Patent Application
20180221636
The present invention pertains generally to the measurement of physical parameters, and particularly to, an insulin delivery system with closed loop feedback glucose monitoring.
A reported 16 million people in the USA alone, and 120 million people world-wide suffer from diabetes. The world-wide number of diabetes sufferers is anticipated to be 300 million by the year 2025. A new case of diabetes is diagnosed every 40 seconds. Diabetes, and specifically the failure to consistently regulate blood glucose concentrations to be within normally tight physiological bounds is directly related to the death of one U.S. citizen every 3 minutes. Almost every major system, organ, and function in the human body is impacted by a lack of glycemic regulation.
Present diabetic therapy protocols comprise multiple injection regimens and external infusion devices that deliver insulin into the peripheral tissue. External, percutaneous, continuous glucose monitors (CGMs) are sometimes used to sample and determine sugar levels in the peripheral tissues and wirelessly report the data to external controllers. Alternatively, testing kits are used to take blood samples. The testing kits are used to measure glucose levels multiple times per day. A dose of insulin based on the blood test kit can be injected into the body to support regulation of the patient glucose levels. It would be of great benefit if a measurement system and delivery system could be provided that better regulates glucose levels.
Various features of the system are set forth with particularity in the appended claims. The embodiments herein, can be understood by reference to the following description, taken in conjunction with the accompanying drawings, in which:
Embodiments of the invention are broadly directed to measurement of physical parameters, and more particularly, to fast-response circuitry that supports accurate measurement of small sensor changes.
The present invention is applicable to a wide range of medical and nonmedical applications including, but not limited to, control of, or alarms for, physical systems; or monitoring or measuring physical parameters of interest with closed loop feedback. The level of accuracy and repeatability attainable in a highly compact sensing module or device may be applicable to many medical applications that benefits from monitoring or measuring physiological parameters throughout the human body. A closed loop feedback system supports real-time measurement of the parameter of interest and adjustment of the measured parameter by introduction of a change agent that maintains the parameter within a predetermined range. Moreover, the closed loop feedback system can be used in support of or as a supplement to the natural system within a body that normally regulates the parameter. For example, a pancreas is an insulin delivery system in the maintenance of glucose levels. Beta cells of the pancreas delivers microbursts of insulin into the portal venus system which is directly delivered to the liver. The liver is gate keeper of the metabolic system that releases sugar or stores sugar as glucogen. Insulin supports sugar transport. Having too little insulin or too much glucose released can lead to a toxic condition. The present invention eliminates human intervention as part of the feedback loop in determining insulin levels such as measuring glucose levels in blood or responding to glucose measurement via an injection. In either case, the timing of the glucose measurement and the delivery of insulin can vary by control of the patient thereby resulting in non-optimal results.
In one embodiment, a closed loop feed back system comprises glucose measurement and insulin delivery where glucose levels are maintained within a predetermined range. Peripheral insulin delivery, regardless of the means, and regardless of the extent to which peripheral glucose measurements are incorporated, carries with it significant physiological lag. This inefficiency is due to the fact that the insulin must first be absorbed and travel systemically before it arrives at the liver, the hub of metabolic function, rather than the other way around (normal physiology—early autonomic nervous system and sensory perception of an impending glucose challenge, GIT food breakdown, portal transport of glucose and pancreatic secretion of insulin and glucagon to the liver first, then systemic dispersion). As understood from applicable feedback theory analysis, the control loop of the blood glucose measurement and subsequent insulin injection must then require behavioral constraints, constant supervision (external blood testing), and significant outside periodic intervention such as compensation, corrective loop dampening or excitation, calibration, and adjustments for the different constraints that can affect glucose levels. The behavioral constraints, supervision, and intervention comprises the control loop (manual intervention) is the burden of the diabetic patient.
Furthermore, ensuing challenges associated with the patient as the control loop results in excess vascular insulin that is difficult to avoid and leads to fat accumulation, weight gain, and the potential building of insulin resistance, thereby increasing the difficulty in achieving glycemic regulation. Since the sensing of glucose is also peripheral, significant lag in the assessment of relevant sugar levels is experienced (reported to be several minutes or more), thus exacerbating loop control inefficiencies and challenges. Although a patient can be reliable as a control loop there are often times due to normal human activity where the glucose levels can vary substantially. Thus, therapy regulation is sub-optimally reactive, rather than optimally proactive as intended by normal physiology. The patient as a “control loop” moves through periods of being over-damped (too much delivered insulin resulting in trending hypoglycemia), under-damped (too little delivered insulin resulting in trending hyperglycemia), and critically damped (multiple interventions and corrective actions required to achieve an oscillating behavior between the boundaries).
Normal physiology where the pancreas is part of the control loop can be said to be pro-active, driving tight closed-loop control by interjecting many small step inputs into just the right place in the control loop such as the portal venous system. An initial first phase insulin release by the pancreas begins even before food is consumed in response to smell and autonomic nervous system behavior as part of closed loop feedback to anticipate changing glucose levels (this is only partially understood). Subsequent phases of insulin release (as part of a closed loop response) continue in response to GIT and portal venous glucose levels, where there are sugar sensitive receptors (again only recently identified and partially understood) that signal the pancreas accordingly. Portal insulin levels are assessed by the liver which modulates the amount of insulin allowed to disperse systemically, where the insulin is used to trigger (gate or catalyze) glucose transport into cells for metabolic use. Insulin is also used by the liver to convert portal glucose into glycogen, in which it is stored in this form.
