+

WO2001039819A2 - Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese - Google Patents

Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese Download PDF

Info

Publication number
WO2001039819A2
WO2001039819A2 PCT/US2000/042473 US0042473W WO0139819A2 WO 2001039819 A2 WO2001039819 A2 WO 2001039819A2 US 0042473 W US0042473 W US 0042473W WO 0139819 A2 WO0139819 A2 WO 0139819A2
Authority
WO
WIPO (PCT)
Prior art keywords
cerebrospinal fluid
fluid
synthetic
location
reservoir
Prior art date
Application number
PCT/US2000/042473
Other languages
English (en)
Other versions
WO2001039819A3 (fr
Inventor
Glenn Frazer
Timothy J. Pelura
Bruce Shook
Original Assignee
Neuron Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuron Therapeutics, Inc. filed Critical Neuron Therapeutics, Inc.
Priority to JP2001541549A priority Critical patent/JP2003515394A/ja
Priority to CA002393221A priority patent/CA2393221A1/fr
Priority to AU45127/01A priority patent/AU4512701A/en
Priority to KR1020027007066A priority patent/KR20020077351A/ko
Priority to EP00992584A priority patent/EP1235602A2/fr
Publication of WO2001039819A2 publication Critical patent/WO2001039819A2/fr
Publication of WO2001039819A3 publication Critical patent/WO2001039819A3/fr

Links

Classifications

    • 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
    • A61M3/00—Medical syringes, e.g. enemata; Irrigators
    • A61M3/02—Enemata; Irrigators
    • A61M3/0229—Devices operating in a closed circuit, i.e. recycling the irrigating fluid
    • 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
    • A61M3/00—Medical syringes, e.g. enemata; Irrigators
    • A61M3/02—Enemata; Irrigators
    • A61M3/0204—Physical characteristics of the irrigation fluid, e.g. conductivity or turbidity
    • A61M3/0216—Pressure
    • 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
    • A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
    • A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
    • A61M2027/004—Implant devices for drainage of body fluids from one part of the body to another with at least a part of the circuit outside the 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological
    • A61M2202/0476—Oxygenated solutions
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/12—General characteristics of the apparatus with interchangeable cassettes forming partially or totally the fluid circuit
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3331—Pressure; Flow
    • A61M2205/3344—Measuring or controlling pressure at the body treatment site
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling
    • A61M2205/3653—General characteristics of the apparatus related to heating or cooling by Joule effect, i.e. electric resistance
    • 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
    • A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
    • A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
    • A61M27/006—Cerebrospinal drainage; Accessories therefor, e.g. valves
    • 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
    • A61M3/00—Medical syringes, e.g. enemata; Irrigators
    • A61M3/02—Enemata; Irrigators
    • A61M3/0201—Cassettes therefor
    • 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
    • A61M3/00—Medical syringes, e.g. enemata; Irrigators
    • A61M3/02—Enemata; Irrigators
    • A61M3/0233—Enemata; Irrigators characterised by liquid supply means, e.g. from pressurised reservoirs
    • A61M3/0254—Enemata; Irrigators characterised by liquid supply means, e.g. from pressurised reservoirs the liquid being pumped
    • A61M3/0258—Enemata; Irrigators characterised by liquid supply means, e.g. from pressurised reservoirs the liquid being pumped by means of electric pumps

