GASTROINTESTINAL BLEEDING

TECHNICAL FIELD

[0001] The invention generally relates to the field of wireless biosensor devices. More particularly, the invention relates to a swallowable wireless biosensor device that can provide real-time detection of gastrointestinal hemorrhage within a patient.

BACKGROUND

[0002] Currently, when a patient seeks medical attention for suspicion of gastrointestinal hemorrhage, medical doctors try to answer at least three questions: whether there is active bleeding; whether there is old blood in the Gl tract but no evidence of active hemorrhage; and whether the blood is derived from an upper gastrointestinal source (as this is potentially more life-threatening). The answers to these questions determine whether the patient should be hospitalized as well as the urgency of endoscopic evaluation and treatment. To answer these questions, doctors rely on a combination of the patient's vital signs, blood-work, and clinical status (for example, whether the patient has vomited blood, whether the patient has old blood on a rectal exam, etc.). However, there are significant limitations to all of these methods including: (1 ) they are slow to return information (2) they are expensive and often invasive and , (3) they are not conclusive. Accordingly, improved systems and methods for detecting blood in the gastrointestinal (Gl) tract of a patient are needed.

BRIEF STATEMENT OF THE INVENTION

[0003] In a first aspect, a system for detecting bleeding or blood in the Gl tract of a patient may include a sensor housing containing an optical system including a light source, a light sensor, and a transmitter, each linked to a controller within the sensor housing , or a non-optical sensor system may be used.. A chemical source in or on the sensor housing may be provided, with the chemical changing color or other property upon contact with blood in the Gl tract. The sensor housing is sized and shaped so that it can be swallowed by the patient. A receiver outside of the patient receives signals from the transmitter in the swallowed sensor housing. If blood is present, the system can detect the resulting change in color or other detected condition, and transmit corresponding information to the receiver.

[0004] In a second aspect, a system for detecting bleeding in the Gl tract of a patient may include a sensor housing sized and shaped to be swallowed by a patient, with the sensor housing containing a sensor and a transmitter, each linked to an electronic controller and an electrical power source within the sensor housing. The sensor is this design is capable of chemically or optically detecting an intravenously introduced chemical present in the Gl tract of the patient. A receiver is provided in the system to receive signals from the transmitter indicative of the presence and/or absence of the chemical. The chemical, for example fluoroscein, is introduced intravenously into the patient. If the patient has bleeding in the Gl tract, the chemical will be present in the Gl tract and will be detected by the system.

[0005] In a method for detecting blood in the Gl tract of a patient, a sensor system within a swallowable sensor housing is activated or turned on. A wireless communication link between the sensor system and a receiving system is established and confirmed. The patient then swallows the sensor housing. A Gl chemical marker is provided into the Gl tract. The Gl chemical marker may be provided in or on the sensor housing. The Gl chemical marker changes color upon contact with blood in the Gl tract. [0006] A light source within or on the sensor housing is turned on or flashed periodically. If blood is present in the Gl tract, the Gl chemical marker changes color, with the color change then detected via a color detector on or in the sensor housing. Information about the detected color change is transmitted from the sensor housing to the receiving system. The color change may be analyzed by an electronic processor within the sensor housing, or in the receiving system, to determine whether the color indicates presence of blood. In all alternative method, the sensor in the sensing housing is adapted to sense an IV chemical intravenously introduced into the patient. In this case the sensor may be an optical sensor or a chemical sensor. These methods may be combined together, with the IV chemical introduced into the patient only if the system detects blood first via the Gl chemical marker color change. The invention resides as well in sub-combinations of the systems and method steps described.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Fig. 1 is an illustration of one implementation of a medical sensor system including a plurality of Wireless Biosensor Devices (WBDs) implanted within a patient.

[0008] Fig. 2 is a schematic illustration showing various components of a WBD, including a power source and fastening clip.

[0009] Fig. 3 illustrates one specific implementation of a WBD having a photodiode, battery, and pH sensor.

[0010] Fig. 4 is an illustration of an example of a ZigBee-based network tree for implementing one embodiment of the system and device.

[0011] Fig. 5 is a schematic diagram of a WBD.