Glucagon is released by the pancreas to be used by the liver to breakdown glycogen and release needed glucose for systemic cellular activity as the body demands. These are integrated but separate processes, the timing of which is crucial to optimal control and regulation. Glucagon production and secretion is an on-going process in pancreatic alpha cells that is actually modulated by the level of insulin (normally produced and secreted by neighboring pancreatic beta cells.) Higher levels of insulin suppress glucagon secretion, while lower levels of insulin stimulate an increase in glucagon secretion. This is logical since an increased insulin secretion is normally tied tightly to an increase in portal glucose levels (i.e., at meal-times) when the body does not need or want to break down glycogen. Conversely, low levels of portal insulin are normally tightly tied to low portal (and systemic) glucose levels, and thus needed glucose must be supplied by the breakdown of glycogen, a process for which glucagon is a needed catalyst. In general, the behavior that glucagon secretion is not regulated according to a direct input from a sugar sensitive physiological element, but is rather secondarily moderated by portal insulin concentration. Thus, from a loop control perspective, failure to regulate insulin appropriately has a multiplicative detrimental effect on loop regulation due to its collateral corresponding effect on glucagon secretion. If too much insulin is administered, not only is there a corresponding drop in systemic blood glucose levels (excess blood glucose clearance into tissues, i.e., lipid cell structures), but there is a reduction in glucagon secretion as well, making the resulting hypoglycemia even worse. Conversely, if not enough insulin is administered, glucagon secretion actually increases making the ensuing hyperglycemia even worse (where excess circulating blood glucose causes destructive and toxic reactions). Add to this the fact that a variety of variables such as activity level, patient health and physical condition make normalizing measured glucose values to an appropriate insulin delivery response very difficult without precise and responsive portal insulin concentration management. Determining a peripheral insulin infusion response on the basis of peripheral glucose measurements is therefor grossly sub-optimal, and thus reliable closed loop therapy using these dynamics is never likely, even with significant patient interaction.
As previously mentioned, system 100 uses one or more sensors to measure parameters of the body. System 100 can comprise one or more devices where each device can have one or more sensors. In the example, system 100 comprises a device 101, a device 102, and a device 104. A device 101 is configured to be placed partially in a mouth or completely in the mouth. Device 101 is configured to measure glucose in saliva of the mouth. Device 101 comprises electronic circuitry coupled to a glucose sensor. The electronic circuitry can transmit measurement data to device 104 or provide measurement data to an outside network for further distribution. As shown, device 104 is outside of the body. In one embodiment, device 104 can be a computer, a mobile device, a tool, or equipment that receives the measurement data. In general, device 101 continuously measures glucose levels while in the mouth. In one embodiment, device 101 is placed completely in the mouth near a saliva duct such that the saliva being measuring is continuously refreshed. Device 101 is designed to stay in the mouth greater than 1 hour to provide continuous glucose measurement data. In other words, it is not a device to take a saliva sample and be removed from the mouth but is intended to stay in the mouth for a period of time and report when the glucose levels in the saliva change. In one embodiment, the measured changes in glucose levels over time are transmitted to device 104. Device 101 has a small form factor and is configured to be comfortable when placed in the mouth and does not interfere with normal mouth activities such as talking, eating, or breathing. Device 101 can be taken out of the mouth for a short period of time when needed and placed back in the mouth to continue glucose measurements. In one embodiment, device 101 is designed to be disposable. A power source within device 101 powers the electronic circuitry for continuous glucose measurements for a predetermined period of time. For example, a power source such as a battery can power device 101 for days or perhaps a week or more. Device 101 can then be disposed of and a new device placed in the mouth for continued glucose measurement prior to the battery being discharged.
In one embodiment, device 104 is in closed loop feedback with device 101. For example, device 104 can be an insulin delivery system. The measurement data from device 101 can support an external insulin pump that is carried by a patient to deliver insulin through a catheter coupled to a vein of the patient. The amount of insulin delivered is based on the glucose measurement data from device 101. Measurement of glucose levels in saliva have been shown to correlate well with glucose levels within the body. The continuous real-time measurements of device 101 can support insulin bursts or micro doses of insulin being provided by the external insulin pump to counter changes in the glucose levels similar to how the pancreas delivers insulin in real-time. Thus, glucose levels can be controlled within a tighter range with continuous sensing and feedback versus the methodology currently used requiring testing a blood sample and injecting insulin in response to the glucose level in the blood sample. The blood sample and injection of insulin is under patient control whereas the continuous detection of glucose in saliva is not. Moreover, an injection can be too large or too small depending on the specific patient situation or status (e.g. just eaten, exercising, etc. . . . ) and when the sample is analyzed since it is a non-periodic or non-continuous measurement situation. Device 101 can include other sensors that can determine patient status along with measurement of glucose levels for better accuracy. In general, closed loop feedback using continuous glucose measurement and mimicking natural insulin delivery as disclosed herein above without requiring patient control can better maintain patient health under varying conditions.