Definitions

  • This invention generally relates to methods and apparatus for accomplishing the closed recirculation of cerebrospinal fluid (CSF), typically synthetic in nature, through the cerebral and spinal regions of the body and the related replenishment and revitalization equipment.
  • CSF cerebrospinal fluid
  • a preferred cassette variation of the inventive assembly includes a modular disposable package of equipment preferably packaged in such a way that it is readily and quickly employed in an emergency.
  • the cassette preferably contains all or most of the components forming the fluid path which accomplishes the conditioning of the recirculated therapeutic CSF as well as its passage from and to the patient.
  • vascular tissue in this penumbra does not exhibit notable necrosis until about 24 hours after the stroke-causing occlusion is formed, vascular tissue and smaller arterioles are susceptible to irreparable damage within 30 minutes of occlusion. Edema also begins to occur throughout the penumbra due to reduced cellular ion pump activity; this will result in swelling of the neural tissue and accelerated neural tissue damage.
  • One method for providing timely therapy to neural tissue under such severe ischemic conditions is introducing an oxygenated fluorocarbon nutrient emulsion (OFNE) through a portion of the ventriculo-subarachnoid spaces surrounding the brain and spinal cord where the cerebrospinal fluid (CSF) exists.
  • OFNE oxygenated fluorocarbon nutrient emulsion
  • Emulsions such as those described in U.S. Patent No.
  • OFNE treatment is intended to provide much-needed oxygen and nutrients to neural and vascular tissue until the occlusion is treated. It offers a powerful emergency therapy for those individuals suffering the first symptoms of ischemic stroke.
  • disorders such as cerebral edema, neurosurgical sequlae, encephalitis, or neoplastic disease, as well as severe head or spinal trauma may present the need for replacing the
  • CSF cerebrospinal fluid
  • This invention relates both to procedures for circulating cerebrospinal fluid through at least a portion of the pathway discussed below or through other various sites in or on the body where a biocompatible oxygen-containing fluid, typically a cerebrospinal fluid (CSF), would be beneficial.
  • CSF cerebrospinal fluid
  • the invention also relates to the system of devices used to safely circulate the CSF through the body and to control the various constituents of the CSF, as well as its temperature and pressure. Central to this invention is the concept that the physical system is closed and that fluid exiting the body is recirculated into the body.
  • Figure 1 in each of Osterholm '797 and Osterholm '085 depict a system for "circulating nutrient emulsion through a cerebrospinal pathway.”
  • a nutrient emulsion reservoir is provided for receiving and retaining that emulsion.
  • the emulsion is introduced into the cerebrospinal pathway after a pH adjustment, filtering, temperature adjustment, oxygenation, and adjustment of the pressure and flow rate of the nutrient input stream.
  • the nutrient input stream is preferably delivered to a ventricle of the brain and more particularly to a lateral ventricle.
  • the output monitor outlined in Osterholm '797 and Osterholm '085 is said continuously to watch various chemical and physical characteristics for such properties as flow rate, hydraulic pressure, potassium and sodium ion concentration, temperature, lactic acid concentration, gamma amino butyric acid (GAB A) and other amino acid concentrations, oxygen concentration, carbon dioxide concentration, enzymes, and ammonia concentration.
  • GAB A gamma amino butyric acid
  • These output fluid characteristics may be used both to inform the physician of certain states of the patient's neurologic tissue and to allow reconstitution, reformulation, or purification of the oxygenated nutrient emulsion to compensate for those patient's deficiencies.
  • the fluid leaving the patient is optionally sterilized and reconstituted to "ensure that the reconstituted fluid satisfies requirements of the nutrient emulsion reservoir.” See, e.g., column 14, line 18 et seq. of Osterholm '085. These documents do not describe the closed procedure for recirculating synthetic cerebrospinal fluid through the body using a closed system, nor do they suggest the closed system described herein.
  • this invention is a closed synthetic cerebrospinal fluid recirculation assembly made up of a fluid entry device, such as a catheter, suitable for introducing a synthetic CSF into an extravascular cerebrospinal pathway or other site in or on the human body, a fluid withdrawal device for withdrawing said cerebrospinal fluid from the body site, a fluid reservoir, and a conditioning circuit having at least an oxygenator.
  • the conditioning circuit may also include a dialysis component or filter (preferably an ultrafilter) for removing endotoxins or metabolites and potentially for introducing drugs into the synthetic CSF. If the oxygenator design does not control carbon dioxide concentration in the synthetic CSF, the conditioning circuit may also utilize a separate carbon dioxide gas exchanger.
  • the conditioning circuit withdraws fluid from the reservoir and reintroduces it into the reservoir.
  • the system may include a flow controller for controlling flow of synthetic CSF back into the body.
  • the system will include various filtration or purification components, in addition to the to dialysis or ultrafiltration units discussed above, to remove or lessen the amount of particulates such as, e.g., blood clots, cells, bacteria, cellular debris, or biochemical/chemical compounds such as metabolic or bacterial or viral toxins, chemicals, therapeutics, or diagnostics.
  • the system may have a diverter valve connected to a fluid collection container for collecting, e.g., a first fluid sample, which may be used for analysis and the like.
  • the fluid reservoir may be insulated for temperature control and may have a sonicator to maintain the CSF dispersion (where needed) and/or a stirrer.
  • the dialyzer or ultrafilter is generally used for the removal of metabolites, toxins, and the like and potentially for introducing nutrients, drugs, or medicine into the CSF without opening the CSF circuit.
  • the dialyzer may be of any of a variety of designs, e.g., a plurality of high surface area polymeric tubes or high surface area polymeric plates.
  • a heat exchanger may be used for controlling the temperature of the exchange fluids, e.g., the drug-containing or metabolite/toxin-free fluids.
  • the dialyzer may also have a closed source of medicine or drugs.
  • One or more sensors for monitoring at least one of pH, albumin, glucose, lactate, bicarbonate ion, amino acids, alpha ketoglutaric acid, Mg ions, Ca ions, K ions, Na ions, and Cl ions concentration in said synthetic CSF may be used either with the reservoir or with a slipstream taking a sample stream from the reservoir.
  • the sensors may be used only to monitor or to control those values.
  • the system usually includes a return pump for controllably returning CSF to the body.
  • Figure 1 shows a general, schematic outline of the components of the inventive system.
  • Figure 2A schematically depicts the conditioning slipstream system.
  • Figure 2B schematically depicts a preferred oxygenator for the conditioning circuit or loop.
  • Figure 3 is a depiction of a preferred cassette variation of the invention in a clinical cabinet.
  • Figure 4 is a schematic depiction of the preferred cassette variation.