[0012] Fig. 6 is a flow chart of a method of the invention. DETAILED DESCRIPTION

[0013] The system includes a Wireless Biosensor Device (WBD). The WBD can be placed inside a patient's body or attached to another location in, on or near the patient as needed. The WBD can be designed in a size and shape so that it can be swallowed by a patient. The WBD may also be designed to attach inside a patient. For example, the WBD can be endoscopically attached to a patient's Gl tissue with, for example, a biodegradable suture or a clip or fastener, or may be included with its own attachment mechanism.. The WBD can include a radio communication subsystem for communicating with one or more devices located external to the patient. The radio communications subsystem may be compliant to IEEE 802.1 5.4, thus providing integration with external networks and other biosensor devices. For example, many hospital systems are now computerized and wirelessly networked; allowing data from the WBD can be directly integrated with such a system.

[0014] Fig. 1 is an illustration of one implementation of a medical sensor system including a plurality of WBDs inside a patient. For certain uses, such as detecting blood, only a single WBD may be needed. WBDs 10 can be swallowed by a patient and can be configured to detect one or more biological conditions of patient 12. WBDs 10 can then communicate biological data describing the condition to a monitor 14 through a wireless communication network. Monitor 14 can be mounted near the skin of patient 12 to improve communication between WBDs 10 and monitor 14. Alternatively, monitor 14 can be worn as a pendant. Monitor 14 is also configured to communicate with external systems 16 such as cell phone or other computers, servers, or medical personnel to relay data describing a condition of patient 12 or to provide information and/or warnings directly to patient 1 2 through a communication mechanism such as a visual interface, speaker, or vibration device.

[0015] The system can include a variety of sensors including, for example, sensors for the measurement of pH, pressure, and/or specific chemicals, proteins or peptides. Such chemicals, proteins or peptides may be endogenous to the patient or be administered to the patient, or be produced by another entity, for example, by a commencile micro-organism in the patient. An optional optical system for providing both illumination and spectrally filtered detection of scattered light can be included within WBD 10 for direct color detection using RGB filters or using a filtered photosensor to detect fluorescence from a medical biomarker used to label blood. The blood can be fresh, i.e. resultant from a recent bleed or a currently active bleed or it can be old, i.e. resultant from a less recent bleed or a currently inactive bleed. Optionally, a non-optical sensing of a change in another property may be performed.

[0016] The optical sensors can be implemented by a photonic integrated circuit (PIC). For direct optical detection, light reflected from a pulsed white Light Emitting Diode (LED) mounted to WBD 10 can be monitored by a group of color- filtered photodiodes. The RGB color value of the reflected light and the color of the observed area can thus be determined. The WBD 10 can then transmit the detected color and/or fluorescence information to a monitor 14. The monitor 14 can perform analysis on the color data, or forward the information to another party or device for analysis.

[0017] Alternatively, the systems and devices can be configured to perform optical detection of fluorescent dyes which can serve as proxies for fresh blood. The dyes, when excited by light of an appropriate wavelength, relax and emit photons at a lower energy. The optical system can include a colored LED providing the initial biomarker excitation and adjacent photodiodes filtered to detect any fluorescence. Multilayer optical filters can be engineered to separate the spectrum of the fluorescence from the LED excitation. In some cases, multiple photodetectors sensitive to different wavelengths detect the peak of the emission spectrum through second derivative analysis. Using these techniques, appropriately tagged substances, such as blood or food, can be detected and differentiated from untagged substances.

[0018] In another embodiment, the systems and devices detect fresh blood using an optical system to detect an electrochemical reaction via a color change. One way of achieving this is to intravenously administer a metal ion (for example, stannous chloride, which is currently administered for technetium-labeling of red- blood cells in bleeding scans). This metal ion can serve as a proxy for fresh blood. It also can serve as a reducing agent for a substance that can be present in the WBD. This substance can be a metal, such as, for example, gold or molybdenum. The reaction of stannous chloride and gold yields a bright purple color which can be detected and molybdenum phosphate is reduced by tin to form a deep blue color (lambda max 720 nm). Therefore, optical detection of this color change in the setting of stannous chloride will reflect active hemorrhage.

[0019] In another embodiment, the systems and devices can detect blood (either old or new) via an optical system that detects a chemical reaction via a color change. One way of achieving this is by providing guaiac resin with the device. This resin turns a bright blue color upon contacting blood. Therefore, optical detection of this color change can reflect hemorrhage, old or new.

