such that multiple frequencies of oscillatory flow and/or pressure may be generated, to various ends. Some embodiments of LCO 100 also include aspiration and/or infusion, and/or other systems, which are omitted in FIG. 1A and FIG. 1B for clarity.

[0194] Relatively Lower-Frequency (LF) Oscillator 102. In the illustrative embodiment depicted in FIGS. 1A and 1B, LF oscillator 102 includes piston 120, cylinder 200, and several actuation elements. In the illustrative embodiment, the actuation elements include motor 180, crankshaft 160, and connecting rod 140. Piston 120, which is disposed within cylinder 200 (shown in cutaway), is coupled to connecting rod 140. Motor 180 rotates crankshaft 160 and connecting rod 140, which, in turn, drives piston 120 to reciprocating movement. Fluid within catheter 220 thereby undergoes oscillatory motion in the axial direction, resulting in repetitive discharge and intake of fluid through distal end of catheter 220.

[0195] FIG. 1A depicts piston 120 at or near Top Dead Center (TDC) such that fluid (typically blood, saline and/or thrombus within catheter 220) has been pushed outward, thus impinging upon thrombus 240. This outward flow pushes thrombus 240 distally; attachments 260 are shown being stretched distally (away from LCO 100).

[0196] At some frequencies and amplitudes (i.e., strokes), the sequential intake and discharge of fluid in the vicinity of thrombus 240 and attachments 260 erodes thrombus 240; this effect may be viscometrically detected in the aspirate. At some frequencies, thrombus 240 undergoes harmonic oscillatory motion, thereby putting alternating stresses on attachments 260. These alternating stresses tend to disrupt fibrous networks within thrombus 240 or attachments 260. At some frequencies, the amplitude of oscillation of thrombus 240 and attachments 260 tend to dislodge or disintegrate thrombus 240/attachments 260. At some frequencies, vessel wall 280 is excited to one or more vibrational modes that cause repetitive increases and decreases in the diameter of vessel wall 280. These vibrational modes augment the stresses within thrombus 240 and attachments 260. Piston 120 and cylinder 220 are operable at variable frequencies (i.e., by changing the speed of motor 180) and variable stroke (crankshaft 160 has multiple holes for stroke selection). Piston 120 typically reciprocates at subsonic (?0.1 Hz to ?20 Hz) to low sonic (?20 Hz to ?50 Hz) frequencies, with stroke appropriate for the frequency and desired pressure or flow amplitude.

[0197] Relatively Higher-Frequency Harmonic Oscillator System (HO) 104. LCO 100 shown in FIG. 1A also depicts a second oscillator system, harmonic oscillator (HO) 104, including sonic transducer 110, acoustic tube 130 and slide 150. Slide 150, depicted in cutaway, is shown in an upward position in FIG. 1A such that acoustic tube 130 is effectively shortened. Sonic transducer 110 operates at low-sonic (?20 Hz) to sonic (up to ?19 kHz) frequencies (i.e., audible frequencies), thus operating at higher frequencies and lower amplitudes than piston 120. Sonic transducer 110 generates one or more standing or traveling waves at one or more frequencies; high frequency standing wave 170 is shown within and emanating from catheter 220. In various embodiments, sonic transducer 110 is a sonic transmitter, a sonic receiver, a sonic transceiver, a hydrophone, a submersible speaker, or the like. For embodiments in which sonic transducer 110 is a sonic transceiver, hydrophone or analogue, the system controller (described in conjunction with FIG. 15) may be operated to intermittently transmit and receive signals in the sonic or audible frequency range.

[0198] The vibrating thrombus 240, attachment 260, catheter 220 and/or vessel wall 280 may emit (as well as absorb) at sonic or subsonic frequencies. In some embodiments, LCO 100 includes a listening mode wherein sonic transducer 110 detects the aforementioned sonic or subsonic frequency emissions to determine vibrational frequencies and/or amplitudes of the system vibrational characteristics.

[0199] FIG. 1B depicts LCO 100 in a different operational configuration in which: (1) piston 120 is at or near Bottom Dead Center (BDC) and (2) acoustic tube 130 is lengthened by moving slide 150 in the downward direction, effectively lengthening acoustic tube 130. In some other embodiments, rollers or pinch valves are used to shorten and lengthen acoustic tube 130. In FIG. 1B, piston 120 is shown at or near BDC such that fluid, generally within catheter 220, has been drawn inward, creating suction that draws thrombus 240 proximally. Attachment 260 is shown stretched proximally in FIG. 1B.

[0200] In FIG. 1B, slide 150 has been moved downward to increase the length of acoustic tube 130, thereby decreasing the frequencies of any standing or traveling waves existent within catheter 220. Low frequency standing wave 190 corresponds to the longer length of acoustic tube 130. In some embodiments, sonic transducer 110 is operated at one or more frequencies that produce standing waves and overtones (n.sup.th harmonics). Some embodiments of the present invention exclude acoustic tube 130 (or a variable-length embodiment thereof), such that fewer or different natural frequencies are generated. Some other embodiments exclude sonic transducer 110, and yet some additional embodiments exclude both sonic transducer 110 and acoustic tube 130. And some additional embodiments include one or both of sonic transducer 110 and acoustic tube 130, but exclude LF oscillator system 102.

[0201] In FIG. 1A and FIG. 1B, two modes of liquid column oscillation and or pressure wave transmission are shown as a single embodiment. LF oscillator 102, shown comprised of piston 120 and cylinder 200, typically operates at relatively lower frequencies and relatively larger (fluid displacement) amplitude. Harmonic oscillator (HO) 104, shown comprised of sonic transducer 110, typically operates at relatively higher frequencies and relatively smaller (fluid displacement) amplitudes. Large-scale movements of thrombus 240 with respect to vessel wall 280 tend occur at lower frequencies. The scale of these movements is expected to be in a range of about 1% to about 50% of a characteristic dimension (e.g., length, diameter, gap, thickness, etc.) of thrombus 240. Such large-scale movements of thrombus 240 tend to stretch, disrupt, break, or disintegrate attachment 260. Small-scale, internal movements of thrombus 240 and attachment 260 occur at relatively higher frequencies and smaller amplitudes. The scale of these movements is expected to range from about 1 nanometer (1 nm) to approximately 5% of a characteristic dimension. These small-scale movements tend to disrupt the structural integrity of both thrombus 240 and attachment 260. The dislodged, disintegrated, or partially disintegrated thrombus 240/attachments 260 are then aspirated.

[0202] Pressure Limiter 10. FIGS. 1C through 1F depict pressure limiter 10 being used in conjunction with LF Oscillator 102. FIG. 1C depicts an exploded/cutaway view of pressure limiter 10, the salient elements of which include: orifice plate 15, pressure limiter piston 20, pressure limiter spring 25, and pressure limiter cylinder 30. Pressure limiter displacement 55 is the distance between pressure limiter piston 20 and orifice plate 15. In the illustrative embodiment, pressure limiter 10 is fluidically coupled to LF oscillator 102 through catheter 220. However, in some other embodiments, pressure limiter 10 is coupled to LF Oscillator 102 via cylinder 200, these two fluid pathways being functionally equivalent.

[0203] Pressure limiter 10 operates by transferring fluid through orifice 17 of orifice plate 15, displacing pressure limiter piston 20 and compressing pressure limiter spring 25. Pressure limiter 10 limits the maximum operational positive pressure (i.e., greater than atmospheric or intravascular pressure) within cylinder 200, but does not limit the extent to which negative pressure (i.e., less than atmospheric or intravascular pressure) is developed. Limiting positive cylinder pressure 45 prevents undesirable outflow of aspirate (or other fluid) through catheter 220. Clinical indications (e.g., antegrade or retrograde native blood flow, risk of embolic release, etc.), might determine the necessity to regulate pressure via pressure limiter 10. Some embodiments of pressure limiter 10 include structures such as a flexible diaphragm, rather than the depicted piston and spring. The pressure limiting setpoint of pressure limiter 10 may be factory or field calibrated or adjusted by, for example, compressing the preload of pressure limiter spring 25. This is accomplished, for example, via a threaded connection between pressure limiter cylinder 30 and orifice plate 15, or an adjustment knob. In some embodiments, orifice 17 is sized to be large enough that flow is unimpeded into (and out of) pressure limiter 10, such that the volume of aspirate outflow (through catheter 220) is diminished or eliminated. Such sizing may be determined by simple experimentation.

[0204] FIG. 1D depicts pressure limiter 10 in operation to limit cylinder pressure 45 in LF oscillator 102. FIG. 1D depicts the compression stroke of LF Oscillator 102. Crankshaft rotation direction 35 depicts counterclockwise rotation of crankshaft 160 such that piston 120 is traveling (to the right) in piston direction 40, thereby increasing cylinder pressure 45. Fluid displaced by the rotation of crankshaft 160 has two potential pathways: (1) through catheter 220 (and into the patient blood stream) and/or (2) through orifice plate 15 and into pressure limiter cylinder 30, thereby increasing pressure limiter pressure 50. As pressure limiter pressure 50 increases, pressure limiter spring 25 becomes compressed as pressure limiter piston 20 is forced downward in FIG. 1D. Neglecting friction between pressure limiter piston 20 and pressure limiter cylinder 30, the magnitude of pressure limiter pressure 50 may be estimated by Hooke's Law, P=kx/A, where P is pressure limiter pressure 50, k is the spring constant of pressure limiter spring 25, A is the area of pressure limiter piston 20, and x is pressure limiter displacement 55, measured from the free length of pressure limiter spring 25.

[0205] FIG. 1E depicts pressure limiter 10 in operation during the intake or suction stroke of LF oscillator 102. Pressure limiter piston 20 is shown in contact with orifice plate 15 such that orifice 17 (not visible in FIG. 1E) is occluded. Piston direction 40 is shown to be to the left in FIG. 1E, and cylinder pressure 45 is generally decreasing throughout the intake or suction stroke. In the event of cavitation or boiling, cylinder pressure 45 may remain approximately constant at approximately the vapor pressure of aspirate, thus achieving maximum vacuum or suction levels (minimum absolute pressure). On the successive (compression) stroke of LF Oscillator 102, cylinder pressure 45 may remain approximately constant (at approximately the vapor pressure) until the vaporized aspirate has condensed to the liquid phase, at which time cylinder pressure 45 may increase.

[0206] Eq. 1 through eq. 8 provide mathematical means to estimate the position, amplitude, velocity, acceleration, and pressure of a finite fluid volume of aspirate within a cylinder 200. Example calculations are provided for given dimensions and at constant operating speed (e.g., Hz, RPM, etc.) for an ideal, massless, inviscid fluid as working fluid or aspirate. In practice, fluid viscosity may limit the fluid velocity and acceleration that develops. As discussed above, some embodiments of LF oscillator 102 include a mechanism to limit maximum pressure, such as pressure limiter 10. Additionally, maximum cylinder pressure 45 may be limited by varying the angular velocity of crankshaft 160 such that the speed of piston 120 is faster on the intake or suction stroke and slower on the successive compression stroke. In this manner, full vacuum (e.g., minimum absolute pressure, cavitation, boiling or vapor pressure, etc.) may be developed during the intake or suction stroke without incurring excessive pressure (and undesirable aspirate outflow) on the compression stroke.

[0207] FIG. 1F depicts an embodiment of pressure limiter 10 that includes exhaust port/tube 22. Pressure limiter piston 20 is depicted displaced downward, compressing pressure limiter spring 25, thereby opening exhaust port/tube 22 (shown open to atmosphere for clarity). Embodiments of pressure limiter 10 with exhaust port/tube 22 include a tube that conveys exhausted fluid to a reservoir or vessel, such as a drain or waste reservoir (not shown). FIG. 1F depicts (LF oscillator 102) piston direction 40 to be rightward, thereby increasing pressure in cylinder 200, catheter 220 and pressure limiter 10. In FIG. 1E, pressure limiter piston 20 is depicted in the upward configuration and thereby closing, occluding or blocking off orifice 17; in FIG. 1F, pressure limiter piston 20 is depicted displaced downwardly, opening both orifice 17 and exhaust port/tube 22. In FIG. 1F, pressurized fluid generally contained within cylinder 200 and catheter 220 flows through orifice 17 and exhaust port/tube 22 to a drain or waste reservoir. The embodiment of FIG. 1F thereby limits pressure generally within catheter 220 to a fixed or adjustable pressure level to a value that is above ambient, atmospheric, or intravascular pressure. This not only limits the magnitude of pressure generally within catheter 220 but also limits, reduces, or diminishes the volume (or mass) of fluid discharged from the distal end of catheter 220 during a compression stroke of LF oscillator 102. Reducing, etc., the volume (or mass) of fluid discharged from the distal end of catheter 220 is often desirable in thrombectomy procedures because downstream vasculature may have decreased diameter that such that a thrombus may be wedged therein due to the flow of discharged fluid.

[0208] Impulse Mechanism 90. FIGS. 1G and 1H depict impulse mechanism 90, which is an alternative to LF oscillator 102 for disrupting or dislodging thrombus 240. It does so by imparting a high pressure, short-duration pressure pulse or and/or travelling wave through catheter 220. Impulse mechanism 90 includes impulse piston 65, cylinder 200, sear 70, hammer 75, and torsion spring 60. Cylinder 200 couples to catheter 220. Vascular access 225 delineates intravascular from extracorporeal portions of catheter 220.

[0209] In FIG. 1G, impulse mechanism 90 is depicted in the cocked or ready configuration. Impulse piston 65 is slidingly engaged within cylinder 200, shown in cutaway view to illustrate impulse piston distance 80. Hammer 75 is shown rotated counterclockwise such that torsion spring 60 is stressed; sear 70 engages in a notch in hammer 75 akin to a firearm hammer/sear assembly.

[0210] FIG. 1H depicts impulse mechanism in the uncocked or fired configuration. Impulse piston distance (referenced as 80 in FIG. 1G) is reduced to effectively zero by the rightward movement of impulse piston 65, displacing fluid distally through catheter 220. In FIG. 1G and FIG. 1H, catheter tip 230 is shown to have penetrated thrombus 240. FIG. 1H does not show any change to the shape of thrombus 240, nor to the interface to catheter tip 230 because any such illustration is speculative. Methodologies of the present invention may include immediate viscometric/flow analysis to assess the thrombectomy efficacy of the fluid impulse imparted by impulse mechanism 90.

[0211] Impulse mechanism 90 imparts a high-pressure, short-duration pressure pulse or and/or travelling wave through catheter 220. The volume of the displaced fluid is approximated by the impulse piston area multiplied by impulse piston distance 80. Typically, the displaced volume is in the range of about 0.01cc to about 5cc. Some embodiments limit the displaced volume to less than approximately 1cc such that undesirable phenomena, including excessive embolization and wedging of a thrombus into a smaller vascular region may be avoided. Impulse mechanism 90 is intended to disrupt or dislodge thrombus 240, but without fragmentation that might release emboli. Impulse mechanism 90 may also be used to clear a clogged or corked catheter 220.

[0212] FIG. 2A through FIG. 2G depict large-scale oscillatory effects of LF oscillator 102 to disrupt, dislodge, or disintegrate thrombus 240 and/or attachments 260. FIGS. 2A through 2D depict a time sequence of thrombus 240 undergoing axial oscillation of amplitude 300 within a blood vessel wall 280. FIGS. 2A through 2D illustrate large scale oscillations of thrombus 240. These large-scale oscillations typically occur at relatively low frequency operational range of the present invention (e.g., approximately 0.1 Hz to 50 Hz).

[0213] FIG. 2A depicts thrombus 240 in a quiescent state and connected to vessel wall 280 by multiple attachments 260. Attachments 260 are shown vertical and unstressed. In the absence of any interventional device, such as a thrombectomy catheter, FIG. 2A represents the thrombus as it exists (generally in static equilibrium) in an untreated patient. Attachments 260 are shown to be symmetrically emanating in multiple radial directions from thrombus 240; clinically, thrombus 240 may exhibit significant asymmetry within vessel wall 280, and attachments 260 may exist in a portion of the perimeter, boundary, or circumference of vessel wall 280.

[0214] FIG. 2B depicts oscillatory flow 290 discharging (in the distal direction) from catheter tip 230 and directed to impinge upon thrombus 240 and/or attachment 260. Forces, including momentum, viscous drag, differential pressure, pressure drag and/erosive forces, are shown to stretch attachments 260 and translate thrombus 240 in the distal direction to generate the configuration shown in FIG. 2B. Oscillatory flow 290 is approximately equal to the sum of flow produced by LF oscillator 102 and any supplemental flow (e.g., aspiration, infusion, etc.) that may simultaneously exist.

[0215] In FIG. 2C, after oscillatory flow 290 (not shown, having an instantaneous zero velocity) from catheter tip 230 has subsided, thrombus 240 has returned to a neutral position and attachments 260 have relaxed to an unstressed configuration. For clarity, thrombus 240 and piston 120 are depicted in phase with one another (i.e., phase angle ((I)) is chosen to be approximately equal to zero).

[0216] FIG. 2D depicts oscillatory flow 290 entering catheter tip 230 (in the proximal direction); thrombus 240 is shown translated proximally and attachment 260 is shown stretched in the proximal direction. Oscillatory flow 290 is shown with a longer arrow in FIG. 2D than in FIG. 2A; this illustrates that a net aspiration inflow exists during this representative cycle.

[0217] In FIG. 2A through FIG. 2D, thrombus 240 is shown to oscillate through amplitude 300 by comparing relative thrombus 240 positions in FIG. 2B (distally extended) to FIG. 2D (proximally retracted). Amplitude 300 may be a function of system process variables (e.g., factors, levels, setpoints, adjustments, etc.) including frequency and stroke of LF oscillator 102 and/or harmonic oscillator (HO) 104. In some embodiments, amplitude 300 is at or near maximum when the frequency is at or near a natural frequency of the system comprising thrombus 240, attachments 260 and vessel wall 280. LF oscillator 102 is capable of generating flow at a variety of different frequencies, more than one of which may cause thrombus 240 to rock, twist, or rotate with respect to vessel wall 280. Other frequencies of flow generated by the system (including harmonic oscillator (HO) 104) are likely to cause internal vibrations within thrombus 240, and compromise the structural integrity thereof.

[0218] In FIG. 2E through FIG. 2G, thrombus 240 is depicted in a substantially stationary position, while vessel wall 280 is depicted as being excited (in vibrational modes) at three representative frequencies, which may be resonant frequencies. FIG. 2E through FIG. 2G depict instantaneous snapshots of vessel wall 280 at any given instant. Each of FIG. 2E through FIG. 2G depict different configurations (shapes) of vessel wall 280, as results from the vibrational mode excited at any given instant in time. It is possible that standing waves will develop in the vasculature or vessel wall.

[0219] In FIG. 2E, vessel wall 280 is shown to be instantaneously distended; this is representative of a first vibrational mode. In this mode, thrombus 240 remains stationary while attachments 260 are stretched (during the distention phase of the oscillation). An associated contraction phase is not shown, wherein vessel wall 280 will have a concave form.