  • this invention is variously: a.) a procedure for circulating an artificial or synthetic cerebrospinal fluid through a body opening, cavity, or pathway or upon the body surface and recycle of the resulting fluid through a control and a revitalization circuit, b.) a start-up variation of the recirculation procedure, c.) apparatus or a system of components for performing such processes, and d.) a cassette version of the system.
  • the system is closed in that artificial cerebrospinal fluid is not retrieved from the recirculation circuit and reconstituted or revitalized for subsequent introduction into the circuit.
  • the closed synthetic cerebrospinal fluid recirculation assembly begins with a device for withdrawing or collecting fluid as it is taken from the body.
  • This fluid withdrawal device may be one or more lumbar, cisterna magna, or intraventricular catheters (100) when the inventive system is used to recirculate the fluid through a cerebro-subarachnoid pathway, or may constitute other collection devices should the circulation system be used, e.g., with a wound treatment package.
  • a suitable, and preferred, lumbar catheter may be found in U.S. Patent Serial No. 09/ 382,136 (Attorney Docket No. 42684-20001.00).
  • Fluid withdrawal device (100) may also comprise a lumbar needle.
  • this device and the related methods may be used to circulate the synthetic or artificial cerebrospinal fluid through the body in the "other" direction, i.e., from the lumbar region or lower back, and exiting from the head.
  • the device and processes may be used both on partial and on full circuits of the cerebrospinal fluid cavity of the body, e.g., ventriculo- lumbar, ventriculo-subarachnoid, ventriculo-cisternal, cisternal-lumbar, cisternal- subarachnoid, lumbar-ventriculo, subarachnoid-ventriculo, cisternal-lumbar, etc.
  • Fluidly connected to fluid withdrawal device (100) is a trap or fluid collection reservoir (102).
  • Fluid collection reservoir (102) is typically used only at the inception of a procedure in conjunction with, e.g., a three-way or diverter valve (104) to collect the first portion of a fluid exiting the body, particularly for diagnosis of maladies from that fluid or for, e.g., removal of fluid in the event that the fluid contains significant bacteria, metabolic or pathologic byproducts, or has a high solids content, as may be the case with a cerebrovascular accident.
  • a type of hemorrhagic stroke known as a subarachnoid hemorrhage, in which an aneurysm in a large artery bursts on or near the dural matter surrounding the brain, blood may enter into the CSF pathway and present the need for capturing and/or filtering the contaminated CSF.
  • One variation of the recirculation procedure described herein involves removing that first exit volume (usually made up of natural CSF) but recirculating the remainder of the fluid, principally containing artificial cerebrospinal fluid.
  • U.S. Patent No. 5,772,607 to Magram.
  • This device includes a rigid, transparent sheath and an inflatable pouch to receive the CSF.
  • the sheath also contains a balloon.
  • Subatmospheric containers are also suitable for collecting this initial volume of effluent. It is highly desirable that the container (102) be automatically self-isolating via valve (104) upon filling. The container need normally be no greater in size than about 500 milliliters. This container (102) typically is believed to generally contain the highest concentration of potential toxins present in the initial effluent.
  • Filter (106) may be either a macro filter for removing osseous particles or the like or a microfilter to remove particles down to and including blood detritus or bacteria.
  • the filter should be of the type which does not upset the micellar dispersion or emulsion of synthetic CSF, should such be present.
  • reservoir (108) This reservoir (108) is central in this overall system.
  • the overall system itself is minimized inside so it has a nominal dead volume. Nevertheless, reservoir (108) contains the largest volume in the recirculation system.
  • Reservoir (108) may be insulated to maintain temperature or in the event it is a polymeric bag, be adapted to allow ease of temperature maintenance.
  • Reservoir (108) may be attached to sonificator (110) or may include a stirring device (112) as desired to promote mixing and to preserve the micellar dispersion or emulsion of the synthetic CSF.
  • the use of a reservoir (108) is highly desirable because it contains a critical mass of the system fluid.
  • the complex mixture of the fluid is not highly perturbed when the fluid leaving the patient for recycle is significantly different in composition (or other physical or chemical or biological parameters) than that introduced to the patient. For instance, if the fluid from the patient has been significantly deoxygenated, then mixing that fluid with the larger volume in the reservoir (which is appropriately oxygenated) will cause only modest perturbation to the otherwise controlled composition in the reservoir. Further, the amount of compositional adjustment needed to correct the perturbation is easily achieved.
  • An auxiliary drug port (130) may be included for quick introduction of materials into the reservoir (108).
  • each of the chemical or biological monitors noted below analyze the circulated fluid either by direct contact with the fluid in the reservoir (108) or via the optional slipstream (114). It is preferred that most of the materials added be added to the reservoir (108) rather than to the slipstream (114) to minimize the interaction between various of the monitoring and analysis devices and to utilize the mixing devices related to the reservoir (108).
  • slipstream (114) a small pump (116) may be desirable to carry the fluid past the analyzer detectors. Utilizing a separate slipstream is often desirable in that it allows the healthcare institution to change the type of monitors utilized for a particular procedure.
  • the analyzers found in analyzer circuit (118) typically will be for monitoring at least one of pO 2 , pCO 2 , pH, albumin, glucose ion, lactate ion, bicarbonate ion, amino acids, alpha ketoglutaric acid, and the like.
  • Ionic balance and concentration i.e., of Mg, Ca, K, Na, and Cl ions, may also be controlled via monitors placed in the slipstream or in the reservoir.
  • Another slipstream (300), or conditioning circuit may be used for adjusting or balancing pO , pCO , and for the addition of medicines or drugs. This slipstream (300) is shown in Figure 2.
  • Circulation pump (302) pulls a controllable volume from the reservoir (108) and passes the stream to an oxygenator (304).
  • Oxygenators are well known devices and often, when used on blood, are used in conjunction with heat exchangers to control the temperature of the fluid, and hence the blood's absorptivity.
  • blood oxygenators may be used on artificial cerebral spinal fluid.
  • Suitable oxygenator designs are well known and typically are comprised of hollow fiber bundles having a significant surface area. The fibers are essentially small pieces of tubing having a desired gas, e.g., oxygen or mixtures of oxygen and carbon dioxide, on one tubing surface and the fluid on the other surface.
  • the so-oxygenated fluid is passed to carbon dioxide gas exchanger (308).
  • the structure of the carbon dioxide exchanger (308) may be the same as that of the oxygenator (304).
  • the partial pressure of carbon dioxide is interrelated to the addition of bicarbonate ion as a buffer and both are used to control pH of the fluid. Control or monitoring of pH is, of course, necessary in any physiologic fluid. However, some additional pH control may be desirable when adding various nutrients, medicines, or drugs to or when removing substances from the fluid in following stage