In one embodiment, device 101 can include an insulin delivery system. Device 101 will continuously monitor glucose levels and deliver insulin to change or modify the glucose levels within a predetermined range. Device 101 can be partially in the mouth or completely in the mouth. In the example, device 101 is placed completely in the mouth. In one embodiment, device 101 is placed between the cheek and gum. Alternatively, device 101 can be placed under the tongue. In either example, the insulin delivery system is adjacent to the venous system of the mouth and is located near one or more saliva ducts. In one embodiment, the insulin delivery system sends the insulin system under pressure through tissue in the mouth. A percentage of the insulin will be absorbed by the high density of capillaries found in the tissue where it is efficiently delivered through the venous system similar to how the pancreas delivers insulin. Thus, a closed loop system can be placed in the mouth that continuously measures glucose levels and responds to the measurement data with insulin bursts or micro doses similar to how the pancreas delivers insulin. Thus, the process of measuring glucose levels and delivering insulin is automatic with device 101 and does not involve patient control. Device 101 can include a reservoir for storing insulin. A pump coupled to the reservoir pumps the insulin under pressure into tissue of the mouth. As mentioned previously, the power source can be a limiting factor on how long device 101 can be kept in the mouth to control blood sugar levels. Alternatively, removal of the device can be a function on the reservoir size. For example, the insulin supply in device 101 will last greater than an hour but typically is designed for at least three days or a week before having to remove device 101 for disposal or to refill insulin and replace the power source.
Device 101 can be used with or without device 102. Similar to device 101, device 102 can be used to monitor glucose levels and transmit measurement data to device 104. In one embodiment, device 102 is a glucose monitoring and insulin delivery system configured to be swallowed, move through the GIT, and attach at a predetermined location within the GIT. Device 102 measures glucose in proximity to the portal venous system. Access to the portal venous system is achieved through a GIT (gastro-intestinal tract). In one embodiment, device 102 comprises an ingested capsule having the closed loop system for monitoring glucose levels and adjusting glucose levels by delivering insulin. Artificial pancreas system 100 further includes device 104 coupled to device 102 configured to receive measurement data. The device can include a processor for analyzing the quantitative measurement data and to provide feedback to adjust insulin delivery to the patient. In the example, device 102 includes an insulin delivery system that is a closed loop with continuous glucose measurement that delivers insulin in a manner very similar as the pancreas. Alternatively, artificial pancreas system 100 can be more than one device (device 101 and device 102) located in different areas on a patient body or in different areas within the patient body for monitoring different areas of the body and providing quantitative measurement data from the locations. For example, device 101 is placed in the mouth to monitor glucose levels in saliva and device 102 can be delivered within the GIT to monitor glucose levels in the GIT. Delivery of insulin can comprise both device 101 and device 102 to maintain glucose levels within a predetermined range. Devices 101 and 102 can comprise closed loop systems independent from one another. Measurement data can be provided to device 104 to analyze the effect of devices 101 and 102 and make adjustments since each device will have different effectiveness and lags in delivering insulin to the body. Also, device 104 can use measured parameters on the patient body status to implement algorithmic release from devices 101 and 102 dependent on body measured parameters such as glucose levels, heart rate, temperature, etcetera.
In one embodiment, device 102 comprises an ingestible capsule that houses insulin along with appropriate buffering, absorption enhancing agents, and precise delivery control mechanisms. Electronic circuitry coupled to a glucose sensor and other sensors are housed within the ingestible capsule. The glucose sensor in device 101 is configured to measure GIT glucose concentrations whereas the glucose sensor in device 101 is configured to measure glucose concentrations in the saliva or breath. Electronics inclusive of signal processing and wireless communications in both the oral sensor construct (device 101) and in the ingestible capsule (device 102) facilitate communication between the system constituents for closed loop autonomous system behavior as well as communications to outside data collection, monitoring, calibration and adjustment means (such as device 104). The external communications facilitates integration into a much larger database system for the collection of data, patient experiences and interactions in order to grow most effectively our collective body of knowledge and understanding of how human factors and the artificial pancreas system can control glucose levels and deliver insulin in a response thereto.
A reservoir 111 stores insulin within ingestible capsule 105. The reservoir can store insulin to maintain glucose levels within a predetermined range for days or weeks. In one embodiment, electronic circuitry 120 couples to electrodes 106, electrodes 112, and a transducer 113 for providing ultrasonic stimulus. Electrodes 106 and 112 are configured to provide a voltage, a current, or variable time/magnitude voltage or current. In one embodiment, the voltage, current, or ultrasonics are coupled to the one or more layers that retain and store the insulin. Dissolution of the one or more layers controls results in the release of insulin.
In one embodiment, three or more structures or layers are used to control the release of insulin. At least one layer comprises an enteric coating to protect the insulin from disintegration in a gastric environment. As shown, structures or layers 108, 109, and 110 prevent insulin from being released within the GIT. Structures or layers 108, 109, and 110 can be controlled (catalyzed, enhanced or suppressed) by electrodes 106 or 112 and/or transducer 113 from inside the ingested device. The insulin (inclusive of possible buffering, transport and absorption enhancement agents) is trapped, stored and protected in between nested layers. Controlled and successive dissolution of the nested coatings from the outside-in releases micro-volumes of insulin layer by layer. Dynamic, time-variant regulation of the entire process is under algorithmic control that uses saliva, systemic, and GIT glucose sensing, pH sensing, temperature sensing, and other sensors for measuring parameters of within the body. For example, one coating or layer can have pore structures that relax and open more with ultrasonic stimulus. Another layer type can fracture and break apart with increasing osmotic pressure. The fracturing can be facilitated by the layer being catalyzed by electric field modulation of the fluid outside the capsule which results in water being drawn into the layer. In one embodiment, the outermost coating may be intended to allow the capsule to move from the stomach into the GIT before glycemic regulating function begins. Indeed, by varying the thickness of the outer coating, the location in the GIT where function begins can be targeted, adjusted or simply made variable.
