University of California

Other

David Arthur Gough

Joseph Y Lucisano

Jeffrey H Price

Drahoslav Lim

Dale A Baker

Joe Lin

Geert W Schmid-Schoenbein

Mark B Catlin

Jana Limova, Legal Representative

Michael C Jablecki

Andrea M Rourke

Brian D McKean

Hwai-Min Tsay

Jon C Armour

Shaghayegh Abbasi

Stefanie Heinz

Disclosed are systems, devices and methods for estimating blood glucose parameters, including blood glucose concentration glucose sensor signals. In some aspects, a method for estimating blood glucose concentration from signals of glucose sensors includes obtaining a set of time-series values that includes tissue glucose sensor values from a glucose sensor and reference blood glucose concentration values associated with a subject; generating a set of matched blood glucose reference values by determining a temporal matching of the tissue glucose sensor values and the reference blood glucose concentration values; isolating error associated with the matched blood glucose reference values to determine a residual error time series, wherein the isolated error includes a composite error comprising a measurement error, a process error, and random error; and producing estimated blood glucose values for true blood glucose of the subject by adding the reference blood glucose concentration values to the residual error time series.

Systems, devices and methods for estimating blood glucose concentrations from signals of sensors deployed in tissue

A membrane for use in an implantable glucose sensor including at least one crosslinked substantially hydrophobic polymer and at least one crosslinked substantially hydrophilic polymer; wherein the first and second polymers are different polymers and substantially form an interpenetrating polymer network, semi-interpenetrating polymer network, polymer blend, or copolymer. The membranes are generally characterized by providing a permeability ratio of oxygen to glucose of about 1 to about 1000 in units of (mg/dl glucose) per (mmHg oxygen). Three methods of making membranes from hydrophobic and hydrophilic monomers formed into polymer networks are provided, wherein according to at least two of the methods, the monomers may be substantially immiscible with one another.

Membranes with controlled permeability to polar and apolar molecules in solution and methods of making same

The invention is the design of a biological measuring device for the determination of the concentration of biomolecules (e.g. glucose) in an environment which is designed for implantation into an individual or for use in the context of an external apparatus. The device contains a composite membrane that is essentially entirely permeable to oxygen and permeable to larger biomolecules only in discrete hydrophilic regions. The membrane diffusionally limits the access of biomolecules to an enzyme, present in the hydrophilic region that catalyzes the oxidation of the biomolecule to produce hydrogen peroxide. A sensor in communication with the hydrophilic region is used to determine the amount of product produced or the amount of excess oxygen present allowing for the concentration of the biomolecule to be determined.

Membrane and electrode structure for implantable sensor

A tissue-implantable sensor for measurement of solutes in fluids and gases, such as oxygen and glucose, is provided. The sensor includes a multiplicity of detectors, constructed and arranged to improve the probability that one or more detectors will have access to a vascular source at points in time sufficient to permit accurate measurements to be taken. Means and methods for calculating solute levels using the sensor device of the invention are also provided.

Tissue implantable sensors for measurement of blood solutes

A sensor probe is disclosed which can measure the hydrogen peroxide content of a single sample using two oxygen sensors whose electrodes are encased in defined membranes. The oxygen reference sensor is encased in a hydrophobic membrane which prevents the transport of hydrogen peroxide or electrochemical poisons or interferents and isolates the electrodes and an electrolyte fluid surrounding the electrodes from the sample fluid. The hydrogen-peroxide-generated oxygen (HPGO) sensor is also is encased in such a hydrophobic membrane, but has in series with and distally of the hydrophobic membrane a hydrophilic membrane which contains an immobilized enzyme such as catalase, peroxidase or other enzymes of a family which catalyzes the reaction of hydrogen peroxide to oxygen and water. At the HPGO sensor, the hydrogen peroxide is catalyzed to oxygen by the enzyme so that the HPGO sensor measures an enhanced concentration of oxygen relative to the oxygen reference sensor. The signals of each of the oxygen sensors are sent to a summer, which subtracts the equal background oxygen concentration of both, yielding a resultant difference signal representative of the concentration of hydrogen peroxide content of the sample itself. A suitable display or data collection device is used to capture the information in visible or digital form. Methods of use of the device for determining hydrogen peroxide content of human or animal tissues or fluids, or environmental or industrial fluids or fluid-containing materials, are also disclosed.