  • Dialysis unit (310) may be used variously to introduce desired various nutrients, drugs, or medicines to the CSF or to remove materials such as metabolites or toxins or even diagnostic and therapeutic media from contaminated CSF.
  • the dialyzer or dialysis component (310) works in the following fashion.
  • the dialyzer (310) may be either one using flat plates or hollow fibers or other high surface structures.
  • the CSF is introduced to one surface of a plate or fiber and fluid containing the desired nutrients, drugs, or medicines is situated on the other side of the polymeric surface.
  • the amount of material infused into the CSF is controllable.
  • dialysis unit (310) may include a line (312) containing a concentration-controlled or temperature-controlled drug-containing solution. That solution is introduced into the dialysis device (310). The drug may be introduced using line (314).
  • Heat exchanger (316) partially controls the rate and concentration of material removal from or drug perfusion into the circulating CSF by varying the temperature of the heat exchange fluid introduced into line (318). It should be understood that the loop containing the fluid passing through the dialysis unit (310) and the heat exchanger (316) is closed. The temperature of line (312) may be controlled in conjunction with the pH of CSF entering dialysis unit (310) at (320) in order to adequately dissolve and maintain the drug in solution.
  • the so-constructed fluid at line (322) may then be returned to the reservoir (108) as shown in Figure 1. It should be apparent that the sequence of steps in the slipstream (300) need not necessarily be in the order shown in Figure 2.
  • makeup fluid e.g., saline solution, CSF, artificial cerebrospinal fluid, or the like
  • a control valve (402) into reservoir (108). It is contemplated that since there are but only two places into which the fluid may go, into the body itself and into the trap (102), little makeup fluid will be necessary.
  • Control valve (402) desirably is controlled by a level monitor found in reservoir (108).
  • auxiliary drug port (132) is shown in the line passing to the patient.
  • Reservoir (108) should contain generally a steady state composition.
  • the fluid may then be introduced to the patient using (if necessary) pump (410).
  • Pump (410) is shown to be a roller pump. This design is a volumetric pump and is often used for pumping blood since it is quite gentle with the fluid and can be used with surgical tubing.
  • the flow of fluid from the pump to the patient may also be controlled using a control valve (not shown).
  • the flow to the patient may be maintained to hold a specific pressure based on a pressure monitor (414) found in the body. It is highly desirable to use a cooler (412) to slightly cool the fluid either for therapeutic purposes or for the purpose of lowering the partial pressure of the blood gases and to lower the potential for any bubbles.
  • this inventive asasembly be as a one-use cassette which is packaged in such a way that the cassette may be may be readily and quickly employed in an emergency situation.
  • the device is not our intent that the device is only for use in the treatment of cerebral edema associated with stroke, it is a device which is also suitable for treatment of a variety of other maladies where an oxygenated artificial fluid such as the noted OFNE is desirable, e.g., such as in the peritoneum.
  • Figure 3 shows a desirable variation of the inventive device.
  • the system is shown as a cassette (500) which is placed into a cabinet (502).
  • Cabinet (502) would normally be clinical equipment to be used again and again as necessary.
  • Cassette (500) desirably is used one time per patient. It is of such a configuration that cassette (500) is dropped into cabinet (502) and the pertinent lines connected to catheters in the patient and, after equilibrium is established in the system, the artificial cerebrospinal fluid is passed into and out of the patient.
  • Figure 3 shows a typical IV bag (504) having artificial cerebrospinal fluid therein.
  • the artificial cerebrospinal fluid is pumped to the patient through a line
  • the lines ((506) and (512) discussed below) are typically of a polymeric, biocompatible tubing used for transport of fluids in surgical situations.
  • the input line (506) is connected to a catheter (508) which is introduced through the skull and into the ventricles.
  • catheter (508) which is introduced through the skull and into the ventricles.
  • the artificial cerebrospinal fluid flows through the subarachnoid space to the lower back where it is withdrawn using catheter (510) and recirculated via line (512) back to the cassette assembly (500) found in cabinet (502).
  • FIG. 4 shows in somewhat greater detail, the components of the cassette variation portrayed in the Figure 3.
  • Figure 4 shows a source of artificial cerebrospinal fluid (504), typically in an IV bag, which is in a fluid communication with the fluid reservoir (530).
  • the fluid which exits from reservoir (530) passes through line (532) and encounters pump (534).
  • Pump (534) may be of any typically used design. For instance, since line (534) preferably is of a polymeric soft surgical tubing, pump (534) may be a roller pump such as may be used in many other fluid delivery devices used in the human body.
  • the artificial cerebrospinal fluid then passes to oxygenator/heat exchanger surface (536). As described above, oxygenator (536) typically involves some manner of heat transfer to control the solubility and equilibrium of CO 2 and of O 2 in the cerebrospinal fluid.
  • a cooperating heat source (538) is also shown but is not incorporated into the modular cassette assembly shown in Figure 4. Referring back to Figure 3, heat source (538) would be integral with, at least a resident in, the cabinet (502) shown in that drawing.
  • heat source (538) would be integral with, at least a resident in, the cabinet (502) shown in that drawing.
  • a stream of mixed oxygen and carbon dioxide is introduced into oxygenator (536) as is needed for proper gas balance in the cerebrospinal fluid circulating in the loop.
  • Dialysis unit (540) may be used in a variety of ways. It may be used to remove materials from the circulating cerebrospinal fluid by a choice of temperatures and exchange fluids. It may be used to introduce drugs or medicines into the circulating cerebrospinal fluid.
  • the dialysis unit (540) will have some filtration function. This filtration capacity will be for removal of smaller materials, e.g. microorganisms, blood cells, etc. It is not likely that the dialyzer-filter unit (540) will be used to remove gross artifacts such as clots or the like. That function is desirably reserved for filter (106) as shown in Figure 1.
  • Heat exchanger is typically a cooler.
  • the cerebrospinal fluid as it leaves the oxygenator is at equilibrium with the gases found in the fluid. Consequently, just as a matter of safety, the fluid is chilled slightly in heat exchanger (548) to maintain the various gases in solution. Of course, it is within the scope of this invention that the fluid be chilled to a still lower temperature for specific therapeutic purposes.
  • Pressure manometer and relief valve (550) is also shown.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Anesthesiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Sustainable Development (AREA)
  • Neurology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Otolaryngology (AREA)
  • External Artificial Organs (AREA)

