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WO2010088914A1 - Dispositif de régulation du débit sanguin sous-cutané - Google Patents

Dispositif de régulation du débit sanguin sous-cutané Download PDF

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Publication number
WO2010088914A1
WO2010088914A1 PCT/DK2010/050032 DK2010050032W WO2010088914A1 WO 2010088914 A1 WO2010088914 A1 WO 2010088914A1 DK 2010050032 W DK2010050032 W DK 2010050032W WO 2010088914 A1 WO2010088914 A1 WO 2010088914A1
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WO
WIPO (PCT)
Prior art keywords
seconds
stimulation
minutes
range
heating
Prior art date
Application number
PCT/DK2010/050032
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English (en)
Inventor
Lars Arendt-Nielsen
Original Assignee
Aalborg Universitet
Gazerani, Parisa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aalborg Universitet, Gazerani, Parisa filed Critical Aalborg Universitet
Publication of WO2010088914A1 publication Critical patent/WO2010088914A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/007—Heating or cooling appliances for medical or therapeutic treatment of the human body characterised by electric heating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00022—Sensing or detecting at the treatment site
    • A61B2017/00057—Light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00022—Sensing or detecting at the treatment site
    • A61B2017/00084—Temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/007—Heating or cooling appliances for medical or therapeutic treatment of the human body characterised by electric heating
    • A61F2007/0075—Heating or cooling appliances for medical or therapeutic treatment of the human body characterised by electric heating using a Peltier element, e.g. near the spot to be heated or cooled
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F2007/0093—Heating or cooling appliances for medical or therapeutic treatment of the human body programmed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F2007/0095—Heating or cooling appliances for medical or therapeutic treatment of the human body with a temperature indicator
    • A61F2007/0096—Heating or cooling appliances for medical or therapeutic treatment of the human body with a temperature indicator with a thermometer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/02—Compresses or poultices for effecting heating or cooling
    • A61F2007/0295—Compresses or poultices for effecting heating or cooling for heating or cooling or use at more than one temperature

Definitions

  • the present invention relates to the field of medical devices. More specifically, the invention relates to a stimulation device arranged for stimulating sensory nerves causing vasomotor activity which thus subsequently increase or decrease subcutaneous blood flow.
  • Diabetes is a serious illness affecting millions of people today. Many diabetic patients require injection of insulin to maintain proper levels of glucose in their blood in order to survive.
  • the pancreas in patients with diabetes type 1 is without the ability to produce insulin, and for this reason they need to inject themselves with insulin.
  • the process on insulin injection is rather complicated, because the glucose level is highly dependent on what, when and how much is eaten and how the activity level is for the patients. Intake of food would make the glucose level rise, where insulin would be produced in the pancreas and counteract the rising glucose level, but only for healthy people. Diabetes patients need to inject themselves with insulin before or after the meal, in order to counteract hyperglycaemia. The problem is that the absorption of insulin injected in respect to insulin produced in the pancreas is much slower.
  • US 2008/0281297 Al discloses an insulin pump providing heat to a skin area during infusion of insulin to increase the insulin absorption.
  • Fig. 25 in US2008/0281297 Al shows a maximum effect after 50 minutes of heating.
  • 50 minutes of constant heating is power consuming even in a limited skin region, and to provide a small battery driven stimulation device, such stimulation is too demanding.
  • WO 2006/086513 A2 discloses system and methods for portably delivering a therapeutic dose of heat to the skin to relieve pain, reduce accommodation of thermal nerve receptors, promote healing, and deliver transcutaneous medications.
  • a stimulation element (1) arranged for receiving a control signal and for generating a physical stimulation accordingly, wherein the physical stimulation is capable of affecting the sensory nerves under the skin surface and thus influences subcutaneous blood flow, and
  • the invention relates to a device arranged for stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow, the device comprising
  • a stimulation element (1) arranged for receiving a control signal and for generating a physical stimulation accordingly, wherein the physical stimulation is capable of affecting the sensory nerves under the skin surface and thus influences subcutaneous blood flow, and
  • a processor (2) arranged to generate the control signal to the stimulation element (1) in order to control parameters including a magnitude and a duration of the physical stimulation
  • the stimulation element is a heating element
  • processor (2) is arranged to generate the control signal to provide a stimulation pattern comprising
  • the above described device has the advantage of being able to stimulate a desired skin area for a defined period of time. E.g. by heating for less than 1 minute, preferably at a rather high but still non-painful temperature, a significant increase in blood flow is obtained which lasts for a period of time which is significantly longer than the time of heating. Even shorter periods of stimulation may be advantageous since it can save battery power in a portable device.
  • a short period of stimulation makes the device more user-friendly.