[0020] In another embodiment, the systems and devices can detect, in real time, molecules that are indicative of the presence of H. pylori. For instance, the system and device can detect excess urea in the patient's stomach. Similarly, as chemical or biomedical markers for other diseases such as cancer are discovered and or publicized, the system can be adapted to detect these markers as well.

[0021] Measurement of pH and pressure by the systems and devices can facilitate determination of the device's location within the gastrointestinal tract. For instance, the transition of the device from the stomach to the small intestine will reflect a change from an acidic environment to a more neutral or slightly alkaline environment (provided the patient is not taking any medications for gastric acid suppression). As a further example, the transition of the device from the stomach to the small intestine will reflect a change in the pattern as well as the intensity of peristaltic waves. Understanding the location of the device within the gastrointestinal tract can help determine the source of hemorrhage.

[0022] The device may also be located in vivo by ultrasound, which is present in most emergency rooms. Radiofrequency tagging (RFID) within the WBD may also optionally be used. An external hand-held device may alternatively locate the internal position of the swallowed WBD by emitting a sound or flashing an LED light when it passes over the WBD. A magnet may also be used for locating the device. For example, an external hand-held device with a built-in Reed switch could demonstrate the internal position of the WBD. In the presence of a magnet, the Reed switch closes, thereby completing the circuit and flashing a LED light or emitting a sound.

[0023] In another embodiment, the systems and devices can operate externally of the patient's body. For instance, when used in the detection of H. pylori, the device can be used to detect substances in feces that are expelled from the patient. The device can also be used to detect substances in sputum expelled from the patient for diagnosing respiratory tract infections or to detect substances in urine expelled from the patient for diagnosing urinary tract infections.

[0024] The systems and devices can also include an ultra-low power microprocessor chip, including, for example, sensor inputs and flash memory for controlling the WBD 10. The microprocessor can be programmed to allow the WBD 10 to be configured for a range of applications.

[0025] Referring back to Fig. 1 , the microprocessor of WBD 10 can be in communication with the monitor 14 located external to the patient. In one embodiment, a WBD 10 uses a wireless communication protocol to transmit data to a monitor 14. Having received the data, the monitor 14 can transmit the data to computers or servers that are in communication with the monitor 14, or display or otherwise communicate the information to a user of the system (e.g., a patient, doctor or any medical service provider that wishes to review the biological data, amongst others).

[0026] The monitor 14 allows a user of the system to extract data from one or more WBDs 10, wirelessly control and program WBDs 1 0, form a network of internal sensors, and connect to existing communication networks (e.g., mobile phone networks, the Internet, etc.) for remote monitoring of patients or for emergency contact with the medical facility.

[0027] Each monitor 14 may act as a node in a Body Sensor Network (BSN). The monitors can include an antenna attached to a surface of the patient to provide an improved Radio Frequency (RF) connection with the internal WBDs. When communicating, WBDs 10 and monitor 14 can use standard communication protocols to establish wireless network connections between monitors 14 at different locations on the body. In addition, one monitor can act as a router or network controller to relay data generated by each WBD to a medical facility via the Internet, cellular phone network, or other communication network, using a Bluetooth wireless networking protocol, for example.

[0028] A BSN with strategically placed WBDs 10 can be used, for example, in the diagnosis, monitoring, and treatment of a diverse range of gastroenterological problems. For example, a WBD 10 with the appropriate optical filter can be configured to recognize a fluorescent substance to identify tagged substances, such as fresh blood or food. After detecting one or more of these potential medical indicators, the WBDs 10 can transmit the collected data to the monitors 14. The monitors 14, after receiving the data, can alert the patient to the condition, or forward the data to a medical center, doctor or other entity for analysis. In this manner, various medical conditions, such as, for example, ulcer bleeding can thus be immediately addressed.

[0029] The molecule used to generate a signal can be fluorescein. Quinine may also be used because it is readily detected using fluorescence and has a half life (1 9 hours), making it suitable for detection. Quinine is also excreted renally, reducing the possibility of false positive detection in the digestive system. Quinine can be administered in a number of manners, for example, orally or intravenously.

[0030] Feridex may also optionally be used to generate a signal. Feridex, is often used for MRI contrast imaging. Feredex consists of iron and carbohydrates. It can be administered intravenously, and is taken up by reticuloendothelial system (RES) cells (including cells of the liver, lymph nodes, and spleen, amongst others). In the liver, the iron dissociates from the carbohydrates and enters the normal iron metabolic pathways. The half-life of molecule is 2.4 hours. The carbohydrate component is renally excreted. The elemental iron is retained in the body for 14-28 days.