[0220] FIG. 2F depicts vessel wall 280 assuming a different shape (from FIG. 2E) wherein an undulating profile is observed; this is representative of a second vibrational mode. In this mode, thrombus 240 remains substantially stationary while some attachments 260 are stretched and other attachments 260 are compressed. FIG. 2G depicts vessel wall 280 assuming a different undulating profile (from FIG. 2F); this is representative of a third vibrational mode.

[0221] The three vibrational modes depicted in FIG. 2E through FIG. 2G are but a few of the many vibrational modes that vessel wall 280 may experience as a function of the operation of LCO 100. Similarly, the vibrational modes depicted in FIG. 2A through FIG. 2D are representative of innumerable vibrational modes that thrombus 240 may experience. In some embodiments, LF oscillator 102 sweeps or continuously varies frequency throughout a range, and may therefore excite vibrational modes of either or both thrombus 240 and vessel wall 280. The vibrational modes of thrombus 240 and vessel wall 280 may be coupled to one another, which may cause constructive or destructive interference of the two vibrating structures.

[0222] The vibrational oscillatory motion of thrombus 240 and vessel wall 280 as depicted in FIG. 2A through FIG. 2G depicts extension and contraction of attachment 260 by changing the distance between thrombus 240 and vessel wall 280. This relative motion repetitively stresses attachment 260, effectively breaking the physical connection such that thrombus 240 is dislodged for aspiration. LF oscillator 102 imparts relative motion between thrombus 240 and vessel wall 280; this motion may be oscillatory and may be a form of generalized harmonic motion. The LCO 100, LF oscillator 102 and/or harmonic oscillator HO 104 thrombectomy system may also impart internal, vibrational stresses within thrombus 240, which leads to partial, significant, or total disintegration of thrombus 240 independently of the relative motions between thrombus 240, vessel wall 280 and attachment 260.

[0223] Some embodiments of the invention analyze data predicated upon deterministic events of the thrombectomy procedure underway and assess thrombectomy efficacy; this may be expanded to include measurement of blood pressure at or near catheter tip 230. An intra-procedural change in blood pressure may also be a quantitative indicator of overall thrombectomy efficacy. For instance, in procedures wherein a catheter is positioned downstream of a thrombotic lesion (i.e., downstream approach), increases in measured blood pressure at or near catheter tip 230 may be indicative of increased flow past a thrombotic lesion. Likewise, in procedures wherein a catheter is positioned upstream of a thrombus (i.e., upstream approach), decreases in measured blood pressure at or near catheter tip 230 may be indicative of increased flow past a thrombotic lesion. Measured increases in native blood flow rate may rationally be attributed to a summation of deterministic events preceding the measurements and also to the current state of thrombectomy efficacy. Some embodiments of the invention thereby provide intra-procedural diagnostic information quantifying the overall (present-state) efficacy of the procedure at any time during the procedure. Thrombus 240 is generally depicted as a solid mass which restricts blood flow through the vasculature; therefore a differential pressure is typically existent on opposite sides of thrombus 240.

[0224] During the course of a thrombectomy procedure, as thrombus 240 is disintegrated, ablated or otherwise diminished in size, native blood flow rate will increase; the consequent (quantitatively measured) change in differential pressure is utilized in some embodiments to intra-procedurally quantify the improvement in native blood flow rate. In procedures wherein catheter 220 is deployed on the downstream side of occlusive thrombus 240 (herein referred to as downstream approach), local blood pressure at catheter tip 230 is typically diminished below optimal values. In procedures wherein catheter 220 is deployed on the upstream side of occlusive thrombus 240 (herein referred to as upstream approach), local blood pressure at catheter tip 230 is typically augmented above optimal values.

[0225] FIG. 2G is illustrative of both upstream approach and downstream approach thrombectomy procedures; a significant difference being the direction of native blood flow. Aspirate flow 295 is depicted in the right-to-left orientation; native blood flow direction may be either parallel or anti-parallel to the direction of aspirate flow 295, depending upon the approach. Downstream approach procedures are performed by deploying catheter tip 230 downstream of thrombus 240. In downstream approaches, native blood flows in aspiration flow direction 294, thereby locating catheter tip 230 on the low pressure side of thrombus 240. In downstream approaches, pressure p1 298 is typically less than pressure p2 299, because thrombus 240 presents a flow restriction. Conversely, upstream approach procedures are performed by deploying catheter tip 230 upstream of thrombus 240. In upstream approaches native blood flows in infusion flow direction 296 (which is anti-parallel to aspiration flow direction 295), thereby locating catheter tip 230 on the high pressure side of thrombus 240. In upstream approach procedures, pressure p1 298 is typically greater than pressure p2 299, because pressure p1 298 is on the upstream side of flow restriction thrombus 240. Intra-procedurally, pressure p1 298 (and time dependent fluctuations, e.g., cardiac cycle) may be measured at any time, whereas pressure p2 298 may generally not be measured without complications such as crossing the lesion. Real-time measurements of blood pressure at or near catheter tip 230 may be taken at any time during a thrombectomy procedure by reducing the aspiration rate (in this context, absolute flow rate) through the catheter to zero or near zero by means such as stopping aspirate pump 440 or closing a valve in alternative embodiments (not shown). At zero or near zero absolute flow rate, pressure p1 298 may be approximately measured by pressure transducer 420 in fluid communication with catheter 220. The accuracy of the blood pressure measurement at or near catheter tip 230 may be improved by substituting saline (??1 cP) for blood (??4 cP) by means such as saline flush or saline exchange because any non-zero flow rate is accompanied by a pressure drop.

[0226] Embodiments of the invention which measure pressure p1 298 proximate to thrombus 240 provide diagnostic information regarding any change in native blood flow rate around thrombus 240. Thrombus 240 is assumed to be quantitatively occlusive (e.g., 20%, 40%, 60%, 100%, etc.); under flowing conditions, a differential pressure between pressure p1 298 and pressure p2 299 will therefore typically exist. In an example downstream approach DVT (Deep Vein Thrombosis) thrombectomy procedure, pressure p1 298 may be initially measured to be approximately 20?3 mmHg. Midway through the procedure, pressure p1 298 may be measured to be approximately 25?4 mmHg and, at the conclusion of the procedure pressure p1 298 may be measured to be approximately 30?5 mmHg. The example 50% increase in average/nominal pressure p1 298, as a result of the thrombectomy procedure, quantitatively measures improvement in native blood flow. In cases of upstream approach thrombectomy procedures, measured pressure p1 298 may be expected to exhibit a decrease as result of the procedure. The initial, intermediate, and final measurement data (of pressure p1 298) may be correlated to predetermined values (e.g., historical data, database, knowledge base, etc.), such that overall procedure efficacy may be quantitatively measured in terms of changes in blood pressure at or near the site of the lesion (thrombus). Thusly, some embodiments of the invention measure native blood flow rateexternal to the catheterby measuring flowing pressure proximate to a thrombus. This is in contrast to prior art methods which collect pressure data and determine characteristics of flow internal to the catheter. Prior art is limited to monitoring (or perhaps measuring) blood flow characteristics or states within the catheter; in contrast, some embodiments of the invention measure intravascular blood flow.

[0227] FIG. 3A through FIG. 3D illustrate an embodiment and example methodology to viscometrically detect the distance between catheter tip 230 and thrombus 240 (herein, viscometric distance sampling); this distance is shown in FIG. 3A through FIG. 3D as tip to thrombus distance 250. In this example embodiment, system controller 810 (depicted in FIG. 8 and FIG. 15) receives data from system instrumentation including pressure transducer 420 and accelerometer 410, and exerts control over system components including aspirate pump 440 and motor 180. Some embodiments of the present invention utilize a method that takes viscometric measurements upon a small sample volume (range of 0.2cc to 5cc), typically in less than one second (range of 0.2s to 5s). If this small sample of aspirate is measured to have viscosity consistent with that of blood (?4 cP), the sample may be determined to be pure or unadulterated with thrombus; this pure sample may be returned to the bloodstream by means such as reversal of aspirate pump 440. Thusly, aspirate samples may be viscometrically measured with negligible, zero or near-zero blood loss.

[0228] FIG. 3A depicts catheter tip to thrombus distance 250 as too large for efficacious thrombus aspiration; catheter tip to thrombus distance 250 is shown to be greater than the diameter of vasculature generally bounded by vessel wall 280. Application of vacuum or suction in this configuration typically results in blood loss without successful harvesting of thrombus 240. The measured viscosity of aspirate samples is typically approximately equal to that of blood. System controller 810 (depicted in FIG. 8 and FIG. 15) may indicate to the clinician that the catheter tip to thrombus distance 250 is too large by any communication means including audiovisual. The clinician may be thereby advised to advance or otherwise reposition the catheter 220, this occurring with a minimum of blood loss in making the distance determination. In alternative embodiments the physical act of advancing, retracting or repositioning of catheter 220 into proper catheter tip to thrombus distance 250 is mechanically executed under mechanized or automated control.

[0229] FIG. 3B depicts catheter in an example optimal position; catheter tip to thrombus distance 250 is shown to be less than the diameter of catheter tip 230. Application of vacuum or suction in the configuration of FIG. 3B may cause thrombus 240, or a portion thereof, to enter catheter tip 230. The measured aspirate viscosity for the configuration of FIG. 3B may range from approximately 4.1 cP to in excess of approximately 50 cP, with a greater measured viscosity being indicative of a smaller catheter tip to thrombus distance 250. As catheter 220 is continuously or incrementally advanced toward thrombus 240, system controller 810 measures a continuous or incremental increase in aspirate viscosity; this viscosity measurement being indicative of the magnitude (and sign) of catheter tip to thrombus distance 250. An optimum catheter tip to thrombus distance 250, (or range of distances) as measured viscometrically may be experimentally determined; this predetermined value may be stored in memory, firmware or software of system controller 810.

[0230] FIG. 3C depicts a negative catheter tip to thrombus distance 250 wherein catheter tip 230 has pierced or penetrated thrombus 240, forming thrombus bolus 245. The measured aspirate viscosity for the configuration of FIG. 3C may range from approximately 51 cP to in excess of 10,000 cP. The configuration of FIG. 3C depicts a scenario wherein a clog or imminent clog is viscometrically detected by system controller 810. System controller 810 may respond to the measured catheter tip to thrombus distance 250 in one or more ways including: mechanically or advising the clinician to advance or retract catheter 220, applying vacuum/suction levels (e.g., reduced, intermittent, interspersed, reversing, etc.) appropriate to the clinically measured catheter tip to thrombus distance 250. System controller 810 employs thrombectomy control flowchart 901, algorithm and/or subroutine (such as distance subroutine 1050, subsequently presented in conjunction with FIG. 9C) to invoke a prescribed course of action (e.g., repositioning of catheter 220, speed of aspirate pump 440, speed of infusion pump 460, etc.). Prescribed course of action may be determined by system controller 810 by means including algebraic, ratiometric or other quantitative method that simultaneously minimizes blood loss and likelihood of clogging or corking catheter 220.

[0231] FIG. 3A through FIG. 3C depict embodiments and methods to efficaciously aspirate thrombus 240 by incorporating measurements of system parameters including viscosity, pressure, % thrombus and/or relative flow rate; these measurements are detailed in co-pending applications listed as references. FIG. 3A depicts a partial cutaway view of LF oscillator 102 in an embodiment that includes: aspirate pump 440, pressure transducer 420 and accelerometer 410. Motor 180 rotates crankshaft 160 such that connecting rod 140 and piston 120 are rotated and/or translated; piston 120 is shown at or near TDC (Top Dead Center) of cylinder 200, shown in cutaway view. Rotation of crankshaft 160 (up to approximately 180? from TDC) causes piston 120 to move leftward, thereby reducing pressure within catheter 220. Sufficiently rapid rotation of crankshaft 160 (up to approximately 180? from TDC) may effect cavitation or boiling pressure to develop within cylinder 200 and catheter 220; alternate embodiments include syringes, linear actuators, evacuated reservoirs, etc. that are equivalently employed to generate low absolute pressure conditions including cavitation or boiling pressure. Cavitation or boiling pressure (within cylinder 200 and/or catheter 220) may represent the minimum pressure physically attainable and may therefore generate the maximum attainable suction to aspirate thrombus 240. Thus, the system in FIG. 3A is shown poised or primed to activate, engage, supply or deliver maximum aspiration suction/vacuum upon rapid rotation of crankshaft 160 or other embodiment analogue such as a syringe. In FIG. 3A however, catheter tip to thrombus distance 250 is measured to be too large for activation or engagement of significant aspiration suction/vacuum.

[0232] The embodiment and configuration of FIG. 3A illustrates another feature of the present invention: the rapid aspiration of a limited volume of aspirate by rapidly rotating crankshaft 160 through angular displacement of approximately 180? (or less). An angular rotation of approximately 180? may occur in less than 1 second (range of approximately 0.1s to 3s). Using the dimensions of a previous example, LF oscillator 102 of dimensions of 1 cm bore and 1 cm stroke and exhibits a displacement of approximately 0.8cc. Thusly, the depicted embodiment and configuration of FIG. 3A is capable of increasing the system volume by approximately 0.8cc in less than one second. In some clinical situations (catheter dimensions, % thrombus, etc.) this volumetric displacement is rapid enough to develop cavitation or boiling pressure within cylinder 200. This embodiment and method provide two desirable attributes: (1) minimum pressure is developed for maximum initial aspiration rate, and (2) the volume of aspirate is limited to the displacement of piston 120 (in this example case, 0.8cc). This is in contrast to prior art thrombectomy systems wherein an evacuated reservoir, syringe or peristaltic pump imposes no limitation on the volume aspirated. Furthermore, the detailed embodiment and method may reduce the likelihood of clogging or corking a catheter 220 due to over-ingestion of thrombus 240. This method enables embodiments of the invention to aspirate thrombus 240 as discretized thrombus bolus 245, which may be sequentially aspirated, thereby avoiding over-ingestion, clogging and/or corking.

[0233] In the configuration of FIG. 3C, depicting negative catheter tip to thrombus distance 250, catheter 220 may be withdrawn slightly (range of approximately 1 to 5 times the diameter of catheter 220) such that successive aspiration is comprised predominantly of blood such that discrete thrombus bolus 245 is successfully aspirated without incurring measured viscosity levels that risk clogging or corking. Embodiments of the present invention thereby limit the measured level of % thrombus by judiciously by withdrawing and/or advising the clinician to withdraw catheter 220 such that blood dilutes the aspirate composition to exhibit a flowable characteristic under aspiration suction/vacuum.

[0234] FIG. 3D depicts a configuration wherein catheter tip 230 has been repositioned (i.e., withdrawn) proximally from the configuration depicted in FIG. 3C; catheter tip to thrombus distance 250 is shown positive such that blood may flow into catheter tip 230 under aspiration. This repositioning of catheter 220 may be effected by automated means or by advising a clinician to execute the withdrawal or retraction. Thrombus bolus 245 is depicted to be separated from thrombus 240, and may be aspirated discretely from thrombus 240. In this manner, the bulk or whole of thrombus 240 may be aspirated as a plurality of discrete instances of thrombus bolus 245. In the configuration of FIG. 3D, thrombus bolus 245 may be aspirated at maximum or near-maximum vacuum/suction provided that viscometric sampling returns a measurement less than a value predetermined to be indicative of a clogged or corked catheter.

[0235] Objectives of some embodiments of the present invention include the measurement, determination or detection of the catheter tip to thrombus distance 250. A knowledge-based thrombectomy system may subsequently regulate, adjust or modulate the vacuum/suction (including cavitation or boiling pressure) to levels appropriate for system parameters including the catheter tip to thrombus distance 250. A further objective of the present invention is to regulate, adjust or modulate the vacuum/suction to levels such that aspiration of thrombus 240 occurs with a minimized occurrence of clogging or corking of catheter 220 or catheter tip 230; clogging or corking of catheter 220 or catheter tip 230 may be exacerbated if maximum or near-maximum levels of suction/vacuum are developed.

[0236] FIG. 3B depicts catheter tip 230 and thrombus 240 to be separated from one another by distance smaller than in FIG. 3A and is purported to be representative of a first favorable or desired catheter tip to thrombus distance 250; values may range from 0 mm to less than approximately the blood vessel diameter or between 0 mm to less than approximately the three times catheter diameter. Catheter tip 230 is depicted in close proximity to thrombus 240 such that bloodflow into catheter tip 230 may be partially impeded or occluded by thrombus 240. Delivering maximum or near-maximum vacuum/suction levels (in the configuration of FIG. 3B) may result in efficacious aspiration of thrombus 240. Accelerometer 410 is shown affixed to catheter 220 such that the clinician input of advancing catheter tip 230 into proximity to thrombus 240 may be measured and the data stored and/or correlated to changes in aspirate viscosity. Accelerometer 410 may be a 3-axis or 6-axis (including gyroscopic) accelerometer or other absolute or relative position sensor. As an example, catheter 220 may have been advanced 4 mm and rotated 90? clockwise to assume the configuration of FIG. 3B. Measured viscosity may have increased from approximately 4 cP (in FIG. 3A) to approximately 10 cP (in FIG. 3B) because inflow of blood into catheter tip 230 may be impeded by the close proximity to thrombus 240 (approximate range of 0.01 mm to 3 mm) without actually penetrating thrombus 240. Appropriate values for measured viscosity (e.g., 10 cP, 30 cP, 50 cP, etc.) which correspond to a favorable or desired catheter tip to thrombus distance 250 may be determined by simple experimentation.

[0237] FIG. 3C depicts a configuration wherein catheter tip 230 has penetrated thrombus 240 and a thrombus bolus 245 has formed; data from accelerometer 410 may quantify the linear and rotational speeds and distances imparted to catheter 220 during this manipulation or maneuver. Catheter tip to thrombus distance 250 is shown to be negative in FIG. 3C; this configuration may arise in the absence of any suction/vacuum being applied because the catheter tip 230 may physically pierce soft variants of thrombus 240. Delivering maximum vacuum/suction levels (in the configuration of FIG. 3C) may result in clogging or corking of catheter tip 230 such that ancillary procedures (e.g., device removal, manual manipulation of guidewire, macerator or obturator, etc.) may be required to clear the clog. The severity of such a clog may be directly related to the vacuum/suction level applied. Some embodiments of the present invention regulate or modulate the vacuum/suction level such that thrombus bolus 245 may be aspirated in a controlled manner such that clogging or corking is avoided. Viscosity measurements for the configuration of FIG. 3C may exceed 500 cP, indicating a clog or impending clog. In some embodiments, data from accelerometer 410 (e.g., advance catheter 220 2 mm at 1 mm/second, rotate counterclockwise 90?, etc.) is correlated to the measured viscosity to determine the efficacy of the manipulation or maneuver.

