Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
  • A61F2/2478—Passive devices for improving the function of the heart muscle, i.e. devices for reshaping the external surface of the heart, e.g. bags, strips or bands
  • A61F2/2481—Devices outside the heart wall, e.g. bags, strips or bands
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
  • A61M60/10—Location thereof with respect to the patient's body
  • A61M60/122—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body
  • A61M60/165—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable in, on, or around the heart
  • A61M60/191—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable in, on, or around the heart mechanically acting upon the outside of the patient's native heart, e.g. compressive structures placed around the heart
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
  • A61M60/20—Type thereof
  • A61M60/289—Devices for mechanical circulatory actuation assisting the residual heart function by means mechanically acting upon the patient's native heart or blood vessel structure, e.g. direct cardiac compression [DCC] devices
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
  • A61M60/40—Details relating to driving
  • A61M60/465—Details relating to driving for devices for mechanical circulatory actuation
  • A61M60/468—Details relating to driving for devices for mechanical circulatory actuation the force acting on the actuation means being hydraulic or pneumatic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
  • A61M60/50—Details relating to control
  • A61M60/508—Electronic control means, e.g. for feedback regulation
  • A61M60/515—Regulation using real-time patient data
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
  • A61M60/80—Constructional details other than related to driving
  • A61M60/839—Constructional details other than related to driving of devices for mechanical circulatory actuation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
  • A61M60/80—Constructional details other than related to driving
  • A61M60/855—Constructional details other than related to driving of implantable pumps or pumping devices
  • A61M60/861—Connections or anchorings for connecting or anchoring pumps or pumping devices to parts of the patient's body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2230/00—Measuring parameters of the user
  • A61M2230/04—Heartbeat characteristics, e.g. ECG, blood pressure modulation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/18—Applying electric currents by contact electrodes
  • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
  • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
  • A61N1/362—Heart stimulators
  • A61N1/3627—Heart stimulators for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy

Definitions

• This present invention relates to a cardiac compression system, and more particularly, to a cardiac resynchronization compression sac system.
• DCC Direct Cardiac Compression
• VADs Ventricular Assist Devices
• This dynamic cardiomyoplasty method uses left latissimus dorsi muscle wrap to compress the decompensated heart. It takes time for muscle training and conversion, requiring patient condition be less emergent and have enough transition time for the muscle wrap to turn functional effective after surgery. Dynamic cardiomyoplasty becomes obsolete due to the short-lived muscle compression effect. Major problems of muscle resistance to fatigue and the transformation of skeletal muscle into cardiac-like muscle were not resolved.
• This category comprises devices such as Anstadt Cup, CardioSupport System, Heart Booster, and HeartPatch, among others.
• Biocompatible material was used as the sac or cuff-like apparatus that deploys the externally applied compression forces. Fixation has been the major design concern of how the device is mounted onto the cardiac skin. Usually persistent suction power, glue adhesion or stay suture were used. Injurious complications include myocardial contusion, ischemia due to coronary artery compression, and frequent arrhythmias caused by asynchronous mechanical compression.
• DCC devices can only be used in a short-term manner notwithstanding great effort has been tried to prolong the DCC usage period.
• HeartPatch DCC uses separate, nonsurround patches placed on the ventricular free walls.
• Acron Cardiac Support Device is a representative apparatus.
• Acron CDS is an elastic textile net that wraps around both ventricles under the atrio-ventricular groove. It was found in chronic clinic trial that Acron net infused with the epicardium and thus caused myocardial fibrosis, leading to the impairment of cardiac contractility.
• CRT Cardiac resynchronization therapy
• CHF congestive heart failure
• LV left ventricle
• Bi-ventricular and left ventricular pacing modes were found most effective in both acute studies and chronic CRT trials.