One of the structures or layers 108, 109, or 110 can have properties that encourage “adhesion” to the mucous rich tissues inside the GIT, whereby the variable dissolution of an outer enteric coating facilitates targeted or variable temporary adhesion to the inside of the GIT for the purpose of slowing down progression through the digestive system and bringing the capsule into more intimate contact with the epithelial structures, thereby enhancing insulin transport, protection and uptake. A network of electrodes 106 and 112 placed around ingestible capsule 105 supports low level electric field modulation for the purpose of opening the absorption channels and facilitating more effective insulin transport into gastric capillaries that feed directly into the portal venous system. Structure or layer 108, 109, or 110 of ingestible capsule 105 can apply local ultrasound stimulation. In one embodiment, ultrasound stimulation using transducer 113 will increase local cavitation and associated disruption of the lipid structures to promote increased efficiency in delivering large molecule transport such as insulin. The electrodes 112 on in and around ingestible capsule 105 can also be used for the purpose of aiding in the buffered protection of the insulin molecules in the GIT by locally modulating pH. A pH sensor can be included in the ingestible system so as to monitor the effectivity of this behavior and track the capsule's progression through the GIT. Ingestible capsule 105 can further include electric field and ultrasonic stimuli that supports the flow of released insulin to the epithelial structures. The combination of these nested coatings offers the ability to dynamically control micro-delivery of insulin without the need for more challenging and expensive technologies.
IDR˜C0*Gm+C1*(d1Gm/dt)+C2*(d2Gm/dt)+C3*(d3Gm/dt) where IDR is an insulin delivery rate, C0-C3 are coefficients, Gm is measured glucose concentration and d/dt is a derivative with respect to time.
Consider a first compartment 120 that comprises an oral cavity or mouth 125 which breaks down food intake and GIT 121. First compartment 120 has a natural first boundary between the GIT and the portal venous system. First compartment 120 includes processes that releases nutrients which are then taken up and transported to the liver. A second compartment 122 comprises both the liver and the pancreas. Second compartment 122 includes processes that are governed by the changes observed at the first boundary along with changing sensory inputs such as sugar sensors in first compartment 120 and autonomic nervous system inputs. Consider a third compartment 123 to be the systemic circulatory system where circulating blood glucose levels are a function of the changes at the second compartment boundary, driven by liver and pancreatic processes, as well as the changes at the boundary with a fourth compartment 124. Fourth compartment 124 comprises cells that need glucose for metabolic function. Thus, there are four compartments 120, 122, 123, and 124 with three boundaries between them where there are dynamic differential changes in glucose concentration, leading to a descriptive model comprising equation 125 that includes the current blood glucose concentration in summation with the first, second and third order differential changes in blood glucose concentrations to more fully capture the dynamics behind what can be observed in the blood. In this way a more predictive and responsive insulin delivery algorithm can be formulated that has the ability to emulate appropriately normal physiology, especially if and when insulin delivered in this way enters the portal venous system directly as our bodies intend. The weighted coefficients of each of the terms such as C0-C3, measured glucose concentration+first+second+third order derivatives of the measured glucose concentration with respect to time, can be dynamically adjusted to optimize loop regulation. Indeed, not only can the weighting be adjusted as a part of an initial calibration process, but it can be dynamically adjusted through a learning algorithm that interprets hypo or hyper-glycemic trends and, taking the magnitude of the deviations from target into consideration, make small iterative adjustments to minimize the error term. Also of note is the possibility to tailor the algorithm to adjust for other variables such as activity, temperature, sleep and fasting. By understanding where in the model these variables have an impact, the coefficients to the appropriate terms can be adjusted. For example, when preparing for sleep and a several hour fast, the coefficient for the third order differential can be de-weighted since food breakdown in the GIT will not be in play, and the algorithm must therefore prioritize those terms that describe second and third boundary changes, recognizing that inputs into the process take place in the second compartment (pancreas and liver) only, and not the first. The adjustments can be made autonomously by tracking systemic glucose trends, by pre-programmed time of day synchronization, by patient interaction with a small wireless programming device or phone application, or even by a distinct capsule type for ingestion prior to bedtime. As well, in the case of exercise and activity, inputs from accelerometers, gyroscopes, and/or piezoelectric transducers already available in external devices (i.e., mobile phones) along with simple patient initiated programming interventions, can be used to assess activity level and adjust coefficients accordingly through wireless programming adjustments. In this case, it may be optimal to add weight to the first order and proportional terms since glucose clearance may carry more influence due to metabolic demand. It can therefore be seen how through experience one can learn how to best dynamically adjust the algorithm and achieve near normal loop regulation dynamics. Of particular interest is the strong benefit that comes with both sensing glucose concentration in the saliva and fluid in the GIT. Saliva glucose measurements not only offer an understanding of system glucose concentrations and associated glucose clearance after food has been ingested, but as well, saliva concentrations offer the opportunity for very early first phase insulin response, helping to mimic normal physiology inclusive of the predictive behaviors as closely as possible. This approach can strongly emulate normal physiology by summing the predictive elements with the present state. The summation coefficients can be autonomously or interactively adjusted to achieve the best closed loop dynamics on a patient by patient, system by system, and even real time basis. The integration and weighting of independent sensor sources, oral and GIT, along with a weighted assessment of exercise and activity level (via accelerometer and/or gyroscope technology, or piezo-electric activity monitoring) and other environmental, physiological influences (i.e., temperature) offers the potential for sophisticated and robust control.