[0238] Some embodiments of the present invention include the determination of an appropriate vacuum/suction level for efficacious aspiration of thrombus 240 or thrombus bolus 245 while minimizing blood loss and phenomena including clogging or corking which may require manual clinician intervention. FIG. 3A is representative of a catheter tip to thrombus distance 250 which may be determined or inferred to be too large for effective aspiration of thrombus. In this configuration, thrombectomy operating modes such as viscometric sampling may be indicated as effective treatment as catheter tip 230 is advanced into closer proximity to thrombus 240. FIG. 3B depicts a representation of a catheter tip to thrombus distance 250 which may be determined or inferred to be appropriate for maximum vacuum/suction levels; limiting the duration of the maximum vacuum/suction levels may be important to facilitate aspiration of thrombus bolus 245 and to avoid the phenomenon of clogging or corking. FIG. 3C is representative of a (negative) catheter tip to thrombus distance 250 which may be determined to be appropriate for intermediate vacuum/suction levels including of short duration; an objective may be to isolate thrombus bolus 245 in order that it may be aspirated discretely from thrombus 245. This may be accompanied or facilitated by withdrawing catheter 220 proximally in order that thrombus bolus 245 becomes physically separated from thrombus 240 for more efficacious aspiration by limiting the % thrombus concentration (or viscosity or relative flow rate) of fluid within catheter 220.

[0239] FIG. 3A through FIG. 3D depict spatial differences which are represented by catheter tip to thrombus distance 250, illustrated as positive and excessive (in FIG. 3A), positive and within optimal range (in FIG. 3B), negative (in FIG. 3C) and positive and within optimal range (in FIG. 3D). This spatial difference may be detected by the measured viscosity, % thrombus or relative flow rate through catheter 220. In FIG. 3A, fluid flow into catheter tip 230 is shown to be unoccluded and the relative flow rate may be measured as maximum by flow measurement means including time-domain viscometry. In FIG. 3B, fluid flow into catheter tip 230 is shown to be partially obscured and a diminished relative flow rate may be measured as an increase in viscosity. In FIG. 3C, fluid flow into catheter tip 230 is shown to be effectively occluded and a relative flow rate that is very low or approaching zero may be measured at low vacuum/suction levels. In this configuration, application of high vacuum/suction levels may induce clogging or corking of catheter 220

[0240] Some embodiments of the present invention may include methods wherein thrombus bolus 245 (as shown in FIG. 3C and FIG. 3D) may be aspirated in conjunction with proximal withdrawal (range between approximately 0.5 mm and 10 mm) of catheter 220 (i.e., to the example configurations of FIG. 3A and/or FIG. 3B). The configuration of FIG. 3D depicts catheter tip to thrombus 250 to be positive and sufficient that blood may flow into catheter tip 230 thereby isolating thrombus bolus 245. Thereby, each discrete thrombus bolus 245 may traverse catheter 220 proximally by means including vacuum/suction aspiration and/or oscillatory fluid motion. Thus, thrombus bolus 245 may be aspirated extracorporeally, while the remaining portion of thrombus 240 remains effectively intact and awaiting aspiration by successive processes. FIG. 3A through FIG. 3D illustrate incorporation or integration of relative flow rate measurement (by means including viscometric sampling and/or time-domain viscometry); this leads to a quantitative determination of appropriate vacuum/suction levels and durations to efficaciously aspirate thrombus independently of any ancillary features or system components (e.g, LCO 100, LF oscillator 102 and or harmonic oscillator HO 104, hydrodynamic lance, macerator, obturator, etc.). Catheter 220 is shown in 4 different axial positions in FIG. 3A, FIG. 3B, FIG. 3C and FIG. 4D (rotation may or may not have occurred) by means including clinician input (manual manipulation) and/or automated or mechanized catheter positioning. Concomitantly, accelerometer 410 may measure, store and/or correlate the displacements to measured thrombectomy efficacy. In some embodiments catheter tip to thrombus distance 250 is effected mechanically enacted by means of system controller 810 and motors, actuators, grippers, etc. (not shown).

[0241] Example control responses from system controller 810 are further detailed in conjunction with FIG. 9A through FIG. 9D. Example thrombectomy system control responses for each configuration of FIG. 3A through FIG. 3D may be defined such as: [0242] a. FIG. 3A, catheter tip to thrombus distance 250 is positive and excessive. Unimpeded flow is measured (e.g., relative flow rate?100% or ??4 cP or). Example control responses include: viscometric sampling, viscometric distance sampling, approximately 5% to 20% aspiration rate. [0243] b. FIG. 3B, catheter tip to thrombus distance 250 is positive and within efficacious range. An intermediate flow restriction or obstruction is measured (e.g., relative flow rate is between approximately 20% and 90% or 10 cP<?<200 cP). Example control responses include: approximately 50% to 100% aspiration rate, invoke other system parameters, factors or means to attrite thrombus (e.g., LF oscillator 102, HO 104, infusion, etc.). [0244] c. FIG. 3C, catheter tip to thrombus distance 250 is negative, clogging may occur. A large flow restriction or obstruction is measured (e.g., relative flow rate is between approximately 0% and 10% or ?>400 cP). Example control responses include: volume-limited aspiration, impulse mechanism 90, repositioning of catheter 220, clog detect/avert subroutine 1060, etc.). [0245] d. FIG. 3D, catheter tip to thrombus distance 250 is positive and within efficacious range, thrombus bolus 245 is within catheter tip 230. Relative flow rate may be increased from FIG. 3C (e.g., relative flow rate may be between approximately 0% and 100% or 4 cP<?<10,000 cP); example control responses include: volume-limited aspiration, impulse mechanism 90, maximum aspiration, viscometric sampling, LF oscillator 102, harmonic oscillator 104, etc.). Some example control responses are codified in example subroutines, (e.g., distance subroutine 1050 and example clog detect/avert subroutine 1060 or similar), as depicted in FIG. 9C and FIG. 9D.

[0246] FIG. 4A depicts fluid pressure vs time waveforms calculated (using Eq. 1 through Eq. 8) to exist within cylinder 200 of low frequency oscillator 102; three example combinations of frequency and stroke are depicted. In FIG. 4A the fluid is water or saline with viscosity of approximately 1 cP. Three characteristic waveforms exist; one waveform for each combination of frequency and stroke. A combination of frequency and stroke may be herein termed FSn, where n represents the n.sup.th such combination under consideration; an example is FS1 (abbreviation for Frequency/Stroke combination 1). FIG. 4A depicts three Frequency/Stroke combinations: FS1 510 (1 Hz, 5 mm stroke), FS2 520 (0.5 Hz, 10 mm stroke) and FS3 530 (2 Hz, 7 mm stroke). With water or saline as working fluid, the amplitude of each waveform (FS1 510, FS2 520 and FS3 530) is generally a function of parameters including stroke, catheter 220 length, diameter and elasticity; the period is generally a function of frequency. The ordinate of FIG. 4A has units of mmHg absolute pressure. Herein it is assumed that the average intravascular pressure may be approximately 40 mmHg (above atmospheric pressure, 760 mmHg) and that the average absolute pressure may be approximately 800 mmHg; 800 mmHg absolute may be termed nominal, intravascular or ambient pressure herein. In accordance with Design Of Experiments (DOE) nomenclature the frequency and stroke (e.g., of low frequency oscillator 102) may be considered factors; specific or approximate frequencies (e.g., 1 Hz, 20 Hz, 37 Hz, etc.) and strokes (e.g., 1 mm, 3.65 mm, 5 mm, etc.) may be considered levels. The example frequency/stroke combinations (FSn) illustrate a two factor (frequency and stroke), three level (0.5 Hz, 1 Hz, 2 Hz and 5 mm, 7 mm and 10 mm) experiment design.

[0247] FIG. 4A illustrates that an LF oscillator 102 (operating at approximately constant angular velocity) theoretically generates approximately sinusoidal pressure waveforms. Waveforms depicted in FIG. 4A (FS1 510, FS2 520 and FS3 530) may be representative of a particular LCO 100 or LF oscillator 102 embodiment; other system component variables including catheter 220 length, diameter and elasticity also influence the amplitude. A short, large diameter catheter 220 may generally operate at lower pressure amplitudes because: (1) for a given differential pressure, a shorter column of liquid may accelerate faster than a longer column of the same liquid because of the difference in mass, and (2) a larger diameter catheter 220 enables greater mass flow at lower velocities with correspondingly less viscous dissipation (frictional losses). The viscosity of the fluid contained within catheter 220 also affects the waveform amplitude. A more viscous fluid requires a greater differential pressure for any given fluid oscillation amplitude, therefore a more viscous fluid typically exhibits waveforms of greater pressure amplitude.

[0248] In FIG. 4A, pressure waveform FS1 510 exhibits amplitude of approximately ?200 mmHg superposed over an 800 mmHg nominal pressure; waveform FS2 520 exhibits amplitude of approximately ?500 mmHg and waveform FS3 530 exhibits amplitude of approximately ?800 mmHg. Waveform FS3 530 correspondingly depicts a minimum pressure of 0 mmHg absolute; cavitation or boiling may occur at any pressure at or below approximately 50 mmHg (the approximate vapor pressure of blood/water at 37? C.). Certain embodiments of an LCO or knowledge based thrombectomy system may employ cavitation within cylinder 200 for reasons including: (1) the physical limits of low pressure (e.g., approximately 50 mmHg absolute) are generated for maximum dislodgement and aspiration effects and (2) the collapse of cavitation or boiling bubbles or voids in cylinder 200 may generate shock waves that traverse the length of catheter 220 and directly impinge upon thrombus 240 and/or attachment 260. Some methods, embodiments and process variables (e.g., FS3, FS5, FS7, FS9, etc.) of the present invention include cavitation-inducing waveforms which generate alternating sequence of maximum vacuum and shock-induced pressure waves; whereas other process variables (e.g., FS1, FS2, FS4, etc.) deliver alternate or non-cavitating waveforms including: other therapeutic waveforms, diagnostic waveforms or viscometric waveforms.

[0249] FIG. 4B depicts a corresponding pressure (amplitude) decay which typically occurs along the length of catheter 220; the pressure decay observed in FIG. 4B may be attributed to factors including: (1) viscous friction (resistance) and (2) system compliance (capacitance). FIG. 4B illustrates that even though pressures exceeding 2bar (1,500+mmHg) absolute and full vacuum may occur within cylinder 200; the amplitude of each pressure waveform is diminished with distance along catheter 220 away from cylinder 200. For the example combination of LCO 100 and FS1 510, FS2 520 and FS3 530 (with water as the working fluid, i.e., the fluid contained within catheter 220) it is evident that the pressure amplitude present at catheter tip 230 is diminished from the pressure amplitude generated within cylinder 200. FS1 510 exhibits pressure amplitude of approximately 200 mmHg within cylinder 200; the pressure amplitude at catheter tip 230 is diminished to approximately 100 mmHg. FS2 520 exhibits pressure amplitude of approximately 500 mmHg within cylinder 200; the pressure amplitude at catheter tip 230 is diminished to approximately 200 mmHg. FS3 530 exhibits pressure amplitude of approximately 800 mmHg within cylinder 200; the pressure amplitude at catheter tip 230 is diminished to approximately 200 mmHg. FIG. 4B is included to illustrate that any pressure or vacuum condition that exists (including extreme examples such as cavitation or boiling) at or near the proximal end of a catheter may not be inferred to be present at the distal end of the catheter, particularly under flowing conditions. FIG. 4B generally illustrates the dissipative (i.e., frictional) effect of viscosity in a fluid. In cases where aspirate is flowing through a catheter, the greater the fluid velocity, the greater the dissipative losses incurred along the length of the catheter. In cases wherein the flow velocity is at or near zero, dissipative losses are at or near zero. In cases of a clogged catheter, a pressure discontinuity may exist across the clog; however, with near zero flow, there exists nearly zero dissipative (frictional) losses as result of viscosity. FIG. 4B is included to illustrate that measuring the pressure at the proximal end of catheter 220, in conjunction with a measurement of aspirate viscosity or flow rate, enables an inference of the pressure (and/or pressure amplitude) at catheter tip 230.

[0250] Some embodiments of the present invention generate a plurality of continuous or discrete pressure waveforms (e.g., FS1 510, FS2 520, FS3 530, . . . , FSn) such that a spectrum of waveforms may be delivered to the target site, e.g., thrombus 240 and surrounding tissue. This increases the likelihood of generating one or more waveforms which excite one or more vibrational modes of any or all of: (1) thrombus 420, (2) attachment 460, (3) vessel wall 280, and (4) catheter 220.

[0251] FIG. 4C depicts a representative functional relationship between pressure waveforms and fluid viscosity; FS1 510 is the frequency/stroke setting of LF oscillator 102; the fluids of different viscosity are shown to generate pressure amplitude waveforms that are typically proportional to the fluid viscosity. In FIG. 4C, water (?1 cP viscosity) is shown to generate the same FS1 510 waveform/pressure amplitude as shown in FIG. 4A; water's pressure amplitude is shown to be approximately ?200 mmHg. Blood (?4 cP viscosity) is shown to generate a waveform with pressure amplitude greater than that of water; blood's pressure amplitude is shown to be approximately ?500 mmHg. SAE 30 motor oil (?35 cP viscosity) is shown to generate a waveform with pressure amplitude of approximately +2,000/?800 mmHg. The pressure amplitude for SAE 30 motor oil indicates that cavitation or boiling may occur because the waveform shows pressures less than approximately 50 mmHg absolute (this being dependent upon parameters including the vapor pressure of SAE 30 motor oil). In cases wherein the pressure falls below the cavitation or boiling pressure (approximately 50 mmHg for saline and/or blood), the positive value of the pressure amplitude is the relevant quantity, because the absolute pressure cannot attain negative values, as shown in FIG. 4C. In some embodiments, an LCO 100 or LF oscillator 102 comprising a pressure measurement device may act as a viscometer; the viscosity of the fluid may be proportional to the (positive) pressure amplitude. In other embodiments an LCO 100 or LF oscillator 102 may act as a viscometer by measuring the current draw to motor 180 because the increased operating pressure (generally within cylinder 200) requires an increase in motor 180 torque.

[0252] FIG. 4A, FIG. 4B and FIG. 4C depict representative, ideal pressure vs time waveforms as generated by an LCO 100 or LF oscillator 102; depicted is the differential pressure between the proximal end of catheter and a second pressure, such as intravascular, nominal or atmospheric pressure. These idealized oscillatory pressure waveforms give rise to oscillatory flow within a catheter (assuming homogeneous, inviscid, massless fluid in the absence of cavitation or boiling). This is because depicted embodiments of LCO 100, LF Oscillator 102 and harmonic oscillator HO 104 are positive displacement apparatus that repetitiously increase and decrease the extracorporeal system volume. Idealized oscillatory flow (in the absence of aspiration or infusion) is positive displacement with zero net flow.

[0253] Oscillatory flow, as implemented in embodiments of the invention, may be distinguished from other forms of positive-displacement pulsatile flow apparatus such as pumping systems including piston pumps, pulse generators, diaphragm or peristaltic pumps. These example pulsatile pumping systems generally exhibit positive displacement characteristics but are designed to deliver flow in a single flow direction. Oscillatory flow may also be distinguished from flow resultant from pulsed or intermittent application of differential pressure from pressurized or evacuated reservoirs. Pressurized or evacuated reservoirs are typically termed dynamic or kinetic pumping systems and exert no control over (or constraint upon) volumetric (or mass) flow rates. The volumetric (or mass) flow rate of dynamic or kinetic pumping systems is dependent upon other system parameters such as fluid viscosity, catheter diameter/length, restrictions, differential pressure, etc. Systems utilizing pressurized/evacuated reservoirs typically exhibit non-zero net flow; in some cases the flow may be reversing (e.g., by actuation of one or more valves and reservoirs) however mere flow reversal in insufficient to meet the criteria of oscillatory flow.

[0254] FIG. 4D is presented in conjunction with FIG. 5A wherein net aspirate flow is superposed over oscillatory flow generated by LCO 100 or LF oscillator 102. FIG. 4E and FIG. 4F show a representative, idealized pressure vs time relationship of an LCO 100 or LF oscillator 102 which generates oscillatory flow, however two pressure limiting embodiments are shown: the effect of embodiments such as pressure limiter 10 is shown in FIG. 4E and the effect of variable crankshaft 160 rotational frequency is shown in FIG. 4F. FIG. 4E depicts representative pressure vs time waveforms for three liquids: water (?1 cP), blood (?4 cP) and SAE 30 motor oil (?35 cP) as working fluids in LCO 100 or LF oscillator 102 that includes pressure limiter 10. As in FIG. 4C, the calculated/observed pressure amplitude increases with increasing viscosity, but in FIG. 4E the maximum pressure is limited to a lower pressure to avoid undesirable aspirate outflow from catheter 220. FIG. 4F depicts a representative pressure vs time relationship for a single liquid, however the LCO 100 or LF oscillator 102 is shown to be operated at 3 Hz during the intake stroke and at 1 Hz during the discharge stroke. Allotting more time for fluid to flow outwardly (i.e., distally, or out through catheter 220) during the 1 Hz discharge stroke effectively limits the maximum pressure developed. The resultant net flow remains approximately zero or near-zero, however the flow rate and corresponding cylinder pressure are diminished by the slow discharge stroke. Embodiments may comprise the selection of a stepper- or servo-motor as motor 180, which may enable variable angular velocity of crankshaft 160, thereby effecting a fast intake stroke and a slow discharge stroke to limit the pressure (e.g., above intravascular) developed.

[0255] FIG. 5A depicts an embodiment of LCO with aspiration and infusion 400 shown comprised of LF oscillator 102 in conjunction with an aspiration system such as aspirate pump 440 and infusion pump 460. Features such as Harmonic Oscillator (HO) 104 and pressure limiter 10 are omitted in FIG. 5A for clarity. Aspirate pump 440 may intermittently or continuously draw fluid out of the patient and into a reservoir such as a waste reservoir (not shown) or waste tube 450; some embodiments of aspiration systems may provide either net inflow or net outflow from the patient.

[0256] Acting alone, aspirate pump 440 may be operated at a steady shaft speed (RPM) and may generate a (steady or pulsatile) unidirectional flow through catheter 220. Acting alone, LF oscillator 102 theoretically generates approximately zero or near-zero net flow (when averaged over time) because the quantity of fluid outflow is typically approximately equal to the quantity of fluid inflow for each cycle. In FIG. 4A, FIG. 4B and FIG. 4C the pressure curves are symmetric about the assumed intravascular pressure of approximately 800 mmHg absolute. FIG. 4A, FIG. 4B and FIG. 4C illustrate oscillatory flow wherein a (generally central to catheter 220) differential fluid volume element within catheter 220 may accelerate, decelerate and reverse repeatedly in the axial direction, returning to approximately the same axial position with each oscillatory cycle.

