US20060030813A1 - Sensing and interactive drug delivery - Google Patents
Sensing and interactive drug delivery Download PDFInfo
- Publication number
- US20060030813A1 US20060030813A1 US11/234,016 US23401605A US2006030813A1 US 20060030813 A1 US20060030813 A1 US 20060030813A1 US 23401605 A US23401605 A US 23401605A US 2006030813 A1 US2006030813 A1 US 2006030813A1
- Authority
- US
- United States
- Prior art keywords
- drug delivery
- drug
- optical probe
- local controller
- data
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
-
- 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
-
- 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
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
-
- 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
- A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
- A61B5/0015—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system
- A61B5/0022—Monitoring a patient using a global network, e.g. telephone networks, internet
Definitions
- the present invention relates to interactive drug delivery systems and methods.
- X-ray or ⁇ -ray radiation, optical radiation, ultrasound waves and magnetic fields have been used to examine and image biological tissue.
- X-rays or ⁇ -rays propagate in the tissue on straight, ballistic lines; that is, their scattering is negligible.
- imaging is based on evaluation of the absorption levels of different tissue types. For example, in roentgenography the X-ray film contains darker and lighter spots.
- CT computerized tomography
- a cross-sectional picture of human organs is created by transmitting X-ray radiation through a section of the human body at different angles and by electronically detecting the variation in X-ray transmission.
- the detected intensity information is digitally stored in a computer that reconstructs the X-ray absorption of the tissue at a multiplicity of points located in one cross-sectional plane.
- NIR Near infrared radiation
- IR infrared
- the use of visible, NIR and infrared (IR) radiation for medical imaging may have several advantages. In the NIR or IR range the contrast factor between a tumor and a tissue is much larger than in the X-ray range. In addition, the visible to IR radiation is preferred over the X-ray radiation since it is non-ionizing and thus, potentially causes fewer side effects. However, the visible or IR radiation is strongly scattered and absorbed in biological tissue, and the migration path cannot be approximated by a straight line, making inapplicable certain aspects of cross-sectional imaging techniques.
- Optical spectroscopy has been used to monitor and image tissue blood oxygenation and volume by measuring absorption of oxyhemoglobin and deoxyhemoglobin in the near infrared (NIR) wavelength region. Below 700 nm, light is strongly absorbed by hemoglobin, and above 900 nm, it is strongly absorbed by water. By making differential measurements at either side of the isosbestic point of oxy-hemoglobin and deoxy-hemoglobin absorbance (near 800 nm), it is possible to quantify the blood oxygenation and volume levels. Typically, these measurements are made at 750 nm and 830 nm.
- NIR spectrometry adapted to the principles of computerized tomography has been used for in vivo imaging.
- This technique utilizes NIR radiation in an analogous way to the use of X-ray radiation in an X-ray CT.
- the X-ray source is replaced by several laser diodes emitting light in the NIR range.
- the NIR-CT uses a set of photodetectors that detect the light of the laser diodes transmitted through the imaged tissue.
- the detected data are manipulated by a computer in a fashion similar to that of the detected X-ray data in an X-ray CT.
- Different NIR-CT systems have recognized the scattering aspect of the non-ionizing radiation and have modified the X-ray CT algorithms accordingly.
- angiogenesis refers to the generation of new blood vessels in a tissue or organ. Under normal physiological conditions humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development and formation of the corpus luteum, endometrium and placenta.
- Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, such as tumor metastasis and abnormal growth by endothelial cells, and supports the pathological damage seen in these conditions.
- the diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenesis dependent or angiogenesis associated diseases. The hypothesis that tumor growth is angiogenesis dependent was first proposed in 1971. (Folkman J., Tumor Angiogenesis: Therapeutic Implications. N. Engl. Jour. Med.
- Tumor ‘take’ has occurred, every increase in tumor cell population must be preceded by an increase in new capillaries converging on the tumor.”
- Tumor ‘take’ is understood to indicate a prevascular phase of tumor growth in which a population of tumor cells occupying a few cubic millimeters' volume and not exceeding a few million cells, can survive on existing host microvessels. Expansion of tumor volume beyond this phase requires the induction of new capillary blood vessels. This explanation was directly or indirectly observed and documented in numerous publications.
- a tumor After a tumor is detected by X-ray mammography, ultrasound, computerized tomography or MRI, the patient undergoes surgery, radiation therapy and/or drug therapy that frequently has negative effects on other organs and tissue of the patient. Furthermore, different patients respond differently to the drug therapy.
- an interactive drug delivery system includes a drug delivery module, an optical probe, and a local controller.
- the drug delivery module delivers selected amounts of a drug into a subject undergoing drug therapy while the optical probe detects the delivered drug, or a manifestation caused by the delivered drug, in a selected tissue region of the subject.
- the local controller receives data from the optical probe and provides signals to the drug delivery module for adjusting the amounts of the drug to be delivered to the body.
- an interactive drug delivery system in another aspect, includes a drug delivery module, an optical probe, a local controller, and a central controller.
- the drug delivery module delivers selected amounts of a drug into a subject undergoing drug therapy while the optical probe monitors a manifestation caused by the delivered drug in a selected tissue region of the subject.
- the local controller receives optical data from the optical probe and transmits data to the central controller.
- the central controller correlates the received data with control data and transmits data back to the local controller.
- the local controller provides signals to the drug delivery module for adjusting the amounts of the drug to be delivered to the body.
- the central controller includes a monitor for displaying the received data and suggested treatment data to a clinician.
- the central controller further includes an input device (e.g., a keyboard, a voice recognition system, a magnetic card reader) for entering control data to the central controller.
- the central controller further includes a data bank with various types of treatment data and optical data.
- the interactive drug delivery system includes several drug delivery modules connected to the local controller.
- the interactive drug delivery system includes several additional probes, such as a temperature probe, an ultrasound probe, or an electrical probe including one or several electrodes that are implanted or attached to the skin. These probes are designed to monitor tissue properties, including the tissue metabolism, the heart rate, EKG, or the tissue temperature, and provide the measured data to the local controller.
- the interactive drug delivery system enables continuous monitoring of a patient and adjusting interactively the drug delivery.
- the patient is able to move around the medical facility or leave the medical facility while undergoing drug therapy.
- an interactive drug delivery method in another aspect, includes delivering by a drug delivery module selected amounts of a drug into a subject; optically detecting in a selected tissue region of said subject a manifestation caused by the delivered drug by an optical probe; and receiving data from or transmitting data to said optical probe and said drug delivery module by a local controller. The method also includes correlating data received from said optical probe to selected data stored in said local controller; and providing signals to said drug delivery module for adjusting the amounts of the drug to be delivered into said subject.
- the interactive drug delivery method includes regulating the rate of the delivered drug based on signals from said local controller.
- FIG. 1 shows an interactive drug delivery system using an optical probe.
- an interactive drug delivery system 10 includes a drug delivery module 12 , an optical probe 14 , a local controller 16 , and a central controller 20 .
- a human subject 11 (or an animal) undergoing a medical treatment wears local controller 16 interfaced with optical probe 14 , drug delivery module 12 , and optionally, additional probes.
- Local controller 16 includes a processor, a memory and one or several interfaces including a wireless interface.
- Drug delivery module 12 delivers selected amounts of a drug into the human body while optical probe 14 measures the concentration of the drug in a selected tissue region, or measures a selected response of a tissue region to the introduced drug, or measures changes in a selected tissue region, for example, a blood solute such as glucose, exogenous contrast agent or endogenous tissue pigment, and a tissue state such as blood volume or oxygenation of a tissue region, blood volume changes due to arterial pulse or the pulse rate.
- a blood solute such as glucose, exogenous contrast agent or endogenous tissue pigment
- tissue state such as blood volume or oxygenation of a tissue region, blood volume changes due to arterial pulse or the pulse rate.
- Drug delivery module 12 and optical probe 14 provide data to local controller 16 , which stores the data and provides the data to central controller 20 via a network 18 , such as the cellular telephone network.
- the system 10 may include additional probes, such as a temperature probe, an ultrasound probe, or an electrical probe including one or several electrodes that are implanted or attached to the skin. These probes are designed to monitor tissue properties, including metabolism, the heart rate or EKG, temperature, perspiration, and provide data to local controller 16 .
- Interactive system 10 may also include several additional drug delivery modules, responsive to local controller 16 , for delivering several drugs according to a selected protocol.
- Optical probe 14 is a non-invasive optical system that employs a CW spectrophotometer described in PCT application PCT/US95/15666, which is incorporated by reference.
- optical probe is a Time Resolved Spectroscopy (TRS) system as described in PCT applications PCT/US94/03518 or PCT/US94/07984 or U.S. Pat. No. 5,119,815 or U.S. Pat. No. 5,386,827, all of which are incorporated by reference.
- optical probe 14 is a phase modulation system described in U.S. Pat. No.
- optical probe 14 is a phased array, phase cancellation system described in PCT application PCT/US93/05868 or an amplitude cancellation system described in PCT application PCT/US95/15694, both of which are incorporated by reference as if fully set forth herein.
- Optical probe 14 monitors directly a tissue constituent or a tissue region including an identified tumor during and after the drug delivery.
- optical probe 14 monitors a selected tissue organ to detect changes in the physiology of the tissue, or to monitor levels of a tissue solute attributable to the delivered drug.
- optical probe 14 measures solute levels, such as glucose levels in the liver using the optical techniques described in the PCT Application PCT/US95/15666. In this process, optical probe 14 evaluates changes in the scattering coefficient associated with the measured solute levels.
- Local controller 16 receives optical data from optical probe 14 . Furthermore, local controller 16 receives the temperature data, the EKG data, the heart rate data or the metabolism data. Local controller 16 compares the received data with stored data and stored instructions reflecting the expected treatment and the physiological changes caused by the delivered drug. After comparing the received data with the stored data, local controller 16 can provide control signals for adjusting or discontinuing the drug delivery performed by drug delivery module 12 . Furthermore, local controller 16 can transmit the detected optical data and the stored data to central controller 20 . Central controller 20 performs a data evaluation and provides the information to a physician. The physician evaluates the provided data and inputs dosing instructions into central controller 20 , which in turn transmits the dosing instructions to local controller 16 for adjusting the drug delivery by drug delivery module 12 . Local controller 16 further includes an input pad constructed and arranged for the human subject to input data including subjective condition of the human subject during the treatment. For example, the human subject can input information about fever, pain, nausea, vomiting, dizziness, or other symptoms.
- Optical probe 14 is further constructed to measure the pulse rate of the subject during the drug delivery.
- Optical probe 14 detects increases in the pulse rate that may correspond to a sudden onset of tachycardia attributable, for example, to an anaphylactic reaction.
- the increase in the pulse rate may be accompanied with a temperature increase, corresponding to a drug related fever, or to an infection due to neutropenia or anemia caused by the delivered drug.
- the temperature probe measures the temperature of the subject and provides the temperature data automatically to local controller 16 .
- optical system 10 is used to monitor a breast tumor.
- Optical probe 14 detects a tumor as described in the PCT Application PCT/US99/02953, entitled “Examination and Imaging of Breast Tissue,” filed on Feb. 11, 1999, incorporated by reference herein.
- One or several drug delivery modules 12 delivers one or several drugs to the subject.
- the drug treatment may include a combination regimen, such as CMF (Cyclophosphamide, Methotrexate and 5-Fluorouracil).
- drug delivery module 12 delivers a conjugated angiogenesis inhibitor for treatment of pathogenetic conditions, as described in U.S. Pat. No.
- Optical probe 14 measures the local blood volume and oxygenation of the tissue region including the detected tumor. Based on the measured blood volume and oxygenation, optical probe 14 monitors the growth and activity of the identified tumor. For example, optical probe 14 detects higher blood oxygenation. Based on this data, a local controller 16 provides signals to drug delivery module 12 for decreasing the drug amount (or vice versa). Furthermore, upon detecting a sudden onset of tachycardia, local controller 16 may direct drug delivery module 12 to reduce or eliminate the delivery of the drug.