Glucose measurement system 202 can be used in the mouth to measure glucose in saliva or in the GIT (gastro-intestinal track) to measure glucose in the intestinal track. In one embodiment, an external insulin delivery system would provide insulin based on the glucose measurement data transmitted from glucose measurement system 202. Glucose measurement system 202 measures glucose level continuously or periodically and can transmit the glucose measurement data and other sensor data remotely. In the example, the insulin delivery system 204 is a device placed within a patient body to deliver insulin to a patient venous system. The insulin delivery system 204 can be used in conjunction with an external glucose monitoring system to support insulin delivery. Insulin delivery system 204 can be placed in the mouth to deliver insulin to the venous system in the mouth or to deliver insulin to the portal venous system within the GIT similar to the pancreas. In a third embodiment, artificial pancreas system 200 is a self-contained closed loop system comprising glucose measurement system 202 and insulin delivery system 204. Artificial pancreas system 200 can be configured to be placed in the mouth to monitor glucose in saliva and deliver insulin to the venous system in the mouth. Similarly, artificial pancreas system 200 can be configured to be swallowed by a patient to monitor glucose in the GIT and deliver insulin to the portal venous system in proximity to the GIT. In general, artificial pancreas system 200 is configured to be kept in the mouth for greater than 1 hour and typically several days to perhaps two weeks. Artificial pancreas system 200 is a disposable system that can be removed from the mouth or leaves the GIT after a predetermined time. After disposal, a new artificial pancreas system can then be placed within the mouth or delivered to the GIT to maintain glucose levels within a predetermined range. In a fourth embodiment, a first artificial pancreas system 200 is placed in the mouth and a second artificial pancreas system 200 is placed in the GIT. Glucose is configured to be monitored in both the GIT and within saliva of the mouth. The first and second artificial pancreas systems 200 are used in concert to maintain patient glucose levels. Indicators in saliva and the GIT can be used to determine the state of the body (e.g. resting, exercising, preparing to eat etc. . . . ) and provide varying levels of insulin delivery into the venous system or the portal venous system taking into account the differing lag times and efficiency differences in the insulin delivery to maintain glucose levels within the predetermined range.
In general, artificial pancreas system 200 is configured as a closed loop system that can measure glucose levels in a fluid and deliver insulin in proximity to the glucose measurement. It should be noted that artificial pancreas system 200 can be separated into a separate glucose measurement device and a separate insulin delivery system for use as disclosed herein above. In the example, electronic circuitry 206 is configured to control glucose measurement and insulin delivery in a closed loop and in proximity to one another. Thus, electronic circuitry 206 couples to and controls a glucose sensor and an insulin pump. Separate electronics are required if glucose measurement and insulin delivery are not in proximity to one another. In one embodiment, artificial pancreas system 200 comprises a single device that is placed in the mouth or in the GIT. Electronic circuitry 206 is also configured to transmit glucose measurement data or insulin delivery data to a remote device or a computer. The glucose measurement data or insulin delivery data can be stored by electronic circuitry 206 in local memory or on non-local memory such as a data server. In one embodiment, glucose measurement data or insulin delivery data is encrypted before transmission to prevent access should the transmission be intercepted.
In the example, artificial pancreas system 200 comprises a flexible interconnect printed circuit board 208. Printed circuit board 208 can have more than one layer of interconnect. A first side of printed circuit board 208 includes interconnect for coupling components 210 and digital logic together to form a circuit for controlling a measurement process and to support delivering medicine. Components 210 can be mounted on the first side and a second side of printed circuit board 208. A majority of electronic circuitry 206 is coupled to a first section 212 of printed circuit board 208. In the example, first section 212 is a central portion of printed circuit board 208. A power source 218 is coupled to the first side of first section 212 of printed circuit board 208 to provide power to electronic circuitry 206. In one embodiment, power source 218 can be a battery. Alternatively, power source 218 can be an inductor, capacitor, or other power source configured to power electronic circuitry 206 for a predetermined time period.