[0257] Acting together, the combined effects of a typical aspiration system and an LF oscillator 102 may be analyzed by the principle of superposition, wherein the net flow of an aspiration system is added to the (ideal) zero-net flow (oscillatory flow) of LF oscillator 102. FIG. 4D depicts the superposition (summation) of the contributions of these two independent systems; the ordinate is fluid velocity within catheter 220. With LCO 100 or LF oscillator 102 operating at FS1 510 (1 Hz, 5 mm stroke, water) and 0.0 aspiration (absolute, relative or arbitrary units), a vertically symmetric velocity curve is shown with maximum and minimum velocity to be approximately ?0.5 (absolute, relative or arbitrary units). This is generally the same curve as in FIG. 4A, however the ordinate is velocity rather than pressure. With aspiration at a flow velocity of 0.25 (absolute, relative or arbitrary units), the velocity curve is shifted upward such that the area above zero is not equal to the area below. The flow is oscillatory in that both positive and negative velocities are shown; there is a net outflow of fluid from the patient. With aspiration at a flow velocity of 0.75 (absolute, relative or arbitrary units), the velocity curve is shifted farther upward such that negative velocities do not exist; there is only outflow from the patient, this is shown as antegrade flow in FIG. 4D. FIG. 4D illustrates that oscillatory flow may exist with equal or unequal velocities in each direction; in the case of aspiration at flow velocity of 0.75, the oscillatory flow is unidirectional (albeit time varying). With the combination of an aspiration system and LCO 100 or LF oscillator 102 operational, the ratio of aspiration velocity to LCO 100 or LF oscillator 102 induced velocity determines whether the resulting flow is bi-directional (balanced or imbalanced) or unidirectional. FIG. 4D depicts three cases of oscillatory flow: balanced bi-directional, imbalanced bi-directional and unidirectional. The fluid velocity scale is shown to be approximately ?0.6 to 1.4 (absolute, relative or arbitrary units); these values are selected for graphical representation only. In FIG. 4A, FIG. 4B, FIG. 4C and FIG. 4D, the stated example magnitudes and ranges of pressure and velocity are chosen for graphical and/or illustration purposes only.

[0258] FIG. 5A depicts an embodiment of an LCO with aspiration and infusion 400; [0259] additional system components such as harmonic oscillator (HO) 104, acoustic tube 130 and sonic transducer 110 are not shown in FIG. 5A for clarity. Viscometric aspiration (described elsewhere in the references) or viscometric sampling is utilized to determine viscosity and/or the aspirate characteristic (e.g., 6 cP viscosity, Qr=67% relative flow rate, 1cc/sec absolute flow rate, clot, clog, free-flow, thrombus, etc.). Saline infusion through infusion tube 320 is incorporated for hydrodynamic effects including: (1) to position or apply force upon catheter 220, (2) to disrupt thrombus 240 and attachment 260 by dilution or direct impingement and/or (3) decrease the viscosity of fluid within catheter 220. The LCO with aspiration and infusion 400 embodiment of FIG. 5A integrates three independent systems to (1) vibrate, (2) mechanically and/or hydrodynamically macerate and (3) aspirate thrombus.

[0260] The LCO with aspiration and infusion 400 embodiment depicted in FIG. 5A is comprised of motor 180, crankshaft 160, and connecting rod 140 operating to actuate piston 120 reciprocally within cylinder 200. This combination of components (LF oscillator 102) generates oscillatory flow within catheter 220, as illustrated in previous figures. Manifold 490 fluidically couples catheter 220, pressure transducer 420 and aspirate pump 440; discharge from aspirate pump 440 is to waste tube 450. Aspirate pump 440 may be a positive displacement pump, such as a peristaltic pump, and there may be approximately zero net flow (into or out of the patient) when aspirate pump 440 is stopped. With the LF oscillator 102 operational (i.e., piston 120 is reciprocating) and aspirate pump 440 stopped, a cyclic pressure waveform may be measured by pressure transducer 120; this waveform is characteristic of the fluid generally contained within catheter 220. The (positive, above intravascular) pressure amplitude of the cyclic pressure waveform may be indicative of the viscosity of any fluid generally contained within catheter 220; a larger amplitude pressure waveform may be indicative of a greater fluid viscosity and vice versa. Thus, the LF oscillator 102 and pressure transducer 420 may combine to form a viscometer which measures the viscosity of any fluid generally contained within catheter 220.

[0261] Aspirate pump 440 and pressure transducer 420 may also combine to form a viscometer as described elsewhere in the references. Thus, the viscosity of fluid generally contained within catheter 220 may be measured with (1) LF oscillator 102 operating, (2) aspirate pump 440 operating or (3) both LF oscillator 102 and aspirate pump 440 operating simultaneously. Viscometry is utilized in the present invention (and co-pending applications) to quantitatively determine the aspirate viscosity or aspirate characteristic of the fluid contained within catheter 220. If the measured viscosity is low (that of viable blood at approximately 4 cP) then catheter 220 may be inferred be aspirating blood; the speed of aspirate pump 440 may be decreased or maintained at a low speed and/or operated intermittently to minimize the loss of viable blood. If the measured viscosity is greater than viable blood, then catheter 220 may be inferred to be aspirating thrombotic material; consequently, the speed of aspirate pump 440 may be increased or adjusted to maximize the extraction efficiency of thrombotic material. Ratiometric or differential viscometry may quantify any changes in viscosity without reference to an external standard such as a calibration standard. The ratio of measured viscosities between diseased and undiseased sites enables a quantitative determination of the respective relative flow rates; herein, this may be termed differential viscometry or ratiometric viscometry. A clogged catheter may exhibit approximately zero relative flow rate; the measured viscosity may be calculated to be very large, e.g., exceeding 10,000 cP. A clogged catheter is an example of a mathematical singularity wherein approximately infinite viscosity is measured and approximately zero relative flow rate may be calculated or observed; computationally (and practically), an experimentally determined value (e.g., 10,000 cP, 10 ?l/sec, etc.) may represent infinite viscosity and zero absolute flow rate. This example illustrates an approximate turndown ratio of 10,000:1 wherein the range of the ratiometric or differential viscometry spans five orders of magnitude.

[0262] The examples given for aspirate characteristic included: 6 cP viscosity, Qr=67%, 1cc/sec flow, clot, clog, free-flow, occlusion score. The first three of these examples (6 cP viscosity, Qr=67% relative flow rate, 1cc/sec absolute flow rate) are quantitative (variable) data. The first two of these examples (6 cP viscosity, Qr=67% relative flow rate) are intensive properties of the fluid; the third example (1cc/sec absolute flow rate) is an extensive property of the system. The final four example aspirate characteristics (clot, clog, free-flow, occlusion score) consist of attribute data (utilized by prior-art) methods to describe flow, flow characteristic, flow state or characteristic of flow. Analysis of variable data (of the present invention) may be utilized to quantitatively measure relative flow rate and/or viscosity as continuous data, whereas attribute data may be utilized to monitor flow for change (e.g., free-flow changes to clog, thrombus changes to clot, etc.). The example measured quantities (viscosity, relative and absolute flow rate) are shown expressed in engineering units (cP, % flow and cc/sec); one or more calibration constants may be invoked in the transformation of pressure data (in units including Pascal, psi, mmHg, bar, etc.) into viscosity and flow data in engineering units. Conversion of variable data (e.g., viscosity, flow rate) into engineering units (e.g., cP, cc/sec) is optional in embodiments of the present invention; the data may be ratiometrically analyzed with or without invoking calibration data.

[0263] The embodiment of LCO with aspiration and infusion 400 depicted in FIG. 5A includes infusion pump 460 and infusion tube 320; fluid for infusion is provided through supply tube 480. Some embodiments feature infusion pump 460 comprised of a positive displacement pump such as a piston, syringe, diaphragm pump, peristaltic, etc.; the infusion pressure may range to in excess of approximately 10,000 psi. Some embodiments feature infusion pump 460 comprised of a variable speed, stepper, or servo-motor; infusion pump 460 may have a controlled pressure and/or flow output which may be adjusted/regulated/set by system controller 810 other entities including a clinician. Some embodiments feature infusion pump 460 comprised of a pressurized reservoir or bladder and valve(s); these embodiments being typically non-pulsatile. Non-pulsatile embodiments of infusion pump 460 may be preferred because cyclic reaction forces bearing upon system components including infusion tube 320, coiled infusion tube 475, catheter 220 and/or catheter tip 230 may generate cyclic transverse displacements of components. Cyclic transverse displacements may cause erratic jet direction and/or vascular trauma. Herein, infusion is considered a factor and the flow rate (or pressure) developed is considered a level. Infusion tube 320 is shown to be internal to catheter 220, other embodiments may include infusion tube 320 external to catheter 220. Infusion tube 320 is shown to protrude or extend past the distal end of catheter 220, other embodiments may include a retracted or extended infusion tube 320.

[0264] FIG. 5B depicts an oblique, cutaway view of an LCO with infusion and aspiration 400 which includes mechanized positioning of coiled infusion tube 475 by means of infusion tube drive motor 470. As shown in FIG. 5B, the distal terminus of coiled infusion tube 475 is located proximally to manifold 490 such that the lumen of catheter 220 is unoccluded by coiled infusion tube 475 between catheter tip 230 and manifold 490 (where aspirate flow may be diverted through aspiration pump 440 and to waste tube 450). Vascular access 225 delineates intravascular from extracorporeal portions of catheter 220. Coiled infusion tube 475 may be advanced or retracted within and/or external to catheter 220 to act as a hydrodynamic or mechanical lance to perform functions that include: (1) mechanical/hydrodynamic lancing of thrombus 240, (2) mechanical/hydrodynamic lancing of thrombus clogging or corking catheter 220 and/or (3) inject saline into catheter 220 at proximal, distal or intermediate positions therein.

[0265] FIG. 5C depicts an oblique, enlarged view of infusion tube 320 (or coiled infusion tube 475) extending distally from catheter tip 230 that depicts a plurality of nozzles (i.e., holes) for liquid discharge; radial nozzle 360 and axial nozzle 340 are shown. Various embodiments of the invention include single or multiple instances of either or both radial nozzle 360 and/or axial nozzle 340; nozzles may be inclined to or offset from any axis to discharge infusion fluid in directions which are combinations of the axial, radial and tangential directions/axes of infusion tube 320. Infusion tube 320 (or coiled infusion tube 475) is shown to extend beyond catheter tip 230 by a distance denoted extension 380. Extension 380 may be a fixed distance; some embodiments of the invention include means to adjust the extension 380. Extension 380 may assume negative values as the infusion tube 320 (475) may be retracted proximally past catheter tip 230 and in the interior of catheter 220; when infusion tube 320 (475) is retracted to negative values of extension 380, the fluid contents of catheter 220 may thereby be modified or altered (e.g., saline flush, etc.). Relative motion between infusion tube 320, 475 and catheter 220 catheter tip 230 may be achieved by manual manipulation of components, or the motion may be mechanized, as depicted in FIG. 5B.

[0266] FIG. 5D depicts a partial cutaway view of the distal (catheter 220) portion of an LCO with infusion and aspiration 400, deployed within vessel wall 280. Infusion tube 320 extends from catheter tip 230 by (positive) distance extension 380. Infusion fluid discharged from radial nozzle and axial nozzle (denoted in FIG. 5C) generates radial jet 560 and axial jet 580. Radial jet 560 and axial jet 580 are shown in the direction of flow; equal and opposite reaction forces are exerted upon infusion tube 320 and supporting or surrounding structures (e.g., catheter, vasculature, other solid surface, etc.). Axial jet 580 bears proximally upon the distal end of infusion tube 320; a limited amount of motion in the axial direction typically occurs because of the column stiffness of catheter 220. Radial jet 560 radially bears upon infusion tube 320 in a direction shown to be transverse or perpendicular to the axis of catheter 220. Consequently, a downward radial force is exerted upon infusion tube 320 and catheter tip 230; radial jet 560 acts to force catheter tip 230 in the downward direction such that catheter 220 and/or catheter tip 230 is/are pressed into contact with vessel wall 280.

[0267] FIG. 5E depicts a similar view to FIG. 5D except that extension 380 is increased such that infusion tube 320 extends to overlap thrombus 240 and/or attachment 260. Radial jet 560 is shown to directly impinge upon and penetrate into thrombus 240; axial jet 580 is shown to impinge upon and penetrate attachment 260. The configuration of FIG. 5E may be advantageous because: (1) infusion tube 320 is in close proximity to or in contact with vessel wall 280, and (2) radial jet 560 directly impinges upon thrombus 240 to erode, macerate, displace or disintegrate it. An advantage of infusion tube 320 being in contact with or close proximity to vessel wall 280 is that axial jet 580 is directed parallel to the surface of vessel wall 280. At higher infusion pressures, either radial jet 560 or axial jet 580 may be capable of inflicting vascular trauma including laceration, perforation, abrasion or inflammatory response in the vessel wall or other tissue. Radial jet 580 acts to acts to keep infusion tube pressed downward/radially outward such that the distance between radial jet 340/radial jet 560 and the upper surface of vessel wall 280 is hydrodynamically forced to a location that may be at or near maximum given the anatomical constraints of the patient. A non-pulsatile or minimally pulsatile infusion pump 460 system may be preferred to minimize cyclic transverse deformations or vibrations (i.e., up and down in FIG. 5C and FIG. 5D). Transverse vibration may cause significant transverse deflection, which may impact vessel wall 280. Embodiments featuring non-pulsatile infusion pressure (e.g., non-isovolumetric pressurized reservoir or bladder, etc.) may be preferred for an infusion supply system.

[0268] A visible difference between FIG. 5D and FIG. 5E is the change in extension 380; infusion tube 320 is shown extended distally in FIG. 5E with respect to FIG. 5D. The physical act of changing extension 380 may enable infusion tube 320 to act as a lance, obturator or probe to pierce, penetrate, scise, abrade or otherwise mechanically interrupt attachment 260 and/or thrombus 240 by means of mechanical and/or hydrodynamic effects. This action may have different effects in the presence or absence of radial jet 560 which may hydrodynamically force infusion tube downward to be in contact with or close proximity to the lower surface of vessel wall 280. Axial jet 580 is shown to be optimally positioned, in contact with or close proximity to vessel wall 280. Axial jet 580 may be therefore oriented to be parallel to vessel wall 280 such that vascular trauma may be kept to a minimum while hydrodynamically eroding thrombus 240 or attachment 260 at the contact interface with vessel wall 280. When infusion tube 380 is pressurized, fluid is discharged at a rate which may be proportional to the pressure (or flow rate) and inversely proportional to the diameters of axial nozzle 340 and/or radial nozzle 360. A larger-diameter nozzle discharges greater mass flow at lower velocities; a smaller-diameter nozzle discharges lesser mass flow at higher velocities. Optimized ratios of the position, diameter and direction of any nozzle may be experimentally determined for optimized ratio of radial jet 560 and axial jet 580 dimensions for any infusion pump 460 embodiment, system, configuration, operating pressure or flow rate.

[0269] An objective of any catheter-based thrombectomy procedure is to aspirate or extract thrombus through a catheter; therefore the successful procedure includes the aspiration of blood and tissue components that are of viscosity greater than that of blood. Throughout a thrombectomy procedure, any measured value of, or increase in, aspirate viscosity (above that of blood), may be indicative of effective therapy being administered; this may arise from the execution of a deterministic event such as an efficacious thrombectomy operating mode. This is in contrast to ineffective therapy which may arise from deterministic events or clinical conditions including: catheter deployed in a healthy (non-thrombotic) location, system process variables (factors/levels) improperly adjusted for thrombus morphology, a rigid/firmly attached thrombus, etc. During periods of a thrombectomy procedure wherein the viscosity of the aspirate is near that of blood, ineffective treatment is being administered; this is detrimental treatment as viable blood is aspirated which may limit the procedure duration, thoroughness and overall efficacy. Embodiments of the present invention systematically execute multiple thrombectomy operating modes to identify and exploit efficacious thrombectomy operating modes in a minimum amount of time and with a minimum amount of loss of healthy blood.

[0270] FIG. 6 depicts a graph Viscosity vs. Time (Thrombectomy Procedure) which may be representative of any portion of a thrombectomy procedure which comprises viscometric aspirate analysis or viscometric sampling. FIG. 6 may be segmented into phases: blood 710 (appears 3 times), phase 1 730, phase 2 750, and phase 3 770. Each of the enumerated phases are responses to deterministic events (e.g., thrombectomy operating mode, repositioning of catheter 220, etc.); responses to deterministic events include phenomena such as: entrainment of thrombus 240, disintegration of thrombus 240, dislodgement of thrombus 240 from vessel wall 280 or any other process by which thrombus 240 is aspirated into catheter 220. FIG. 6 depicts an initial viscosity which may be inferred to be that of blood 710; subsequently, phase 1 730 is shown to exhibit a rapid increase in viscosity (or % thrombus in aspirate, or decrease in flow rate, etc.), followed by a leveling off, and followed by a slower decline in viscosity. Each of the depicted phases (e.g., phase 1 730, phase 2 750, and phase 3 770, etc.) has undergone any or all of the following deterministic events: (1) efficacious positioning of catheter tip to thrombus distance 250 by viscometric distance sampling (e.g., distance subroutine 1050, etc.), (2) viscometric determination a first efficacious thrombectomy operating mode, (3) determination of optimal aspiration/infusion rate or other system factors and levels (e.g., effect subroutine 1000, etc.), by system controller 810. Phase 1 730 may be inferred to have identified an effective or preferred combination of factors and levels whereby thrombus 240, attachment 260 and/or vessel wall 280 are disrupted which causes disintegration of one or more attachments 260 such that thrombotic material is released and aspirated. The viscosity of phase 1 730 is shown to diminish as the effectiveness of the identified thrombectomy operating mode is diminished or exhausted. Phase 1 730 is followed by another period of blood 710; during this time, deterministic events including changes to system process variables (factors and/or levels); device placement may be changed (by means such as distance subroutine 1050, etc.). The onset of phase 2 750 may be inferred to detect a second preferred combination of factors and levels which is characterized by a rapid increase and decrease in viscosity. Phase 2 750 may be illustrative of the disintegration and aspiration of a small thrombus 240 or subcomponent thereof. Phase 3 770 is illustrative of a gradual increase in viscosity which may be indicative of approaching a preferred frequency or efficacious thrombectomy operating mode, followed by a rapid increase in viscosity which may be indicative that a preferred frequency or efficacious thrombectomy operating mode has been identified. A gradual decline in viscosity just after the peak may be indicative of a decreasing amount of thrombotic material in the aspirate, such as may occur when an eroded or vibrating mass of thrombus 240 is depleted and has been aspirated. A more rapid decline in viscosity may be indicative that one or more factors and/or levels are not in an efficacious range. Subsequent to phase 3 770, the aspirate viscosity returns to that of blood 710; this may mark a procedure endpoint as one, two or three thrombi 240 may have been aspirated, or a compound-type thrombus 240 may have been disintegrated and aspirated in three distinct phases.