- system 10 is used to monitor the liver during a combination regiment for treatment of carcinoma.
- the CMF regiment causes optically detectable changes of one or several solutes in the liver.
- optical probe 14 detects changes in the solute concentration and provides the data to local controller 16 , which adjusts the drug delivery.
- optical probe 14 is used to monitor drug delivery directly into the liver in treatment of hepatocellular carcinoma.
- interactive system 10 is used to monitor the drug delivery for treatment of diseases such as diabetes or cardiomyopathy.
- drug delivery module 12 includes an insulin pump, for providing controlled amounts of insulin to a patient.
- Optical probe 14 is located on the abdominal region near the liver so that the detected optical radiation passes through the liver.
- Optical probe 14 detects the level of glucose as described in the PCT Application PCT/US95/15666, which is incorporated by reference as if fully provided herein.
- local controller 16 directs the insulin pump to reduce or discontinue the insulin delivery.
- the monitoring for hypoglycemia or hyperglycemia is also performed during the sleep of the patient to provide the data to local controller 16 , which not only reduces the insulin delivery, but also sends a message to central controller 20 and a clinician receiving information at central controller 20 .
- optical probe 14 measures the blood volume and saturation while drug delivery module 12 delivers the butamine, dopamine, or another drug.
- optical probe 14 is a TRS system, a phase modulation system, a phased array, phase cancellation system, or an amplitude cancellation system for detecting fluorescent radiation.
- the principles of detecting fluorescent radiation were described by J. R. Lakowicz in “Principles of Fluorescence Spectroscopy,” Plenum Press, N.Y., 1983.
- the delivered drug is “tagged” with an optically active contrast agent such as light absorbing contrast agent or a fluorescing contrast agent (e.g., ICG).
- optical probe 14 uses a wavelength sensitive to the contrast agent, for example, a fluorescing contrast agent naturally occurring or delivered into the examined tissue.
- the delivered drug is “tagged” with a signal generator of high optical sensitivity and specificity, such as a molecular beacon.
- Molecular beacons are sense or antisense oligonucleotide probes that become fluorescent only in the presence of specific sequences of target nucleic acids. (Described by Tyagi, S. and Kramer, F. R., “Molecular beacons: probes that fluoresce upon hybridization,” Nature Biotech. 14: 303-8 (1996).) They consist of hairpin shaped molecules containing a loop of specific sequence nucleotide that is complementary to the target nucleic acid.
- the 3′- and 5′-ends of this loop contain 5-8 nucleotide strands that are complementary to each other; upon hybridization they form a ‘stem’ which holds the ends of the loop together.
- Attached to one of the stem oligonucleotides is a short linker with a fluorophore at its end; attached to the other stem is a linker connected to a quencher.
- the linkers are designed to juxtapose the fluorophore and quencher. Since fluorescence energy transfer (FET) depends on the inverse sixth power of the donor-acceptor distance, the molecular beacon is non-fluorescent when the stem segments are hybridized to each other; the transferred energy is dissipated as heat.
- FET fluorescence energy transfer
- the hydrogen bonds between the complementary stem nucleotides are broken (since there are many more hydrogen bonds formed between the loop and the target), separating the fluorophore and quencher and producing detectable fluorescence.
- the length of the loop is chosen to optimize the approximation of the fluorophore and the quencher.
- Molecular beacons have been used to detect specific amino acids in homogeneous solution. (See Tyagi, S. and Kramer, F. R., “Molecular beacons: probes that fluoresce upon hybridization,” Nature Biotech. 14: 303-8 (1996).) They are particularly useful for situations in which it is either not possible or desirable to isolate the probe-target hybrids, such as for real-time monitoring of polymerase chain reactions in sealed tubes or for detection of specific nucleic acids in cells. (See, Gao, W., Tyagi, S., Kramer, F. R.
- Molecular beacons have been used to detect specific RNAs in hamster fibroblasts and human leukemia cells. (See, Sokol, D. L., Zhang, X., Lu, P. and Gewirtz, A.
- the molecular beacons are active in the near-infrared region and contain sense or antisense oligonucleotides targeted at specific mRNAs of solid tumors in vivo.
- This type of near infra-red fluorescent probe can be delivered by a variety of vehicles, such as apoE-directed lipid vesicles for targeting tumor cells which overexpress low density lipoprotein (LDL) receptors, (see Rensen, P. C. N., Schiffelers, R. M., Versluis, J., Bijsterbosch, M.
- LDL low density lipoprotein
- Optical probe 14 evaluates the tumor by evaluating the tissue and angiogenesis or by using enhanced fluorescent probe signaling cancer tissue based upon molecular abnormalities.
- a specific molecular beacon is used for detection of specific RNAs in specific tumors by targeting one or several enzymes.
- Several molecular beacons have been prepared with dyes detectable in the visible range of the optical spectrum, as described in Sokol, D. L., Zhang, X., Lu, P. and Gewirtz, A. M., “Real time detection of DNA/RNA hybridization in living cells,” Proc. Natl. Acad. Sci. USA 95: 11538-43 (1998).
- a molecular beacon has its natural fluorescence quenched by hybridization in a target sequence. When duplex formation occurs, the fluorophores become separated and quenching is no longer possible.
- a dual wavelength system is used for absorption measurements and fluorescent measurements, as described above. The measurements are used to detect intrinsic and angiogenesis (or deoxygenation) signals from the tumor. The two wavelengths are encoded with different radio frequencies. Depending on the optical characteristic of optical module 14 , ICG or Li-COR (manufactured by Li-Cor Company, Lincoln, Nebr.) is detected using the dual wavelength excitation measurement.
- optical probe 14 is a dual wavelength phase cancellation system described in U.S. Pat. No. 5,807,263, which is incorporated by reference.
- the dual wavelength system uses laser diodes emitting light at 754 nm and 800 nm.
- the examined tissue is illuminated with either one of the wavelengths. These wavelengths excite fluorescence in ICG at 754 nm for low concentrations and at 800 nm for higher concentrations.
- the detected optical data is processed for phase detection or amplitude cancellation.
- the dual wavelength system detects the sum of the detected optical signals at the two wavelengths to determine blood volume.
- the system also displays the difference of the two detected signals at the two wavelengths to determine the oxygenation of hemoglobin, or may display the individual detected optical signals obtained from the absorption measurement.
- the detected 800 nm signal reflects the absorption of ICG and other agent and its derivatives.
- the fluorescence of the ICG and other agents at 830 nm is measured with the 754 nm and 800 nm excitation.
- This system employs optical primary and secondary filters as described in the above-mentioned publication by J. R. Lakowicz.
- Drug delivery module 12 may be based on electrotransport, such as iontophoresis that involves electrically induced transport of charged ions, or electroosmosis that involves the movement of the liquid through a biological membrane such as the skin, or electroporosis that involves the transport of an agent through transiently existing pores formed in a biological membrane under the influence of the electric field.
- the electrotransport-based module includes at least two electrodes in contact with a portion of the skin, mucous membrane, or another body surface, and at least one reservoir or source of the agent to be delivered to the body.
- the donor reservoir is connected to the donor electrode and positioned between the two electrodes to provide a renewable source of one or more agents or drugs.
- the drug delivery module also includes an electrical controller designed to regulate the rate of the drug delivery based on the signals from local controller 16 .
- Drug delivery module 12 may use different delivery devices described in U.S. Pat. No. 5,697,896, entitled “Electrotransport Delivery Device”; described in U.S. Pat. No. 5,445,609, entitled “Electrotransport Agent Delivery Device Having a Disposable Component and a Removable Liner”; described in U.S. Pat. No. 4,942,883, entitled “Drug Delivery Device”; described in U.S. Pat. No. 5,006,108, entitled “Apparatus for lontophoretic Drug Delivery”; described in U.S. Pat. No. 4,474,570, entitled “Iontophoresis Device”; described in U.S. Pat. No.
- drug delivery module 12 may use different devices described in U.S. Pat. No. 5,681,285, entitled “Infusion Pump with an Electronically Loadable Drug Library and a User Interface for Loading the Library”; described in U.S. Pat. No. 5,061,243, entitled “System and Apparatus for the Patient-Controlled Delivery of a Beneficial Agent, and set Therefor”; described in U.S. Pat. No. 5,464,392, entitled “Infusion System Having Plural Fluid Input Ports and at Least One Patient Output Port”; described in U.S. Pat. No. 4,468,222, entitled “Intravenous Liquid Pumping System and Method”; described in U.S. Pat. No.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Radiology & Medical Imaging (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Heart & Thoracic Surgery (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Surgery (AREA)
- Dermatology (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
Abstract
An interactive drug delivery system includes a drug delivery module, an optical probe, a local controller, and an optional central controller. The drug delivery module is constructed and arranged to deliver selected amounts of a drug into a subject. The optical probe is constructed and arranged to detect in a selected tissue region of the subject a manifestation caused by the delivered drug. The local controller is constructed and arranged to receive data from or transmit data to the optical probe and the drug delivery module. The local controller is arranged to correlate optical data, received from the optical probe, to selected data and provide signals to the drug delivery module for adjusting the amounts of the drug to be delivered into the subject.
Description
- This application is a continuation of U.S. application Ser. No. 09/383,476, filed on Aug. 26, 1999, which claims priority from U.S. Provisional Application 60/098,017, filed on Aug. 26, 1998, both of which are incorporated by reference
- The present invention relates to interactive drug delivery systems and methods.
- X-ray or γ-ray radiation, optical radiation, ultrasound waves and magnetic fields have been used to examine and image biological tissue. X-rays or γ-rays propagate in the tissue on straight, ballistic lines; that is, their scattering is negligible. Thus, imaging is based on evaluation of the absorption levels of different tissue types. For example, in roentgenography the X-ray film contains darker and lighter spots. In more complicated systems, such as computerized tomography (CT), a cross-sectional picture of human organs is created by transmitting X-ray radiation through a section of the human body at different angles and by electronically detecting the variation in X-ray transmission. The detected intensity information is digitally stored in a computer that reconstructs the X-ray absorption of the tissue at a multiplicity of points located in one cross-sectional plane.
- Near infrared radiation (NIR) has been used to study non-invasively biological tissue including oxygen metabolism in the brain, finger, or ear lobe, for example. The use of visible, NIR and infrared (IR) radiation for medical imaging may have several advantages. In the NIR or IR range the contrast factor between a tumor and a tissue is much larger than in the X-ray range. In addition, the visible to IR radiation is preferred over the X-ray radiation since it is non-ionizing and thus, potentially causes fewer side effects. However, the visible or IR radiation is strongly scattered and absorbed in biological tissue, and the migration path cannot be approximated by a straight line, making inapplicable certain aspects of cross-sectional imaging techniques.
- Optical spectroscopy has been used to monitor and image tissue blood oxygenation and volume by measuring absorption of oxyhemoglobin and deoxyhemoglobin in the near infrared (NIR) wavelength region. Below 700 nm, light is strongly absorbed by hemoglobin, and above 900 nm, it is strongly absorbed by water. By making differential measurements at either side of the isosbestic point of oxy-hemoglobin and deoxy-hemoglobin absorbance (near 800 nm), it is possible to quantify the blood oxygenation and volume levels. Typically, these measurements are made at 750 nm and 830 nm.