  • a surprisingly stable and high blood flow can be maintained over a long period, e.g. more than 30 minutes.
  • a high drug absorption can be obtained for a long period, thereby providing an efficient drug absorption with a low power requirement.
  • a faster absorbance of a drug results in a faster systemic clearance of a drug, which in the case of insulin reduces the risk for later hypoglycaemia.
  • sensor nerves causing vasomotor activity A nerve or its related sensory receptor which is activated directly or indirectly by an adequate external stimulus.
  • duration of stimulation is to be understood a period in which the stimulation is within a target range of stimulation magnitude, i.e. an effective stimulation.
  • a target range of stimulation magnitude i.e. an effective stimulation.
  • it will in practice take some time from activating a heating element until a target skin temperature of e.g. 42-43 °C is reached, and thus by “duration of stimulation” is understood the period where the target temperature is applied, and not the duration of activating the heating element.
  • electrical stimulation it is the duration of the single or repeated electrical pulses.
  • the processor is programmed to generate a control signal so as to provide the physical stimulation with a limited duration of 5-240 seconds, such as 5-180 seconds, such as 30-180 seconds, such as 5-120 seconds, such as 10- 90 seconds, such as 10-60 seconds, such as 10-59 seconds, such as 20-59 seconds, such as 20-50 seconds, such as 5-40 seconds, such as 5-30 seconds, such as 5-20 seconds, such as 20 seconds, such as 30 seconds and such as 40 seconds.
  • 5-240 seconds such as 5-180 seconds, such as 30-180 seconds, such as 5-120 seconds, such as 10- 90 seconds, such as 10-60 seconds, such as 10-59 seconds, such as 20-59 seconds, such as 20-50 seconds, such as 5-40 seconds, such as 5-30 seconds, such as 5-20 seconds, such as 20 seconds, such as 30 seconds and such as 40 seconds.
  • the processor is arranged to generate a control signal so as to provide a repeated stimulation with an intermediate interval.
  • the intermediate interval is within the range 1-20 minutes, such as 1-15 minutes, such as 1-10 minutes, such as 1-5 minutes, such as 30-120 seconds, such as 3-15 minutes, such as 3-10 minutes, such as 2-5 minutes, or such as 3-5 minutes.
  • the stimulation element may be switched off the device during these intermediate intervals, so as to save power.
  • the processor is arranged to switch off the stimulation element in the intermediate interval.
  • the inventors have discovered the surprising effect that repeating heat stimulation can stimulate sensory nerves causing vasomotor activity which results in an increased blood flow in the skin.
  • no basal level of heat needs to be applied in the intermediate interval for maintaining the effect for a longer period of time.
  • the lifetime of the battery can be substantially prolonged. This is important for handheld devices (e.g. an insulin pen) which have to sustain power by the use of a battery.
  • WO 2006/086513 A2 discloses that a basal heating level should be sustained for providing pain relief.
  • switching off in the present context also relates to situations where the stimulation element is reduced in power by 50- 100% such as 75-100%, such as 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-95%, such as 95-100%, or such as 100%.
  • the % may be calculated by the reduction of input power or the change of the parameter.
  • the processor is arranged to generate a control signal providing a number of repeated stimulations within the range 2-100 times, such as 3-50 times, such as 4-25 times, or such as 5-10 times.
  • the processor 2 is arranged to generate the control signal based on a feedback signal, in order to adjust at least one of the parameters of the physical stimulation selected from the group consisting of: duration, magnitude and intermediate interval between repeated stimulations, in response to the feedback signal, such as both of the duration and a temperature, such as both of the duration and intermediate interval between repeated stimulations, such as both of the a temperature and the intermediate interval between repeated stimulations.
  • the one or more parameters may vary during a stimulation sequence and may be changed during the stimulation sequence based on a feed-back mechanism from the one or more sensors.
  • magnitude it is to be understood that it refers to the intensity of the stimulation.
  • heating and cooling it refers to temperature
  • electric stimulation an applied voltage and/or current may be used to define stimulation magnitude.
  • the device may include at least one sensor arranged to sense a physical quantity and to generate the feedback signal accordingly.
  • the sensor may be at least one of: a temperature sensor, a blood-flow sensor, a skin impedance sensor, an infrared sensor, a skin colour sensor, a reflectivity sensor, a unit for receiving a blood sample and for measuring one or more blood values accordingly, and sensors which can directly measure blood-values by light.
  • a sensor capable of directly measuring blood-values by light is e.g. provided by RSP systems A/S.
  • the feedback signal is shifted in time in relation to the stimulation, such as the processor (2) being arranged to receive the feedback signal prior to generating the control signal, such as the processor 2 being arranged to receive the feedback signal after generating the control signal.