[0271] The abscissa of FIG. 6 is shown as time, this is consistent with prior art and the figures presented heretofore in this disclosure; however, in FIG. 6, the abscissa is subdivided into attribute data regions or phases (blood 710, phase 1 730, phase 2 750, phase 3 770). The graphical representation of FIG. 6 illustrates a distinction of the invention over prior art; some embodiments of the invention correlate measured (or monitored) system response (e.g., aspirate viscosity, pressure, flow, etc.) to deterministic events (e.g., thrombectomy operating modes, catheter positioning, combination of system factors and levels, etc.). In the prior art, measured responses are, at most, correlated to the passage of time. In prior art, measurement data are converted to attribute data and the attribute data are monitored for a change of state (e.g., flow state). Upon detection of a change of state, prior art fails to provide any quantitative description of the control response, examples of non-qualitative control responses include open/close a valve, adjust a pump, etc. The prior art is limited to monitoring for a detectable change, and then reacting to the detecting by opening or closing valves or adjusting a pump. Conversely, some embodiments of the invention execute deterministic events, and measure the system response in quantitative terms; a system response that is relevant in a thrombectomy procedure is the amount of thrombus that is contained within the catheter at any time. If there is no thrombus in the catheter, the thrombectomy efficacy is zero; an inference from this data is to change a system variable (e.g., catheter position, suction level, etc.). If there is too much thrombus in the catheter (e.g., clog or corking), the thrombectomy efficacy is also zero, because there is no flow. A first inference from this data is that aspiration may have been adjusted to an improper setpoint; this may be addressed by software firmware updates. A second inference from this data is that anti-clogging or anti-corking means (e.g., impulse mechanism 90, LCO 100, etc.) be implemented.

[0272] Embodiments of a representative LCO/HO thrombectomy system with aspiration and infusion 400 may comprise any plurality of multiple independent systems (factors) including (as examples): (1) variable-frequency LF oscillator, (2) variable LF oscillator stroke (e.g., piston in cylinder, tube compression, peristaltic pump oscillation, etc.), (3) variable high frequency, small amplitude sonic transducer (HO, including sonic transceiver), (4) variable length acoustic tube, (5) variable infusion tube extension, (6) variable viscometric aspiration and (7) variable infusion rates; each independent system may be termed a process variable or factor. Any number of these independent systems (factors) may be selected to operational depending upon factors including: clinical indication, catheter specific factors or features, clinician preference, etc. Typically, each factor has a plurality of setpoints (levels) that may be updated (whereupon an updated, new or different and/or repeated setpoint combination is selected); this happening a plurality of times during the course of a thrombectomy procedure. The thrombectomy system setpoints (factors and levels) may be manually adjusted by a clinician; some embodiments employ feedback and/or thrombectomy control flowcharts or algorithms to adjust or update one or more setpoints (levels) in response to measurement data (e.g., viscosity, relative flow rate, % thrombus concentration, etc.). Catheter-based thrombectomy systems may utilize a clinician to select/identify/target one or more thrombi (including through the utilization of fluoroscopy, IVUS, or other imaging system) and advance a catheter into proximity; thereafter, manual and/or automated processes may be executed by the thrombectomy system and/or clinician to provide suction, aspiration, infusion, mechanical or hydrodynamic maceration, or other methodologies to the target site. Setpoint/level control is automated in some embodiments; clinician input may also comprise one or more feedback inputs in the determination of setpoint/level control of each factor (or adjustable system process variable).

[0273] Embodiments of LCO 100 thrombectomy systems including LCO with aspiration and infusion 400 comprise a control system that updates any or all system factors, process variables, setpoints/levels (e.g., frequency, stroke, acoustic tube length, aspiration, infusion, etc.) by means of feedback from one or more measuring instruments (e.g., viscometer, pressure transducer, sonic receiver, flowmeter, accelerometer, etc.). An objective of a catheter-based thrombectomy system is to aspirate fluid that is measured to exhibit viscosity greater than a baseline value of viable blood (at approximately 4 cP); therefore aspirate viscosity comprises an example feedback input for updating system process variables (factors) and/or setpoints (levels) in some embodiments of the present invention. Some embodiments comprise feedback input from data sources including: pressure transducers, flowmeters (e.g., Coriolis, ultrasonic, etc.), sonic receivers, motor current measurements, clinician input, accelerometers, etc. Co-pending applications describe the methods and mathematical transformation of pressure data (e.g., from a pressure transducer, in units of pressure) to viscometric data (in units of viscosity, e.g, cP, Stokes, Pa's, etc.) in time domain. Herein the terms pressure data, viscometric data, flow data, % thrombus data, thrombus load, etc. may be used to describe quantitative data which may be implemented as a feedback mechanism in embodiments of the present invention. Viscometric measurements, as implemented by the invention and references, comprise pressure measurements and further comprise methods or algorithms for the transformation of pressure data into measurements of viscosity, relative flow rate, % thrombus concentration or similar derived or calculated unit or measurement. Some methods and measurements of the invention comprise determination of quantitative descriptors of intensive physical properties of the aspirate; this is in contrast to prior art embodiments that monitor extensive system properties including flow state, characteristic of flow, occlusion score, clot, free-flow, etc.

[0274] The example thrombectomy control algorithms, flowcharts, methodologies and/or strategies (presented herein as embodiments) illustrate distinctions of some embodiments of the present invention: system control over a plurality of system factors and/or setpoints/levels. In some embodiments, this is accomplished by algorithms executing algebraic operations upon variable data from quantitative instrumentation comprising the thrombectomy system. This is in contrast to prior art, wherein variable data (e.g., pressure, differential pressure, etc.) are first assigned an attribute (e.g., clot, free-flow, 0, 1, 2, occlusion score=3, etc.) and then the attribute states are counted or monitored for change. Furthermore, in methodologies of the prior art, any event of a change of state, or change of characteristic, or change of score, may only be correlated to the passage of time. Methodologies of the invention include correlation of measurement data (of physical properties of the aspirate) to deterministic events that predicated the value returned as measurement. The scope of the invention is encompassing of the philosophy that some intensive physical properties of aspirate (e.g., viscosity, % thrombus, relative flow rate, etc.) are predicated upon deterministic events (instead of random events or the passage of time). In other words, the measured physical properties of the aspirate change with time; prior to the measurement, the sequence of deterministic events is herein identified as the cause of the physical property state that is subsequently measured. An example methodology is to correlate a physical property measurement to time and correlate one or more deterministic events to the same time scale; measurement data of a physical property may be correlated to predicating deterministic events.

[0275] FIG. 7 depicts a representative list of example factors 780 identified by an integer (the factor loop index, i) for computational efficiency; factor variable 782 describes each factor in words (e.g., LFO frequency 860, LFO stroke 880, HO frequency 865, acoustic length 875, aspiration 885, infusion 895, and extension 897, etc.). The level 788 of each factor variable 782 may be expressed with units 784 (e.g., Hz, mm, rpm, on/off, etc.) and may be experimentally/procedurally evaluated within a range 786 of levels 788. The combination of range 786 and levels 786 enables calculation of a number of levels 790 such that a loop termination 792 index (an integer) is determined. For example: when factor loop index (i) is equal to 1 (i=1), factor 780 is shown defined to be LFO frequency 860; LFO frequency 860 may be incremented (50 times) from 0 Hz to 50 Hz in 1 Hz increments. When level loop index (j) is equal to 50 (j=50), the loop is terminated because loop termination index 792, m(i=1)=50. Similarly, when factor loop index (i) is equal to 2 (i=2), factor(i) 780 is shown defined to be LFO stroke 880; LFO stroke 880 may be incremented (20 times) between 0.1 mm and 10.1 mm in 0.5 mm increments. When level loop index (j) is equal to 20 (j=20), the loop is terminated because loop termination index 792, m(i=2)=20. FIG. 7 is shown constructed in a manner convenient for programming in any selected computer language by persons of ordinary skill in computer programming.

[0276] Some embodiments of the present invention comprise a thrombectomy system featuring a number of independent system process variables (factors) under setpoint (level) control by any entities (or combination thereof) including: system controller 810, database/compiler 2020 and/or a clinician, etc.. FIG. 6 depicts three representative viscosity vs. time waveforms or phases (of a thrombectomy procedure). Example phase 1 730 depicts a rapid increase in measured viscosity; this may result from many causes including a vibrational response at LFO frequency 860 at a level (e.g., 25 Hz, 2 Hz, 17 Hz, etc.), or a combination such as: LFO frequency 860 level and LFO stroke 880 level (e.g., 0.5 mm, 4 mm, 0.25 mm, 3 mm, etc.) along with other factors/levels may provide efficacious thrombus aspiration. Some embodiments of the present invention may sweep a plurality of levels of one or more factors, such as by incrementally or continuously increasing/decreasing the speed of motor 180 or the frequency of a sonic transducer 110. Phase 1 730 of FIG. 6 may arise from incrementing LFO frequency 860 from 0 Hz to 50 Hz at 1 Hz increments; LFO frequency 860 may be defined as factor(1) or factor1. Factor(1) may be incremented (a representative) 50 times throughout this range, indicated by number of levels 790. A computer loop is well suited for this repetitive task; this loop may be a FOR/NEXT, a DO, or a DO WHILE loop, etc. as provided by the programming language. Phase 1 730 may have initiated at 25 Hz setpoint/level of factor(1); a DO WHILE (e.g., viscosity>4 cP, slope>0, etc.) may thereby hold factor(1) at 25 Hz level while the viscosity increases and decreases as shown in FIG. 7A. In FIG. 7A, any portion of the graph where the viscosity is greater than that of blood 710 is indicative of effective therapy being delivered. Some embodiments may hold factor(1) (e.g., at 25 Hz, 5 Hz, 40 Hz, etc.) while incrementing/decrementing the levels 788 of other factors(i?1).

[0277] In some embodiments, loops (including nested loops) may vary any or all of the remaining factor variables 782 while any factor (e.g., frequency) remains at a fixed level (e.g., 25 Hz, 5 Hz, 1 Hz, etc.); objectives of any such loop may be to identify thrombectomy operating modes which exhibit an increase or maintenance of the viscosity of the aspirate above that of blood 710. A positive viscosity slope (viscosity is increasing) may be indicative of increasing therapeutic treatment, a negative slope being indicative of the diminishing thrombus in the aspirate; however, some embodiments may comprise an algorithm which waits for the viscosity to return to that of blood 710. In some embodiments, as any loop terminates, a successive loop may be executed; each loop may terminate as the loop termination index 792 reaches the value of m(i), or control may be diverted by means of conditional statements such as IF (condition) THEN NEXT i.

[0278] FIG. 8 depicts an example embodiment of system controller 810, with inputs (shown above) and outputs (shown below); each output may have a setpoint (e.g., factor(1) 780 is set to a level 788 of 25 Hz, factor(2) 780 is set to a level 788 of 1 mm, etc.) assigned by system controller 810. FIG. 8 depicts eight example outputs: LFO frequency 860, LFO stroke 880, aspirate pump 440, infusion pump 460, acoustic tube length 130, extension length 380, HO frequency 865, and clinician data 890. A plurality of these outputs may be identified by factor 780 and a level 788 which may be assigned by entities including system controller 810 or clinician input 895. Three example inputs are shown in FIG. 8: pressure transducer 420, sonic transducer 110 and clinician input 895, which may include data from accelerometer 410. The methods and mathematical transformation of pressure data from pressure transducer 420 into viscometric or quantitative flow data is presented elsewhere in the references. Other inputs to system controller 810 may comprise flowmeters, conductivity meters, spectrometers, etc. Clinician data 890 may comprise analog or digital data (e.g., viscosity, flow, slope, setpoints, etc.) which may comprise display monitor, audio speaker, cellular phone or other remote console, etc.; clinician input 895 may comprise any of: accelerometer 410, joystick, mouse, keypad, footpedal, knobs, etc. Clinician data 890 may comprise data stored as thrombectomy procedure log file 1300. System controller 810 is presented in further detail in conjunction with FIG. 15.

[0279] FIG. 9A depicts a representative thrombectomy control flowchart 901 (algorithm) as may be utilized by system controller 810 or other thrombectomy control system embodiment. Start 905 may comprise any clinical preparations including power-up self-tests, catheter purge, calibrations, etc. Initialize setpoints 910 may include calculation/measurement/calibration of blood viscosity and assigning that value to V.sub.0,0, initializing the levels for factors such as: acoustic tube length 130, extension length 380, LFO stroke 480, etc. Position catheter 920 may be executed by the clinician; data from accelerometer 410 may be collected, stored and/or correlated to any or all subsequent steps. Distance subroutine 1050 (FIG. 9C) is invoked to infer the distance between the catheter tip and thrombus. If the measured or inferred distance is too large, (e.g., by a threshold arbitrary constant ?.sub.1, etc), then Advance Catheter 944 is executed by manual or automated means. If the measured or inferred distance is negative or too small, (e.g., by a threshold arbitrary constant ?.sub.2, etc.), then Retract Catheter 948 is executed by manual or automated means. Position Catheter 920 and Distance Subroutine 1050 represent an example set of machine instructions to obtain proper catheter positioning prior to further experimentation to ablate and aspirate thrombus. Distance Subroutine 1050 invokes Viscosity/Slope Subroutine 1070 (FIG. 9E); therein, methods such as Time-Domain Viscometry (as disclosed in the references) are employed to measure the viscosity and slope of the aspirate. With the catheter 220 in position with respect to thrombus 240, a sequence of experiments is conducted utilizing a representative computer loop structure of FIG. 9A. In FIG. 9A through FIG. 9D, the measured viscosity at loop indices i and j, is denoted as V(i,j), the measured slope is denoted as S(i,j). In some embodiments, a plurality of values of V(i,j) and S(i,j) are stored in memory, in some embodiments a list of efficacious values of i and j are compiled (e.g., by sorting) and stored in a file of preferred values. These preferred values may be used subsequently in the procedure (e.g., by assigning loop indices to be from the preferred values file). A preferred values file is, for example, comprised of loop index values (i and j) that positively correlate to thrombectomy efficacy or the measured amount of thrombus in the catheter. The extension to any number of factors 780, levels 788, multiple independent loops, nested loop levels (with indices such as i, j, k, l, m, n, etc.), etc. is straightforward and anticipated.

[0280] FIG. 9C depicts representative distance subroutine 1050 that utilizes measured viscometric data to infer catheter tip to thrombus distance 250 and invoke an appropriate control response by system controller 810. Distance subroutine 1050 is so named because an objective is to enact or enable a clinician to reposition catheter 220 such that catheter tip 230 is positioned for improved thrombectomy efficacy. Distance subroutine 1050 invokes Viscosity/Slope Subroutine 1070 to be executed and return the measured viscosity value, V(i,j); this value is algebraically compared to known values and/or arbitrary constants such as the viscosity of blood, V.sub.0, and prermined threshold values, ?.sub.1 and ?.sub.2, etc.. Aspirate samples that yield measured aspirate viscosity less than ?.sub.1V.sub.0 infer that the catheter tip to thrombus distance 250 too large for efficacious aspiration of thrombus 240 without unnecessary blood loss. The arbitrary constant, ?.sub.1 is predetermined experimentally and typically lies in the approximate range of 1.00<?.sub.1<2.00, and V.sub.0 is the measured viscosity of blood (?4 cP). Catheter 220 is advanced into closer proximity to thrombus 240 by manual manipulation or automated methods; manual manipulation may be facilitated by audiovisual communication to clinician such as ADVANCE CATHETER being played over an audio speaker.

[0281] Aspirate samples that yield measured aspirate viscosity greater than ?.sub.2V.sub.0 infer that the catheter tip to thrombus distance 250 is negative or too small for efficacious aspiration of thrombus 240 without excessive risk of clogging or corking catheter 220. The arbitrary constant, ?.sub.2, is experimentally predetermined and typically lies in the approximate range of ?.sub.2>30. Catheter 220 is retracted to farther proximity from thrombus 240 by manual manipulation or automated methods; manual manipulation may be facilitated by audiovisual communication to clinician such as RETRACT CATHETER being played over an audio speaker.

[0282] For example, by selecting representative values of ?.sub.1=1.1 and ?.sub.2=50, the control response of distance subroutine 1050 is depicted to be: IF the measured aspirate viscosity is less than ?4.4 cP (ratiometrically compared to prior values of the patient blood assumed to be ?4.0 cP) THEN ADVANCE CATHETER, and IF the measured aspirate viscosity is greater than ?1,000 cP THEN RETRACT CATHETER. Thus, catheter tip 230 may be manipulated and/or positioned to an optimum position, and control is returned to factor loop 930 of thrombectomy control flowchart 901.

[0283] Among the functionalities of representative thrombectomy control flowchart 910 is to sequentially execute a plurality of experiments in thrombus aspiration, each experiment comprising operation of the apparatus and measurement of the aspirate viscosity. Typically, experiments may be conducted in approximately 1 second (range of approximately 0.2 s to 5 s). Thrombectomy control flowchart 901 depicts a representative computer loop structure, wherein loop indices (e.g, i, j, k, l, etc.) are used to incrementally increment and/or decrement setpoint values (levels 788) of system parameters (factors 780).

[0284] FORNEXT factor loop 930 is an outer loop to sequentially increment (and thereby select) each of the n factors; in the example embodiment presented herein, n=7. FIG. 7 depicts representative factor variables 782, range 786, increment 788 and loop termination index 792 corresponding to each factor 780. During the first execution of FORNEXT factor loop 930, i=1; when i=1 the levels 788 of factor 780 (LFO Frequency 860) are incremented. With each increment (or change) to the apparatus setpoints, Operate Apparatus 902 is executed, wherein the systems (e.g., LCO 100, aspirate pump 420, infusion pump 460, etc.) of the apparatus are activated or turned on. Viscosity/Slope Subroutine 1070 (FIG. 9E) is invoked to measure the viscosity of the aspirate. In this manner, an experiment is conducted (with factor 780 and levels 788 assigned by i and j loop indices), and a physical property (e.g., viscosity) of the aspirate is measured.

[0285] Referencing FIG. 7, nested FORNEXT level loop 940 increments the level 788 of LFO frequency 860 (when i=1) from 0 Hz to 50 Hz in 1 Hz increments as j is incremented from 1 to 50. At each j value of level loop 940, Operate Apparatus 902 and measure viscosity and slope 950 are executed. After each experiment, control is transferred to effect subroutine 1000; a representative example subroutine is shown in FIG. 9B. In other embodiments, loop indices may be decremented (e.g., FOR j=n to 0 STEP ?1) or a loop index may be changed, updated or reassigned by a command line. As examples, decrementing loop indices results in a reverse sweep which ranges from higher levels to lower levels of a factor; statements such as j=j?5 may result in repeating the five (5) prior levels 788 of any factor 780, which is defined by the factor loop 930 index, i. As depicted for illustration purposes, FIG. 9A is a nested loop with two loop indices (i and j); this abridged flowchart does not generate full factorial, fractional or other DOE matrix for the representative LCO 100 embodiment which features seven independent subsystems. Additional nested loops and loop indices (e.g, k, l, m, n, etc.) are required to generate more complete experimentation within the matrix of combinations of factors and levels. FIG. 9A through FIG. 9E are abridged for brevity and clarity; however, these figures illustrate (1) a set of machine instructions for executing tasks (e.g., Operate Apparatus 902, etc.), (2) a method of invoking subroutines to execute tasks (e.g., Measure Viscosity/Slope 1070, Operate Impulse Mechanism 90, etc.), and (3) a method to evaluate conditional statements to adapt future experiments for efficacious thrombectomy efficacy.