Abstract

De manière générale, cette invention concerne des procédés et des dispositifs permettant de mettre en oeuvre une recirculation en circuit fermé de liquide céphalo-rachidien (LCR), en principe d'origine synthétique, à travers les régions cérébrales et rachidiennes du corps et l'équipement de régénération et de revitalisation. Dans une réalisation préférée présentée sous forme d'une cassette, ce dispositif comprend un ensemble modulaire de matériel jetable, arrangé de préférence d'une manière permettant une utilisation rapide et aisée en cas d'urgence. Cette cassette contient de préférence tous les composants ou la plupart des composants qui composent le circuit de liquide permettant le conditionnement du LCR thérapeutique recirculé en provenance et en direction du patient.
PCT/US2000/042473 1999-12-03 2000-12-01 Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese WO2001039819A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2001541549A JP2003515394A (ja) 1999-12-03 2000-12-01 合成脳脊髄液の閉鎖系再循環法および装置
CA002393221A CA2393221A1 (fr) 1999-12-03 2000-12-01 Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese
AU45127/01A AU4512701A (en) 1999-12-03 2000-12-01 Method and apparatus for closed recirculation of synthetic cerebrospinal fluid
KR1020027007066A KR20020077351A (ko) 1999-12-03 2000-12-01 합성 뇌척수액의 폐쇄 재순환을 위한 방법 및 기구
EP00992584A EP1235602A2 (fr) 1999-12-03 2000-12-01 Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45489399A 1999-12-03 1999-12-03
US09/454,893 1999-12-03