- NIR spectrometry adapted to the principles of computerized tomography has been used for in vivo imaging. This technique utilizes NIR radiation in an analogous way to the use of X-ray radiation in an X-ray CT. The X-ray source is replaced by several laser diodes emitting light in the NIR range. The NIR-CT uses a set of photodetectors that detect the light of the laser diodes transmitted through the imaged tissue. The detected data are manipulated by a computer in a fashion similar to that of the detected X-ray data in an X-ray CT. Different NIR-CT systems have recognized the scattering aspect of the non-ionizing radiation and have modified the X-ray CT algorithms accordingly.
- The above-mentioned techniques have been used to detect a tissue tumor. The term “angiogenesis” refers to the generation of new blood vessels in a tissue or organ. Under normal physiological conditions humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development and formation of the corpus luteum, endometrium and placenta.
- Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, such as tumor metastasis and abnormal growth by endothelial cells, and supports the pathological damage seen in these conditions. The diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenesis dependent or angiogenesis associated diseases. The hypothesis that tumor growth is angiogenesis dependent was first proposed in 1971. (Folkman J., Tumor Angiogenesis: Therapeutic Implications. N. Engl. Jour. Med. 285: 1182-1186, 1971.) In its simplest terms it states: “Once tumor ‘take’ has occurred, every increase in tumor cell population must be preceded by an increase in new capillaries converging on the tumor.” Tumor ‘take’ is understood to indicate a prevascular phase of tumor growth in which a population of tumor cells occupying a few cubic millimeters' volume and not exceeding a few million cells, can survive on existing host microvessels. Expansion of tumor volume beyond this phase requires the induction of new capillary blood vessels. This explanation was directly or indirectly observed and documented in numerous publications.
- After a tumor is detected by X-ray mammography, ultrasound, computerized tomography or MRI, the patient undergoes surgery, radiation therapy and/or drug therapy that frequently has negative effects on other organs and tissue of the patient. Furthermore, different patients respond differently to the drug therapy.
- In one aspect, an interactive drug delivery system includes a drug delivery module, an optical probe, and a local controller. The drug delivery module delivers selected amounts of a drug into a subject undergoing drug therapy while the optical probe detects the delivered drug, or a manifestation caused by the delivered drug, in a selected tissue region of the subject. The local controller receives data from the optical probe and provides signals to the drug delivery module for adjusting the amounts of the drug to be delivered to the body.
- In another aspect, an interactive drug delivery system includes a drug delivery module, an optical probe, a local controller, and a central controller. The drug delivery module delivers selected amounts of a drug into a subject undergoing drug therapy while the optical probe monitors a manifestation caused by the delivered drug in a selected tissue region of the subject. The local controller receives optical data from the optical probe and transmits data to the central controller. The central controller correlates the received data with control data and transmits data back to the local controller. The local controller provides signals to the drug delivery module for adjusting the amounts of the drug to be delivered to the body.
- Preferred embodiments of these aspects include one or more of the following features:
- The central controller includes a monitor for displaying the received data and suggested treatment data to a clinician. The central controller further includes an input device (e.g., a keyboard, a voice recognition system, a magnetic card reader) for entering control data to the central controller. The central controller further includes a data bank with various types of treatment data and optical data.
- The interactive drug delivery system includes several drug delivery modules connected to the local controller. The interactive drug delivery system includes several additional probes, such as a temperature probe, an ultrasound probe, or an electrical probe including one or several electrodes that are implanted or attached to the skin. These probes are designed to monitor tissue properties, including the tissue metabolism, the heart rate, EKG, or the tissue temperature, and provide the measured data to the local controller.
- The interactive drug delivery system enables continuous monitoring of a patient and adjusting interactively the drug delivery. Thus, the patient is able to move around the medical facility or leave the medical facility while undergoing drug therapy.
- In another aspect, an interactive drug delivery method includes delivering by a drug delivery module selected amounts of a drug into a subject; optically detecting in a selected tissue region of said subject a manifestation caused by the delivered drug by an optical probe; and receiving data from or transmitting data to said optical probe and said drug delivery module by a local controller. The method also includes correlating data received from said optical probe to selected data stored in said local controller; and providing signals to said drug delivery module for adjusting the amounts of the drug to be delivered into said subject.
- The interactive drug delivery method includes regulating the rate of the delivered drug based on signals from said local controller.
- Other features and advantages will become apparent from the following detailed description and the accompanying
FIG. 1 , which shows an interactive drug delivery system using an optical probe. - With reference to
FIG. 1 , an interactivedrug delivery system 10 includes adrug delivery module 12, an optical probe 14, alocal controller 16, and acentral controller 20. A human subject 11 (or an animal) undergoing a medical treatment wearslocal controller 16 interfaced with optical probe 14,drug delivery module 12, and optionally, additional probes.Local controller 16 includes a processor, a memory and one or several interfaces including a wireless interface. -
Drug delivery module 12 delivers selected amounts of a drug into the human body while optical probe 14 measures the concentration of the drug in a selected tissue region, or measures a selected response of a tissue region to the introduced drug, or measures changes in a selected tissue region, for example, a blood solute such as glucose, exogenous contrast agent or endogenous tissue pigment, and a tissue state such as blood volume or oxygenation of a tissue region, blood volume changes due to arterial pulse or the pulse rate. -
Drug delivery module 12 and optical probe 14 provide data tolocal controller 16, which stores the data and provides the data tocentral controller 20 via a network 18, such as the cellular telephone network. Thesystem 10 may include additional probes, such as a temperature probe, an ultrasound probe, or an electrical probe including one or several electrodes that are implanted or attached to the skin. These probes are designed to monitor tissue properties, including metabolism, the heart rate or EKG, temperature, perspiration, and provide data tolocal controller 16.Interactive system 10 may also include several additional drug delivery modules, responsive tolocal controller 16, for delivering several drugs according to a selected protocol. - Optical probe 14 is a non-invasive optical system that employs a CW spectrophotometer described in PCT application PCT/US95/15666, which is incorporated by reference. Alternatively, optical probe is a Time Resolved Spectroscopy (TRS) system as described in PCT applications PCT/US94/03518 or PCT/US94/07984 or U.S. Pat. No. 5,119,815 or U.S. Pat. No. 5,386,827, all of which are incorporated by reference. In another embodiment, optical probe 14 is a phase modulation system described in U.S. Pat. No. 4,972,331; 5,122,974; 5,187,672; 5,553,614 or 5,564,417, which are incorporated by reference. In another embodiment, optical probe 14 is a phased array, phase cancellation system described in PCT application PCT/US93/05868 or an amplitude cancellation system described in PCT application PCT/US95/15694, both of which are incorporated by reference as if fully set forth herein.
- Optical probe 14 monitors directly a tissue constituent or a tissue region including an identified tumor during and after the drug delivery. Alternatively, optical probe 14 monitors a selected tissue organ to detect changes in the physiology of the tissue, or to monitor levels of a tissue solute attributable to the delivered drug. For example, optical probe 14 measures solute levels, such as glucose levels in the liver using the optical techniques described in the PCT Application PCT/US95/15666. In this process, optical probe 14 evaluates changes in the scattering coefficient associated with the measured solute levels.
-
Local controller 16 receives optical data from optical probe 14. Furthermore,local controller 16 receives the temperature data, the EKG data, the heart rate data or the metabolism data.Local controller 16 compares the received data with stored data and stored instructions reflecting the expected treatment and the physiological changes caused by the delivered drug. After comparing the received data with the stored data,local controller 16 can provide control signals for adjusting or discontinuing the drug delivery performed bydrug delivery module 12. Furthermore,local controller 16 can transmit the detected optical data and the stored data tocentral controller 20.Central controller 20 performs a data evaluation and provides the information to a physician. The physician evaluates the provided data and inputs dosing instructions intocentral controller 20, which in turn transmits the dosing instructions tolocal controller 16 for adjusting the drug delivery bydrug delivery module 12.Local controller 16 further includes an input pad constructed and arranged for the human subject to input data including subjective condition of the human subject during the treatment. For example, the human subject can input information about fever, pain, nausea, vomiting, dizziness, or other symptoms. - Optical probe 14 is further constructed to measure the pulse rate of the subject during the drug delivery. Optical probe 14 detects increases in the pulse rate that may correspond to a sudden onset of tachycardia attributable, for example, to an anaphylactic reaction. The increase in the pulse rate may be accompanied with a temperature increase, corresponding to a drug related fever, or to an infection due to neutropenia or anemia caused by the delivered drug. The temperature probe measures the temperature of the subject and provides the temperature data automatically to
local controller 16. - In another embodiment, as shown in
FIG. 1 ,optical system 10 is used to monitor a breast tumor. Optical probe 14 detects a tumor as described in the PCT Application PCT/US99/02953, entitled “Examination and Imaging of Breast Tissue,” filed on Feb. 11, 1999, incorporated by reference herein. One or severaldrug delivery modules 12 delivers one or several drugs to the subject. For example, the drug treatment may include a combination regimen, such as CMF (Cyclophosphamide, Methotrexate and 5-Fluorouracil). Alternatively,drug delivery module 12 delivers a conjugated angiogenesis inhibitor for treatment of pathogenetic conditions, as described in U.S. Pat. No. 5,762,918 entitled “Methods of Using Steroid-Polyanionic Polymer-Based Conjugated Targeted to Vascular Endothelial Cells” or as described in U.S. Pat. No. 5,733,876 entitled “Method of Inhibiting Angiogenesis,” both of which are incorporated by reference. Optical probe 14 measures the local blood volume and oxygenation of the tissue region including the detected tumor. Based on the measured blood volume and oxygenation, optical probe 14 monitors the growth and activity of the identified tumor. For example, optical probe 14 detects higher blood oxygenation. Based on this data, alocal controller 16 provides signals todrug delivery module 12 for decreasing the drug amount (or vice versa). Furthermore, upon detecting a sudden onset of tachycardia,local controller 16 may directdrug delivery module 12 to reduce or eliminate the delivery of the drug. - In another embodiment,
system 10 is used to monitor the liver during a combination regiment for treatment of carcinoma. The CMF regiment causes optically detectable changes of one or several solutes in the liver. By measuring changes in the scattering coefficient at the measured wavelength, optical probe 14 detects changes in the solute concentration and provides the data tolocal controller 16, which adjusts the drug delivery. Alternatively, optical probe 14 is used to monitor drug delivery directly into the liver in treatment of hepatocellular carcinoma. - In another embodiment,
interactive system 10 is used to monitor the drug delivery for treatment of diseases such as diabetes or cardiomyopathy. When treating diabetes,drug delivery module 12 includes an insulin pump, for providing controlled amounts of insulin to a patient. Optical probe 14 is located on the abdominal region near the liver so that the detected optical radiation passes through the liver. Optical probe 14 detects the level of glucose as described in the PCT Application PCT/US95/15666, which is incorporated by reference as if fully provided herein. Upon detecting a low glucose level by optical probe 14,local controller 16 directs the insulin pump to reduce or discontinue the insulin delivery. The monitoring for hypoglycemia or hyperglycemia is also performed during the sleep of the patient to provide the data tolocal controller 16, which not only reduces the insulin delivery, but also sends a message tocentral controller 20 and a clinician receiving information atcentral controller 20. When treating cardiomyopathy, optical probe 14 measures the blood volume and saturation whiledrug delivery module 12 delivers the butamine, dopamine, or another drug. - Alternatively, optical probe 14 is a TRS system, a phase modulation system, a phased array, phase cancellation system, or an amplitude cancellation system for detecting fluorescent radiation. The principles of detecting fluorescent radiation were described by J. R. Lakowicz in “Principles of Fluorescence Spectroscopy,” Plenum Press, N.Y., 1983. The delivered drug is “tagged” with an optically active contrast agent such as light absorbing contrast agent or a fluorescing contrast agent (e.g., ICG). Then, optical probe 14 uses a wavelength sensitive to the contrast agent, for example, a fluorescing contrast agent naturally occurring or delivered into the examined tissue.