  • a feedback measured after a first stimulation has been finalized can be used to determine magnitude and/or duration and/or length of intermediate interval of the next stimulation.
  • the processor 2 is arranged to determine an amount of drug, such as an amount of insulin, to be delivered in accordance with the feedback signal, such as a feedback signal indicative of a surface skin temperature.
  • the stimulating element includes at least one of: a heating element, an electric stimulator, a cooling element, and a combination of a heating and cooling element.
  • the stimulation element is a heating element arranged to apply heat to a skin surface in accordance with the control signal.
  • the heating element is one of: a heating foil arranged for heating upon application of an electric signal, a Peltier element, chemicals, and heating electrodes.
  • a stimulation surface of the heating element has an area with the range 1-40 cm 2 , such as 1-30 cm 2 , such as 1-20 cm 2 , such as 1-10 cm 2 , or such as 1-5 cm 2 .
  • the temperature of the heating element is important to accurately control, since a too high temperature will be damaging to the skin and may also be painful, e.g. skin temperatures above some 43-45 0 C.
  • the processor is programmed to provide a control signal to the heating element so as to provide a surface skin temperature in the range of 37-45°C, such as 38-44°C, such as 39- 43°C, such as 41-45 0 C, such as 41-43 0 C, such as 42-44 0 C, such as 40-41 0 C, such as 41-42 0 C, such as 42-43 0 C, such as 43-44 0 C, and such as 40-42 0 C.
  • the processor is programmed to provide a control signal to the heating element so as to provide a surface skin temperature in the range 41- 43 0 C, wherein the limited duration of application of heat to the skin surface is in the range 20-59 seconds.
  • the processor is programmed to repeat said control signal to the heating element with an intermediate interval in the range 1-20 minutes, such as in the range 2-15 minutes, such as in the range 3-10 minutes.
  • the stimulation element 1 includes an electric stimulator, such as an electric stimulator arranged to apply an electric stimulation to a surface of the skin, such as an electric stimulator arranged to apply an intracutaneous electric stimulation.
  • an electric stimulator such as an electric stimulator arranged to apply an electric stimulation to a surface of the skin, such as an electric stimulator arranged to apply an intracutaneous electric stimulation.
  • an electric stimulator circuit When the electric stimulation is to be provided intracutaneously, it may be advantageous to connect an electric stimulator circuit to a syringe which can also be used for injecting a substance (e.g. insulin). Another advantage of this setup is that the current is provided exactly at the same site as the substance is positioned under the skin, and thus only the sensory nerves close to the substance deposit site are affected.
  • Specific examples of electric stimulations are e.g. 20 mA constant current stimulation delivered at 10 Hz for 10 seconds.
  • the duration of electric stimulation could be 5-120 seconds, such as 5-60 seconds, such as 10-45 seconds, such as 20-30 seconds, and such as 30-60 seconds.
  • the stimulation element includes a syringe arranged for drug injection, wherein the syringe has at least an electrically conducting portion connected with an electric stimulator circuit arranged to apply an electric stimulation signal to the conducting portion in accordance with the control signal.
  • a physical stimulation including cooling a skin area may also increase or decrease the blood flow under the skin.
  • the stimulation element includes or is a cooling element.
  • Specific examples of stimulation temperatures are 0-15 0 C, such as 0-10 0 C, such as 5-10 0 C, such as 0-5 0 C, and such as 1-5°C.
  • the period of cooling could be such as 5-120 seconds, such as 5-60 seconds, such as 10-45 seconds, such as 20-30 seconds, and such as 30-60 seconds.
  • intermediate intervals between cooling stimulations may be such as 15-180 seconds, such as such as 30-180 seconds, such as 60-180 seconds, such as 60-120 seconds, or such as 60-90 seconds.
  • Cooling stimulation can be provided a number of times within the range 2-100 times, such as 3-50 times, such as 4-25 times, or such as 5-10 times.
  • a stimulation element which is also able to cool a skin area, which may lead to decreased blood flow, thus a tight control of blood flow and therefore also a tight control of uptake of e.g. a subcutaneously positioned drug may be obtained.
  • Cold pulses of different duration can cause vaso-constriction or vaso- dilation depending on the stimulus configuration and intensity.
  • This tight control may preferably be obtained when the device according to the invention includes at least one sensor (3) arranged to sense a physical quantity and to generate the feedback signal accordingly. In this specific example it may be a blood flow or temperature sensor which would be the most suited.
  • a drug storage container in the device.
  • drugs which can be used with the device of the invention are analgesics (or compounds also shown to provide pain relief e.g. nicotin), insulin, incretin mimetics such as GLP-I (Glucagon-like peptide-1), GLP-I Agonists such as exenatide and liraglutide, incretin.