• Electrophysiological alterations were frequently observed among advanced heart failure patients receiving chronic left ventricular assist device (LVAD) circulation support. It was reported that LVAD support resulted in immediate QRS interval decrease on the EKG waveform, indicating myocardial stress condition alteration. Moreover, QT interval, which reflects the repolarization of myocytes, shows an initial acute prolongation followed by a chronic shortening. Both QT prolongation and dispersion, and increased QRS duration are abnormal action potential characteristics associated with chronic heart failure. LVAD unloading, which immediately mitigates the pathological myocardial stretch due to excessive loading condition, may produce an acute inward current change across the ion channel, leading to the initial QT interval prolongation.
• LVAD chronic left ventricular assist device
• CRCSS Cardiac Resynchronization Compression Sac System
• the design of the present "Cardiac Resynchronization Compression Sac System (CRCSS)" aims at avoiding the aforementioned drawbacks associated with those previously developed DCC devices.
• the present CRCSS is intended to provide therapeutic systolic assistance as well as diastolic containment in a long-term manner to support the advanced heart failure.
• Bridge-to-recovery is set as the design objective, which requires that the implanted device be chronically applied without complications and be conveniently removed at the end of support. Therefore, hard-fixation methods such as persistent vacuum suction, suture, and epicardial adhesion fixations were discarded because they do not serve the present design objective of long-term application and bridge-to-recovery.
• the systolic support via epicardial compression may contribute to hemodynamic as well as electrophysiological trend reversals.
• the exertion of bi-ventricular compression at both right and left ventricular free walls would be of particular significance in the remedy of the conduction abnormalities, as implied in those electric CRT treatments.
• Mechanical and electrical behaviors of heart are mutually interactive. Except for refractory heart failure, by mechanically unloading a diseased heart, the action potential dysfunction associated with maladapted myocytes can be regressed toward a restored healthier state. Conversely, by a synchronous stimulation of myocardium, either inter-ventricularly or intra- ventricularly, the electric conduction renormalization can encourage a more homogeneous cardiac contraction, resulting in a higher mechanical contractile efficiency.
• DCC enforcement which comes by extraneously increasing the overall ventricular contraction force rather than by reducing the vascular afterload, equivalently, may create a milieu of myocardial unloading.
• the reverse remodeling reflected in electrophysiological changes due to vascular afterload reduction observed in LVAD-supported group would also be expected to appear in patients with DCC assistance.
• Epicardial compression can effectively reduce or nullify the transmural tension over the epicardial area it contacts. Free wall DCC actuation can immediately relieve the myocardial stress condition around the most conduction-sensitive region, hence is hypothesized to be the best forcing scenario for DCC to stimulate therapeutic electrophysiologic renormalization which might lead to cellular reverse remodeling for the moderate diseased heart.
• Pacing-type CRT may not rectify intra- ventricular conduction delay and dispersion for ventricles having infarcted myocardium with scarred tissue.
• Pacing-induced synchronous contraction in principle, cannot be achieved when myocardial conduction network is damaged and the damaged part cannot be bypassed by extraneous route or by initiating another independent stimulation which ignores the zone of conduction block.
• Mechanical -type CRCSS has no such restriction. As long as appropriate timing is scheduled for activating sac compression, the assisted myocardium will follow the EKG-referenced DCC forcing rhythm as a whole, no matter whether the conduction network is sound or not. Electrophysiological reverse remodeling, should it arise, is thereby taken as a value-added outcome rather than the causal factor of a resynchronized, stress relieved myocardial contraction when a heart is supported by the present CRCSS means.
• the present CRCSS invention takes full advantage of these electromechanical interactions associated with the cardiac cellular behaviors. No matter viewed from mechanical or conduction perspective, ventricular free wall is the best candidate region for DCC application. In order to consistently hold CRCSS in position for precise bi-ventricular free wall compression, CRCSS requires a special forcing alignment and structural arrangement in which fixation design is essential. A soft-fitness strategy is considered herein, which is augmented by an EKG-referenced feedback control system. Special care was exercised in the CRCSS drive line and fluid supply control design, aiming at giving a synchronized, simultaneous right and left ventricular compression. BRIEF DESCRIPTION OF THE DRAWINGS
• Figure 1A shows the perspective view of one representative embodiment of the present invention (cardiac resynchronization compression sac, CRCS) and the constituent components.