A first side of second section 216 of printed circuit board 208 comprises a glucose sensor 220. Glucose sensor 220 is a non-invasive sensor that does not require a skin puncture to continuously monitor glucose levels. In one embodiment, a second glucose sensor can be on a second side of second section 216 of printed circuit board 208. Having at least two glucose sensors can provide redundant glucose measurements, provide a second sensor to extend a period over which glucose can be measured, or to operate each glucose sensor during a period of optimal sensitivity and measurement accuracy. Electronic circuitry 206 can have a switch to enable each glucose sensor individually or together to provide glucose measurement data. In the example, glucose sensor 220 is configured to be bathed in a fluid such as saliva or fluid in the GIT such that glucose levels can be measured continuously or periodically. In the example, glucose sensor 220 is configured to be placed between a cheek and gum of a patient such that glucose sensor 220 is near a saliva duct. Saliva transport is over the surface of glucose sensor 220 that is continuously replenished as saliva is delivered from the saliva duct and older saliva is removed or swallowed from the mouth. Alternatively, glucose sensor 220 can be placed under the tongue whereby saliva is introduced to a surface of glucose sensor 220, removed, and replenished. Glucose sensor 220 can comprise two or more electrodes and include one or more chemicals configured to support glucose measurement. In one embodiment, glucose sensor 220 comprises a working electrode 224 and a counter electrode 222. The one or more chemicals can be coupled to the surface of glucose sensor 220 and can be configured to dissolve over time as glucose is measured. In one embodiment, the chemistry is coupled to working electrode 224. For example, the one or more chemicals can be printed or layered onto a metalized pad of working electrode 224. In one embodiment, counter electrode 222 does not have any chemicals on a metalized pad of counter electrode 222. In general, working electrode 224 and counter electrode 222 have a predetermined spacing between the metalized pads. In one embodiment, a voltage bias is applied across working electrode 224 and counter electrode 222. In the example, working electrode 224 is coupled to ground and a voltage is applied to counter electrode 222. A current is conducted between counter electrode 222 and working electrode 224 that can include ions from the one or more chemicals introduced to the saliva. Furthermore, the one or more chemicals on working electrode 224 can react with glucose in the saliva. The current flowing from counter electrode 222 to working electrode 224 corresponds to the amount of the glucose in the saliva. In one embodiment, the glucose is continuously measured or measured with predetermined time intervals such that changes in glucose levels can be reacted to by artificial pancreas system 200 to maintain glucose levels within a predetermined range or to adjust based on patient status or activity. The glucose measurement data can be analyzed by electronic circuitry 206 to adjust insulin delivery in real-time, can be stored in memory on artificial pancreas system 200, or transmitted to a device exterior to the patient.
A three electrode glucose sensor can also be used. The three electrode glucose sensor comprises a working electrode, a counter electrode, and a reference electrode. The working electrode can have one or more layers of chemistry to facilitate glucose measurement in saliva or glucose measurement in fluids of the GIT. A bias voltage can be applied to the counter electrode to determine current flow such that glucose levels can be accurately measured. The reference electrode is configured to reference the working electrode and the counter electrode. The reference electrode can be modulated for measurement accuracy or changing chemistry. Similarly, the reference electrode can be adapted to support recalibration of glucose measurement electrically. In general, continuous glucose monitoring is less invasive and has less side effects that monitoring glucose with a catheter beneath the skin. The size of glucose sensor 220 corresponds to measurement of lower glucose levels but can easily fit between cheek and gum of the mouth.
A first side of third section 214 of printed circuit board 208 comprises a portion of insulin delivery system 204. Insulin delivery system 204 comprises an outlet port 226, an electrode 228 and an electrode 230. Outlet port 226 is configured to deliver insulin or another medicine. In one embodiment, outlet port 226 is placed adjacent to tissue in the mouth or tissue within the GIT. A pump couples to outlet port 226 to deliver the insulin. Insulin comprises a large molecule that will breakdown over time if not delivered to the liver. Ideally, the insulin is delivered to the portal venous system which couples to the liver and is similar to how the pancreas delivers insulin. Alternatively, the insulin can be delivered to the venous system albeit at a slight loss in efficiency before being delivered to the liver. The insulin would be pumped through the heart before being delivered to the system thereby introducing lag. Artificial pancreas system 200 can deliver insulin to the portal venous system when placed in the GIT. In one embodiment, outlet port 226 is placed adjacent to buccal tissue in the mouth. Buccal tissue has a capillary network that is not too distant from the surface of the tissue in the cheek of the mouth. Outlet port 226 couples to a pump for delivering insulin. In one embodiment, insulin is pumped near or on the buccal tissue where a portion of the delivered insulin is absorbed by the capillary network below the surface of the tissue of the cheek such that the insulin is delivered through the venous system to the liver. Buccal tissue has a large capillary network beneath the surface tissue in the mouth. Artificial pancreas system 200 includes pumping methods and electrical stimulation methods to place the insulin much closer to the capillary network within and beneath the buccal tissue. In one embodiment, channels can be formed in the buccal tissue to more efficiently place the insulin closer to the capillary network thereby by increasing the efficiency of insulin absorption and reducing lag. A first method for forming channels or placing the insulin closer to the capillary network is to pump, push, or pulse the insulin at high frequency. For example, a 125 hertz pump cycle can be configured to deliver a predetermined volume of insulin. In one embodiment, the 125 hertz pump cycle comprises a fill cycle and a delivery cycle. In one embodiment, the insulin can be excited ultrasonically. For example, the pump can be can be operated at ultrasonic frequencies during the delivery of insulin or after the insulin is delivered to pulse or vibrate insulin or saliva into the buccal tissue or into channels formed by the pulsed liquid. For example, the insulin can be pulsed at an ultrasonic frequency such as 1-1.5 megahertz. In one embodiment, pulsed or vibrated insulin can disrupt the buccal tissue to form channels in which the insulin can flow. The channels are disruptions or gaps in the buccal tissue that are closer to the capillary network. Note that the pump output is adjacent or near to the buccal tissue. Thus, the channels or gaps are also formed where the insulin is delivered. The insulin is driven into the channels near the network capillaries below the tissue surface to be absorbed by the venous system and the insulin delivered to the liver before breaking down.