  • analgesics or compounds also shown to provide pain relief e.g. nicotin
  • insulin incretin mimetics
  • GLP-I Glucagon-like peptide-1
  • GLP-I Agonists such as exenatide and liraglutide, incretin.
  • GLP-I Agonists such as exenatide and liraglutide, incretin.
  • drugs include: anesthetics, anti-arthritis drugs, antiinflammatory drugs, anti-migraine drugs, cardiovascularly active drugs, smoke cessation drugs, hormones.
  • Other potential drugs include, but are not limited to: androgen, estrogen, non-steroidal anti-inflammatory agents, anti-hypertensive agents, analgesic agents, anti-depressants, antibiotics, anti-cancer agents, local anesthetics, antiemetics, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, agents for smoking cessation, and anti-obesity agents.
  • androgen include, but are not limited to: androgen, estrogen, non-steroidal anti-inflammatory agents, anti-hypertensive agents, analgesic agents, anti-depressants, antibiotics, anti-cancer agents, local anesthetics, antiemetics, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, agents for smoking cessation, and anti-obesity agents.
  • Specific drugs can include without limitation nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine, lidocaine, fentanyl, sufentanil, alfentanil and other potent mu-receptor agonists, progestrone, Vitamin A, Vitamin C, Vitamin E, prilocaine, bupivacaine, sumatriptan, scopolamine and dihydroergotamine.
  • the device comprises a drug storage container. It is to be understood that the drug storage container is intended to be connected to an injection unit such as a syringe or a catheter.
  • the device further comprises an injection unit connected to the drug storage container.
  • the invention may be especially suited in connection with patients diagnosed with diabetes, since administration of insulin under the skin is wide-spread.
  • the invention relates to a device, wherein the device is an insulin injection pen including an insulin storage container and with a first end arranged for attachment of a syringe.
  • the heating element in an insulin pen.
  • a person using the device can first heat the skin by using e.g. a pre-installed stimulation pattern and subsequently inject the insulin. It may also be advantageous to heat the area of the skin positioned over the drug deposit site after injection if a faster flow of the drug into the circulation system is desired.
  • the stimulation element may be a heating element, wherein the heating element is arranged in an end of the insulin injection pen, opposite the first end.
  • a drug be transdermally absorbed.
  • One well-known substance which can be absorbed through the skin is nicotine, which is often deposited in a patch, but other drugs can be absorbed through the skin in a similar manner.
  • Phosphagenics Limited claims to have developed a version of insulin which can be absorbed through the skin.
  • the patches deliver a fixed amount of drugs per time unit and the reservoir in the skin is passively absorbed.
  • Actively controlled absorption by single or repeated thermal cutaneous pulses is a novel way of "bolus" administration. Increased on demand absorption and hence increase in plasma concentration of the active drug is required if patients expect to do certain activities (e.g. getting out of bed) which is expected to cause pain (break through pain).
  • This feature of on demand delivery combined by the convenience of patch application would potentially further increase the use of patches and open up new areas of applications (e.g. post-operative pain).
  • the device comprises a patch integrated with the stimulation element.
  • the device comprises a catheter for drug delivery.
  • catheters also includes syringes and micro-needles
  • the device may be equipped with one or more indicators which bring important information to the user.
  • the device comprises an injection unit it would be appropriate to have an indication of the amount of drug which is going to be injected.
  • the device comprises an indicator for indicating to a user a value of at least one parameter being one of: skin temperature, temperature of heating element, time of interval between stimulations, amount of drug to be injected.
  • the device may also have one or more setting possibilities. In this way a desired stimulation pattern can be chosen. Similar an amount of drug to inject can be chosen, if the device is equipped with an injection unit. It is to be understood that the device may also be equipped with pre-installed programs combining one or more of the features in a pattern of physical stimulation pattern, i.e. magnitude, stimulation duration, intermediate intervals between repeated stimulations, number of stimulations in a sequence, etc. Thus, in an embodiment the device further comprises at least one of the setting possibilities selected from the group consisting of: drug amount, skin temperature, temperature of heating element, time of stimulation, time of interval between stimulations and the periods of stimulations in a stimulation pattern.
  • the present invention also relates to a method for modulating vascular absorbtion of a substance.
  • the invention relates to method for modulating vascular absorption of a substance, the method comprising the steps of
  • the invention relates to a method for modulating vascular absorption of a substance, the method comprising the steps of
  • the invention in another aspect relates to a method for modulating vascular absorption of a substance, the method comprising the steps of
  • a person or subject is provided who already has the substance/medicament positioned in or on the skin.