[0031] Other options include use of feraheme, which has characteristics similar to feridex but contains 10-15 times the amount of elemental iron, and gadolinium (gadopentate dimeglumine), a para-magnetic agent frequently used for MRI contrast imaging. This molecule, which can be administered intravenously, is renally excreted. Its excretion kinetics are as follows: 80% of the molecule is excreted by 6 hours; 91 % is excreted by 24 hours. Methylene blue or an isosulfan dye may similarly be used.

[0032] Metal ions may also be used to generate a signal. These ions, including Tc, Sn, Cu and Sn, amongst others, may be adequately detected electrochemically or potentiometrically in a biosensor system or device. Tc, in the form of DTPA, which is renally cleared, can be used.

[0033] Fig. 2 is a schematic illustration showing various components of a WBD 10, including a power source 30. The WBD 10 includes a casing 32 to contain and protect several of the components of the WBD 10. The casing 32 can include any material that can withstand the Gl tract environment such as medical grade metals, plastics, or composites. The casing can also be smooth in texture and shaped to facilitate swallowing and minimize the risk of damage to the Gl tract during transit.

[0034] The casing may be coated with a polymer, for example, Hypromellose ( hydroxypropylmethylcellulose) (HPMC), a semi synthetic, inert, viscoelastic polymer used as an ophthalmic lubricant or tablet coating material. Such polymers cause the casing to be 'slippery' when wetted by saliva or water, thereby facilitating swallowing and/or transit. [0035] The casing 32 contains a power source 30 for powering the electronics of the WBD 10. The power source 30 can be connected to electronic systems 36, 44, and sensors 38a-c, 40 and 42, to provide electrical energy and can include a battery, capacitor, or other energy storing or generation device. In some embodiments, the electronic and sensor system 36 contains the primary electronic and sensor systems for the WBD 10, while the electronic and sensor systems 44 contain secondary systems. Electronic systems 36 and 44 can include microprocessors, flash memory or other data storage mechanisms, and radio modulation systems for implementing the functionality of WBD 10.

[0036] Fig. 3 illustrates an embodiment of WBD 10 having a photodiode, a battery and a pH sensor. Fig. 3 shows some of the internal components of the WBD 10, including a power source or battery 64, an electronics chip 66 connected to a sensor 68 and filtered diodes 70a-c, antenna connectors 74 and an LED 72. An external casing allows for the device to be swallowed.

[0037] Each WBD 10 can be wirelessly connected to one or more monitors 14 located on the surface of the body of the patient using wireless communication protocols. To connect the BSN to a medical facility, or other external systems, one or more of the monitors 14 can act as a gateway between the BSN and a mobile phone network or the Internet, i.e. through a Bluetooth connection. Each monitor 14 can be further configured to display information or warnings to the patient, such as by flashing an LED or displaying information on an LCD screen. The warnings can also be relayed to a medical facility, along with real-time data by monitors 14 via a suitable communications network.

[0038] Each WBD 10 communicates with each monitor 14 using a wireless communications protocol. For example, a first system implementation of the WBD 10 includes an ultra-low power radio frequency (RF) chip connected to the clips of the WBD 10 to generate a radiated signal. Control of the system can be implemented by a low power microprocessor (for example, less than 30 microwatts (μνν)). The radio system, microprocessor, and a flash memory subsystem can all be contained, for example, on a single ultra-low power chip, such as the ChipCon CC2430 or the Ember EM250. Power consumption can be reduced to very low levels by keeping WBD 10 in sleep mode until it is awakened by an external query from the monitor 14, or another system component. The WBD 10 can then transmit short data packets containing the biological data.

[0039] The WBD 10 can be configured to use Radio Frequency ID (RFID) technology to broadcast biological data to the monitor 14. In that case, the monitor 14 illuminates the WBD 10 with an RF signal. In response, the WBD 10 transmits a reflected RF signal to the monitor 14. The reflected RF signal can be modulated by alternately connecting the two halves of the dipole antenna formed by the clips of the WBD 10 using a Field Effect Transistor (FET). Any such modulation of the reflected RF signal can encode data, and, when using an appropriate multiplexing protocol, be read out by the monitor 14. In this embodiment, each WBD 10 consumes only relatively low amounts of power as the RF carrier is generated outside the patient by the monitor 14, thus enhancing the battery lifetime of WBD 10. Depending on the antenna geometry and configuration of the WBD's 10 power source, one can recharge WBD 10 using a similar technique.