• CRCS cardiac resynchronization compression sac
• Figure 1B shows the perspective view of another embodiment of the present invention (cardiac resynchronization compression sac, CRCS) and the constituent components.
• CRCS cardiac resynchronization compression sac
• Figure 2 shows the soft-fixation of CRCS as installed onto heart.
• Figure 3 shows the sectional view A-A of CRCS depicted in Fig. 1A at the end of diastole.
• Figure 4 shows the sectional view A-A of CRCS depicted in Fig. 1 A during systole.
• Figure 5 shows the sectional view A-A of CRCS depicted in Fig. 1 B at the end of diastole.
• Figure 6 shows the sectional view A-A of CRCS depicted in Fig. 1B during systole.
• Figure 7 shows the perspective, enlarged, and sectional perspective view B-B of drive line pressure regulator mounted on CRCS.
• Figure 8 shows the CRCS system control layout (the driver line, solid line; the control line, dashed line).
• CRCS enforcement Major issues associated with CRCS enforcement include fixation and synchronous sac actuation in response to heart contraction and relaxation.
• pumping assist should be applied over the ventricular free wall region.
• the present CRCS design intends to deliver bi-ventricular epicardium compression in synchrony with the heart rhythm, for which atrioventricular conduction delay control and simultaneous right and left heart assistance are the design objectives to achieve.
• fixation method and cardiac resynchronization pumping design are explained.
• Hard-fixation methods such as vacuum suction, glue adhesion and stay suture are excluded presently. Instead, a soft-fixation strategy which allows a non-interfering sac be snuggly placed around the heart is considered.
• Soft-fixation means a fixation that restricts or wraps the device around a target object with low contact pressure and minimal allowable clearance. By this definition, soft-fixation would not jeopardize the original functional objective when attaching a device onto its target object, nor will it induce undesirable side effects due to excessive tightness of contact created in installment. Wearing a pair of shoes is a good illustrative example. The shoes are intended to be put on the feet without interfering or hampering the function of walking.
• the outer shell of CRCS is configured using a geometrically similar, but a bit larger, proportional form made from the imaged contour of the targeted heart.
• This extra space, in general 5 to 15 cc, created in between the native heart and the CRCS outer shell will be reserved for fitness adjustment, as explained later.
• the a priori conformal shape tailoring enables CRCS to be placed securely in the patient's chest cavity. Soft-fixation, therefore, can best be achieved when the dissected pericardium is sutured back, as close as possible in fitting with the cardiac anatomy, to embrace the CRCS implant.
• Sandwiching CRCS in between heart skin and pericardium makes pericardial space a natural cradle to house the implanted sac.
• Pericardial fluid will be generated in the process of healing and this interstitial fluid may work as a lubricant which protects the heart skin from injurious contact during sac actuation.
• non-distensibility requirement guides the determination of the shell thickness.
• a thickness of 0.2-1.5 mm is sufficient when, for instance, biocompatible polyurethane is considered as the sac material.
• This non-distensible, anatomically-fitted outer shell will help direct compression force inward toward the heart when external forcing is applied.
• the constructed CRCS is deformable and shape conformal in general. During insertion, the sac would be stabilized in its most fitted orientation after a few pumping strokes.
• a suitable CRCS implant should not affect the diastolic filling which can be reflected from the venous return pressure.
• FIGS 1A and 1B show two possible embodiments of the present CRCS design 100A and 100B.
• the conical shape makes CRCS structurally reinforced around the apex. This hardened apex helps CRCS be easily inserted into the dissected pericardial space and is an ideal place for exiting the drive line 105.
• a Teflon cuff can be mounted around the connection site of the drive line to the sac. When closing the pericardium, this cuff can be sewn onto the pericardium, providing an additional guarantee to the soft-fixation.