- For example, the delivered drug is “tagged” with a signal generator of high optical sensitivity and specificity, such as a molecular beacon. Molecular beacons are sense or antisense oligonucleotide probes that become fluorescent only in the presence of specific sequences of target nucleic acids. (Described by Tyagi, S. and Kramer, F. R., “Molecular beacons: probes that fluoresce upon hybridization,” Nature Biotech. 14: 303-8 (1996).) They consist of hairpin shaped molecules containing a loop of specific sequence nucleotide that is complementary to the target nucleic acid.
- In the loop, the 3′- and 5′-ends of this loop contain 5-8 nucleotide strands that are complementary to each other; upon hybridization they form a ‘stem’ which holds the ends of the loop together. Attached to one of the stem oligonucleotides is a short linker with a fluorophore at its end; attached to the other stem is a linker connected to a quencher. The linkers are designed to juxtapose the fluorophore and quencher. Since fluorescence energy transfer (FET) depends on the inverse sixth power of the donor-acceptor distance, the molecular beacon is non-fluorescent when the stem segments are hybridized to each other; the transferred energy is dissipated as heat. When the loop hybridizes with the target nucleic acid, the hydrogen bonds between the complementary stem nucleotides are broken (since there are many more hydrogen bonds formed between the loop and the target), separating the fluorophore and quencher and producing detectable fluorescence. The length of the loop is chosen to optimize the approximation of the fluorophore and the quencher.
- Molecular beacons have been used to detect specific amino acids in homogeneous solution. (See Tyagi, S. and Kramer, F. R., “Molecular beacons: probes that fluoresce upon hybridization,” Nature Biotech. 14: 303-8 (1996).) They are particularly useful for situations in which it is either not possible or desirable to isolate the probe-target hybrids, such as for real-time monitoring of polymerase chain reactions in sealed tubes or for detection of specific nucleic acids in cells. (See, Gao, W., Tyagi, S., Kramer, F. R. and Goldman, E., “Messenger RNA release from ribosomes during 5′-translational blockage by consecutive low-usage arginine but not leucine codons in Eschericia coli,” Mol. Microbiol. 25: 707-716 (1997); and Matsuo, T., “In situ visualization of mRNA for basic fibroblast growth factor in living cells,” Biochim. Biophys. Acta 1379: 178-84 (1998).) Molecular beacons have been used to detect specific RNAs in hamster fibroblasts and human leukemia cells. (See, Sokol, D. L., Zhang, X., Lu, P. and Gewirtz, A. M., “Real time detection of DNA/RNA hybridization in living cells,” Proc. Natl. Acad. Sc. USA 95: 11538-43 (1998).) Here, the molecular beacons are active in the near-infrared region and contain sense or antisense oligonucleotides targeted at specific mRNAs of solid tumors in vivo. This type of near infra-red fluorescent probe can be delivered by a variety of vehicles, such as apoE-directed lipid vesicles for targeting tumor cells which overexpress low density lipoprotein (LDL) receptors, (see Rensen, P. C. N., Schiffelers, R. M., Versluis, J., Bijsterbosch, M. K., van Kuijk-Meuwissen, M. E. M. J. and van Berkel, T. J. C., “Human recombinant apolipoprotein E-enriched liposomes can mimic low density lipoproteins as carriers for the site-specific delivery of antitumor agents,” Molec. Pharmacol. 52: 445-455 (1997)), or such as B16 melanoma cells, (see de Smith, P. C. and van Berkel, T. J. C., “Prolonged serum half-life of antineoplastic drugs by incorporation into the low density lipoprotein,” Cancer Res. 50: 7476082 (1990)) which will serve as a model tumor system for our study.
- Optical probe 14 evaluates the tumor by evaluating the tissue and angiogenesis or by using enhanced fluorescent probe signaling cancer tissue based upon molecular abnormalities. A specific molecular beacon is used for detection of specific RNAs in specific tumors by targeting one or several enzymes. Several molecular beacons have been prepared with dyes detectable in the visible range of the optical spectrum, as described in Sokol, D. L., Zhang, X., Lu, P. and Gewirtz, A. M., “Real time detection of DNA/RNA hybridization in living cells,” Proc. Natl. Acad. Sci. USA 95: 11538-43 (1998).
- A molecular beacon has its natural fluorescence quenched by hybridization in a target sequence. When duplex formation occurs, the fluorophores become separated and quenching is no longer possible. A dual wavelength system is used for absorption measurements and fluorescent measurements, as described above. The measurements are used to detect intrinsic and angiogenesis (or deoxygenation) signals from the tumor. The two wavelengths are encoded with different radio frequencies. Depending on the optical characteristic of optical module 14, ICG or Li-COR (manufactured by Li-Cor Company, Lincoln, Nebr.) is detected using the dual wavelength excitation measurement. For example, optical probe 14 is a dual wavelength phase cancellation system described in U.S. Pat. No. 5,807,263, which is incorporated by reference. The dual wavelength system uses laser diodes emitting light at 754 nm and 800 nm. The examined tissue is illuminated with either one of the wavelengths. These wavelengths excite fluorescence in ICG at 754 nm for low concentrations and at 800 nm for higher concentrations. The detected optical data is processed for phase detection or amplitude cancellation.
- The dual wavelength system detects the sum of the detected optical signals at the two wavelengths to determine blood volume. The system also displays the difference of the two detected signals at the two wavelengths to determine the oxygenation of hemoglobin, or may display the individual detected optical signals obtained from the absorption measurement. The detected 800 nm signal reflects the absorption of ICG and other agent and its derivatives. The fluorescence of the ICG and other agents at 830 nm is measured with the 754 nm and 800 nm excitation. This system employs optical primary and secondary filters as described in the above-mentioned publication by J. R. Lakowicz.
-
Interactive system 10 is constructed for using various drug delivery modules.Drug delivery module 12 may be based on electrotransport, such as iontophoresis that involves electrically induced transport of charged ions, or electroosmosis that involves the movement of the liquid through a biological membrane such as the skin, or electroporosis that involves the transport of an agent through transiently existing pores formed in a biological membrane under the influence of the electric field. The electrotransport-based module includes at least two electrodes in contact with a portion of the skin, mucous membrane, or another body surface, and at least one reservoir or source of the agent to be delivered to the body. The donor reservoir is connected to the donor electrode and positioned between the two electrodes to provide a renewable source of one or more agents or drugs. The drug delivery module also includes an electrical controller designed to regulate the rate of the drug delivery based on the signals fromlocal controller 16. -
Drug delivery module 12 may use different delivery devices described in U.S. Pat. No. 5,697,896, entitled “Electrotransport Delivery Device”; described in U.S. Pat. No. 5,445,609, entitled “Electrotransport Agent Delivery Device Having a Disposable Component and a Removable Liner”; described in U.S. Pat. No. 4,942,883, entitled “Drug Delivery Device”; described in U.S. Pat. No. 5,006,108, entitled “Apparatus for lontophoretic Drug Delivery”; described in U.S. Pat. No. 4,474,570, entitled “Iontophoresis Device”; described in U.S. Pat. No. 5,013,293, entitled “Pulsating Transdermal Drug Delivery System”; described in U.S. Pat. No. 5,540,665, entitled “Gas Driven Dispensing Device and Gas Generating Engine Therefor”; or described in U.S. Pat. No. 5,057,318, entitled “Delivery System for Beneficial Agent Over a Broad Range of Rates,” all of which are incorporated by reference. - Alternatively,
drug delivery module 12 may use different devices described in U.S. Pat. No. 5,681,285, entitled “Infusion Pump with an Electronically Loadable Drug Library and a User Interface for Loading the Library”; described in U.S. Pat. No. 5,061,243, entitled “System and Apparatus for the Patient-Controlled Delivery of a Beneficial Agent, and set Therefor”; described in U.S. Pat. No. 5,464,392, entitled “Infusion System Having Plural Fluid Input Ports and at Least One Patient Output Port”; described in U.S. Pat. No. 4,468,222, entitled “Intravenous Liquid Pumping System and Method”; described in U.S. Pat. No. 5,785,688, entitled “Fluid Delivery apparatus and Method”; described in U.S. Pat. No. 4,828,545, entitled “Pressure Responsive Multiple Input Infusion system”; and also described in U.S. Pat. No. 5,100,380, entitled “Remotely Programmable Infusion System,” all of which are incorporated by reference. - Additional embodiments are within the following claims:
Claims (27)
1. An interactive drug delivery system comprising:
a drug delivery module constructed and arranged to deliver selected amounts of a drug into a subject;
an optical probe constructed and arranged to detect in vivo in a selected tissue region of said subject a manifestation caused by the delivered drug; and
a local controller constructed and arranged to receive data from or transmit data to said optical probe and said drug delivery module; said local controller being arranged to correlate optical data received from said optical probe to selected data and provide signals to said drug delivery module for adjusting the amounts of the drug to be delivered into said subject.
2. The system of claim 1 further including a central controller remotely located from and in wireless communication with said local controller, central controller constructed and arranged to receive data from said local controller and provide to said local controller data for adjusting the amounts of said drug to be delivered into said subject.
3. The system of claim 1 further including a temperature probe coupled to said local controller.
4. The system of claim 3 wherein said temperature probe uses an infra-red beam to measure a local temperature of a tissue region.
5. The system of claim 1 further including an electrical probe coupled to said local controller.
6. The system of claim 1 wherein said optical probe is a time-resolved (TRS) system.
7. The system of claim 1 wherein said optical probe is a phase modulation system.
8. The system of claim 1 wherein said optical probe is a phased array.
9. The system of claim 1 wherein said optical probe is phase cancellation system.
10. The system of claim 1 wherein said optical probe is an amplitude cancellation system.
11. The system of claim 1 wherein said drug delivery module includes an electrical controller designed to regulate the rate of the delivered drug based on the signals from said local controller.
12. An interactive drug delivery method comprising:
delivering by a drug delivery module selected amounts of a drug into a subject;
optically detecting in vivo in a selected tissue region of said subject a manifestation caused by the delivered drug by an optical probe;
receiving data from or transmitting data to said optical probe and said drug delivery module by a local controller;
correlating data received from said optical probe to selected data stored in said local controller; and
providing signals to said drug delivery module for adjusting the amounts of the drug to be delivered into said subject.
13. The interactive drug delivery method of claim 12 further including regulating the rate of the delivered drug based on signals from said local controller.
14. The interactive drug delivery method of claim 12 including measuring tissue temperature.
15. The interactive drug delivery method of claim 14 wherein said measuring temperature includes using an infra-red beam for measuring a local temperature of a tissue region.
16. The interactive drug delivery method of claim 12 further including measuring electrical signals with an electrical probe.
17. An interactive drug delivery system comprising:
a drug delivery module constructed and arranged to deliver selected amounts of a drug into a subject;
an optical probe including a light source and a light detector constructed and arranged to examine in vivo in a selected biological tissue region of said subject during the operation of said drug delivery module, said optical probe being constructed to detect optical signal related to a manifestation in the examined biological tissue region caused by the delivered drug in the tissue region; and
a local controller constructed and arranged to communicate with said optical probe and said drug delivery module; said local controller being arranged to correlate data related to said manifestation with selected data and provide signals to said drug delivery module for adjusting the amounts of the drug to be delivered into said subject.
18. The system of claim 17 wherein said optical probe includes a time-resolved spectroscopy (TRS) system.
19. The system of claim 17 wherein said optical probe includes a phase modulation system.
20. The system of claim 17 wherein said optical probe includes a phased array.
21. The system of claim 17 wherein said optical probe includes phase cancellation system.
22. The system of claim 17 wherein said optical probe includes an amplitude cancellation system.
23. The system of claim 17 said optical probe includes an array of optical input ports optically coupled to several light sources and an array of detection ports optically coupled to several light detectors.