[0040] The WBD 10 may include one or more RFID chips for broadcasting information to the monitor 14. Each RFID chip in the WBD 10 has the single task of returning its hard-coded ID number upon receiving a radio query. To communicate particular information to the monitor 14, for a WBD 10 including two different RFID chips, each having different ID numbers, or a single RFID chip having two ID numbers, the WBD 10 can respond to the radio query by broadcasting one of the two ID numbers. In that case, the broadcast of one ID number can signify "OK" while the broadcast of the other ID number can signify "Emergency" (for example, after the WBD 10 has detected bleeding).

[0041] The dielectric constant of the stomach can be approximately 68 £S to 62 £S for RF frequencies in the range of 400 MHz to 2.4 GHz with free space wavelengths of 75 cm to 12.5 cm. The free space wavelengths correspond to wavelengths in the stomach of 9.1 cm to 1 .6 cm. As such, in one embodiment of the system and device, the signal carrier frequency is set to approximately 2.4 GHz. At 2.4 GHz, because RF energy is absorbed as it passes through the human body, the power of an isotropically radiated 2.4 GHz signal, detected immediately outside the body (-10 cm away), is attenuated 40 to 60 dB by absorption and by the solid angle covered by the receiving antenna. Further losses can be incurred through imperfect conversion of the electrical to radiated signal at the antenna (insertion loss) and vice versa. Even in view of these losses, however, a strong wireless connection between WBD 10 and monitor 14 can be established. For example, the ChipCon CC2430 chip has RF output power 0.6 dBm (1 .15 mW) and a receiver sensitivity of -92 dBm. Assuming 60 dB attenuation of the signal during propagation, a reliable wireless link can be established, with a margin of approximately 30 dB.

[0042] The monitors 14 can be placed at convenient locations outside the body on a surface of the patient 12. To improve the RF link between the monitor 14 and the WBD 10, the monitors 14 can be attached to the skin of the patient using an adhesive such as an adhesive medical patch, or other mechanical coupling mechanisms. Because the monitors 14 are generally mounted outside the body, the power consumption of the monitor 14 is not a primary concern, unlike the power consumption of the WBD 10. As such, the monitors 14 can be assigned relatively high-power consumption responsibilities such as supplying a wireless carrier signal for communication, performing a majority of the data analysis, or implementing remote networking.

[0043] Using communication protocols, such as the IEEE 802.15.4 standard, the monitors 14 can form a wireless network that establishes a data connection between a number of WBDs 10 and monitors 14 at different locations around the body. A monitor 14 can also act as a router, to connect the BSN to external system components via a cell phone network, the Internet, or other communications network to relay alarms and data to a remotely located medical facility. If many WBDs 10 are scattered throughout the Gl tract, multiple WBDs 10 can provide a wireless link between any pair of sensors, regardless of the physical distance. Additionally, the collection of monitors 14 located about the body can enable the system to triangulate the position of each WBD 10 by measuring the power of the RF signal of WBD 10 within their wireless reach, which decays via signal attenuation and spreading loss.

[0044] Each WBD 10 and monitor 14 may be configured to implement the IEEE 802.15.4 (ZigBee) wireless communication standard for communicating data between each of the WBDs 10 and monitors 14. The standard is oriented towards the implementation of a low cost, ultra-low-powered, long-life wireless sensor network for home automation, remote sensing, energy management, hospital care, and telecommunication. In some cases, ZigBee technology has been developed and miniaturized to offer a more powerful alternative to RFIDs.

[0045] An example ZigBee-based network tree for implementing the present system is illustrated in Fig. 4 . Each monitor 14 operates as a router between a WBD 10 star network and other monitors 14, forming a mesh network at the ZigBee Router level. One monitor 14 is designated the ZigBee Coordinator. The Coordinator can communicate with a local computer or mobile phone via a communications network, enabling remote patient monitoring. In some cases, a monitor 14 simultaneously functions as both a Router and Coordinator. As such, the simplest network of a single monitor 14 and single WBD 10 can still enable communication with external networks (e.g., Internet networks or mobile phone networks).