Publications (2)

Publication Number Publication Date
WO2001039819A2 true WO2001039819A2 (fr) 2001-06-07
WO2001039819A3 WO2001039819A3 (fr) 2002-03-14

Family

ID=23806494

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/042473 WO2001039819A2 (fr) 1999-12-03 2000-12-01 Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese

Country Status (7)

Country Link
EP (1) EP1235602A2 (fr)
JP (1) JP2003515394A (fr)
KR (1) KR20020077351A (fr)
CN (1) CN1433328A (fr)
AU (1) AU4512701A (fr)
CA (1) CA2393221A1 (fr)
WO (1) WO2001039819A2 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6689756B2 (en) * 2001-03-02 2004-02-10 Integra Lifesciences Corporation Treatment of neurological disease
WO2004043313A3 (fr) * 2002-11-12 2004-07-29 Ross E Mantle Dispositif pour la recirculation extravasculaire de liquide dans des cavites corporelles
JP2006512976A (ja) * 2003-01-09 2006-04-20 エドワード・ウォング 脳及び脊髄の温度制御及び治療のための医療器具及び方法
EP2086573A2 (fr) * 2006-10-09 2009-08-12 Neurofluidics, Inc. Système de purification de fluide cérébrospinal
US7699799B2 (en) 2005-08-26 2010-04-20 Ceeben Systems, Inc. Ultrasonic material removal system for cardiopulmonary bypass and other applications
WO2011114260A1 (fr) * 2010-03-19 2011-09-22 Pfizer Inc. Système de purification de liquide céphalorachidien
US8100880B2 (en) 2007-04-05 2012-01-24 Velomedix, Inc. Automated therapy system and method
US8439960B2 (en) 2007-07-09 2013-05-14 Velomedix, Inc. Hypothermia devices and methods
US8672884B2 (en) 2005-10-21 2014-03-18 Velomedix, Inc. Method and apparatus for peritoneal hypothermia and/or resuscitation
US8956379B2 (en) 2005-07-21 2015-02-17 The Cleveland Clinic Foundation Medical oscillating compliance devices and uses thereof
US9011378B2 (en) 2007-11-02 2015-04-21 The Cleveland Clinic Foundation Device for increasing cerebral blood flow
WO2017062606A1 (fr) 2015-10-06 2017-04-13 Minnetronix, Inc. Dispositifs et procédés pour apporter un refroidissement local au cerveau et à la moelle épinière
US9622670B2 (en) 2010-07-09 2017-04-18 Potrero Medical, Inc. Method and apparatus for pressure measurement
AU2016304020B2 (en) * 2015-08-05 2019-09-19 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US10569064B2 (en) 2013-03-13 2020-02-25 Minnetronix, Inc. Devices and methods for providing focal cooling to the brain and spinal cord
US10632237B2 (en) 2006-10-09 2020-04-28 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US10850235B2 (en) 2006-10-09 2020-12-01 Minnetronix, Inc. Method for filtering cerebrospinal fluid (CSF) including monitoring CSF flow
US11147540B2 (en) 2015-07-01 2021-10-19 Minnetronix, Inc. Introducer sheath and puncture tool for the introduction and placement of a catheter in tissue
US20220211541A1 (en) * 2005-10-21 2022-07-07 Theranova, Llc Method and apparatus for peritoneal oxygenation
GR1010335B (el) * 2022-02-11 2022-11-09 Αναστασιος Γεωργιου Τσογκας Συσκευη αποτροπης πνευμοκεφαλου
WO2023003888A1 (fr) * 2021-07-19 2023-01-26 Enclear Therapies, Inc. Plateforme de diagnostic du liquide céphalorachidien (lcr)
US11577060B2 (en) 2015-12-04 2023-02-14 Minnetronix, Inc. Systems and methods for the conditioning of cerebrospinal fluid
AU2021271803B2 (en) * 2020-05-11 2024-09-26 Minnetronix Neuro, Inc. Filtering cassettes and filtering systems

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10695545B2 (en) 2006-10-09 2020-06-30 Minnetronix, Inc. Systems and methods for the conditioning of cerebrospinal fluid
US8123714B2 (en) * 2007-06-29 2012-02-28 Codman & Shurtleff, Inc. Programmable shunt with electromechanical valve actuator
CN103706025A (zh) * 2013-12-23 2014-04-09 李桂亮 一种埋置式蛛网膜下腔微量缓释注射器
JP2020536618A (ja) * 2017-10-05 2020-12-17 ミネトロニクス， インコーポレイテッド 中枢神経系に沿って治療を行うためのシステム、カテーテル、及び方法
CN107993546B (zh) * 2018-01-16 2019-09-06 西安市红会医院 一种脑脊液循环体外模型及脑积水体外模拟方法
CN110575573B (zh) * 2019-09-24 2020-12-22 福建医科大学附属第一医院 一种用于人工脑脊液持续净化治疗的一次性管路安装系统
US11559626B2 (en) * 2020-04-08 2023-01-24 Medtronic, Inc. Means to treat Alzheimer's disease via flushing of brain parenchyma
WO2022181126A1 (fr) * 2021-02-26 2022-09-01 テルモ株式会社 Dispositif de traitement pour troubles cérébrovasculaires