A second method to support transport of the insulin to the network of capillaries in the mouth is to apply a voltage across electrodes 228 and 230. In one embodiment, the voltage can be modulated to produce a repeating voltage change across electrodes 228 and 230. The changing voltage across electrodes 228 and 230 generate a varying electric field that disrupts fat cells in the epithelial boundary to open up channels in the fat system to increase absorption of large molecules. Similar to the ultrasonic excitation of the insulin or saliva, the electrical stimulation is micro targeted to the sight where insulin is being released. Note that the electrodes 228 and 230 are placed on opposing sides of outlet port 226. Similar to the ultrasonic disruption disclosed herein above, the electrical stimulation can separate tissue or support a channel forming process to expose the capillary system in the mouth. In one embodiment, both high frequency excitation of insulin or saliva in conjunction with electrical stimulation is used to form channels and enhance large molecule exposure to the dense capillary system in the mouth or GIT to results in rapid absorption into venous system.
As mentioned previously, a glucose sensor 252 can be formed on a second side of second section 216 of printed circuit board 208. Thus, artificial pancreas system 200 has a first glucose sensor 220 and a second glucose sensor 252 that can be used redundantly, to maintain optimal measurement sensitivity, or to extend a time frame for continuous glucose measurement. Glucose sensor 252 comprises a working electrode 258 and a counter electrode 260. Glucose sensor 252 is bathed in saliva or GIT fluid to measure glucose. Alternatively, glucose sensor 252 can include a “wicking” material such as cotton gauze to capture saliva for measurement. In the example, glucose sensor 252 is placed near a saliva duct in the cheek or under the tongue of the mouth. Similar to glucose sensor 220, the working electrode 258 is configured to be coupled to ground and can include one or more chemical layers thereon to support glucose measurement. Counter electrode 260 is configured to receive a voltage. A measured current from counter electrode 260 to working electrode 258 corresponds to a glucose level in saliva or fluids of the GIT. In one embodiment, working electrode 258 can be coupled to working electrode 224 on the first side of the second section 216 of printed circuit board 208 by a thru hole via 254. In one embodiment, counter electrode 260 can be coupled to counter electrode 222 on the first side of the second section 216 of printed circuit board 208 by a thru hole via 256. Alternatively, counter electrode 260 and working electrode 258 can be controlled independently from counter electrode 222 and working electrode 224. An interconnect 262 is configured to couple counter electrode 222 to electronic circuitry 206 on the second side of printed circuit board 208.
Processor 270 includes one or more inputs from sensors that generate measurement data. An accelerometer 276 couples to processor 270 to measure motion of the artificial pancreas system. In one embodiment, accelerometer 276 is configured as an activity monitor to measure patient status such as exercising or resting. Accelerometer 276 can further be used to detect a vibration such as chewing in the mouth to measure the onset of a glucose load from eating. In one embodiment, accelerometer 276 has digital outputs that can directly be coupled to processor 270.
A pH sensor 290, a temperature sensor 292, or one or more sensors 294 can be coupled to a sensor interface 298. Temperature sensor 292 or pH sensor 290 can be used to monitor patient status. The patient status can relate to glycemic regulation such as if the patient is sick, running a fever, or impacted by environmental factors. Patient status can further include patient activity as disclosed herein above. Sensors 294 can be any other sensor used in the artificial pancreas system. For example, sensors 294 can include an enzyme detector sensor, an insulin concentration sensor, breath analyzer, fructose sensor, sucrose sensor, or cortisol sensor to support glycemic regulation by providing measurement data on patient status. Each sensor coupled to processor 270 can provide different analog waveforms that may require translation when converted to digital. In general, sensor interface, 298, analog signal processing 296, and ADC 278 buffers, translates, and converts an analog signal output by a sensor to digital that is received by processor 270. Sensors are typically limited in their ability to drive a load. For example, the glucose sensor can be coupled to sensor interface 298. The glucose sensor disclosed herein outputs a current signal. Sensor interface 298 provides an interface that couples to the glucose sensor without degrading the current signal output by the glucose sensor for measurement. The input of sensor interface 298 can have high resistance and low capacitance to lightly load an output of a sensor. In one embodiment, the current signal of the glucose sensor can be translated to a voltage signal. Sensor interface 298 can provide a signal buffer that can drive loads at levels typically required by circuitry that a sensor by itself cannot drive. Analog signal processing 296 couples to the output of sensor interface 298 and provides a translated signal. The translated signal output by sensor interface 298 is of a form that can then be received by ADC 278 for conversion to a digital format that is received by processor 270.