[0046] ZigBee networks are comprised of nodes which can have three different roles: ZigBee Coordinator (ZC), ZigBee Router (ZR), and ZigBee End- Device (ZED). Because each ZigBee node can fulfill any of these three roles, the same communication device can be used at each location in the network. The ZED only communicates with its parent ZR, which in turn forms the basis of the ZigBee mesh network, allowing routing of data between any two points in the system. One of the ZR routers will be chosen to function as a ZC, being responsible for the synchronization of all nodes, monitoring network topology, dynamically reconfiguring data paths to reflect the current state of the network, and communicating with external networks, such as a cellular phone network, or a computer connected to the Internet to transmit data.

[0047] As shown in Fig. 4 , each WBD 10 is a ZED, each monitor 14 is a ZR, and one monitor 14' is made a ZC. The ZC monitor 14' can then communicate data received from each WBD 10 to external system components such as a computer 100 or a mobile phone 102. Using the computer 100, for example, a monitor 14' can transmit data to a medical facility 104 using the Internet 106. Alternatively, the monitor 14' can use a mobile phone 102 and the network to which the mobile phone 102 is connected to transmit data to the medical facility 106.

[0048] In one embodiment, it is possible to swallow the WBD 10 in order to monitor one or more conditions throughout the Gl tract. The system and device can be configured to sense bleeding, pH, pressure, and bodily fluids (including blood) tagged by fluorescent materials, metal ions, and other exogenous substances or the color changes that take place in the setting of said fluorophore, metal ions, and other exogenous substances. The sensors and electronics can be small enough to be fit inside a WBD suitable for swallowing. An onboard battery or other power source, combined with an programmable ultra-low power microprocessor, flash memory, and RF communication can permit WBD 10 to sense, store, and wirelessly transmit data out of the body to external monitors. The monitors enable the sensors to share data and can also analyze the data to alert the patient of a dangerous condition, and alert a medical facility through a cellular phone network or the Internet.

[0049] Fig. 5 shows an alternative WBD including a battery 64, voltage regulators 65, an LED 72, a microcontroller 67 with memory 69, A/D converter 71 , digital I/O and Zigbee radio circuitry, optionally within a module 75 or on an ASIC. As shown, a crystal oscillator 75, passive decouplers 76 and RF and antenna 77, and an optical sensor 78 are also included. Data on the color detected by the sensor(s) may be processed and analyzed by the microcontroller 67 and stored in the memory 69 shown in Fig. 5. Alternatively, the data may be transmitted to the receiver and processes at the receiver or a computer linked to the receiver.

[0050] Fig. 6 shows a flow chart of a method of the invention. In this method, a chemical marker is released into the Gl tract, optionally from the WBD itself. A flashing filtered LED illuminates the area around the WBD. If no blood is present, no color change is detected and the method ends. If blood is present, the chemical marker changes color. The photodiode then detects the color change, indicative of the presence of blood. The WBD communicates this data to the receiver. The user of the system is instructed to inject an IV chemical into the patient, The IV chemical may be fluoroscein. If the patient is actively bleeding into the Gl tract, the IV chemical will promptly be present in the Gl tract, where it is detected by the WBD and reported to the receiver. The patient is then treated accordingly. If the WBD does not detect the IV chemical, this result which is indicative off old blood in the Gl tract, rather than active bleeding (new blood), is similarly transmitted to the receiver. The Gl chemical marker, such as guaiac, is referred to as a marker since it produces a color change which is detected, rather than detecting the substance itself. The IV chemical, such as fluroscein, on the other hand, is generally detected directly and is referred to as an IV chemical, rather than a marker (although in some cases the IV chemical may also be selected to produce a detectable color change as well).

[0051] Further, the systems and devices can detect the presence of disease- associated bacteria in the patient. For example, H. pylori is associated with gastric/duodenal ulcers. These systems and devices can provide real time H. pylori detection. Although the systems and methods are described primarily with reference to human patients, they may be used for treatment of animals.

[0052] Priority Claim for the United States Only

[0053] This Application is a Continuation-in-Part of International Application No. PCT/US2010/058061 filed November 24, 2010 and now pending, which claims priority to U.S. Provisional Patent Application No. 61 /264,548 filed November 25, 2009. This Application also claims priority to U.S. Provisional Patent Application No. 61/379,123 filed September 1, 2010. These applications are incorporated herein by reference.