  • the positioning of the substance in or on the subject does not form part of the invention.
  • the limited duration of stimulation may be 5-240 seconds, such as 5- 180 seconds, such as 30-180 seconds, such as 5-120 seconds, such as 5-90 seconds, such as 10-60 seconds, such as 10-59 seconds, such as 20-59 seconds, such as 20-50 seconds, such as 5-40 seconds, such as 5-30 seconds, such as 5- 20 seconds, such as 20 seconds, such as 30 seconds and such as 40 seconds. It may also be reasonable to increase the time of stimulation to e.g. 120-800 seconds, such as 120-600 seconds, such as 120-400 seconds, or such as 120-240 seconds.
  • the stimulation is repeated with an intermediate interval.
  • the intermediate interval may be within the range 1-20 minutes, such as 1- 15 minutes, such as 1-10 minutes, such as 1-5 minutes, such as 30-120 seconds, such as 3-15 minutes, such as 3-10 minutes, such as 2-5 minutes, such as 3-5 minutes.
  • the stimulations may be repeated within the range 2-100 times, such as 3-50 times, such as 4-25 times, such as 5-10 times with intermediate intervals.
  • a stimulation surface may have an area within the range 1-40 cm 2 , such as 1-30 cm 2 , such as 1-20 cm 2 , such as 1-10 cm 2 , or such as 1-5 cm 2 .
  • the stimulation is heating, cooling or electric stimulation.
  • the surface skin temperature may be heated to a temperature in the range of 37-45 0 C, such as 38-44 0 C, such as 39-43 0 C, such as 41-45 0 C, such as 41-43 0 C, such as 42-44 0 C, and such as 40-42 0 C.
  • the surface skin temperature is heated to a temperature in the range 41-43 0 C, and wherein the limited duration of application of heat to the skin surface is in the range 20-59 seconds. More specifically, an intermediate interval in the range 1-20 minutes, such as in the range 2-15 minutes, such as in the range 3-10 minutes without heating may be included before the limited duration of application of heat is repeated.
  • the limited duration of application of heat may be repeated 2-100 times, such as 3-50 times, such as 4-25 times, such as 5-10 times with intermediate intervals.
  • A Heat delivery of 38 0 C, 41 0 C and 43 0 C for 15 seconds.
  • B Heat delivery of 38 0 C, 41 0 C and 43 0 C for 30 seconds.
  • C Heat delivery of 38 0 C, 41 0 C and 43 0 C for 60 seconds.
  • A Heat delivery of 38 0 C, 41 0 C and 43 0 C for 15 seconds.
  • B Heat delivery of 38 0 C, 41 0 C and 43 0 C for 30 seconds.
  • C Heat delivery of 38 0 C, 41 0 C and 43 0 C for 60 seconds.
  • A Heat delivery of 43 0 C for 30 seconds.
  • B Heat delivery of 43 0 C for 60 seconds.
  • Fig. 6 shows blood flow according to cold stimulation of 0 0 C applied 3 times for 3 different durations (10, 20 and 30 seconds) at the volar forearm. Evaluation of blood flow for a sequence of 5 minutes is shown.
  • Fig. 7 shows a diagram showing a device embodiment with an integrated feedback mechanism.
  • Fig. 8 shows a device embodiment in the form of an insulin pen with an integrated heating element.
  • Fig. 9 shows a device embodiment in the form of a drug patch with an integrated heating element.
  • Fig. 10 shows a heat stimulation pattern of 120 seconds of 4O 0 C stimulation with intervals without heating for 5 minutes applied to the right and left abdomen.
  • X- axis time;
  • Y-axis Blood flow?
  • Fig. 11 shows 300 seconds of heating with different temperatures.
  • X-axis shows temperature;
  • Y-axis shows blood flow. Blood flow mean value as well as upper and lower 95% confidence intervals are indicated for each temperature point.
  • Fig. 12 shows the blood flow during a stimulation pattern of 300 seconds of stimulation at 43 0 C followed by an intermediate interval of 300 seconds with no stimulation. This pattern was repeated numerous times. The stimuli rekindled the flow and kept it around a 10 fold increase. Thus, this figure shows the mean blood flow over 30 minutes when the skin is repeatedly reheated to 43 0 C.
  • the study was designed in a way that the subjects were blinded to the selected temperature and duration of heat application.
  • the site of the application was chosen in random.
  • the measurement techniques were objective. An interval of 24 hours was considered between the two visits.
  • the subject relaxed on a comfortable bed at a supine position and exposed the test sites.
  • subject was familiarized with the environment. All experiments were done in a quiet room with a constant temperature (23-24°C). Subjects were asked to keep their eyes closed at the time of scanning because of the laser beam. For the forehead part special goggles were given.