Sensor probe for determining hydrogen peroxide concentration and method of use thereof

Cement compositions including initiation systems containing at least one peroxide or amine which has a higher molecular weight than the heretofore-employed peroxide BPO and amine DMpT, respectively. In particular, derivatives of peroxides and amines bearing large substituents relative to BPO and DMpT and polymeric peroxides and amines are suitably employed in the reaction mixture. Through the use of these initiator systems in which one or more of the components has reduced mobility relative to the materials employed in the conventional mixtures, it is possible to control the exothermicity and the peak temperature of the polymerization, while nonetheless achieving timely and adequate polymerization of the material. Concurrently, the choice of components for use in the initiation system advantageously results in a reduction in the generation of waste products and in the potential toxicity of the composition. In general, initiators having structures with substituents attached to the benzoyl peroxide or the amine skeleton and equivalent to at least about 4 additional carbon atoms are preferred. Porosity and shrinkage of cement products are addressed through selection of appropriate comonomers for use with or in place of methyl methacrylate. Hydrophilic comonomers and/or monomers with lower vapor tension than methyl methacrylate are preferred for this purpose. These modifications are broadly useful in a wide variety of vinyl-based polymerization systems, including but not limited to those used in biomedical applications.

Polymers from vinylic monomer(s) peroxides and amines

Methods are described for extending the service life of implantable sensors having a silver-containing anodic reference electrode maintained at a high impedance, at least one noble metal cathodic working electrode, and at least one noble metal anodic counter electrode maintained at a low impedance, particularly sensors for the in vivo detection of oxygen and/or glucose in bodily fluids. The methods described involve increasing the input impedance of the reference electrode up to a maximum for implanted circuitry and shielding said electrode, and/or alternating the operating roles of the reference and working electrodes, switching the working electrodes with counter electrodes in the circuit, reversing the polarities of the reference and working electrodes, and sequentially activating each electrode in a plurality of working and/or reference electrodes in the circuit. All of the circuitry means needed to control the steps described can be implanted with the sensor so that the steps can be performed while the sensor is in use in a patient.

Method for increasing the service life of an implantable sensor

An operator independent image cytometer having a method for image segmentation. Image segmentation comprises the steps of filtering a digital image of a cellular specimen and thresholding the resultant image. In addition, the thresholding may include the sorting of features extracted from the filtered image. The present invention also includes a method for cytometer autofocus that combines the benefits of sharpening and contrast metrics. The present invention further includes an arc lamp stabilization and intensity control system. The image cytometer has broad applications in determining DNA content and other cellular measurements on as many as 10.sup.5 individual cells, including specimens of living cells. Image segmentation applications include PAP smear analysis and particle recognition.

Arc lamp stabilization and intensity control for imaging microscopy

Reliable autofocus is required to obtain accurate measurements of fluorescent stained cellular components from a system capable of scanning multiple microscope fields. Autofocus could be performed directly with fluorescence images, but due to photobleaching and destructive fluorescence by-products, it is best to minimize fluorescence exposure for photosensitive specimens and live cells. This exposure problem could be completely avoided by using phase-contrast microscopy, implemented through the same optics as fluorescence microscopy. Functions for both phase-contrast and fluorescence autofocus were evaluated using the present invention and the suitability of phase-contrast autofocus for fluorescence microscopy was determined. The present autofocus system for scanning microscopy can be performed at least as fast as 0.25 s/field without loss of precision.

Autofocus system for scanning microscopy

In an image segmentation system that processes image objects by digital filtration, a digital filter is defined. The digital filter includes a neighborhood operator for processing intensity values of neighborhoods of pixels in a pixel array. A first pixel array is received defining a pixelated image including one or more objects and a background and a second pixel array is received that defines a reference image. The reference image includes at least one object included in the pixelated image in a background. In the reference image, pixels included in the at least one object are distinguished from pixels included in the background by a predetermined amount of contrast. Pixels of the first and second images are compared to determine a merit value; the merit value is used to compute neighborhood operator values; and, the neighborhood operator is applied to images in order to create or enhance contrast between objects and background in the images.

Method and means of least squares designed filters for image

Operator independent image cytometer

Enzyme electrode assembly suitable for sensing physiologically important molecules such as glucose wherein the rate of accessibility of enzyme substrates to the enzyme is differentially regulated by suitably positioning material with selective permeability properties around the sensing region of the electrode assembly.

Two-dimensional diffusion glucose substrate sensing electrode

A transparent electrochemical oxygen sensor for simultaneously determining oxygen concentration at different locations on a biological surface that is capable of being positioned over the region sought to be measured and includes an array of independently functioning oxygen-sensitive electrodes, a counter electrode, and a reference electrode.

Transparent multi-oxygen sensor array and method of using same

An electrochemical system includes a sensor module suitable for implantation in the body to monitor glucose and oxygen levels therein. The module has two oxygen sensors situated in an oxygen-permeable housing, arranged in a tandem relationship, and recessed in the housing, one sensor being unaltered and the other contacting glucose oxidase allowing for differential measurement of oxygen content in bodily fluids or tissues indicative of glucose levels. The module includes a communication capability for transmitting measurement information to an external recording device outside the body.

Growing community of inventors

Cardiff, CA, United States of America

David Arthur Gough