24. The system of claim 17 said optical probe is constructed to detect said optical signal including fluorescent light emitted as manifestation of said delivered drug.
25. The system of claim 17 further including a central controller remotely located from and in wireless communication with said local controller, central controller constructed and arranged to receive data from said local controller and provide to said local controller data for adjusting the amounts of said drug to be delivered by said drug delivery module into said subject.
26. The system of claim 17 , wherein said optical probe is further constructed to detect infra-red light to measure a local temperature of a tissue region.
27. The system of claim 26 wherein said local controller is constructed and arranged to receive said local temperature data provide to said drug delivery module data for adjusting the amounts of said drug to be delivered into said subject.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/234,016 US20060030813A1 (en) | 1998-08-26 | 2005-09-24 | Sensing and interactive drug delivery |
US12/459,279 US20100049172A1 (en) | 1998-08-26 | 2009-06-29 | Sensing and interactive drug delivery |
US13/135,473 US20110270157A1 (en) | 1998-08-26 | 2011-07-05 | Sensing and interactive drug delivery |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9801798P | 1998-08-26 | 1998-08-26 | |
US09/383,476 US6949081B1 (en) | 1998-08-26 | 1999-08-26 | Sensing and interactive drug delivery |
US11/234,016 US20060030813A1 (en) | 1998-08-26 | 2005-09-24 | Sensing and interactive drug delivery |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/383,476 Continuation US6949081B1 (en) | 1998-08-26 | 1999-08-26 | Sensing and interactive drug delivery |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/459,279 Continuation US20100049172A1 (en) | 1998-08-26 | 2009-06-29 | Sensing and interactive drug delivery |
Publications (1)
Publication Number | Publication Date |
---|---|
US20060030813A1 true US20060030813A1 (en) | 2006-02-09 |
Family
ID=34992582
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/383,476 Expired - Fee Related US6949081B1 (en) | 1998-08-26 | 1999-08-26 | Sensing and interactive drug delivery |
US11/234,016 Abandoned US20060030813A1 (en) | 1998-08-26 | 2005-09-24 | Sensing and interactive drug delivery |
US12/459,279 Abandoned US20100049172A1 (en) | 1998-08-26 | 2009-06-29 | Sensing and interactive drug delivery |
US13/135,473 Abandoned US20110270157A1 (en) | 1998-08-26 | 2011-07-05 | Sensing and interactive drug delivery |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/383,476 Expired - Fee Related US6949081B1 (en) | 1998-08-26 | 1999-08-26 | Sensing and interactive drug delivery |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/459,279 Abandoned US20100049172A1 (en) | 1998-08-26 | 2009-06-29 | Sensing and interactive drug delivery |
US13/135,473 Abandoned US20110270157A1 (en) | 1998-08-26 | 2011-07-05 | Sensing and interactive drug delivery |
Country Status (1)
Country | Link |
---|---|
US (4) | US6949081B1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090112178A1 (en) * | 2007-10-25 | 2009-04-30 | Yashar Behzadi | Fluid transfer port information system |
US20090118594A1 (en) * | 2006-07-07 | 2009-05-07 | Mark Zdeblick | Smart parenteral administration system |
US20090131767A1 (en) * | 2007-11-19 | 2009-05-21 | Arne Lawrence W | Body-associated fluid transport structure evaluation devices |
US20100036310A1 (en) * | 2008-08-05 | 2010-02-11 | Hillman Robert S | Integrated patient management and control system for medication delivery |
US8332020B2 (en) | 2010-02-01 | 2012-12-11 | Proteus Digital Health, Inc. | Two-wrist data gathering system |
US9014779B2 (en) | 2010-02-01 | 2015-04-21 | Proteus Digital Health, Inc. | Data gathering system |
US9763581B2 (en) | 2003-04-23 | 2017-09-19 | P Tech, Llc | Patient monitoring apparatus and method for orthosis and other devices |
Families Citing this family (173)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7167748B2 (en) | 1996-01-08 | 2007-01-23 | Impulse Dynamics Nv | Electrical muscle controller |
JP4175662B2 (en) | 1996-01-08 | 2008-11-05 | インパルス ダイナミクス エヌ.ヴイ. | Electric muscle control device |
US8825152B2 (en) | 1996-01-08 | 2014-09-02 | Impulse Dynamics, N.V. | Modulation of intracellular calcium concentration using non-excitatory electrical signals applied to the tissue |
US9289618B1 (en) | 1996-01-08 | 2016-03-22 | Impulse Dynamics Nv | Electrical muscle controller |
US8321013B2 (en) | 1996-01-08 | 2012-11-27 | Impulse Dynamics, N.V. | Electrical muscle controller and pacing with hemodynamic enhancement |
US9713723B2 (en) | 1996-01-11 | 2017-07-25 | Impulse Dynamics Nv | Signal delivery through the right ventricular septum |
US6018673A (en) | 1996-10-10 | 2000-01-25 | Nellcor Puritan Bennett Incorporated | Motion compatible sensor for non-invasive optical blood analysis |
US9468378B2 (en) | 1997-01-27 | 2016-10-18 | Lawrence A. Lynn | Airway instability detection system and method |
US8932227B2 (en) | 2000-07-28 | 2015-01-13 | Lawrence A. Lynn | System and method for CO2 and oximetry integration |
US9042952B2 (en) | 1997-01-27 | 2015-05-26 | Lawrence A. Lynn | System and method for automatic detection of a plurality of SPO2 time series pattern types |
US20070191697A1 (en) | 2006-02-10 | 2007-08-16 | Lynn Lawrence A | System and method for SPO2 instability detection and quantification |
US9521971B2 (en) | 1997-07-14 | 2016-12-20 | Lawrence A. Lynn | System and method for automatic detection of a plurality of SPO2 time series pattern types |
EP0996482B1 (en) | 1997-07-16 | 2007-02-14 | Metacure NV | Smooth muscle controller |
US6949081B1 (en) * | 1998-08-26 | 2005-09-27 | Non-Invasive Technology, Inc. | Sensing and interactive drug delivery |
US8666495B2 (en) | 1999-03-05 | 2014-03-04 | Metacure Limited | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
US9101765B2 (en) | 1999-03-05 | 2015-08-11 | Metacure Limited | Non-immediate effects of therapy |
US8700161B2 (en) | 1999-03-05 | 2014-04-15 | Metacure Limited | Blood glucose level control |
US6675031B1 (en) | 1999-04-14 | 2004-01-06 | Mallinckrodt Inc. | Method and circuit for indicating quality and accuracy of physiological measurements |
US7190997B1 (en) * | 1999-06-04 | 2007-03-13 | Impulse Dynamics Nv | Drug delivery device |
US7171263B2 (en) * | 1999-06-04 | 2007-01-30 | Impulse Dynamics Nv | Drug delivery device |
US7092753B2 (en) * | 1999-06-04 | 2006-08-15 | Impulse Dynamics Nv | Drug delivery device |
US6614452B1 (en) * | 1999-11-15 | 2003-09-02 | Xenogen Corporation | Graphical user interface for in-vivo imaging |
US7831305B2 (en) | 2001-10-15 | 2010-11-09 | Advanced Neuromodulation Systems, Inc. | Neural stimulation system and method responsive to collateral neural activity |
US7756584B2 (en) | 2000-07-13 | 2010-07-13 | Advanced Neuromodulation Systems, Inc. | Methods and apparatus for effectuating a lasting change in a neural-function of a patient |
US9053222B2 (en) | 2002-05-17 | 2015-06-09 | Lawrence A. Lynn | Patient safety processor |
US20060195041A1 (en) | 2002-05-17 | 2006-08-31 | Lynn Lawrence A | Centralized hospital monitoring system for automatically detecting upper airway instability and for preventing and aborting adverse drug reactions |
US6754516B2 (en) | 2001-07-19 | 2004-06-22 | Nellcor Puritan Bennett Incorporated | Nuisance alarm reductions in a physiological monitor |
WO2003084395A1 (en) * | 2002-04-01 | 2003-10-16 | Healthetech, Inc. | System and method of determining an individualized drug administration dosage |
US20050075680A1 (en) | 2003-04-18 | 2005-04-07 | Lowry David Warren | Methods and systems for intracranial neurostimulation and/or sensing |
US7006856B2 (en) | 2003-01-10 | 2006-02-28 | Nellcor Puritan Bennett Incorporated | Signal quality metrics design for qualifying data for a physiological monitor |
US7016715B2 (en) | 2003-01-13 | 2006-03-21 | Nellcorpuritan Bennett Incorporated | Selection of preset filter parameters based on signal quality |
US11439815B2 (en) | 2003-03-10 | 2022-09-13 | Impulse Dynamics Nv | Protein activity modification |
JP2006519663A (en) | 2003-03-10 | 2006-08-31 | インパルス ダイナミックス エヌヴイ | Apparatus and method for delivering electrical signals for regulating gene expression in heart tissue |
US8792985B2 (en) | 2003-07-21 | 2014-07-29 | Metacure Limited | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
ES2656114T3 (en) * | 2004-01-27 | 2018-02-23 | Altivera L.L.C. | Diagnostic radiofrequency identification sensors and their applications |
US7120479B2 (en) | 2004-02-25 | 2006-10-10 | Nellcor Puritan Bennett Inc. | Switch-mode oximeter LED drive with a single inductor |
US7190985B2 (en) | 2004-02-25 | 2007-03-13 | Nellcor Puritan Bennett Inc. | Oximeter ambient light cancellation |
US7194293B2 (en) | 2004-03-08 | 2007-03-20 | Nellcor Puritan Bennett Incorporated | Selection of ensemble averaging weights for a pulse oximeter based on signal quality metrics |
US8611977B2 (en) * | 2004-03-08 | 2013-12-17 | Covidien Lp | Method and apparatus for optical detection of mixed venous and arterial blood pulsation in tissue |
US7534212B2 (en) | 2004-03-08 | 2009-05-19 | Nellcor Puritan Bennett Llc | Pulse oximeter with alternate heart-rate determination |
US7277741B2 (en) | 2004-03-09 | 2007-10-02 | Nellcor Puritan Bennett Incorporated | Pulse oximetry motion artifact rejection using near infrared absorption by water |
US11779768B2 (en) | 2004-03-10 | 2023-10-10 | Impulse Dynamics Nv | Protein activity modification |
US8352031B2 (en) | 2004-03-10 | 2013-01-08 | Impulse Dynamics Nv | Protein activity modification |
WO2006119467A2 (en) | 2005-05-04 | 2006-11-09 | Impulse Dynamics Nv | Protein activity modification |
EP1786510A4 (en) | 2004-07-15 | 2009-12-02 | Northstar Neuroscience Inc | Systems and methods for enhancing or affecting neural stimulation efficiency and/or efficacy |
US20060106430A1 (en) * | 2004-11-12 | 2006-05-18 | Brad Fowler | Electrode configurations for reducing invasiveness and/or enhancing neural stimulation efficacy, and associated methods |
CA2594673A1 (en) | 2004-12-09 | 2006-07-13 | Impulse Dynamics Nv | Protein activity modification |
WO2006093966A2 (en) * | 2005-02-28 | 2006-09-08 | The Trustees Of Princeton University | Sem cathodoluminescent imaging using up-converting nanophosphors |
US7392075B2 (en) | 2005-03-03 | 2008-06-24 | Nellcor Puritan Bennett Incorporated | Method for enhancing pulse oximetry calculations in the presence of correlated artifacts |
WO2006097934A2 (en) | 2005-03-18 | 2006-09-21 | Metacure Limited | Pancreas lead |