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378797A (en) 1980-04-14 1983-04-05 Thomas Jefferson University Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4686085A (en) 1980-04-14 1987-08-11 Thomas Jefferson University Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4981691A (en) 1980-04-14 1991-01-01 Thomas Jefferson University Oxygenated fluorocarbon nutrient solution
US5772607A (en) 1995-06-06 1998-06-30 The Nemours Foundation Body fluid collection apparatus
US5823987A (en) 1996-01-11 1998-10-20 Medtronic, Inc. Compact membrane-type blood oxygenator with concentric heat exchanger
US5855201A (en) 1996-04-26 1999-01-05 Fuji Systems Corporation Gas exchange apparatus

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988008728A1 (fr) * 1987-05-15 1988-11-17 The Dis Corporation Dispositif et procede de perfusion d'une tete d'animal
US5716318A (en) * 1995-04-14 1998-02-10 The University Of North Carolina At Chapel Hill Method of treating cardiac arrest and apparatus for same
EP0910423A4 (fr) * 1996-03-08 1999-12-29 Life Resuscitation Tech Procede et dispositif de ventilation liquide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378797A (en) 1980-04-14 1983-04-05 Thomas Jefferson University Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4686085A (en) 1980-04-14 1987-08-11 Thomas Jefferson University Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4981691A (en) 1980-04-14 1991-01-01 Thomas Jefferson University Oxygenated fluorocarbon nutrient solution
US5772607A (en) 1995-06-06 1998-06-30 The Nemours Foundation Body fluid collection apparatus
US5823987A (en) 1996-01-11 1998-10-20 Medtronic, Inc. Compact membrane-type blood oxygenator with concentric heat exchanger
US5855201A (en) 1996-04-26 1999-01-05 Fuji Systems Corporation Gas exchange apparatus

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6689756B2 (en) * 2001-03-02 2004-02-10 Integra Lifesciences Corporation Treatment of neurological disease
WO2004043313A3 (fr) * 2002-11-12 2004-07-29 Ross E Mantle Dispositif pour la recirculation extravasculaire de liquide dans des cavites corporelles
JP2006512976A (ja) * 2003-01-09 2006-04-20 エドワード・ウォング 脳及び脊髄の温度制御及び治療のための医療器具及び方法
US8956379B2 (en) 2005-07-21 2015-02-17 The Cleveland Clinic Foundation Medical oscillating compliance devices and uses thereof
US7699799B2 (en) 2005-08-26 2010-04-20 Ceeben Systems, Inc. Ultrasonic material removal system for cardiopulmonary bypass and other applications
US11446177B2 (en) 2005-10-21 2022-09-20 Theranova, Llc Method and apparatus for peritoneal oxygenation
US20220211541A1 (en) * 2005-10-21 2022-07-07 Theranova, Llc Method and apparatus for peritoneal oxygenation
US8672884B2 (en) 2005-10-21 2014-03-18 Velomedix, Inc. Method and apparatus for peritoneal hypothermia and/or resuscitation
EP2086573A4 (fr) * 2006-10-09 2011-06-29 Neurofluidics Inc Système de purification de fluide cérébrospinal
US8435204B2 (en) 2006-10-09 2013-05-07 Neurofluidics, Inc. Cerebrospinal fluid purification system
US11529452B2 (en) 2006-10-09 2022-12-20 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US12280229B2 (en) * 2006-10-09 2025-04-22 Neurofluidics, Inc. Cerebrospinal fluid purification system
US20200046954A1 (en) 2006-10-09 2020-02-13 Neurofluidics, Inc. Cerebrospinal fluid purification system
EP2086573A2 (fr) * 2006-10-09 2009-08-12 Neurofluidics, Inc. Système de purification de fluide cérébrospinal
US20210386981A1 (en) * 2006-10-09 2021-12-16 Neurofluidics, Inc. Cerebrospinal fluid purification system
US11065425B2 (en) 2006-10-09 2021-07-20 Neurofluidics, Inc. Cerebrospinal fluid purification system
US9895518B2 (en) 2006-10-09 2018-02-20 Neurofluidics, Inc. Cerebrospinal fluid purification system
EP3827841A1 (fr) * 2006-10-09 2021-06-02 Neurofluidics, Inc. Système de purification de fluide cérébrospinal
US10850235B2 (en) 2006-10-09 2020-12-01 Minnetronix, Inc. Method for filtering cerebrospinal fluid (CSF) including monitoring CSF flow
US10398884B2 (en) 2006-10-09 2019-09-03 Neurofluidics, Inc. Cerebrospinal fluid purification system
US10632237B2 (en) 2006-10-09 2020-04-28 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US8480648B2 (en) 2007-04-05 2013-07-09 Velomedix, Inc. Automated therapy system and method
US8100880B2 (en) 2007-04-05 2012-01-24 Velomedix, Inc. Automated therapy system and method
US8439960B2 (en) 2007-07-09 2013-05-14 Velomedix, Inc. Hypothermia devices and methods
US9011378B2 (en) 2007-11-02 2015-04-21 The Cleveland Clinic Foundation Device for increasing cerebral blood flow
WO2011114260A1 (fr) * 2010-03-19 2011-09-22 Pfizer Inc. Système de purification de liquide céphalorachidien
US9931044B2 (en) 2010-07-09 2018-04-03 Potrero Medical, Inc. Method and apparatus for pressure measurement
US9622670B2 (en) 2010-07-09 2017-04-18 Potrero Medical, Inc. Method and apparatus for pressure measurement
US10758135B2 (en) 2010-07-09 2020-09-01 Potrero Medical, Inc. Method and apparatus for pressure measurement
US10569064B2 (en) 2013-03-13 2020-02-25 Minnetronix, Inc. Devices and methods for providing focal cooling to the brain and spinal cord
US11147540B2 (en) 2015-07-01 2021-10-19 Minnetronix, Inc. Introducer sheath and puncture tool for the introduction and placement of a catheter in tissue
AU2021218067B2 (en) * 2015-08-05 2023-03-16 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US12290785B2 (en) 2015-08-05 2025-05-06 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
AU2016304020B2 (en) * 2015-08-05 2019-09-19 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
WO2017062606A1 (fr) 2015-10-06 2017-04-13 Minnetronix, Inc. Dispositifs et procédés pour apporter un refroidissement local au cerveau et à la moelle épinière
EP3359071A4 (fr) * 2015-10-06 2019-06-05 Minnetronix Inc. Dispositifs et procédés pour apporter un refroidissement local au cerveau et à la moelle épinière
AU2019226194B2 (en) * 2015-10-06 2020-07-09 Minnetronix, Inc. Devices and methods for providing focal cooling to the brain and spinal cord
US11577060B2 (en) 2015-12-04 2023-02-14 Minnetronix, Inc. Systems and methods for the conditioning of cerebrospinal fluid
AU2021271803B2 (en) * 2020-05-11 2024-09-26 Minnetronix Neuro, Inc. Filtering cassettes and filtering systems
US12156962B2 (en) 2020-05-11 2024-12-03 Minnetronix Neuro, Inc. Filtering cassettes and filtering systems
WO2023003888A1 (fr) * 2021-07-19 2023-01-26 Enclear Therapies, Inc. Plateforme de diagnostic du liquide céphalorachidien (lcr)
GR1010335B (el) * 2022-02-11 2022-11-09 Αναστασιος Γεωργιου Τσογκας Συσκευη αποτροπης πνευμοκεφαλου