[0286] Representative effect subroutine 1000, depicted in FIG. 9B, and so named because the subroutine analyzes the effect of a previously executed cause (e.g., thrombectomy operating mode, combination of factors and levels, clinician manipulation, etc.). Effect Subroutine 1000 invokes Clog Detect/Avert Subroutine 1060 (FIG. 9D); if this subroutine detects that the viscosity, V(i,j), exceeds arbitrary constant V.sub.clog, then countermeasures are invoked. The example countermeasures include impulse mechanism 90, LCO 100, infusion pump 460, etc.

[0287] Effect subroutine 1000 numerically analyzes data by executing conditional statements and determines one or more subsequent steps or thrombectomy operating modes to be executed. Effect subroutine 1000 is shown to execute representative conditional IFTHEN (THEN may be omitted by allowable BASIC syntax and for compactness) statements with viscosity and/or slope as (variable data) arguments. Other conditional statements and arguments may comprise other generalized subroutines. Effect subroutine 1000 is shown such that control may be transferred to various locations within thrombectomy control flowchart 901 depending upon the magnitude and/or slope of aspirate viscosity or other system measurement, parameter and/or clinician input. Returning control to level loop 940 resets j to j=1 and the sweep (of the levels 788 of the selected factor 780) is repeated; returning control to measure viscosity and slope 950 re-measures viscosity and slope after a predetermined dwell time. Returning control to NEXT Level 970 continues the sweep of factor 780. These example thrombectomy control flowchart 901, effect subroutine 1000 are representative of any thrombectomy control algorithm to continuously or incrementally vary any or all of the system parameters (e.g., factors and levels). Incrementing, decrementing or otherwise changing loop index (i) changes the factor 780 (e.g., factor variable 782 is equal to: LFO Stroke 880 when i=2, HO Frequency 865 when i=3, acoustic length 875 when i=4, etc.). Effect subroutine 1000 is shown to be comprised of predetermined dwell times and conditional statements (IF-THEN statements), in general, subroutines may be comprised of loops (FORNEXT, DO, DO WHILE, etc. loops) and nested subroutines. Dwell times (D0, D1, D2, . . . D.sub.last) may be experimentally determined; if a dwell time is longer or shorter than required, the procedure efficacy and/or duration may be adversely affected. In some embodiments arguments of conditional statements include quantitative or qualitative system parameters such as: flow, flow rate, flow state, characteristic of flow, etc.

[0288] The representative conditional IF-THEN statements (of example effect subroutine 1000) are used to compare the measured value and/or slope of the aspirate viscosity to previous iterations (i.e., thrombectomy operating modes or experiments) and/or other predetermined values. If the measured viscosity of the aspirate is within the range of 4 cP<V(i,j)<V.sub.clog, then the thrombectomy system may be inferred to be operating in a desired regime of extracting thrombus. Predetermined dwell times (e.g., D0, D1, D2, . . . ) may be executed prior to returning control to a location within thrombectomy control flowchart 901. Likewise if the slope of the viscosity is increasing {i.e., S(i,j)>S(i,j?1)} then the thrombectomy system may be inferred to be operating in a desired regime of extracting thrombus and that the concentration or composition quality of thrombus in the aspirate is increasing. The duration of dwell may be a function of the slope (e.g., IF {S(i,j)>S(i,j?1)} THEN DWELL S(i,j)?D1); this may provide a modified dwell in response to an increasing slope. The ratio of slopes may be compared to an arbitrary, experimentally determined constant, ?, {S(i,j)/S(i,j?1)>?} so that the dwell or other system parameters may be altered if the ratio of slopes does or does not exceed any threshold value. The arbitrary or experimentally determined constant, K, typically is in the range of 1.0<?<5.0; if the slope, S(i,j) increases by greater than a factor of five between successive measurements a clog or impending clog may be inferred, this may require manual or automated clog countermeasures.

[0289] Dwell may be comprised of any or all of the following: (1) all levels 788 (setpoints) are retained for a specific period of time (e.g., D0=1s, D1=5s, etc.), (2) all levels 788 are retained for a variable amount of time (e.g., DWELL (S(i,j)?D0), DWELL (?S(i,j)?D1, etc.), and/or (3) one or more levels 788 may be independently incremented or decremented during the dwell. The latter (case 3) gives rise to additional subroutines which may invoke one or more loops using additional loop indices (e.g., k, l, m, etc.) to increment or decrement the levels 788 of one or more of factor variable 782 such as factor 780 (e.g., 5, 6, 7, etc.). Such a subroutine may sweep the levels of factor variable 782; for example, aspiration 885, factor(i=5) 780 levels 788 may be incremented or decremented throughout all or a portion of range 786 under loop index k while maintaining loop indices i and j constant. The example number of factor variables 782 is shown to be 7; therefore nested loops (e.g., 2, 3, 4, 5, 6, or 7 deep, etc.) including parallel nested loops also may comprise the present invention.

[0290] Some embodiments of the knowledge-based thrombectomy system comprise a control algorithm (e.g., thrombectomy control flowchart 901) which causes operation of the apparatus and increments, decrements or otherwise sweeps the levels 788 of one or more factor variables 782 (e.g., LFO frequency 860, HO frequency 865, etc.) while other factor variables 782 may be held constant (e.g, at initial, previous, nominal or zero values). The viscosity of the aspirate is measured for quantitative presence of thrombus; an efficacious combination of factor variables 782 may thereby be identified by a measured value of (or increase in) aspirate viscosity greater than that of blood, but below that of V.sub.clog. Some embodiments of the invention may then hold constant that combination of factor variables 782 and levels 788 while any or all remaining factor variables 782 (e.g., aspiration 885, infusion 895, extension 897, etc.) are independently explored, incremented, decremented or swept. The measured viscosity of the aspirate intermittently or continuously provides feedback data which is evaluated as arguments of conditional statements (e.g., IF-THEN, DO WHILE, DO, etc.); the outcome of the conditional statements is utilized to update the setpoint of factor 780 and/or level 788 (e.g., increment, decrement, reset, increase, maintain, decrease, discontinue, repeat, etc.). For compactness, a single nested loop (with loop indices i and j) is shown in representative thrombectomy control flowchart 901, the extension to multiple nested loops with a greater number of loop indices (e.g., k, l, m, n, etc.) may be features of other embodiments of the present invention.

[0291] These examples are specific in that the number (n) of factors 780 is chosen to be seven; more generally, any number of factors 780 may arbitrarily be selected in other embodiments depending upon the system/catheter features and clinical indications. Similarly, viscosity and/or slope is/are chosen as the example of measurement data which may be employed as arguments to conditional statements (IF, WHILE, UNTIL, . . . ). Other embodiments may collect input data from sonic transducer 110 to determine the frequency and magnitude of any vibrational modes existing within the thrombectomy system or the patient vasculature. Other embodiments may collect data from other measurement technologies (e.g., flowmeter, conductivity meter, optical meters, spectrometers, etc.). The data utilized in the representative flowcharts are variable data, namely viscosity and slope; in some embodiments, attribute data (e.g., characteristic of flow, flow state, aspirate characteristic, etc.) are utilized as arguments in conditional statements. Different or multiple arguments (of conditional statements, e.g., IFTHEN, DOWHILE, etc.) may arise in other embodiments not presented herein. Aspects of the present invention comprise the selection of one or more factor variables 782, selecting an appropriate range 786 for each, and exploring any or all factor variables 782 at a plurality of levels 788 while measuring the aspirate for thrombus. The listed examples of factor variable 782 and level 788 are presented in conjunction with the disclosure of embodiments including: LFO frequency 860, LFO stroke 880, HO frequency 865, acoustic length 875, aspiration 885 and extension 897. Some embodiments exercise control over different system parameters such as valves, regulators, and effect changes such as: open a valve, close a valve, increase a pressure, etc.

[0292] Embodiments of the present invention invoke the physics of a forced system of mass, spring and damper, wherein an example forcing function may be an oscillating or reciprocating surface. The fluid mass of the system generally comprises the mass of the fluid within cylinder 200, catheter 220 and in the localized bloodstream, generally bounded by vessel wall 280. Elasticity of components, including vessel wall 280, may provide a spring component while damping may be provided by fluid viscosity. Example reciprocating surfaces include the face of piston 120 and/or a corresponding structure of sonic transducer 110, such as a reciprocating piston, vibrating diaphragm, pinch valve, roller pump, etc. Some example reciprocating structures induce oscillatory motion of matter (fluids and solids); this motion may be harmonic, off harmonic or anharmonic. Oscillatory motion of fluid generally within catheter 220 may be of any combination of low, medium or high frequencies within the range of 0.1 Hz to approximately 19,000 Hz (subsonic and sonic ranges). At lower frequencies, a finite, reciprocating fluid displacement may exist; at higher frequencies a series of fluid compressions and expansions may result in infinitesimal displacements. A net inflow or outflow may exist such that the fluid oscillates but does not change direction; in all such cases, the fluid motion is oscillatory. The presented embodiments describe discrete increases (increments) in setpoint values (levels); continuous variation of setpoint values is anticipated by the present invention.

[0293] An objective of the present invention is to attrite, disintegrate or dislodge matter that is in contact with or adhered to a wall of a fluid reservoir (e.g., patient vascular system, bloodstream, pipe, tube, tank, etc.) and to subsequently aspirate the matter. Embodiments of the present invention comprise a catheter designed for deployment within a vein or artery, thus creating a system that may be described as a conduit (catheter, etc.) in fluid communication with a reservoir (the bloodstream). Fluid may be discharged from the catheter tip at velocity sufficient to induce characteristic fluid motion within the reservoir (e.g., blood vessel, pipe, tank, etc.). In a large reservoir, such as where the characteristic reservoir dimension (e.g., diameter, width, height, etc.) is greater than approximately 10 times the diameter of the catheter, the jet of fluid discharged from the catheter tip will be dispersed and dissipated within a few catheter diameters.

[0294] In some embodiments, the present invention comprises the utilization of oscillatory fluid motion to perform action at a distance by intermittently discharging liquid into a surrounding environment of characteristic topology. Depending upon the target vascular site, the vasculature topology may be contracting, expanding or constant-diameter; the diameter of target vascular site may range from 1 to approximately 50 times the diameter of the catheter. In some applications, the catheter and vessel diameter may be approximately equal. In cases wherein the catheter and vascular diameters are approximately equal, the vascular flow regime may be dominated by LCO 100 and the action (dislodging a thrombus) may be carried out over a greater distance (between the catheter tip and the thrombus). The LCO thrombectomy system may thereby provide treatment access to anatomical locations previously unreachable due to native or diseased vascular contractions, constrictions, tortuosity, etc. Partial or total occlusions, which are distal to the catheter tip and otherwise inaccessible by other devices, may thereby be disrupted, dislodged or disintegrated at a greater distance than that which may be attained by prior art.

[0295] FIG. 6 depicted a representative graph of viscosity vs time as factor variables 782 and levels 788 are changed, however FIG. 6 does not present information about the magnitude or values of factor variables 782 and levels 788 that evoked each response. A speculation was provided based upon reasonable assumptions. However, other data analysis and graphical techniques enable a correlation between system settings (e.g., factor variables 782 and levels 788, etc.) and measured viscosity. FIG. 10 and FIG. 11 depict graphical two- and three-factor response surfaces as a plurality of factor variables 782 and levels 788 are explored. FIG. 10 and FIG. 11 are included for illustrative purposes, there is generally no need to contemplate generating such graphs. Furthermore, as the number of factor variable 782 exceeds three, graphical depiction is not generally possible.

[0296] FIG. 10 depicts a representative graphical example of a two-factor response surface 1100 where the first factor is frequency 1110 and the second factor is amplitude or stroke 1120; the ordinate (i.e., vertical axis) is aspirate viscosity 1130. Embodiments of the present invention include a broad array of catheter lengths, diameters and features (e.g., infusion tube 320, extension length 380, obturator, macerator, rotating cutter, etc.) to meet the clinical needs of a variety of thrombus types in a variety of anatomical locations. Example clinical indications include: pulmonary embolism 1150, deep vein thrombosis 1160, chronic total occlusion 1170, ischemic stroke 1180, etc. Two factor response surface 1100 depicts an increase in aspirate viscosity 1130 at four regions of the frequency-stroke plane or space. At low frequency 1110 and medium stroke 1120, a peak in aspirate viscosity 1130 is annotated pulmonary embolism 1150; this may be consistent with an inference from eq. 11 which predicts a low frequency response of a thrombus of generally larger mass. At higher frequency 1110 and lower stroke 1120, a peak in aspirate viscosity 1130 is annotated deep vein thrombosis 1160; again this may be consistent with eq. 11 which predicts a generally intermediate frequency response of a thrombus of generally intermediate mass. At higher frequency 1110 and medium stroke 1120, a peak in aspirate viscosity 1130 is annotated chronic total occlusion 1170; this may be consistent with eq. 11 which predicts a high frequency response of a thrombus of generally smaller mass. At higher frequency 1110 and short stroke 1120, a peak in aspirate viscosity 1130 is annotated ischemic stroke 1180; this may be consistent with eq. 11 which predicts a high frequency response of a thrombus of generally smaller mass; furthermore, the short stroke of the peak identified as ischemic stroke 1180 is anticipated because of the delicate nature of the surrounding vasculature. The graphical data presented in FIG. 10 is speculative; however it is based upon clinical indications and the governing equations of motion. Differences between appropriately-selected catheters (e.g., length, diameter, features, etc.) also influence the locations of each peak; a larger diameter catheter may generally tolerate a longer stroke because of the relationships outlined in Eq. 1 through Eq. 8. Historical data, including the location and expected value of each peak may be employed to minimize procedure times as the entire frequencystroke plane or space need not be explored given the clinical indications and selected catheter. This foreknowledge of efficacious factors 780, levels 788, initial values, ranges 786, etc. may be supplied by means such as analysis of similar, previously-conducted thrombectomy procedures (historical data).

[0297] FIG. 11 depicts a representative example of a more general three factor response surface 1200 where generalized factors (e.g., factor(1) 1210, factor (2) 1220 and factor (3) 1230, etc.) are varied throughout the space to locate the (generally closed) response surfaces which are shown to bound a response volume. FIG. 11 depicts that, at low levels of factor (1) 1210 and factor (2) 1220 combined with intermediate levels of factor (3) 1230, type 1 thrombus 1255 appears as an oval, oblate spheroid or surface of revolution. The location, orientation, size and shape of oval representing type 1 thrombus 1255 may be determined by measuring aspirate viscosity 1130 or other means of determining the concentration of thrombus in the aspirate (e.g., flowmeter, optical density, etc.). Type 2 thrombus 1260 (response surface/volume) is illustrated at moderate levels of factor (1) 1210 and factor (2) 1220 and a higher level of factor (3) 1230. Type 3 thrombus 1270 is shown to be responsive to a range of levels of factor (1) 1210, factor (2) 1220 and factor (3) 1230. Type 4 thrombus 1280 is shown to be responsive to a limited range of levels of factor (2) 1220, a moderate range of levels of factor (3) 1230 and a broad range of levels of factor (1) 1210.

[0298] Heretofore in this disclosure, embodiments have been generally presented to execute cause and effect or stimulus/response methods that detect and exploit efficacious thrombectomy operating modes based upon intra-procedural data. The representative flowcharts of FIG. 9A through FIG. 9D evaluate viscometric measurement data with respect to other data including: baseline data (e.g., V.sub.0, 4 cP, etc.), historical data, intra-procedural data, and/or arbitrary constants (e.g., ?.sub.1, ?.sub.2, ?, V.sub.clog, etc.) etc. FIG. 7 depicts an example array of factors 780, factor variables 782 and levels 788 which had been predetermined by speculation or other undisclosed means. FIG. 7 is representative of a very large (and undetermined) number of combinations of the example factors 780 and levels 788; the number of combinations is certainly in excess of 1 million. It is therefore an objective of embodiments of the present invention to pare down the number of possible combinations (of factors and levels) to a manageable number, such as fewer than 50,000 possible combinations. It is a further objective of embodiments and methods of the present invention to utilize and contribute to a knowledge base of efficacious thrombectomy operating modes (e.g., in terms such as factors 780, factor variables 782 and levels 788) in order that initial values for levels 788, ranges 786 and number of levels 790 are selected that minimize procedure time and maximize thrombectomy efficacy.

[0299] For instance, a thrombectomy procedure to treat ischemic stroke will typically utilize a single-lumen catheter of small diameter (range of approximately 1F to 6F); therefore certain factors (e.g., infusion 895, extension 897, etc.) are typically not present in an ischemic stroke thrombectomy procedure. Likewise, in a typical ischemic stroke procedure, factor variable 782, LFO stroke 880 is typically limited to small values (e.g., 0.1 mm to 1.0 mm, etc.). This knowledge of clinical indication and catheter selection enable the selection of a predetermined set of arbitrary constants such as threshold values (e.g., ?.sub.1, ?.sub.2, ?, V.sub.clog, etc.) and/or initial values such as loop indices (e.g., i=7, j=2, k=9, l=4, m=17, n=0, etc.) that are specific to the clinical indication and catheter.

[0300] FIG. 12 illustrates a representative data storage, analysis and communication pathway suitable for determining and implementing new or updated system parameters (e.g., thrombectomy control flowcharts 901, threshold values and initial values for loop indices, etc.) that are specific to a clinical indication and catheter, etc., and derived from inter-procedural or historical data. A block diagram of an embodiment of a knowledge-based thrombectomy system is presented in FIG. 12 which depicts procedure data from multiple procedures being logged, transmitted to and compiled by database/compiler 2020. System A 2000, system B 2100, and system C 2200, are illustrated wherein a system may comprise any or all of the following: thrombectomy machine (by model number, serial number, location, etc.), catheter (model number, length, diameter, features, e.g., hydrodynamic jet, variable geometry, rotating cutter, obturator, etc.), system factors/parameters (e.g., LFO/HO, variable geometry, hydrodynamic jet, etc.), clinical indication (e.g., ischemic stroke, deep vein thrombosis, chronic total occlusion, pulmonary embolism, etc.), operator, etc. System A 2000 is shown to sequentially perform a first procedure denoted as system A procedure #1 2001; and subsequent procedures denoted as system A procedure #2 2002, system A procedure #3 2003 and system A procedure #n 2004. System A procedure #1 2001 is depicted to contain procedure log file 500; each procedure #x similarly contains procedure log file 500, however many instances are omitted in FIG. 12 for clarity. System B 2100 is shown to sequentially perform a first procedure denoted system B procedure #1 2101; and subsequent procedures denoted system B procedure #2 2102, system B procedure #3 2103 and B procedure #n 2104. System C 2200 is shown to sequentially perform a first procedure denoted system C procedure #1 2201; and subsequent procedures denoted system C procedure #2 2202, system C procedure #3 2203 and system C procedure #n 2204. Each procedure is shown to generate a procedure data log file, thus the n.sup.th procedure is shown to generate an n.sup.th procedure data log file for each procedure completed (for each system, e.g., A, B, C, etc.).