  • Mild heat temperatures 38, 41, 43°C were delivered by a custom made heat inducing device (Aalborg University) for short durations of 15, 30 and 60 seconds.
  • the thermal head dimension was 1.5x 1.5 cm. The device was placed on the skin of the desired region to deliver the short heat pulse.
  • Blood flow changes in the microvasculature of the skin were measured using a laser Doppler system and associated software (Moor Instruments, Devon, UK), which produces an output signal that is proportional to the blood cell perfusion (or flux). Measurements of blood flow were taken for 5 min prior to heat test and 5- 10-15 min post test. An area of 7.5 x 7.5 cm covering the test site was scanned at a distance of 30 cm with a resolution of 118 x 70 pixels and a speed of 4 ms/pix. The mean blood flow was calculated using relative flux (arbitrary units).
  • thermography camera Thermovision, Scanner 900 SW-TE, AGEMA Infrared System, Sweden. The pictures were taken for 5 min prior to heat test and 5-10-15 min post test. The temperature resolution of the device was 0.1 0 C. Thermographic images were stored on computer's hard disk for off-line analysis of the profile and local changes of skin temperature. Any report for pain, irritation or discomfort was recorded in a safety profile sheet.
  • Example 1 Heating the skin at the forehead
  • Fig. 1 shows an increased blood flow when a skin area is heated for a defined period of time at a specific temperature.
  • three different temperatures 38°C, 41°C and 43°C
  • three different times 15, 30 and 60 seconds
  • Fig. IB the time of heating is increased to 30 seconds. A clear increase in blood flow is still present after 10 minutes, when the temperature is 41°C and 43°C.
  • figure 1C the time of heating is increased to 60 seconds. A clear increase in blood flow is still present after 15 minutes, when the temperature is 41°C and 43°C.
  • Figs. 3A-B illustrate that an increased blood flow can be maintained over a longer period of time by only applying short pulses of heat with defined intervals without heat. Furthermore, even after a longer period without heating the increased blood flow can be reinstated by a single pulse of heating. Similarly Figs. 4A-B illustrate that an increased skin temperature can be maintained using repeated pulses of heating. The results show that repeated application of heat maintains the vasomotor response.
  • Example 4
  • Fig. 5 illustrates data from laser scanning showed that the raise in the blood flow was higher in the first 5 min of the measurement (125 ⁇ 15% compared with baseline) and after 10 minutes, the change was back to the baseline (102 ⁇ 10%).
  • the heat application paradigm was 43 0 C for 60 seconds.
  • Fig. 5 illustrates blood flow changed reached to its peak at 5 min after the application of the heat (145 ⁇ 21% compared with baseline). At 10 min it was 110% and it came back to the normal, (100% ⁇ 10 of the baseline) after 15 min.
  • the heat application paradigm was 43 0 C for 60 seconds.
  • Fig. 5 illustrates Recordings from the abdomen showed a significant change in the blood flow 5 min after the application of the heat (148% ⁇ 15 compared with baseline). The changes came back to the baseline after 10 min.
  • the heat application paradigm was 43 0 C for 60 seconds.
  • Fig. 6 illustrates results of experiments, where cooling stimulation in the form of stimulation of 0 0 C was applied for 3 different durations (10 seconds, 20 seconds and 30 seconds) at the volar forearm. Blood flow was scanned before the cold stimulation and 5 subsequent times right after the stimulation so that an evaluation of blood flow for a sequence of 5 minutes can be seen. Control scanning was done without cold stimulation. A clear increase in blood flow was measured for all periods of cooling for at least 3 minutes.
  • cooling of the skin can also be applied for increasing the blood flow beneath the skin and for increasing the uptake of a drug positioned beneath the skin. Cooling may be an alternative to heating when a drug which is going to enter circulation is sensitive to temperatures above e.g. 37 0 C. Some insulin types are known to be heat sensitive.
  • FIG. 7 shows how a device according to the invention may be arranged.
  • a stimulation element 1 which can be a heating element, a cooling element or an electric stimulator receives signals from a processor 2 which provides information like temperature, interval between stimulations and number of repeated stimulations. It may be advantageous to have pre-installed stimulation patterns installed in the processor, but also individual settings may be applied.
  • the processor may also receive signals from one or more sensors 3, which may form part of the device. Based on these inputs, the processor may adjust the signals which are sent to the stimulation element and in this way modify part of a stimulation pattern. Arrows indicate in which directions signals are communicated between the different elements of the device.
  • Fig. 8 shows an insulin injection device 4 comprising a stimulation element 1 one or more sensors 3, a processor 2 and a syringe 5.