• the inner diaphragm 102 is thin in general, typically of a thickness about 10 ⁇ 100 micron. This shape-conformal, pliable diaphragm 102 may easily be attached onto the heart skin, in particular when inert polymeric material is used as the diaphragm material. Contrary to the previous DCC devices, the fluid (liquid or gas) contained in the space bounded by outer shell 101 and inner diaphragm 102 is not used as the direct force-transmitting medium. Rather, it serves as a buffer or a cushion which can be adjusted to achieve an optimal anatomic fitness either peri-operationally or post-operationally.
• a vent tube 107 and skin button assembly can be connected to the CRCS outer shell (see embodiment depicted in Fig. 1A), allowing extra-corporeal cushion fluid adjustment be performed whenever deemed necessary.
• Figures 3 and 4 further illustrate the relationship among pericardium, ventricles, CRCS diaphragm 102, balloons 103 and 104, and outer shell 101 in the systolic and diastolic phases, respectively.
• Figure 1B depicts another embodiment which requires no cushion fluid adjustment.
• the openings 101a (such as perforations) punched through the outer shell make the pericardial fluid be freely communicated across the sac wall. This design permits an automatic cushion fluid adjustment be carried out on a beat-to-beat basis.
• Ischemia complication has been reported for DCC application because epicardial compression may compress the coronary vascular bed during systolic assist. This complication can be mitigated by the present sac design. Except for the free wall region, the soft contact provided by non-pressurized diaphragm wrapping will leave most coronary arteries unaffected when compression force is applied. b. Cardiac Resynchronization DCC Support
• a pair of balloons 103 and 104 is used for DCC enforcement for the present CRCS design.
• Figure 2 shows the positions of balloon placement in relation to the assisted heart morphology. These left and right balloons are hung on the inward side of the outer shell with their centroids aligned with the centers of the left and right ventricular free walls, respectively.
• the balloon stroke volume, 20-80 cc can be selected depending on the cardiac condition specific to each patient at different implantation stages. A full capacity can be delivered in the initial assist phase to, for instance, increase the cardiac output required. However, as heart recovers with chamber volume and muscle mass decreased, the balloon stroke volume can be reduced accordingly, providing a progressive assist reduction for heart to wean off the sac support.
• the adjustment of the balloon stroke volume should particularly take into account the ventricular shrinkage effect. For instance, for the situation of a shrinking heart during recovery, a constant stroke volume pumping will gradually lose its DCC pumping effectiveness because the gap between the CRCS shell 101 and epicardium is enlarged. Whether or not the pumping stroke volume should be changed after CRCS implantation, in fact, depends on the patient's condition and the therapeutic plan designed by the physician.
• the present balloon pumping is purposely designed to dispose the compression force over the most critical ventricular free wall area.
• the cushion fluid bounded between the outer shell 101 and the inner diaphragm 102 will redistribute to void the space displaced by balloon inflation. Since the stroke volume of heart is usually larger than that of the balloon, the further ventricular contraction beyond the CRCS stroke limit requires the influx of pericardial fluid to fill up the voided space although the inward movement of the outer shell 101 may account for some of the fluid volume adjustment.
• Fig. 1B is a preferred design which allows a quick epicardial fluid communication across the numerous CRCS shell openings 101a. Note that for Fig. 1A embodiment balloon moves against the sac diaphragm 102 rather than in direct contact with the heart skin, the relative movement resulting from DCC actuation and epicardial motion can thus be minimized. This unique feature can ameliorate frictional contusion and myocardial fibrosis due to long-term injurious contact of the moving sac relative to the epicardium.
• the present CRCS intends to generate a kick-off type DCC support to assist the systolic contraction.
• balloon stroke volume is set lesser than that of the ventricles, typically 20 to 50 percent of the natural stroke volume.
• Balloon actuation as timed in conjunction with the QRS interval, will booster the contractile motion starting from the isovolumetric contraction to at most the peak ejection only.
• Epicardial compression assistance hence, will diminish before maximum contraction is attained, leaving cardiac relaxation uninfluenced during heart diastole. Electrophysiologically, this may render repolarization of action potential be minimally interfered by the externally applied compression.
• kick-off type DCC support only unloads the heart at the initial myocardial shortening stage, and leaves heart contraction on its own beyond the kick-off boosting period.