[0301] Database/Compiler 2020 is shown to exist remotely and is in shown in communication with system A 2000, system B 2100, and system C 2200 through data exchange 2025. Data exchange 2025 may comprise bi-directional wired or wireless communication or storage devices, e.g., Ethernet/internet, Bluetooth, WiFi, USB connection or storage devices, etc. Data collected from multiple thrombectomy procedures (e.g., as a plurality of procedure data log files, etc.) may be compiled and analyzed by database/compiler 2020 to identify effective treatment regimens (e.g., thrombectomy operating modes, initial values, arbitrary values, sequences or combinations thereof, etc.) that may significantly improve procedure efficacy. Database/compiler 2020 may then provide (data-driven) software or firmware updates to systems of the network (e.g., System A 2000, system B 2100, and system C 2200, etc.). Embodiments of the present invention integrate real-time measurement of thrombectomy efficacy (e.g., viscosity, relative flow rate, % thrombus, etc.) with correlation to a plurality of therapeutic treatments (thrombectomy operating modes) to enable cause/effect or stimulus/response analysis to be conducted both intra-procedurally and post-procedurally. FIG. 12 illustrates how inter-procedural data may be utilized in embodiments of the present invention because, for instance, a plurality of procedures conducted upon system A 2000 may precede subsequent similar procedure conducted upon system B 2100 and system C 2200, etc. A plurality of data log files 500 may be locally compiled and analyzed by individual systems (e.g., system A 2000, system B 2100, system C 2200, etc.) or by database/compiler 2020.

[0302] Embodiment of database/compiler 2020 is depicted, among other functionalities, as a repository for a plurality of procedure log files 500, each of which represents a statistically significant number of experiments (i.e., thrombectomy operating modes, range of approximately 100 to 20,000 per procedure) correlated to thrombectomy efficacy (e.g., viscosity, slope, % thrombus, relative flow rate, etc.). FIG. 12 is instrumental in conveying the quantity of data comprising embodiments of knowledge-based thrombectomy systems. Subsequent to any single procedure, clinicians, reviewers, analysts, algorithms or software may identify efficacious thrombectomy operating modes as well as inefficacious modes. These data are available to database/compiler 2020 for analysis including statistical analysis and development of robust thrombectomy control algorithms, initial values and arbitrary constants for system parameters such as: factors 780, factor variables 782, ranges 786, levels 790 and number of levels 790, etc. Updated software/firmware comprising knowledge-based thrombectomy control flowcharts 901 may be transmitted to and installed in individual thrombectomy systems (e.g., system A 2000, system B 2100, system C 2200, etc.) by data transfer means such as data exchange 2025, flash drives, CD-ROM, DVD-ROM, cloud storage, etc.

[0303] FIG. 13A, FIG. 13B and FIG. 13C show excerpts of a representative thrombectomy procedure data log file 500. This example thrombectomy procedure log file illustrates many of the functions of thrombectomy control flowchart 901, including adaptive dwell times, identifying efficacious combinations of i and j (loop indices) that positively correlate to thrombus in the catheter, updating loop indices to new values, etc. This example thrombectomy procedure log file illustrates an example progression or sequence of factors and levels consistent with a loop thrombectomy control flowchart 901 such as depicted in FIG. 9A; loops may be single, multiple or nested. ID block 1300 shows column headers including: time 1370, factor 1 1210, factor 2 1220, factor 3 1230, factor 4 1240, factor 5 1250, viscosity 1380 and slope 1390. Factors may be enumerated or a word description (e.g., 1, 2, 3, 4, etc. or infusion pressure, aspiration rate, LFO, HO frequency, etc.) may be shown (e.g., as headers) in a thrombectomy procedure log file. Thrombectomy procedure log file, including ID block 1300, may comprise data including, but not limited to: patient data, clinical indication, thrombectomy system, catheter, facility, clinician, software/firmware version, etc.

[0304] FIG. 13A depicts representative loop 1 1310 commencing at 13:00:00 hours and the initial time increment is shown to be 1 second; some data are omitted for brevity. Factor 1 1210 is initialized to level 1, factor 2 1220 is initialized to level 3, factor 3 1230 is initialized to level 5, factor 4 1240 is initialized to level 7, factor 5 1250 is initialized to level 1. The initial value levels may be predetermined (e.g., by knowledge-base, software/firmware, clinician input, etc.) or assigned arbitrary values; initial values may reflect historical data such that established, therapeutically efficacious, settings are selected. Loop 1 increments factor 1 1210 while the remaining factors and levels are held constant in this loop. Factor 1 1210 is shown to be incremented from 1 to 11 and an increase in aspirate viscosity is detected at level 6; the maximum measured viscosity (viscosity?30) in loop 1 1310 is shown to occur at level 9 of factor 1 1210. Viscosity 1380 decreases to the nominal value for blood (approximately 4 cP) as factor 1 1210 is incremented to 11; loop 1 1310 is shown to be terminated after the experiment at level 11 returns a measured viscosity of blood (viscosity?4). Level 9 of factor 1 1210 may be stored in memory as an efficacious level; in subsequent example loops, levels 8, 9 and 10 are shown to be upon.

[0305] Data from representative loop 1 1310 illustrate a feature of some embodiments of thrombectomy control flowchart 901, wherein efficacious thrombectomy operating modes are operated for a longer duration than less efficacious ones. For instance, at time 13:00:00, the measured aspirate viscosity and the duration of operation is approximately one second. At time 13:00:49, the measured aspirate viscosity is 30 cP, and the duration of operation is approximately 20 seconds. The representative data log files 500 (shown in FIG. 13A, FIG. 13B and FIG. 13C) illustrate how Effect Subroutine 1000 (among other capabilities) utilizes fixed and/or variable dwell times to extend the operating duration of efficacious thrombectomy operating modes (experiments).

[0306] Representative loop 2 1320 commences at 13:05:45 and holds factor 1 1210 level constant at the previously determined value of 9. Loop 2 1320 increments factor 2 1220, between 1 and 9, holding the remaining factors and levels constant. In loop 2 1320, the maximum measured viscosity (viscosity=50) is shown to occur at level 5 and returns to the measured viscosity of blood (viscosity?4) at level 9 of factor 2 1220; loop 2 1320 is terminated when the measured viscosity decreases to that of blood (viscosity?4). Level 5 of factor 2 1220 may be stored in memory as an efficacious level; in subsequent loops, levels 5 and 4 are experimented upon.

[0307] In FIG. 13B, loop 3 1330 commences at 13:09:50. Factor 3 1230 is incremented between 1 and 13 in loop 3 1330 while factor 1 1210 is held constant at level 8 (determined during loop 1 1310) and factor 2 1220 is held constant at level 5 (determined during loop 2 1320). The remaining factors and levels remain at initial values. Loop 3 1330 is shown to have two viscosity peaks occurring at level 5 (viscosity=15) and level 10 (viscosity=30); loop 3 1330 is terminated at level 13 of factor 3 1230. Levels of 5 and 10 of factor 3 1230 may be stored in memory as efficacious levels; in subsequent loops levels 4 and 9 of factor 3 1230 are explored. Deviations from the efficacious levels (e.g., 5; 10, etc.) are subsequently experimented upon (e.g., 4 and 6 as deviations from 5; 8, 9, 11 and 12 as deviations from 10, etc.).

[0308] Loop 4 1340 commences at 13:14:10; factor 4 1240 is incremented between levels 0 and 13. In loop 4 1340, factor 1 1210 is held constant at level 10, factor 2 1220 and factor 3 1230 are held constant at level 4; these levels (or deviations therefrom) had been determined during previous loops. Loop 4 1340 is shown to have two viscosity peaks occurring at level 5 (viscosity=150) and level 8 (viscosity=140). Levels of 5 and 8 of factor 3 1230 may be stored in memory as efficacious levels; in subsequent loops, only level 5 of factor 3 1230 is shown to be explored (for brevity).

[0309] FIG. 13C shows loop 5 1350 commencing at 13:19:00; factor 5 1250 is incremented between levels 0 and 9. In loop 5 1350, factor 1 1210 is held constant at level 10, factor 2 1220 is held constant at level 4, factor 3 1230 is held constant at level 9 and factor 4 1240 is held constant at level 5. In loop 5 1350, four of the five factors have levels that were determined in previous loops. Loop 5 1350 is shown to have a viscosity peak occurring at level 5 (viscosity=160). Level 5 of factor 4 1240 may be stored in memory as an efficacious level; in loop 6 1360, only level 5 of factor 5 1250 is shown to be explored (for brevity).

[0310] Loop 6 1360 commences at 13:21:15. No factors are incremented in loop 6 1360; all factors and levels were determined in previous loops. Loop 6 1360 illustrates that all factors and levels may be held constant (experiments are repeated) while the measured viscosity decreases from 60 (at 13:21:15) to 4 (at 13:22:00).

[0311] Log summary 1400 depicts total procedure time 1370 (0:37:23), average % thrombus 1410 (11%), total aspiration 1420 (126cc), total infusion 1430 (50cc), and total thrombus 1450 (41.25cc). Log summary 1365 is a procedure scorecard of a thrombectomy procedure data log file; the relevant data may be averaged, statistically analyzed, compiled or otherwise manipulated and organized into relevant contributions to a knowledge base. A thrombectomy procedure featuring: minimum procedure time 1370, coupled with a maximum average % thrombus 1410, minimum total aspiration 1420 (blood loss) and maximum total thrombus 1450 is desirable.

[0312] Thrombectomy procedure log file 500 (as illustrated in FIG. 13A, FIG. 13B and FIG. 13C) is shown to contain measurement data (viscosity and slope) that were used as arguments of conditional statements (e.g., IF-THEN, DOWHILE, etc.) within a thrombectomy control flowchart 901. In this manner, data are utilized intra-procedurally to identify and select combinations of factors 780 and levels 788 for extended operation (e.g., by means such as dwell commands, repeating combinations, etc.) or for further experimentation. Thrombectomy procedure log file 500 also illustrates how efficacious combinations of factors 780 and levels 788 may be stored as predetermined values for subsequent loops and/or procedures. Subsequent procedures sharing common clinical indications and equipment (e.g., PE with catheter XYZ, DVT with catheter ABC, etc.) may benefit from any (or all) prior thrombectomy procedure data log files to provide predetermined thrombectomy system settings including: initial values, ranges, dwell times, threshold values, selected factors and ranges, etc.

[0313] Procedure log file 500 illustrates how example thrombectomy control algorithm 901 responds to the data and correlation in two ways: (1) the dwell time is increased for efficacious configurations, and (2) efficacious configurations/setpoints (e.g., Factor 1 1210 set to level 788=10, Factor 2 1220 set to level 788=4, etc.) are repeated a plurality of times throughout the remainder of the procedure. Thrombectomy control algorithm 901 prescribes a sequence of operations of a thrombectomy apparatus; each operation of the apparatus occurring for a duration sufficient to take a measurement of thrombus in the catheter. Upon detection of an operation that positively correlates to thrombus, thrombectomy control algorithm 901 invokes actions (e.g., DWELL, j=j-1, etc.) that interrupt or change the prescribed sequence. Embodiments of the invention thereby implement control strategies that are adaptive to increase the procedure time wherein flowing thrombus is present in the catheter.

[0314] Procedure log file 500 illustrates a difference between intra-procedural and inter-procedural (post-procedural or historical) data as utilized by some embodiments of the invention. The example procedure utilized initial values (for apparatus or system setpoints) of (1, 3, 5, 7, 1) and a set of arbitrary constants, levels, ranges and threshold values (e.g., ?.sub.1, ?.sub.2, ?, etc.). During the course of the procedure, it was determined that setpoint configuration (10, 4, 9, 5, 5) exhibited strong correlation to viscosity. Had the procedure utilized the initial values (10, 4, 9, 5, 5), the procedure efficiency may have been increased. Embodiments of the invention compile a plurality of similar procedure log files 500 and calculate improved initial values; improved values for levels, ranges and threshold values may be calculated or otherwise obtained by the historical data. The improved set of initial values, levels, ranges and threshold values may be transmitted to each system controller 810 such as by software or firmware update. Thrombectomy control algorithm 901 may be improved by observation or analysis of historical data such that a more efficient set of machine instructions may be transmitted to each system controller 810 such as by software or firmware update.

[0315] FIG. 14 depicts a physical relationship and communication pathways representative of some embodiments of a generalized knowledge-based thrombectomy system 2302. FIG. 14 depicts a block diagram of a knowledge-based thrombectomy system 2302 with respect to the patient and patient vascular system 2310, surgical suite 2340 (the location where the thrombectomy procedure is performed) and remote database/compiler 2020, that may typically be at an off-site and/or centralized location. Catheter 200 and infusion tube 320 are shown to access patient vascular system 2310 which is shown to contain thrombus 240.

[0316] Knowledge based thrombectomy system 2302 is shown comprising any or all of system controller 810, LF Oscillator 102, Harmonic Oscillator 104, LCO with aspiration and infusion 400, accelerometer 410, pressure transducer 420, aspirate pump 440, infusion pump 460, infusion tube drive motor 470, and manifold 500; other embodiments may comprise a greater or lesser number of components or features which may be implemented to aspirate thrombus 240. System controller 810 is shown in communication with clinician input 895 and clinician data 890; communication with database/compiler 2020 is shown through data exchange 2025.

[0317] FIG. 15 depicts a block diagram of an illustrative system controller 810 operating in accordance with aspects and implementations of the present disclosure. As shown in FIG. 15, system controller 810 comprises processor 2402, main memory 2404, storage device 2406, analog/digital I/O 2408, motor drivers 2410, audio generator 2412, video generator 2414, interconnected as shown (e.g., via one or more busses, etc.). System controller 810 may comprise proprietary hardware or off-the-shelf components including PC's, microcontrollers (e.g., Arduino, Raspberry Pi, etc.) that may be programmed in any appropriate computer language including Visual Basic, C++, Python, etc. Syntax from BASIC and FORTRAN computer programming languages are incorporated herein including: FORNEXT loops, IF-THEN conditional statements, DO loops, DO WHILE loops, GOSUB, GOTO, etc.

[0318] Processor 2402 represents one or more general-purpose processing devices such as a microprocessor, central processing unit, or the like. More particularly, processor 2402 may be a complex instruction set computing (CISC) microprocessor, reduced instruction set computing (RISC) microprocessor, very long instruction word (VLIW) microprocessor, or a processor implementing other instruction sets or processors implementing a combination of instruction sets. Processor 2402 may also be one or more special-purpose processing devices such as an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), a digital signal processor (DSP), network processor, or the like. Processor 2402 is capable of executing instructions stored in main memory 2404 and storage device 2406, including instructions corresponding to the methods exemplified in FIG. 9A through FIG. 9D; of reading data from and writing data into main memory 2404 and storage device 2406; and of receiving input signals and transmitting output signals to analog/digital I/O 2408. While a single processor is depicted in FIG. 15 for simplicity, system controller 810 might comprise a plurality of processors.

[0319] Main memory 2404 is capable of storing executable instructions and data, including instructions and data corresponding to the methods exemplified in FIG. 9A through FIG. 9D, and may include volatile memory devices (e.g., random access memory [RAM]), non-volatile memory devices (e.g., flash memory), and/or other types of memory devices. Software /firmware 2416 may comprise a list of executable instructions and data and may be integrated to main memory 2404 or as a standalone, discrete component.

[0320] Storage device 2406 is capable of persistent storage of executable instructions and data, including instructions and data corresponding to the method exemplified in FIG. 9A through 9D, and may include a magnetic hard disk, a Universal Serial Bus [USB] solid state drive, a Redundant Array of Independent Disks [RAID] system, a network attached storage [NAS] array, etc. While a single storage device is depicted in FIG. 15 for simplicity, system controller 810 might comprise a plurality of storage devices.

[0321] Analog/Digital I/O 2408 receives input signals from one or more devices including pressure transducer 420, accelerometer 410 and/or a user of system controller 810. Analog/Digital I/O 2408 forwards corresponding signals to processor 2402, receives signals from processor 2402, and emits corresponding output signals that can control system functions (e.g., aspirate pump 440, infusion pump 460, infusion tube drive motor 470, LCO 100, etc.) and/or be sensed by the user. The input mechanism of analog/digital I/O 2408 might be a footswitch, a knob, an alphanumeric input device (e.g., a keyboard, etc.), a touchscreen, a cursor control device (e.g., a mouse, a trackball, etc.), a microphone, etc., and the output mechanism of analog/digital I/O 2408 might be a liquid-crystal display (LCD), a cathode ray tube (CRT), a speaker, etc. While a single I/O device is depicted in FIG. 15 for simplicity, system controller 2402 might comprise a plurality of I/O devices.

[0322] Audio generator 2412 and/or video generator 2414 may produce information, data or signals which are conveyed to the clinician by means including a speaker and/or a touchscreen, and/or a LCD and/or CRT display. Motor drivers 2410 may produce signals which provide control over electric devices such as motors, step motors, servo motors, linear actuators, solenoids, valves etc. Database/compiler 2020 is shown in communication with system controller 810 by communication means such as data exchange 2025. Data exchange 2025 may provide unidirectional or bi-directional communication with system controller 810 by which information including data log file 500, and/or software/firmware 2416 updates are transmitted. Data exchange 2025 may comprise wired connection (e.g., USB port, DB-9, DB-25 connections, etc.) or may comprise wireless communication (e.g., Bluetooth, WiFi, cloud storage or other wireless network communication protocol.)

[0323] It is to be understood that the above-described embodiments are merely illustrative of the present invention and that many variations of the above-described embodiments can be devised by those skilled in the art without departing from the scope of the invention. For example, in this specification, numerous specific details are provided in order to provide a thorough description and understanding of the illustrative embodiments of the present invention. Those skilled in the art will recognize, however, that the invention can be practiced without one or more of those details, or with other methods, materials, components, etc.

[0324] Furthermore, in some instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the illustrative embodiments. It is understood that the various embodiments shown in the figures are illustrative, and are not necessarily drawn or labeled to scale. Reference throughout the specification to one embodiment or an embodiment or some embodiments means that a particular feature, structure, material, or characteristic described in connection with the embodiment(s) is included in at least one embodiment of the present invention, but not necessarily all embodiments. Consequently, the appearances of the phrase in one embodiment, in an embodiment, or in some embodiments in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, materials, or characteristics can be combined in any suitable manner in one or more embodiments. It is therefore intended that such variations be included within the scope of the appended claims and their variants or equivalents.