Also Published As

Publication number Publication date
CN1433328A (zh) 2003-07-30
AU4512701A (en) 2001-06-12
WO2001039819A3 (fr) 2002-03-14
JP2003515394A (ja) 2003-05-07
CA2393221A1 (fr) 2001-06-07
EP1235602A2 (fr) 2002-09-04
KR20020077351A (ko) 2002-10-11

Similar Documents

Publication Publication Date Title
WO2001039819A2 (fr) Procede et dispositif permettant la recirculation en circuit ferme d'un liquide cephalo-rachidien de synthese
EP1009276B1 (fr) Systeme de therapie dirigee
EP0088954B1 (fr) Appareil pour utilisation dans le traitement de l'apoplexie utilisant la circulation extravasculaire d'un liquide alimentaire synthétique oxygéné pour le traitement de désordres hypoxiques et ischémiques tissulaires
US4445500A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4450841A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4686085A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
DE69922354T2 (de) Vorrichtung und verfahren zur ganzkörper-hyperthermiebehandlung
US4378797A (en) Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4830849A (en) Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4446154A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4451251A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US5152743A (en) Apparatus and method for selective separation of blood cholesterol
JP5636385B2 (ja) 腹膜透析を実施するためのシステムおよび方法
TWI302103B (en) Metabolic detoxification system and method
US20050165342A1 (en) Method and system for treating tissue swelling
US4446155A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4445887A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4758431A (en) Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4445514A (en) Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4445888A (en) Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
Short et al. Neonatal extracorporeal membrane oxygenation: a review
WO2001054766A1 (fr) Systemes et procedes permettant l"echange de liquide cephalo-rachidien
Faulhauer et al. Experimental hydrocephalus and hydrosyringomyelia in the cat: radiological findings
DE202019005458U1 (de) System zur extrakorporalen Hyperthermie-Perfusions-(EHP-)Therapie
US20020179504A1 (en) Portable hemodialyzer

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 1020027007066

Country of ref document: KR

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 541549

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 2393221

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2000992584

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 008187541

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2000992584

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020027007066

Country of ref document: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 2000992584

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载