In one embodiment, processor 270 couples to digital logic 274. Digital logic 274 is configured to provide an interface to drive circuitry and further control outputs such as status outputs 282, E-stim outputs 284, US-stim outputs 286, and pump outputs 288. Digital logic 274 can comprise a programmable logic array (PLA). Analog circuitry can be coupled to digital logic 274 if required. Status outputs 282 can be one or more outputs for providing status of the artificial pancreas system. Status outputs 282 can couple to visual, audible, or haptic devices for providing different status indicators of the artificial pancreas system. E-stim outputs 284 corresponds to a signal for electrical stimulation. Referring briefly to
Pump outputs 288 drive pump 240 of
Diagram 354 illustrates action at inlet port 310. A delivery cycle occurs during pulse 358 and pulses 360 such that inlet flap 314 is closed, outlet flap 316 is open. No medicine or insulin is provided into chamber 308 via inlet port 310 during the delivery cycle. The fill cycle occurs after the delivery cycle ends. Piezo-electric membrane 304 flexes diaphragm 302 closing outlet flap 316 and opens inlet flap 310 by increasing the volume of chamber 308. Medicine or insulin coupled to inlet port 310 is coupled past inlet flap 314 to fill chamber 308. The pattern of insulin delivery and filling chamber 308 of pump 240 can be repeated as many times as necessary to deliver a predetermined amount. Diagram 356 corresponds to electrical stimulation provide by electrodes 228 and 230 to tissue in proximity to outlet port 226 of
In one embodiment, piezo-electric membrane 304 cannot operate at ultrasonic frequencies. In other words, applying ultrasonic stimulus to piezo-electric membrane 304 may not generate pulses or vibration of the diaphragm 302 of sufficient magnitude to generate channels or disrupt tissue to enhance insulin delivery. A piezo-electric membrane 306 may be used to provide the ultrasonic pulsing of the insulin as it is delivered. Piezo-electric membrane 306 can couple to US-stim outputs 286 of
In one embodiment, the ultrasonic pulsing is used to create cavitation in proximity to the tissue where the medicine or insulin is being pumped for absorption. Pulsing or vibrating to move a liquid at ultrasonic frequencies can create voids related to the force acting on the liquid. The voids have no liquid in them. In the example, pump 240 is pumping medicine or insulin near tissue of the mouth or tissue within the GIT. There will also be saliva or GIT fluid respectively in the mouth or the GIT. In general, the voids are formed by rapid changes of pressure in the liquid where the pressure is low. Implosion of the voids can create shock waves that can be used to disrupt the tissue in the area of the cavitation to form channels or openings. Pump 240 can deposit medicine or insulin into the channels or openings formed by cavitation where large molecules such as insulin can enter. The channels place the insulin close to the capillary system beneath the tissue where it can be absorbed and delivered by the venous system.
In one embodiment, pump 240 pumps fluid adjacent to tissue and near outlet port 226 to support large molecule transport past buccal tissue near capillaries for absorption. In one embodiment, pump 240 delivers medicine at a rate of 125 hertz. In one embodiment, piezo-electric membrane 304 modulates diaphragm 302 with a 1.5 megahertz signal. In one embodiment, the 1.5 megahertz modulation occurs on the back half of the 125 hertz delivery cycle of pump 240. In one embodiment, the ultrasonic movement of the fluid occurs proximity to output port 226 of pump 240. This can produce local cavitation due to the excitation of the fluid, medicine, or insulin near output port 226 or tissue adjacent to output port 226. In general, the ultrasonic excitation occurs where medicine or insulin is being targeted. In one embodiment, output port 226 is about 2 millimeters in diameter. In one embodiment, the delivery of medicine or insulin comprises more than 20 delivery cycles each having ultrasound pulses super imposed on the last half of the delivery cycle. In one embodiment, the repetition rate of 20 or more delivery cycles can be repeated approximately every 30 seconds or as slow as several minutes until the appropriate amount of medicine or insulin has been delivered. This type of delivery of small quantities of insulin delivered over an extended time period is similar to how a pancreas delivers insulin. It should be noted that a signal at pump outputs 288 of
Inlet port 310 of pump 240 is configured to receive the medicine or insulin. Outlet port 226 of pump 240 is configured to pump out the medicine or insulin. A gasket 408 couples to inlet port 310 and outlet port 226 of pump 240. Gasket 408 includes openings for inlet port 310 and outlet port 226. A stim lead 402 extends from electrode 230. Similarly, a stim lead 404 extends from electrode 228. Stim leads 402 and 404 are configured to couple to tissue adjacent to artificial pancreas system 200 when placed in the mouth or GIT. Stim leads 402 and 404 provide a varying electric field to the tissue to support absorption of the medicine or insulin delivered by pump 240. In one embodiment, stim leads 402 and 404 stimulate tissue with electric fields. In one embodiment, electric field stimulation of tissue with ultrasonic excitation of the fluid, medicine, or insulin being delivered can open up channels in mucous tissue. In one embodiment, cavitation due to ultrasound fluid excitation with electrical stimulation opens up tissue or disrupts tissue in proximity to outlet port 226 to electrochemically receive large molecules and place them closer to a venous system for more rapid absorption.
Discharge port 450 is an opening in funnel structure 470 on the surface of structure 436. Funnel structure 470 extends from the surface of structure 436 to couple to gasket 408 thereby sealing funnel structure 470 around outlet port 226 of pump 240. During a delivery cycle of pump 240, medicine or insulin is output from pump 240 into funnel structure 470 where the medicine or insulin is delivered to tissue adjacent to discharge port 450 when placed in the mouth. Stim electrodes 402 and 404 are shown extending through openings in the surface of structure 436 to touch tissue when placed in the mouth. Stim electrodes 402 and 404 apply an electrical field to the tissue to support the ingress of medicine or insulin past the tissue near capillaries of the venous system for absorption and delivery to the liver.
While the present invention has been described with reference to particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present invention. Each of these embodiments and obvious variations thereof is contemplated as falling within the spirit and scope of the invention.
| Number | Date | Country | |
|---|---|---|---|
| 62351243 | Jun 2016 | US |