US7856263B2 (en) * | 2005-04-22 | 2010-12-21 | Travanti Pharma Inc. | Transdermal systems for the delivery of therapeutic agents including granisetron using iontophoresis |
US7725147B2 (en) | 2005-09-29 | 2010-05-25 | Nellcor Puritan Bennett Llc | System and method for removing artifacts from waveforms |
US7725146B2 (en) | 2005-09-29 | 2010-05-25 | Nellcor Puritan Bennett Llc | System and method for pre-processing waveforms |
US20070106126A1 (en) | 2005-09-30 | 2007-05-10 | Mannheimer Paul D | Patient monitoring alarm escalation system and method |
US7856264B2 (en) * | 2005-10-19 | 2010-12-21 | Advanced Neuromodulation Systems, Inc. | Systems and methods for patient interactive neural stimulation and/or chemical substance delivery |
US20070100220A1 (en) | 2005-10-28 | 2007-05-03 | Baker Clark R Jr | Adjusting parameters used in pulse oximetry analysis |
US7668579B2 (en) | 2006-02-10 | 2010-02-23 | Lynn Lawrence A | System and method for the detection of physiologic response to stimulation |
ITMI20060306A1 (en) * | 2006-02-20 | 2007-08-21 | Bc System S R L | SYSTEM AND METHOD FOR THE ADMINISTRATION OF A COSMETIC COMPOSITION TO A SUBJECT |
US8702606B2 (en) | 2006-03-21 | 2014-04-22 | Covidien Lp | Patient monitoring help video system and method |
US8380271B2 (en) | 2006-06-15 | 2013-02-19 | Covidien Lp | System and method for generating customizable audible beep tones and alarms |
US8064975B2 (en) | 2006-09-20 | 2011-11-22 | Nellcor Puritan Bennett Llc | System and method for probability based determination of estimated oxygen saturation |
US8696593B2 (en) | 2006-09-27 | 2014-04-15 | Covidien Lp | Method and system for monitoring intracranial pressure |
US7922665B2 (en) | 2006-09-28 | 2011-04-12 | Nellcor Puritan Bennett Llc | System and method for pulse rate calculation using a scheme for alternate weighting |
US8175667B2 (en) | 2006-09-29 | 2012-05-08 | Nellcor Puritan Bennett Llc | Symmetric LED array for pulse oximetry |
US8068891B2 (en) | 2006-09-29 | 2011-11-29 | Nellcor Puritan Bennett Llc | Symmetric LED array for pulse oximetry |
US8728059B2 (en) | 2006-09-29 | 2014-05-20 | Covidien Lp | System and method for assuring validity of monitoring parameter in combination with a therapeutic device |
US7698002B2 (en) | 2006-09-29 | 2010-04-13 | Nellcor Puritan Bennett Llc | Systems and methods for user interface and identification in a medical device |
US7706896B2 (en) | 2006-09-29 | 2010-04-27 | Nellcor Puritan Bennett Llc | User interface and identification in a medical device system and method |
US8068890B2 (en) | 2006-09-29 | 2011-11-29 | Nellcor Puritan Bennett Llc | Pulse oximetry sensor switchover |
US7925511B2 (en) | 2006-09-29 | 2011-04-12 | Nellcor Puritan Bennett Llc | System and method for secure voice identification in a medical device |
US20080081956A1 (en) | 2006-09-29 | 2008-04-03 | Jayesh Shah | System and method for integrating voice with a medical device |
US8160668B2 (en) | 2006-09-29 | 2012-04-17 | Nellcor Puritan Bennett Llc | Pathological condition detector using kernel methods and oximeters |
US7848891B2 (en) | 2006-09-29 | 2010-12-07 | Nellcor Puritan Bennett Llc | Modulation ratio determination with accommodation of uncertainty |
US8265724B2 (en) | 2007-03-09 | 2012-09-11 | Nellcor Puritan Bennett Llc | Cancellation of light shunting |
US8417311B2 (en) | 2008-09-12 | 2013-04-09 | Optiscan Biomedical Corporation | Fluid component analysis system and method for glucose monitoring and control |
US20090016404A1 (en) * | 2007-07-13 | 2009-01-15 | International Business Machines Corporation | Intelligent thermometer |
JP4569615B2 (en) * | 2007-09-25 | 2010-10-27 | ブラザー工業株式会社 | Printing device |
CA2702116C (en) | 2007-10-10 | 2021-01-05 | Optiscan Biomedical Corporation | Fluid component analysis system and method for glucose monitoring and control |
US8204567B2 (en) | 2007-12-13 | 2012-06-19 | Nellcor Puritan Bennett Llc | Signal demodulation |
US8092993B2 (en) | 2007-12-31 | 2012-01-10 | Nellcor Puritan Bennett Llc | Hydrogel thin film for use as a biosensor |
US20090171174A1 (en) * | 2007-12-31 | 2009-07-02 | Nellcor Puritan Bennett Llc | System and method for maintaining battery life |
US20090177147A1 (en) | 2008-01-07 | 2009-07-09 | Michael Blomquist | Insulin pump with insulin therapy coaching |
US8986253B2 (en) | 2008-01-25 | 2015-03-24 | Tandem Diabetes Care, Inc. | Two chamber pumps and related methods |
US8275553B2 (en) | 2008-02-19 | 2012-09-25 | Nellcor Puritan Bennett Llc | System and method for evaluating physiological parameter data |
US8750953B2 (en) | 2008-02-19 | 2014-06-10 | Covidien Lp | Methods and systems for alerting practitioners to physiological conditions |
US8140272B2 (en) | 2008-03-27 | 2012-03-20 | Nellcor Puritan Bennett Llc | System and method for unmixing spectroscopic observations with nonnegative matrix factorization |
US8437822B2 (en) | 2008-03-28 | 2013-05-07 | Covidien Lp | System and method for estimating blood analyte concentration |
US8112375B2 (en) | 2008-03-31 | 2012-02-07 | Nellcor Puritan Bennett Llc | Wavelength selection and outlier detection in reduced rank linear models |
US8364224B2 (en) | 2008-03-31 | 2013-01-29 | Covidien Lp | System and method for facilitating sensor and monitor communication |
US8292809B2 (en) | 2008-03-31 | 2012-10-23 | Nellcor Puritan Bennett Llc | Detecting chemical components from spectroscopic observations |
CA2722773C (en) | 2008-05-07 | 2015-07-21 | Lawrence A. Lynn | Medical failure pattern search engine |
US8112290B2 (en) | 2008-05-16 | 2012-02-07 | Adolor Corporation | Methods for delivering a drug to a hospital patient for short-term use while minimizing long-term use of the drug |
USD626562S1 (en) | 2008-06-30 | 2010-11-02 | Nellcor Puritan Bennett Llc | Triangular saturation pattern detection indicator for a patient monitor display panel |
US9895068B2 (en) | 2008-06-30 | 2018-02-20 | Covidien Lp | Pulse oximeter with wait-time indication |
USD626561S1 (en) | 2008-06-30 | 2010-11-02 | Nellcor Puritan Bennett Llc | Circular satseconds indicator and triangular saturation pattern detection indicator for a patient monitor display panel |
US8862194B2 (en) | 2008-06-30 | 2014-10-14 | Covidien Lp | Method for improved oxygen saturation estimation in the presence of noise |
US8416405B2 (en) * | 2008-08-08 | 2013-04-09 | Chemimage Corporation | Raman chemical imaging of implantable drug delivery devices |
US7959598B2 (en) | 2008-08-20 | 2011-06-14 | Asante Solutions, Inc. | Infusion pump systems and methods |
US8408421B2 (en) | 2008-09-16 | 2013-04-02 | Tandem Diabetes Care, Inc. | Flow regulating stopcocks and related methods |
CA2737461A1 (en) | 2008-09-19 | 2010-03-25 | Tandem Diabetes Care, Inc. | Solute concentration measurement device and related methods |
US8386000B2 (en) | 2008-09-30 | 2013-02-26 | Covidien Lp | System and method for photon density wave pulse oximetry and pulse hemometry |
US8433382B2 (en) | 2008-09-30 | 2013-04-30 | Covidien Lp | Transmission mode photon density wave system and method |
US8417309B2 (en) | 2008-09-30 | 2013-04-09 | Covidien Lp | Medical sensor |
US8968193B2 (en) | 2008-09-30 | 2015-03-03 | Covidien Lp | System and method for enabling a research mode on physiological monitors |
CA2741044A1 (en) * | 2008-10-31 | 2010-05-06 | Nellcor Puritan Bennett Llc | System and method for facilitating observation of monitored physiologic data |
US8622916B2 (en) * | 2008-10-31 | 2014-01-07 | Covidien Lp | System and method for facilitating observation of monitored physiologic data |
US8221319B2 (en) | 2009-03-25 | 2012-07-17 | Nellcor Puritan Bennett Llc | Medical device for assessing intravascular blood volume and technique for using the same |
EP3284494A1 (en) | 2009-07-30 | 2018-02-21 | Tandem Diabetes Care, Inc. | Portable infusion pump system |
US8494786B2 (en) | 2009-07-30 | 2013-07-23 | Covidien Lp | Exponential sampling of red and infrared signals |
US8494606B2 (en) | 2009-08-19 | 2013-07-23 | Covidien Lp | Photoplethysmography with controlled application of sensor pressure |
US8494604B2 (en) | 2009-09-21 | 2013-07-23 | Covidien Lp | Wavelength-division multiplexing in a multi-wavelength photon density wave system |
US8704666B2 (en) | 2009-09-21 | 2014-04-22 | Covidien Lp | Medical device interface customization systems and methods |
US8788001B2 (en) | 2009-09-21 | 2014-07-22 | Covidien Lp | Time-division multiplexing in a multi-wavelength photon density wave system |
US8798704B2 (en) | 2009-09-24 | 2014-08-05 | Covidien Lp | Photoacoustic spectroscopy method and system to discern sepsis from shock |
CA2771856A1 (en) | 2009-09-24 | 2011-03-31 | Nellcor Puritan Bennett Llc | Determination of a physiological parameter |
US8923945B2 (en) | 2009-09-24 | 2014-12-30 | Covidien Lp | Determination of a physiological parameter |
US8571621B2 (en) * | 2009-09-24 | 2013-10-29 | Covidien Lp | Minimax filtering for pulse oximetry |
US8376955B2 (en) | 2009-09-29 | 2013-02-19 | Covidien Lp | Spectroscopic method and system for assessing tissue temperature |
US8515511B2 (en) | 2009-09-29 | 2013-08-20 | Covidien Lp | Sensor with an optical coupling material to improve plethysmographic measurements and method of using the same |
US9554739B2 (en) | 2009-09-29 | 2017-01-31 | Covidien Lp | Smart cable for coupling a medical sensor to an electronic patient monitor |
US8401608B2 (en) * | 2009-09-30 | 2013-03-19 | Covidien Lp | Method of analyzing photon density waves in a medical monitor |
WO2011092710A2 (en) | 2010-02-01 | 2011-08-04 | Metacure Limited | Gastrointestinal electrical therapy |
US8391943B2 (en) | 2010-03-31 | 2013-03-05 | Covidien Lp | Multi-wavelength photon density wave system using an optical switch |
US8498683B2 (en) | 2010-04-30 | 2013-07-30 | Covidien LLP | Method for respiration rate and blood pressure alarm management |
US8930145B2 (en) | 2010-07-28 | 2015-01-06 | Covidien Lp | Light focusing continuous wave photoacoustic spectroscopy and its applications to patient monitoring |
US9380982B2 (en) | 2010-07-28 | 2016-07-05 | Covidien Lp | Adaptive alarm system and method |
US8610769B2 (en) | 2011-02-28 | 2013-12-17 | Covidien Lp | Medical monitor data collection system and method |
US8428709B1 (en) | 2012-06-11 | 2013-04-23 | Incline Therapeutics, Inc. | Current control for electrotransport drug delivery |
US8301238B2 (en) | 2011-03-31 | 2012-10-30 | Incline Therapeutics, Inc. | Two-part electrotransport device |
US8428708B1 (en) | 2012-05-21 | 2013-04-23 | Incline Therapeutics, Inc. | Self-test for analgesic product |