[0325] This disclosure of the invention incorporates multiple embodiments including means to attrite thrombus, means to aspirate thrombus and means to measure thrombus; additionally, methods to conduct deterministic events (experiments) and correlate measurement data to apparatus configuration (e.g., setpoints, positions, etc.). The multiple embodiments and multiple methods disclosed herein gives rise to a large combinations thereof. A non-exhaustive list of combinations of embodiments and methods is provided herein for completeness. Some embodiments of the invention comprise (in addition to other structures, mechanisms or embodiments) any combination of: Liquid Column Oscillator (LCO), Low Frequency Oscillator, Harmonic Oscillator, impulse mechanism, pressure limiter, hydrodynamic lance, mechanical lance, manifold, valve, obturator, guidewire, rotating cutter, stent retriever, capture mesh, filter, variable catheter geometry, system controller, peristaltic pump, pressurized or evacuated reservoir, liquid pump, gas/vapor/vacuum pump, syringe, syringe pump, non-isovolumetric component, stepper motor, servo motor, linear actuator, pressure transducer, flowmeter, stent retriever, capture mesh, thrombectomy procedure data log files, visual display, audio speaker, clinician input, footpedal, knobs, keypad, manual or automated positioning of, and position measurement of devices including: catheters, guidewires, obturators, etc. Some embodiments of the invention utilize methods including any combination of: time-domain viscometry, viscometric sampling, viscometric distance sampling, determination of % thrombus, determination of thrombus load, determination of (relative and absolute) flow rate, determination of thrombectomy efficacy, clog detection, clog aversion, dynamic or adaptive modification of a sequence of machine instructions, data analysis, software or firmware updates, communication pathways, determination of threshold values, determination of ranges and increments for setpoint adjustment of an apparatus, pressure limitation, causing cavitation or boiling, determination and excitation of resonant frequencies, cause and effect (stimulus/response) experimentation, valve actuation, DOE, SPC, thrombectomy control algorithms, effect subroutines, distance subroutines, clog detect/avert subroutines, viscosity/slope measurement subroutines, thrombectomy procedure data log files, graphical depiction, clinician instructions, clinician feedback, clinician input, calibration procedure and subroutine, apparatus operation, setpoint changes, etc.

[0326] In order to provide a clear and consistent understanding of the disclosure and the appended claims, including the scope to be given such terms, the following glossary of terms and definitions is provided.

[0327] Liquid Column Oscillator (LCO): any combination of an oscillating or reciprocating surface fluidically coupled to a fluid-filled catheter operating in the range of approximately 0.1 Hz to 19,000 Hz. LCO embodiments may comprise a plurality of oscillating or reciprocating surfaces including: LF oscillator and Harmonic Oscillator (HO).

[0328] LF Oscillator (low frequency): A Liquid Column Oscillator characterized by imparting fluid translation within a catheter on a length scale of approximately 0.5 mm to 500 mm and a frequency range of approximately 0.1 Hz to 50 Hz. The abbreviation LFO may be used herein; the terms LCO, Low Frequency Oscillator and LFO may be used interchangeably in context herein.

[0329] HF Oscillator (High Frequency or Harmonic Oscillator): A Liquid Column Oscillator characterized by imparting pressure or mechanical waves within a fluid medium wherein the fluid translation is typically less than approximately 0.5 mm and a frequency range of approximately 20 Hz to 19,000 Hz. The terms LCO, HO, Harmonic Oscillator, HF Oscillator and High Frequency Oscillator may be used interchangeably in context herein.

[0330] Fluid: any homogeneous or heterogeneous matter comprised of vapors, gasses, liquids, solids, suspensions or slurries thereof that may be transferred into a tube, pipe or catheter by means of a differential pressure existent within the tube, pipe or catheter. The terms Fluid and Liquid may be used interchangeably herein.

[0331] Viscositythe resistance of a fluid to flow; herein including the resistance of a homogeneous fluid or inhomogeneous mixture of fluids and/or solids to flow through a catheter or conduit. An inhomogeneous mixture of thrombus and blood might be uniformly distributed or might be non-uniform (spatially discrete) along the length of a catheter. The viscosity of an inhomogeneous mixture in a catheter may be measured by methods such as time-domain viscometry. The measured viscosity may be approximately inversely proportional to the rate of flow through the catheter. Herein, viscosity may be construed to mean the average or effective viscosity of fluid contained within a conduit or catheter. Eq. 0 provides a mathematical description where {circumflex over (?)} is the viscosity of a differential fluid volume element; the effective or average viscosity may be calculated by integrating the viscosities of the differential fluid volume elements along the length (L) of the catheter.

[00006]$\begin{array}{cc}\mathrm{.Math.}?\frac{1}{L}{?}_0^L\widehat{\mathrm{.Math.}}\mathrm{dx}& \mathrm{Eq}.0\end{array}$

[0332] Note that if even a single differential fluid volume element has a very large value of {circumflex over (?)} (e.g., greater than approximately 10,000 cP) the measured, effective or average value of ? will also increase to a large value. Thus, a clogged or corked catheter might be indicated by a very large measured value of ?.

[0333] Viscometric SamplingA method of measuring the viscosity of aspirateora method of determining an aspirate characteristic, wherein a small aspirate sample (range of approximately 0.2cc to 5.0cc) is withdrawn from a patient vasculature to quantitatively measure the viscosity. In cases wherein the measured aspirate viscosity is approximately equal to blood, the sample may be returned to the patient vasculature, such as by reversal of an aspirate pump. Viscometric sampling may thereby be conducted with small, zero or near-zero blood loss. Viscometric sampling data in excess of threshold values (e.g., 500 cP, 1,000 cP, etc. as may be experimentally determined) may detect a clog, imminent clog or corking of the catheter.

[0334] Viscometric Distance SamplingA method of viscometric sampling that includes an inference to the distance between the catheter tip and a thrombus. As the catheter tip is physically moved (i.e., advanced) into closer proximity (i.e., smaller distance) to a thrombus, the magnitude of data from viscometric sampling increases in inverse relation to distance. Viscometric distance sampling data in excess of threshold values (e.g., 500 cP, 1,000 cP, etc. as may be experimentally determined) may detect a clog, imminent clog or corking of the catheter.

[0335] Corking (of a Catheter)A case of clogging a catheter wherein an excess of thrombus is ingested such that ordinary differential pressure (e.g., steady, interrupted, non-oscillatory, etc. suction/vacuum from a syringe, evacuated reservoir, etc.) forces are ineffective in establishing or restoring flow. Corking of a catheter typically occurs when suction /vacuum exceeds maximum levels imposed by constraints including mass, diameter, length, rheology, viscosity, solids content, rigidity, elasticity, etc. of thrombus with respect to the catheter dimensions.

[0336] Aspirate (noun)any fluid, liquid, solid, slurry, homogeneous or heterogeneous matter that may be transferred through a conduit or catheter; also the contents of the conduit or catheter.

[0337] Aspirate or aspirating (verb)employ(ing) differential pressure to transfer any fluid, liquid, solid, gas, vapor, slurry or heterogeneous matter through a conduit or catheter. Sources of differential pressure include: pumps, evacuated reservoirs, syringes, compliance chambers, atmospheric pressure, intravascular pressure, phase change, gravity, etc.

[0338] Attribute Data: Attribute data, also known as categorical data, consists of discreet categories or labels that represent different qualities or characteristics. These categories are typically non-numeric and qualitative in nature. Attribute data is typically used to describe characteristics that can be counted or categorized. Attribute data are typically graphically depicted as frequency distributions, histograms, bar charts, pie charts, etc.

[0339] Variable Data: Variable data, also known as numerical data or continuous data, consists of numeric values that can take any real number value within a certain range. These values can be measurements of physical properties and are quantitative in nature. Variable data may be expressed in engineering units including: cP, Pa, ? C., etc.; variable data may be ratiometric or expressed as percentages. Variable data may be acted upon using mathematical methods of algebra, linear algebra, calculus, differential equations, etc.

[0340] Experiment: herein, the act of exposing a system to external stimuli and measuring the system response. Example: a thrombectomy apparatus is operated wherein the setpoint(s) of the apparatus have been adjusted to specific values (e.g., aspiration pump speed=10%, infusion pump speed=20%, LCO frequency=15 Hz, etc.); this operation is maintained for a duration enabling measurement of the system response (e.g., viscosity=10 cP, % thrombus=10%, relative flow rate=40%, etc.). Also, an investigation and attempt to demonstrate the cause and effect relationship between two or more variables (factors and/or levels).

[0341] Experiment array: herein, a shorthand notation that indicates the setpoint(s) of the apparatus during an experiment. Example experiment arrays: [aspiration pump speed=10%, infusion pump speed=20%, LCO frequency=15 Hz, infusion=0%, rotating cutter=0 rpm, HO frequency=3,000 Hz] or simply [10, 20, 15, 0, 0, 3,000].

[0342] Correlation: herein, connecting or associating an experiment or experiment array with the measured system response (e.g., viscosity=10 cP, % thrombus=10%, relative flow rate=40%, etc.). The correlation may be termed positive correlation when the measured system response is measured to be outside of baseline values (e.g., viscosity>4 cP, % thrombus>0%, relative flow rate<100%, etc.). Positive correlation may be quantitative. Example: experiment X [10, 20, 15, 0, 0, 3,000] is correlated to a measured % thrombus of 30%. Experiment X is positively correlated to % thrombus at 30% significance, or [10, 20, 15, 0, 0, 3,000] is positively correlated to a measured % thrombus at 30% significance.

[0343] Deterministic event: herein, any prescribed event that affects, influences or changes the outcome of successive events, observations or measurements. Herein, conducted experiments are deterministic events that affect, influence or change the outcome of thrombus attrition or thrombectomy efficacy measurements.

[0344] Design of Experiments (DOE): a systematic, efficient method that enables study of the relationship between multiple input variables (i.e., factors), at multiple input setpoints (i.e., levels), and key output variables (i.e., responses, e.g., thrombectomy efficacy). It is a structured approach for collecting and analyzing data.

[0345] Thrombectomy Operating Mode: Any combination of factors (e.g., aspiration, infusion, LCO/HO, rotating cutter, obturator, hydrodynamic jet, variable geometry, catheter positioning, etc.) and levels (e.g., on/off, 375 Hz, 10% speed, 0.8cc/s flow rate, 40% pressure, direct impingement, 10% extension, 5 mm withdrawal, etc.) which may be executed in the course of a thrombectomy procedure.

[0346] Thrombectomy Control Flowchart (or Thrombectomy Control Algorithm): An algorithm to execute a plurality of thrombectomy operating modes and measure the thrombectomy efficacy of each thrombectomy operating mode. A thrombectomy control flowchart algorithm may invoke intra-procedural data, clinician input, predetermined values, historical data and/or conditional statements to improve the efficacy of a thrombectomy procedure by identifying and exploiting efficacious thrombectomy operating modes.

[0347] Thrombectomy and/or Procedure Data Log File: a generally tabular, matrix or graphical form of collected data comprising thrombectomy system settings (e.g., factors and levels, parameters and setpoints, thrombectomy operating mode, etc.) correlated to measured thrombectomy efficacy.

[0348] Thrombectomy Efficacy: (1) An intra-procedural quantitative score system to assess the amount of thrombus and the flow rate within the catheter at any point in time. Thrombectomy efficacy may be defined to be zero at any time if either the % thrombus in the catheter is zero or if the flow rate is zero (e.g., due to a clog). (2) A post-procedural quantitative score system to assess measured quantities such as the amounts of thrombus, blood loss and procedure time.

[0349] Factor: an adjustable apparatus, machine or system parameter (e.g., speed, frequency, pressure, length, temperature, etc.); factors are typically setpoint controlled.

[0350] Level: a setpoint of a factor (e.g., speed setpoint=10 mph, frequency setpoint=375 Hz, pressure setpoint=50 psi, length setpoint=10 mm, temperature setpoint=298K, etc.). In some cases (e.g., involving manual manipulation), the level may be measured (e.g., catheter position, obturator position, etc.).

[0351] Setpoint: (1) automated systems: the desired value of any adjustable process variable (e.g., pressure, flow rate, rpm, frequency, length, etc.). (2) manually operated systems: a stated or measured value of any adjustable process variable (e.g., catheter position, footpedal position, knob adjustment, regulator adjustment, etc.).

[0352] Characteristic of Flow: A language-based descriptor of flow of aspirate within a catheter which is expressed in attribute data terms including: free flow, open flow, restricted flow, clot, clog, etc. Also termed Flow State. Characteristic of flow may be monitored for change.

[0353] Relative Flow Rate (Qr): An intensive property of fluid within a catheter calculated from viscosity measurements. Relative flow rate may be normalized to a reference fluid such as blood or saline. Relative flow rate is generally independent of scale (e.g., catheter length/diameter, differential pressure, etc.). Qr (calculated for the i.sup.th sample) may be defined in a manner such as: Qr.sub.i=(?.sub.blood)/(?.sub.i) (where Qr.sub.i is the relative flow rate of the i.sup.th sample and ?.sub.i is the viscosity of the i.sup.th sample) or a similar expression.

[0354] Absolute Flow Rate (Q) and Absolute Flow Velocity: extensive properties of a flow field that may be quantitatively expressed in units such as liters per minute (I/min) or meters per second (m/s). Absolute flow rate and absolute flow velocity are generally dependent upon differential pressure, catheter dimensions, etc. Absolute flow rate and absolute flow velocity may be interconverted multiplying/dividing by the diameter of the catheter, tube or pipe; this conversion may be approximate because of phenomena including fluid velocity profile.

[0355] % Thrombus or % T: An intensive property of aspirate (within a catheter) derived or calculated from viscosity measurements. % Thrombus is relevant in thrombectomy vernacular because: (1) larger is better, (2) the measurement data has been converted to intuitively familiar units. % Thrombus (calculated for the i.sup.th sample) may be defined in a manner such as % T.sub.i=(1?Qr.sub.i)?100% (where % T.sub.i is the calculated % thrombus for the i.sup.th sample) or a similar expression.

[0356] Thrombus Load: a quantitative property of aspirate (within a catheter) derived or calculated from viscosity measurements in conjunction with historical data that identify threshold viscosities that, if exceeded, are likely to cause clogging or corking of a catheter. For example, in cases wherein thrombus load is calculated to be 30%, maximum aspiration may be continued (perhaps increasing the thrombus load). In cases wherein thrombus load is calculated to be 90%, actions such as: reduced aspiration rates, catheter repositioning, saline flush, etc. are indicated to avert imminent clogging or corking of the catheter.

[0357] Means to Attrite Thrombus: herein, any apparatus, structure, mechanism or system to attrite thrombus by mechanical, hydrodynamic, pressure or oscillatory forces or actions. Examples include: Liquid Column Oscillator, Low Frequency Oscillator, Harmonic Oscillator, obturator, guidewire, hydrodynamic lance, hydrodynamic jet, rotating cutter, snare, stent retriever, catheter, aspiration system, thrombolytic compounds, etc. Example setpoints include: 3 Hz, 10 RPM, 3 mm, 30%, 10 mmHg, 100 psi, 3 seconds, 3 revolutions, on/off, open/closed, deployed, etc.

[0358] Means to Aspirate Fluid: herein, any apparatus or mechanism, such as a pump (liquid, gas or vapor) or pumping system, valve, differential pressure reservoir, etc., that causes flow of fluid through a catheter. A means to aspirate fluid may also comprise a means to attrite thrombus. Examples include: peristaltic pump, positive displacement liquid pump, evacuated reservoir, vacuum pump, dynamic pump, hydrodynamic jet, valve, syringe, syringe pump, etc. Example setpoints include: 3 Hz, 10 RPM, 3 mm, 10 mmHg, 100 psi, 3 seconds, 3 revolutions, 30%, on/off, open/closed, etc.

[0359] Means to Measure Thrombus: herein, any instrument or system that directly or indirectly measures the amount of thrombus within a catheter, including measurements of a fluid's resistance to flow through a catheter. Examples: viscometer, time-domain viscometer, flowmeter, differential pressure flowmeter, pressure transducer, densitometer, thermistor, etc.

[0360] The following referencing numbers are used in this disclosure:

TABLE-US-00001 10 Pressure Limiter 15 orifice plate 17 orifice 20 pressure limiter piston 22 exhaust port/tube 25 pressure limiter spring 30 pressure limiter cylinder 35 crankshaft rotation direction 40 piston direction 45 cylinder pressure 50 pressure limiter pressure 55 pressure limiter displacement 60 torsion spring 65 impulse piston 70 sear 75 hammer 80 impulse piston distance 90 impluse mechanism 100 Liquid Column Oscillator (LCO) 102 LF oscillator (LF) 104 harmonic oscillator (HO) 110 sonic transducer 120 piston 130 acoustic tube 140 connecting rod 150 slide 160 crankshaft 170 high frequency standing wave 180 motor 190 low frequency standing wave 200 cylinder 220 catheter 225 vascular access 230 catheter tip 240 thrombus 245 thrombus bolus 250 tip to thrombus distance 260 attachments 280 vessel wall 290 oscillatory flow 294 aspiration flow direction 295 aspirate flow 296 infusion flow direction 298 P1 299 P2 300 thrombus amplitude 320 infusion tube 340 axial nozzle 360 radial nozzle 380 extension 400 LCO with aspiration and infusion 410 accelerometer 420 pressure transducer 440 aspirate pump 450 waste tube 460 infusion pump 470 infusion tube drive motor 475 coiled infusion tube 480 supply tube 490 manifold 500 log file 510 FS1 520 FS2 530 FS3 560 radial jet 580 axial jet 710 blood 730 phase 1 750 phase 2 770 phase 3 780 factor 782 factor variable 784 units 786 range 788 levels 790 number of levels 792 loop termination 810 system controller 860 LFO Frequency 865 HO Frequency 875 acoustic length 880 LFO Stroke 885 aspiration rpm 890 clinician data 895 clinician input 895 infusion rpm 897 extension length 901 thrombectomy control flowchart 902 operate apparatus 905 start 910 initialize setpoints 920 position catheter 930 factor loop 940 level loop 944 advance catheter 946 TOM = f{V(i, j)} 948 retract catheter 950 measure viscosity and slope 960 GOSUB 1000 970 next level 980 next factor 1000 effect subroutine 1000 1050 distance subroutine 1050 1060 clog detect/avert subroutine 1060 1070 viscosity/slope subroutine 1070 1100 two-factor response surface 1110 frequency 1120 stroke 1130 aspirate viscosity 1150 pulmonary embolism 1160 deep vein thrombosis 1170 chronic total occlusion 1180 ischemic stroke 1200 three factor response surface 1210 factor 1 1220 factor 2 1230 factor 3 1240 factor 4 1250 factor 5 1255 type 1 thrombus 1260 type 2 thrombus 1270 type 3 thrombus 1280 type 4 thrombus 1300 title block 1310 loop 1 1320 loop 2 1330 loop 3 1340 loop 4 1350 loop 5 1360 loop 6 1370 time 1380 viscosity 1390 slope 1400 log summary 1410 % thrombus 1420 aspiration 1430 infusion 1450 thrombus 2000 System A 2001 system A procedure #1 2002 system A procedure #2 2003 system A procedure #3 2004 system A procedure #n 2020 Database/Compiler 2025 Data Exchange 2100 System B 2101 system B procedure # 1 2102 system B procedure #2 2103 system B procedure #3 2104 system B procedure #n 2200 System C 2201 system C procedure # 1 2202 system C procedure #2 2203 system C procedure #3 2204 system C procedure #n 2302 Thrombectomy System 2310 patient vascular system 2320 data log file 2340 surgical suite 2402 processor 2404 main memory 2406 storage device 2408 analog/digital I/O 2410 motor drivers 2412 audio generator 2414 video generator 2416 software/firmware