  • a stimulation element e.g. a heating element
  • a person can pre-heat the skin area where an injection is going to be performed. Since the device of the invention can operate with very short stimulation periods it is not particular inconvenient to the user of he/she has to preheat for a single period below e.g. 1 minute before injecting the insulin. Subsequent to the injection the user may reapply heat for a short period to injection site, e.g. 5 minutes after injection, to maintain a high blood flow.
  • the user may apply a stimulation pattern to the injection site to maintain a high blood flow. It is important to note that by having a stimulation device with installed stimulation sequences with periods without using power to the stimulation element, battery power is saved, while an increased blood flow is maintained.
  • sensors which may be incorporated in the device of the invention are a temperature sensor, a blood-flow sensor, a skin impedance sensor, an infrared sensors, a skin colour sensor, a reflectivity sensor, a unit for receiving a blood sample and for measuring one or more blood values accordingly, and sensors which can directly measure blood-values by light.
  • a device which can directly measure blood-values by light is e.g. provided by RSP systems A/S.
  • Fig. 9 shows an embodiment of the invention wherein the stimulation element 5 is integrated in a patch 6.
  • the processor 2 may be linked to the patch by wires 7.
  • the processor and battery 8 can be stored e.g. in a pocket while the patch is in direct contact with the skin.
  • the processor is integrated in the patch while the battery is connected to the patch and the processor by wires. Thus, only the battery is physically separated from the patch.
  • the patch, the processor and the battery are integrated in a compact device.
  • the patches according to the invention may also comprise one or more sensors, as previously described. Since such patch devices are likely to be powered by batteries the use of stimulation sequences compared to a constant stimulation will save battery power.
  • the patches of the invention may be drug patches and thus contain one or more drugs which can be transdermally absorbed through the skin. A person skilled in the art knows how drug patches are constructed.
  • the invention can be implemented by means of hardware, software, firmware or any combination of these.
  • the invention or some of the features thereof can also be implemented as software running on one or more data processors and/or digital signal processors.
  • the individual elements of an embodiment of the invention may be physically, functionally and logically implemented in any suitable way such as in a single unit, in a plurality of units or as part of separate functional units.
  • the invention may be implemented in a single unit, or be both physically and functionally distributed between different units and processors.
  • Fig. 10 shows that a stimulation pattern of 120 seconds of 40 0 C repeated every 5 minute can sustain an increased blood flow over a longer period of time. Stimulation was applied to the right and left abdomen.
  • Fig. 11 shows that the increase in blood flow depends on the provided temperature.
  • the blood flow may be tightly controlled.
  • Fig. 12 shows that by using the stimulation patterns according to the invention an increased blood flow can be maintained for a longer period of time.
  • the invention provides a stimulating device for stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow.
  • the device includes a stimulation element (1), e.g. a heating element, for generating a physical stimulation, e.g. heating applies to a skin surface, according to a control signal.
  • the physical stimulation is capable of affecting the sensory nerves under the skin surface and thus influences subcutaneous blood flow.
  • a processor (2) generates the control signal to the stimulation element (1) in order to control parameters including magnitude and duration of the physical stimulation.
  • the processor (2) generates the control signal to provide a limited duration of the physical stimulation within the range 5 to 120 seconds, preferably 15-60 seconds.
  • the rather short term stimulations may be repeated, e.g.
  • the device is an insulin pen (4) with a heating element (1) mounted in one end.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Thermotherapy And Cooling Therapy Devices (AREA)

Abstract

L'invention porte sur un dispositif de stimulation destiné à stimuler les nerfs sensoriels afin de provoquer une activité vasomotrice qui augmente ou diminue ainsi ultérieurement le débit sanguin sous-cutané. Le dispositif comprend un élément de stimulation (1), par exemple un élément chauffant, destiné à générer une stimulation physique, par exemple de la chaleur appliquée à une surface cutanée, en fonction d'un signal de commande. La stimulation physique est capable d'affecter les nerfs sensoriels sous la surface de la peau et ainsi d'influencer le débit sanguin sous-cutané. Un processeur (2) génère le signal de commande de l'élément de stimulation (1) afin de régler des paramètres de commande comprenant l'amplitude et la durée de la stimulation physique. Le processeur (2) génère le signal de commande de manière à donner une durée limitée à la stimulation physique, dans la plage de 5 à 300 secondes, de préférence 15 à 60 secondes. Les stimulations, de durée relativement courte, peuvent être répétées, par exemple à des intervalles intermédiaires de 1 à 10 minutes, tels que 2 à 5 minutes, et on peut ainsi obtenir une augmentation stable à long terme du débit sanguin au moyen de stimulations physiques très courtes sous la forme de chaleur, de froid ou de stimulations électriques. Le chauffage de la surface de la peau à une température de 41 à 43°C est efficace, cependant il n'est pas douloureux. Un tel dispositif peut augmenter de manière significative l'absorption sous-cutanée de médicaments sous-cutanés, par exemple de l'insuline injectée ou des médicaments contre la douleur administrés par voie transdermique. Une telle absorption rapide de médicament est désirable dans de nombreux types de thérapie, par exemple la thérapie contre le diabète, dans laquelle on peut obtenir une meilleure régulation à la fois de l'hypoglycémie et de l'hyperglycémie. Dans un mode de réalisation, le dispositif est un stylo injecteur (4) comprenant un élément de chauffage (1) monté dans une extrémité.