US9833146B2 (en) | 2012-04-17 | 2017-12-05 | Covidien Lp | Surgical system and method of use of the same |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9555186B2 (en) | 2012-06-05 | 2017-01-31 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
US9238100B2 (en) | 2012-06-07 | 2016-01-19 | Tandem Diabetes Care, Inc. | Device and method for training users of ambulatory medical devices |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
JP2016515019A (en) * | 2013-03-15 | 2016-05-26 | セノ メディカル インストルメンツ,インク. | System and method for diagnostic vector classification support |
US9492608B2 (en) | 2013-03-15 | 2016-11-15 | Tandem Diabetes Care, Inc. | Method and device utilizing insulin delivery protocols |
US9561324B2 (en) | 2013-07-19 | 2017-02-07 | Bigfoot Biomedical, Inc. | Infusion pump system and method |
GB2523989B (en) | 2014-01-30 | 2020-07-29 | Insulet Netherlands B V | Therapeutic product delivery system and method of pairing |
US9721409B2 (en) * | 2014-05-02 | 2017-08-01 | Qualcomm Incorporated | Biometrics for user identification in mobile health systems |
CN111905188B (en) | 2015-02-18 | 2022-07-22 | 英赛罗公司 | Fluid delivery and infusion device and method of use |
US10368810B2 (en) | 2015-07-14 | 2019-08-06 | Welch Allyn, Inc. | Method and apparatus for monitoring a functional capacity of an individual |
US11116397B2 (en) | 2015-07-14 | 2021-09-14 | Welch Allyn, Inc. | Method and apparatus for managing sensors |
US20170112388A1 (en) * | 2015-10-22 | 2017-04-27 | Welch Allyn, Inc. | Method and apparatus for performing biological measurements |
US10918340B2 (en) | 2015-10-22 | 2021-02-16 | Welch Allyn, Inc. | Method and apparatus for detecting a biological condition |
ITUB20159819A1 (en) * | 2015-12-31 | 2017-07-01 | Biopulse S R L | BIPHASIC WAVE TERANOSTIC ELECTROPORATOR FOR DIAGNOSIS OF PATHOLOGICAL AREAS AND THERAPEUTIC TRANSFER OF MOLECULES AND ITS PROCEDURE |
US10275573B2 (en) | 2016-01-13 | 2019-04-30 | Bigfoot Biomedical, Inc. | User interface for diabetes management system |
EP3374004B1 (en) | 2016-01-14 | 2023-06-28 | Bigfoot Biomedical, Inc. | Adjusting insulin delivery rates |
CN105796086B (en) * | 2016-04-14 | 2019-03-08 | 京东方科技集团股份有限公司 | A kind of intelligent wearable device |
US10791994B2 (en) * | 2016-08-04 | 2020-10-06 | Welch Allyn, Inc. | Method and apparatus for mitigating behavior adverse to a biological condition |
WO2018058041A1 (en) | 2016-09-23 | 2018-03-29 | Insulet Corporation | Fluid delivery device with sensor |
EP3500161A4 (en) | 2016-12-12 | 2020-01-08 | Bigfoot Biomedical, Inc. | Alarms and alerts for medication delivery devices and related systems and methods |
EP3568859A1 (en) | 2017-01-13 | 2019-11-20 | Bigfoot Biomedical, Inc. | Insulin delivery methods, systems and devices |
WO2018132754A1 (en) | 2017-01-13 | 2018-07-19 | Mazlish Bryan | System and method for adjusting insulin delivery |
USD928199S1 (en) | 2018-04-02 | 2021-08-17 | Bigfoot Biomedical, Inc. | Medication delivery device with icons |
EP3788628A1 (en) | 2018-05-04 | 2021-03-10 | Insulet Corporation | Safety constraints for a control algorithm-based drug delivery system |
AU2019347755B2 (en) | 2018-09-28 | 2023-02-02 | Insulet Corporation | Activity mode for artificial pancreas system |
EP3864668A1 (en) | 2018-10-11 | 2021-08-18 | Insulet Corporation | Event detection for drug delivery system |
USD920343S1 (en) | 2019-01-09 | 2021-05-25 | Bigfoot Biomedical, Inc. | Display screen or portion thereof with graphical user interface associated with insulin delivery |
US11801344B2 (en) | 2019-09-13 | 2023-10-31 | Insulet Corporation | Blood glucose rate of change modulation of meal and correction insulin bolus quantity |
US11935637B2 (en) | 2019-09-27 | 2024-03-19 | Insulet Corporation | Onboarding and total daily insulin adaptivity |
WO2021113647A1 (en) | 2019-12-06 | 2021-06-10 | Insulet Corporation | Techniques and devices providing adaptivity and personalization in diabetes treatment |
US11833329B2 (en) | 2019-12-20 | 2023-12-05 | Insulet Corporation | Techniques for improved automatic drug delivery performance using delivery tendencies from past delivery history and use patterns |
JP7512395B2 (en) | 2020-01-06 | 2024-07-08 | インスレット コーポレイション | Predicting dietary and/or exercise behavior based on persistence residuals |
US11551802B2 (en) | 2020-02-11 | 2023-01-10 | Insulet Corporation | Early meal detection and calorie intake detection |
US11986630B2 (en) | 2020-02-12 | 2024-05-21 | Insulet Corporation | Dual hormone delivery system for reducing impending hypoglycemia and/or hyperglycemia risk |
US11547800B2 (en) | 2020-02-12 | 2023-01-10 | Insulet Corporation | User parameter dependent cost function for personalized reduction of hypoglycemia and/or hyperglycemia in a closed loop artificial pancreas system |
US11324889B2 (en) | 2020-02-14 | 2022-05-10 | Insulet Corporation | Compensation for missing readings from a glucose monitor in an automated insulin delivery system |
US11607493B2 (en) | 2020-04-06 | 2023-03-21 | Insulet Corporation | Initial total daily insulin setting for user onboarding |
US11684716B2 (en) | 2020-07-31 | 2023-06-27 | Insulet Corporation | Techniques to reduce risk of occlusions in drug delivery systems |
US11904140B2 (en) | 2021-03-10 | 2024-02-20 | Insulet Corporation | Adaptable asymmetric medicament cost component in a control system for medicament delivery |
WO2023049900A1 (en) | 2021-09-27 | 2023-03-30 | Insulet Corporation | Techniques enabling adaptation of parameters in aid systems by user input |
US11439754B1 (en) | 2021-12-01 | 2022-09-13 | Insulet Corporation | Optimizing embedded formulations for drug delivery |
Citations (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3449121A (en) * | 1967-01-13 | 1969-06-10 | Barnes Eng Co | Infrared thermometer |
US4468222A (en) * | 1976-05-24 | 1984-08-28 | Valleylab | Intravenous liquid pumping system and method |
US4474570A (en) * | 1981-07-10 | 1984-10-02 | Kabushikikaisya Advance Kaihatsu Kenkyujo | Iontophoresis device |
US4756706A (en) * | 1985-01-23 | 1988-07-12 | American Hospital Supply Corporation | Centrally managed modular infusion pump system |
US4825545A (en) * | 1986-03-18 | 1989-05-02 | Sabre International Products Limited | Knives with molded protective cover and handle |
US4942883A (en) * | 1987-09-29 | 1990-07-24 | Newman Martin H | Drug delivery device |
US4972331A (en) * | 1989-02-06 | 1990-11-20 | Nim, Inc. | Phase modulated spectrophotometry |
US5006108A (en) * | 1988-11-16 | 1991-04-09 | Noven Pharmaceuticals, Inc. | Apparatus for iontophoretic drug delivery |
US5013293A (en) * | 1987-05-28 | 1991-05-07 | Drug Delivery Systems Inc. | Pulsating transdermal drug delivery system |
US5057318A (en) * | 1988-12-13 | 1991-10-15 | Alza Corporation | Delivery system for beneficial agent over a broad range of rates |
US5061243A (en) * | 1985-08-06 | 1991-10-29 | Baxter International Inc. | System and apparatus for the patient-controlled delivery of a beneficial agent, and set therefor |
US5100380A (en) * | 1984-02-08 | 1992-03-31 | Abbott Laboratories | Remotely programmable infusion system |
US5119815A (en) * | 1988-12-21 | 1992-06-09 | Nim, Incorporated | Apparatus for determining the concentration of a tissue pigment of known absorbance, in vivo, using the decay characteristics of scintered electromagnetic radiation |
US5122974A (en) * | 1989-02-06 | 1992-06-16 | Nim, Inc. | Phase modulated spectrophotometry |
US5187672A (en) * | 1989-02-06 | 1993-02-16 | Nim Incorporated | Phase modulation spectroscopic system |
US5211626A (en) * | 1987-05-01 | 1993-05-18 | Product Innovation Holdings Ltd. | Medical infusion apparatus |
US5338157A (en) * | 1992-09-09 | 1994-08-16 | Pharmacia Deltec, Inc. | Systems and methods for communicating with ambulatory medical devices such as drug delivery devices |
US5368028A (en) * | 1989-08-11 | 1994-11-29 | Cb-Carmel Biotechnology Ltd. | System for monitoring and controlling blood and tissue constituent levels |
US5386827A (en) * | 1993-03-30 | 1995-02-07 | Nim Incorporated | Quantitative and qualitative in vivo tissue examination using time resolved spectroscopy |
US5445609A (en) * | 1993-05-28 | 1995-08-29 | Alza Corporation | Electrotransport agent delivery device having a disposable component and a removable liner |
US5540665A (en) * | 1994-01-31 | 1996-07-30 | Alza Corporation | Gas driven dispensing device and gas generating engine therefor |
US5553614A (en) * | 1988-12-21 | 1996-09-10 | Non-Invasive Technology, Inc. | Examination of biological tissue using frequency domain spectroscopy |
US5564417A (en) * | 1991-01-24 | 1996-10-15 | Non-Invasive Technology, Inc. | Pathlength corrected oximeter and the like |
US5681285A (en) * | 1992-10-15 | 1997-10-28 | Baxter International Inc. | Infusion pump with an electronically loadable drug library and a user interface for loading the library |
US5697896A (en) * | 1994-12-08 | 1997-12-16 | Alza Corporation | Electrotransport delivery device |
US5733876A (en) * | 1994-04-26 | 1998-03-31 | The Children's Medical Center Corporation | Method of inhibiting angiogenesis |
US5762918A (en) * | 1992-03-23 | 1998-06-09 | Board Of Regents The University Of Texas System | Methods of using steroid-polyanionic polymer-based conjugated targeted to vascular endothelial cells |
US5782755A (en) * | 1993-11-15 | 1998-07-21 | Non-Invasive Technology, Inc. | Monitoring one or more solutes in a biological system using optical techniques |
US5785688A (en) * | 1996-05-07 | 1998-07-28 | Ceramatec, Inc. | Fluid delivery apparatus and method |
US5807263A (en) * | 1992-06-17 | 1998-09-15 | Non-Invasivie Technology, Inc. | Imaging of biological tissue using photon migration with high directionality techniques |
US5935099A (en) * | 1992-09-09 | 1999-08-10 | Sims Deltec, Inc. | Drug pump systems and methods |
US5995860A (en) * | 1995-07-06 | 1999-11-30 | Thomas Jefferson University | Implantable sensor and system for measurement and control of blood constituent levels |
US6175752B1 (en) * | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
US20020017299A1 (en) * | 1998-06-03 | 2002-02-14 | Hickle Randall S. | Apparatus and method for providing a conscious patient relief from pain and anxiety associated with medical or surgical procedures |
US6949081B1 (en) * | 1998-08-26 | 2005-09-27 | Non-Invasive Technology, Inc. | Sensing and interactive drug delivery |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5555885A (en) | 1988-12-21 | 1996-09-17 | Non-Invasive Technology, Inc. | Examination of breast tissue using time-resolved spectroscopy |