• This partial support feature forms a natural rehabilitation mechanism that prevents heart from complete mechanical unloading which might be detrimental to the subsequent myocardial recovery and device weaning.
• External energy supply is required for pumping CRCS.
• Either extracorporeal or intracorporeal energy supply system can be considered.
• the differences lie in the working fluid and drive line 105 characteristics adopted.
• extracorporeal pneumatic system with percutaneous drive line 105 will be used for illustrating the operational principles.
• the percutaneous drive line 105 after entering the chest cavity or pericardium, will bifurcate into left and right branches 105a and 105b, each shuttling the driving fluid respectively to the desired destination.
• balloon pressurization depends on the inertia and resistance associated with the drive line 105 in addition to the reactant pressure exerted by the assisted ventricle wall.
• the lengths and lumen diameters of the right and left branches 105b and 105a ought to be properly tailored.
• This differential inertia/resistance design may allow a collective left and right heart assistance be executed in better synchrony with the heart contraction and relaxation.
• the advantage associated with the single drive line 105 design is that it has only one percutaneous penetration and therefore minimizes the risk of post-operational infection complication.
• the disadvantage lies in the control aspect because, for bi-ventricular assistance, optimal pumping level and peak pressure timing control for both left and right ventricles, in principle, cannot be achieved using only one pressure supply and timing control.
• the preferred CRCS embodiment adopts the single drive line 105 design as illustrated in Fig. 1A and 1B.
• Sub-optimal control is set as the control objective to pursue. Pressure level and peak pressure timing will be determined primarily based on the left ventricle DCC requirements.
• Right heart control parameters will be decided by tailoring the drive line 105 length and lumen diameter so as to attain the appropriate pumping pressure level and minimize the inconsistency between the systolic peak pressures associated respectively with the right and left heart support.
• the fine tune of the pumping synchrony is accomplished using a pressure regulator 108 comprising a pair of pressure regulator screws 108a mounted on the bifurcation juncture of the drive line 105, as illustrated in Fig. 7.
• a pressure regulator 108 comprising a pair of pressure regulator screws 108a mounted on the bifurcation juncture of the drive line 105, as illustrated in Fig. 7.
• the left-and-right pumping synchrony is predetermined in an a priori analysis concerning the optimal assignment of differential right-left inertia/resistance parameters.
• Fine tune is carried out during sac implantation, which provides surgeon with a freedom in peri-operational adjustment to seek the optimal cardiac contractile synchrony.
• Synchronous pumping control design is shown in Fig. 8.
• Both left and right CRCS balloons 803 and 804 are equipped with pressure sensors.
• the pressure waveforms can be obtained and shown on the monitor during surgical operation.
• EKG signal 801 can also be obtained using, for instance, skin cathodes, and hence transmitted to the CRCS controller 805.
• Algorithm detecting R-wave and balloon pressure peaks will translate the right and left DCC assist into time delays relative to the R-wave.
• a scheduled atrioventricular conduction delay 802, electrically coupled with the CRCS controller 805, dictates the CRCS pumping console 806 in delivering the pressurized fluid to the actuation balloons.
• Right-and-left pumping synchrony will be manually controlled by adjusting the pressure regulator 108.
• balloon stroke volume is predetermined and set fixed, typically selected in a range around 20-80 cc.
• the console driving pressure magnitude hence, mainly controls the speed of balloon inflation. Hence, there will be no concern regarding the over-compression of the ventricles.
• kick-off support can minimize the fixation interference with the assisted heart and allow the cardiac muscle to contract, to a greater extent, according to its natural cardiac dynamics.
• This kick-off type DCC assist provided by the present CRCS design is believed to be a unique merit whose contribution is significant in promoting both mechanical and electrophysiological function recovery of a diseased heart.

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• 2008
  • 2008-12-31 CN CN2008801174342A patent/CN101939050B/zh not_active Expired - Fee Related
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  • 2008-12-31 EP EP08870129A patent/EP2229213A4/de not_active Withdrawn
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