PCT/DK2010/050032 2009-02-05 2010-02-03 Dispositif de régulation du débit sanguin sous-cutané WO2010088914A1 (fr)

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
CN103869708A (zh) * 2012-12-14 2014-06-18 上海机电工程研究所 一种支持多光谱交战级仿真的复杂红外环境建模方法
WO2014108626A1 (fr) * 2013-01-11 2014-07-17 Vantrepote Hervé Dispositif de diffusions thermiques localisées
WO2014183790A1 (fr) * 2013-05-15 2014-11-20 Koc Universitesi Système pour diminuer le flux sanguin de l'artère d'un organe ciblé au moyen d'une stimulation électrique
JP2018153649A (ja) * 2018-04-27 2018-10-04 健二 了▲徳▼寺 血流量を増加させる方法
GB2580947A (en) * 2019-01-30 2020-08-05 Mdmi Ltd A heating device
WO2021247425A1 (fr) * 2020-06-01 2021-12-09 Tivic Health Systems Inc. Dispositif de traitement de cibles de sinus

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WO1993000959A1 (fr) * 1991-07-03 1993-01-21 Baer Bradford W Procede et appareil de traitement de tissus
WO2001052931A1 (fr) * 2000-01-21 2001-07-26 Impulse Dynamics Nv Regulateur d'ecoulement sanguin
WO2006086513A2 (fr) 2005-02-08 2006-08-17 Carewave, Inc. Appareil et procede d'utilisation d'un dispositif thermique portatif pour reduire l'adaptation de recepteurs nerveux
EP1829580A1 (fr) * 2006-03-04 2007-09-05 The Dezac Group Limited Dispositif de thérapie
US20080281297A1 (en) 2007-03-19 2008-11-13 Benny Pesach Method and device for drug delivery

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WO1993000959A1 (fr) * 1991-07-03 1993-01-21 Baer Bradford W Procede et appareil de traitement de tissus
WO2001052931A1 (fr) * 2000-01-21 2001-07-26 Impulse Dynamics Nv Regulateur d'ecoulement sanguin
WO2006086513A2 (fr) 2005-02-08 2006-08-17 Carewave, Inc. Appareil et procede d'utilisation d'un dispositif thermique portatif pour reduire l'adaptation de recepteurs nerveux
EP1829580A1 (fr) * 2006-03-04 2007-09-05 The Dezac Group Limited Dispositif de thérapie
US20080281297A1 (en) 2007-03-19 2008-11-13 Benny Pesach Method and device for drug delivery

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103869708A (zh) * 2012-12-14 2014-06-18 上海机电工程研究所 一种支持多光谱交战级仿真的复杂红外环境建模方法
WO2014108626A1 (fr) * 2013-01-11 2014-07-17 Vantrepote Hervé Dispositif de diffusions thermiques localisées
FR3000891A1 (fr) * 2013-01-11 2014-07-18 Herve Vantrepote Dispositif de diffusions thermiques localisees
WO2014183790A1 (fr) * 2013-05-15 2014-11-20 Koc Universitesi Système pour diminuer le flux sanguin de l'artère d'un organe ciblé au moyen d'une stimulation électrique
US9579507B2 (en) 2013-05-15 2017-02-28 Koc Universitesi System for decreasing the blood flow of a targeted organ's artery with an electrical stimulation
JP2018153649A (ja) * 2018-04-27 2018-10-04 健二 了▲徳▼寺 血流量を増加させる方法
GB2580947A (en) * 2019-01-30 2020-08-05 Mdmi Ltd A heating device
GB2580947B (en) * 2019-01-30 2021-11-10 Mdmi Ltd A heating device
US11883321B2 (en) 2019-01-30 2024-01-30 Plexaa Ltd Heating device
WO2021247425A1 (fr) * 2020-06-01 2021-12-09 Tivic Health Systems Inc. Dispositif de traitement de cibles de sinus

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