US5853370A (en) * | 1996-09-13 | 1998-12-29 | Non-Invasive Technology, Inc. | Optical system and method for non-invasive imaging of biological tissue |
US5673701A (en) * | 1994-10-07 | 1997-10-07 | Non Invasive Technology, Inc. | Optical techniques for examination of biological tissue |
DE69627477T2 (en) | 1995-01-03 | 2004-03-18 | Non-Invasive Technology, Inc. | OPTICAL COUPLING DEVICE FOR IN-VIVO EXAMINATION OF BIOLOGICAL TISSUES |
WO1999040840A1 (en) * | 1998-02-11 | 1999-08-19 | Non-Invasive Technology, Inc. | Detection, imaging and characterization of breast tumors |
WO1999040841A1 (en) | 1998-02-11 | 1999-08-19 | Non-Invasive Technology, Inc. | Imaging and characterization of brain tissue |
DE69941975D1 (en) | 1998-02-13 | 2010-03-18 | Non Invasive Technology Inc | INVESTIGATION, OBSERVATION AND IMAGE DISPLAY OF ABDOMINAL TISSUE |
-
1999
- 1999-08-26 US US09/383,476 patent/US6949081B1/en not_active Expired - Fee Related
-
2005
- 2005-09-24 US US11/234,016 patent/US20060030813A1/en not_active Abandoned
-
2009
- 2009-06-29 US US12/459,279 patent/US20100049172A1/en not_active Abandoned
-
2011
- 2011-07-05 US US13/135,473 patent/US20110270157A1/en not_active Abandoned
Patent Citations (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3449121A (en) * | 1967-01-13 | 1969-06-10 | Barnes Eng Co | Infrared thermometer |
US4468222A (en) * | 1976-05-24 | 1984-08-28 | Valleylab | Intravenous liquid pumping system and method |
US4474570A (en) * | 1981-07-10 | 1984-10-02 | Kabushikikaisya Advance Kaihatsu Kenkyujo | Iontophoresis device |
US5464392A (en) * | 1984-02-08 | 1995-11-07 | Abbott Laboratories | Infusion system having plural fluid input ports and at least one patient output port |
US5100380A (en) * | 1984-02-08 | 1992-03-31 | Abbott Laboratories | Remotely programmable infusion system |
US4756706A (en) * | 1985-01-23 | 1988-07-12 | American Hospital Supply Corporation | Centrally managed modular infusion pump system |
US5061243A (en) * | 1985-08-06 | 1991-10-29 | Baxter International Inc. | System and apparatus for the patient-controlled delivery of a beneficial agent, and set therefor |
US4825545A (en) * | 1986-03-18 | 1989-05-02 | Sabre International Products Limited | Knives with molded protective cover and handle |
US5211626A (en) * | 1987-05-01 | 1993-05-18 | Product Innovation Holdings Ltd. | Medical infusion apparatus |
US5013293A (en) * | 1987-05-28 | 1991-05-07 | Drug Delivery Systems Inc. | Pulsating transdermal drug delivery system |
US4942883A (en) * | 1987-09-29 | 1990-07-24 | Newman Martin H | Drug delivery device |
US5006108A (en) * | 1988-11-16 | 1991-04-09 | Noven Pharmaceuticals, Inc. | Apparatus for iontophoretic drug delivery |
US5057318A (en) * | 1988-12-13 | 1991-10-15 | Alza Corporation | Delivery system for beneficial agent over a broad range of rates |
US5119815A (en) * | 1988-12-21 | 1992-06-09 | Nim, Incorporated | Apparatus for determining the concentration of a tissue pigment of known absorbance, in vivo, using the decay characteristics of scintered electromagnetic radiation |
US5553614A (en) * | 1988-12-21 | 1996-09-10 | Non-Invasive Technology, Inc. | Examination of biological tissue using frequency domain spectroscopy |
US5122974A (en) * | 1989-02-06 | 1992-06-16 | Nim, Inc. | Phase modulated spectrophotometry |
US5187672A (en) * | 1989-02-06 | 1993-02-16 | Nim Incorporated | Phase modulation spectroscopic system |
US4972331A (en) * | 1989-02-06 | 1990-11-20 | Nim, Inc. | Phase modulated spectrophotometry |
US5368028A (en) * | 1989-08-11 | 1994-11-29 | Cb-Carmel Biotechnology Ltd. | System for monitoring and controlling blood and tissue constituent levels |
US5564417A (en) * | 1991-01-24 | 1996-10-15 | Non-Invasive Technology, Inc. | Pathlength corrected oximeter and the like |
US5762918A (en) * | 1992-03-23 | 1998-06-09 | Board Of Regents The University Of Texas System | Methods of using steroid-polyanionic polymer-based conjugated targeted to vascular endothelial cells |
US5807263A (en) * | 1992-06-17 | 1998-09-15 | Non-Invasivie Technology, Inc. | Imaging of biological tissue using photon migration with high directionality techniques |
US5338157B1 (en) * | 1992-09-09 | 1999-11-02 | Sims Deltec Inc | Systems and methods for communicating with ambulat |
US5338157A (en) * | 1992-09-09 | 1994-08-16 | Pharmacia Deltec, Inc. | Systems and methods for communicating with ambulatory medical devices such as drug delivery devices |
US5935099A (en) * | 1992-09-09 | 1999-08-10 | Sims Deltec, Inc. | Drug pump systems and methods |
US5681285A (en) * | 1992-10-15 | 1997-10-28 | Baxter International Inc. | Infusion pump with an electronically loadable drug library and a user interface for loading the library |
US5386827A (en) * | 1993-03-30 | 1995-02-07 | Nim Incorporated | Quantitative and qualitative in vivo tissue examination using time resolved spectroscopy |
US5445609A (en) * | 1993-05-28 | 1995-08-29 | Alza Corporation | Electrotransport agent delivery device having a disposable component and a removable liner |
US5782755A (en) * | 1993-11-15 | 1998-07-21 | Non-Invasive Technology, Inc. | Monitoring one or more solutes in a biological system using optical techniques |
US5540665A (en) * | 1994-01-31 | 1996-07-30 | Alza Corporation | Gas driven dispensing device and gas generating engine therefor |
US5733876A (en) * | 1994-04-26 | 1998-03-31 | The Children's Medical Center Corporation | Method of inhibiting angiogenesis |
US5697896A (en) * | 1994-12-08 | 1997-12-16 | Alza Corporation | Electrotransport delivery device |
US5995860A (en) * | 1995-07-06 | 1999-11-30 | Thomas Jefferson University | Implantable sensor and system for measurement and control of blood constituent levels |
US5785688A (en) * | 1996-05-07 | 1998-07-28 | Ceramatec, Inc. | Fluid delivery apparatus and method |
US6175752B1 (en) * | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
US20020017299A1 (en) * | 1998-06-03 | 2002-02-14 | Hickle Randall S. | Apparatus and method for providing a conscious patient relief from pain and anxiety associated with medical or surgical procedures |
US6949081B1 (en) * | 1998-08-26 | 2005-09-27 | Non-Invasive Technology, Inc. | Sensing and interactive drug delivery |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9763581B2 (en) | 2003-04-23 | 2017-09-19 | P Tech, Llc | Patient monitoring apparatus and method for orthosis and other devices |
US20090118594A1 (en) * | 2006-07-07 | 2009-05-07 | Mark Zdeblick | Smart parenteral administration system |
US9084566B2 (en) | 2006-07-07 | 2015-07-21 | Proteus Digital Health, Inc. | Smart parenteral administration system |
US20090112178A1 (en) * | 2007-10-25 | 2009-04-30 | Yashar Behzadi | Fluid transfer port information system |
US9125979B2 (en) | 2007-10-25 | 2015-09-08 | Proteus Digital Health, Inc. | Fluid transfer port information system |
US8419638B2 (en) | 2007-11-19 | 2013-04-16 | Proteus Digital Health, Inc. | Body-associated fluid transport structure evaluation devices |
US20090131767A1 (en) * | 2007-11-19 | 2009-05-21 | Arne Lawrence W | Body-associated fluid transport structure evaluation devices |
WO2010017279A1 (en) * | 2008-08-05 | 2010-02-11 | Automedics Medical System, Inc. | Integrated patient management and control system for medication delivery |
US20100036310A1 (en) * | 2008-08-05 | 2010-02-11 | Hillman Robert S | Integrated patient management and control system for medication delivery |
US8332020B2 (en) | 2010-02-01 | 2012-12-11 | Proteus Digital Health, Inc. | Two-wrist data gathering system |
US9008761B2 (en) | 2010-02-01 | 2015-04-14 | Proteus Digital Health, Inc. | Two-wrist data gathering system |
US9014779B2 (en) | 2010-02-01 | 2015-04-21 | Proteus Digital Health, Inc. | Data gathering system |
US10376218B2 (en) | 2010-02-01 | 2019-08-13 | Proteus Digital Health, Inc. | Data gathering system |
Also Published As
Publication number | Publication date |
---|---|
US20110270157A1 (en) | 2011-11-03 |
US20100049172A1 (en) | 2010-02-25 |
US6949081B1 (en) | 2005-09-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6949081B1 (en) | Sensing and interactive drug delivery | |
US6632183B2 (en) | Perfusion sensitive biopsy extractor | |
CN105769214B (en) | Noninvasive measurement of blood oxygen saturation | |
EP1054620B1 (en) | Transabdominal examination, monitoring and imaging of tissue | |
EP1054618B1 (en) | Detection, imaging and characterization of breast tumors | |
JPH11508792A (en) | Implantable sensors and systems for blood component level measurement control | |
US20160310055A1 (en) | Apparatus, systems and methods for determining tissue oxygenation | |
US5928155A (en) | Cardiac output measurement with metabolizable analyte containing fluid | |
US10064554B2 (en) | Fiber optic flow and oxygenation monitoring using diffuse correlation and reflectance | |
US20080221408A1 (en) | System and methods for optical sensing and drug delivery using microneedles | |
US20090209828A1 (en) | Method and device microcalorimetrically measuring a tissue local metabolism speed, intracellular tissue water content, blood biochemical component concentration and a cardio-vascular system tension | |
US20030083566A1 (en) | Apparatus and method for delivering ablative laser energy and determining the volume of tumor mass destroyed | |
JP2004528917A (en) | A method for measuring cardiac output and circulating blood volume by noninvasively detecting indicator dilution. | |
US20230099024A1 (en) | System and method for controlling supersaturated oxygen therapy based on patient parameter feedback | |
US20120035583A1 (en) | Multimode neurobiophysiology probe | |
CN108113668A (en) | One-piece type depth of anesthesia and cerebral blood oxygen saturation detection sensor | |
WO1990007907A1 (en) | Infrared oximetry measuring device | |
EP4157443A1 (en) | Devices and related methods for light-based modulation of foreign body responses in living tissue | |
Jarm et al. | Oxygenation and blood flow in tumors treated with hydralazine: evaluation with a novel luminescence-based fiber-optic sensor | |
WO2017115124A1 (en) | Theranostic electroporator with biphasic wave for diagnosis of pathological areas and transfer of therapeutic molecules | |
TSONEVA | Electrochemotherapy of skin cancer treatment results estimated by in vivo autofluorescence measurements | |
Esenaliev | Novel, Noninvasive Techniques for Diagnostics and Therapy: Animal and Clinical Studies | |
Borisova et al. | Optical biopsy–tool for initial cancer diagnosis and monitoring of therapy | |
Mayevsky et al. | Monitoring of NADH in Human Brain and Body Organs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |