Product

Bringing Smile to Diabetic Patients with
Non-invasive Glucose Monitoring

True 3rd generation CGMS

The first-generation blood glucose meter (BGM) measures blood glucose level (BGL) through an electrochemical reaction of an enzyme with blood collected using finger pricking with a needle, 4 or 5 times a day. This technique has the limitation for continuous blood glucose measurement required for continuous insulin management in type-1 diabetic patients caused by abnormal insulin secretion.

The second-generation blood glucose meter does not draw blood every time, but inserts needle of an enzyme-based sensor into the interstitial fluid about 5 mm below the skin, and continuously measures blood glucose level at every 5-minute for a week. Weekly replacement causes a large cost burden (about $100) on patients, also causes skin troubles due to adhesion tapes required to hold the sensor. A time delay is also inherent in the measurement of BGL from the interstitial fluid. This may cause a risk of hypoglycemia shock.

SB Solution’s third-generation real-time CGMS, unlike enzyme or fluorescence-based sensors, does not degrade over time. So, it is possible to use electromagnetic (EM) sensor under the skin for a long-term and the cost burden is dramatically reduced. There is no contact dermatitis problem, and it is a product that solves the risk of hypoglycemia through real-time BGL measurement.

Uniqueness of SB Solution’s CGMS

  • EM-based multimode sensor fusion
  • New concept of continuous blood glucose measurement system
  • Multi-sensor analysis algorithm

Senseonics, USA introduced subcutaneous CGMS to the market after receiving European CE approval in 2016 and US FDA approval in 2018. Senseonics succeeded in commercializing subcutaneous implantable CGMS by extending the sensor lifespan to 3 months based on fluorescent material, but the cost burden is high. The sensor costs over $1,000 and has to be replaced every 3 months which is inconvenient due to frequent replacements. The risk factors such as hypoglycemic shock have not been resolved due to the time delay caused by glucose measurement in the interstitial fluid. So, it is generally evaluated as 2.5 generation CGMS.

The 3rd generation CGMS developed by SB Solutions is EM-based sensor that can be used for several years without the need of a battery under the skin in a manner similar to Senseonics. The power required for sensor operation is delivered from an external device using WPT technology.

BGL information is measured from the interstitial fluid and transmitted to the external device in every 5 minutes. The accumulated blood glucose data can be viewed by linking with the patient’s smartphone via Bluetooth. It has a built-in function to pre-alert the patient using on-body vibration before a possible event of hypoglycemic shock. In short, our CGMS consists of an embedded sensor, an external device, and an app on a smartphone.

The existing 2/2.5 generation CGMS has a problem of delay due to measurement from only interstitial fluid. Our CGMS can save the golden time to prevent hypoglycemic shock by measuring large BGL changes in blood vessels in real-time with external EM sensors. It is a true 3rd generation CGMS that can solve the risk factors caused by time delay.

다중모드일러스트

Core technology overview
Unlike enzyme or fluorescent based blood glucose sensors, EM-based sensor does not degrade over time. It is an implant and external sensors that operate in invasive mode (Mode-1) and single mode (Mode-2) to continuously measure blood glucose. In addition, to overcome the time delay problem of 2 ~ 2.5 generation CGMS, we developed an external EM sensor that operates in the array mode (Mode-3) that can directly monitor large blood glucose changes in blood vessels in real time.

MODE-1
(Invasion mode)
침습모드 This mode has the key role of precise blood glucose measurement. It measures change in blood glucose diffused in the interstitial fluid at every 5-minute through an ultra-small EM sensor. With a diameter less than 3 mm, it can be inserted with an injector under the skin.

The invasive mode sensor scans the vicinity of the sensor with a fine frequency resolution over a wide band. It can precisely measure changes in frequency due to the changes of permittivity (changes in blood glucose) based on the strength of reflection.

Compared to the external EM-based non-invasive blood sugar sensor proposed by several other research institutes, our sensor excludes the effect of pressure, temperature, humidity, and movement during measurement. This EM-based continuous blood glucose sensing technology is developed by SB solutions.
MODE-2
(single mode)
단일모드 The mode is responsible for measuring blood glucose from outside of the body with a little lower precision than mode-1. In the single mode, the EM sensor attached on skin measures changes in blood glucose in the interstitial fluid at every 5-minute similar to invasive mode.

The single-mode is a non-invasive blood glucose sensing mode. It measures blood glucose by analyzing changes in coupling strength of EM-waves penetrating through the interstitial fluid.

This single mode functions as coarse scanning of blood glucose level. The invasive mode precisely detects (fine scanning) within the determined range. The fusion of redundant information from mode-1 and mode-2 sensors can estimate accurate blood glucose over a wide range of 40 - 600 mg/dl.
MODE-3
(array mode)
배열모드 This mode detects the danger in real time when there is a large change In blood glucose from outside of the body. The EM-wave from sensor passes through the interstitial fluid and monitors the blood glucose change in the blood vessel located deeper in real time.

The blood glucose level in the interstitial fluid has a time delay of 5 ~ 20 minutes compared to the actual blood glucose level in the blood vessels. The array mode sensor uses multiple sensors in parallel to increase the penetration depth of EM-waves for sensing blood vessels.

Overcoming the time delay problem with a continuous blood glucose measurement system and a smartphone application

어플리케이션

  • The 3rd generation CGMS technology is the convergence of ultra-small biosensor and system on chip (SoC) technology. It can be expanded to the field of wearable devices and has a technologically significant effect on life of diabetes.
  • The dielectric constant based blood glucose measurement technology can be improved to build an accurate electromagnetic database on body tissues and compositions. This can be applied to all bio-signal prediction technologies e.g., diagnostic devices for detecting abnormal cells and malignant tumors.
  • When the beam focusing technology with the array mode and the ultra-small WPT solution are combined, strong energy can be induced in the small area to suppress the growing of abnormal cells. Furthermore, it can be extended to the field of portable medical devices for therapeutic purposes.

  • Implantable biomedical-SoC is one of the key technologies required to develop advanced medical devices. It provides essential elements such as high energy harvesting efficiency, miniaturization through integrated Si-based electronics, and integrated AI-based algorithms. The SoC design technology developed for this task has a technological impact that enables ultra-low power, highly miniaturized, simultaneous WPT and data communications for advanced medical devices.

알고리즘

Mode 1 (invasive mode) sensor advancement based on near-field technology

  • Advancement of sensor design based on actual data obtained from in-vivo experiments on rodent animals (mouse and rat) and mid-sized animals (swine and beagle)
  • Based on the electrical parameter analysis of the sensor for continuous blood glucose sensing with maximum sensitivity (refer to Figure 1)

그림1Figure 1. Simulation result of Mode-1 sensor and electromagnetic wave distribution

Mode1 Sensor: SoC with embedded wireless power reception and external device with wireless power transmission

  • Since SoC with the wireless power reception is located inside the implant sensor, it has a size limitation. It is designed to receive power wirelessly with a 0.5 mm x 8 mm chip size to provide a stable power required to drive the sensor.
  • The power transmission circuit of the external device is also designed to supply the power required for the implanted sensor, and it includes rectifier, LDO, overvoltage protector, low voltage circuit breaker, analog-to-digital converter (ADC) and LSK for SWIPT communication, & etc.

MCU-based wireless power transfer algorithm for SWIPT implementation (refer to Figure 2)

  • In order to simultaneously transmit power and communicate by LSK, we developed a power control algorithm after designing a block of a hardware platform with MCU first and then commercial devices.
  • We designed on-chip MCU circuit with high memory efficiency and low power consumption with ARM's 32-bit RISC Cortex-M0 core.

그림2Figure 2. SWIPT SoC of simultaneously transmitting power and data communication for driving Model1 sensor

SoC circuit design for ultra-small size and ultra-low power Mode-1 sensor

  • Using the SoC the S-parameter characteristics of the EM-based mode-1 sensor is measured and converted to digital data. Then it is transmitted to the external module outside of the body
  • After analyzing the voltage and power for each block, the power and band required performance of each circuit block constituting the subcutaneous insertion sensor interface SoC are determined.

Determination of required performance for each circuit and design with system-level analysis

  • We design the circuits according to the required performance, such as Low-noise Amplifier (LNA), Subcutaneously Inserted Sensor Interlocking Frequency-Selective Filter, Envelope Detector, Base-Band Amplifier (BB AMP), and analog-to-digital converter (ADC) circuit design for digital conversion of sensor S-parameter values as the main building blocks that make up the SoC sensor interface (refer to Figure 3)

그림3Figure 3. Interface configuration diagram of Mode 1 SoC Sensor

Mode-2 (single-mode) sensor development based on resonance moment analysis

  • Mode-2 sensor is based on a high Q-factor sensor. Multipolar moment is analyzed from the surface current induced in the EM sensor that confirms a sub-radiative resonance to improve Q-factor (Figure 4).
  • Representative sub-radiative moments include magnetic dipoles, quadrupoles, and octa-poles. We implemented magnetic dipole resonance by applying a stacked asymmetric ring structure.

그림4Figure 4. resonance moment analysis for Mode-2 sensor

Mode-3 (array mode) sensor to improve coupling strength and penetration depth

  • The EM array mode sensor is made of multiple sensors that can control distribution of the near-field in the body, to penetrate until the depth of blood vessels. We developed suitable sensors that satisfies above characteristics in parallel operation.
  • We reviewed various types and shapes of sensors, and selected the optimal prototype for Mode 3 sensor. We analyzed the sensor performance by EM modeling and simulation.

그림5Figure 5. Antenna Analysis for Mode-3 sensor

In vitro biocompatibility evaluation according to ISO standards

  • The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay is to evaluate the efficacy and physiological activity of a specific substance or to develop a new drug, The MTT assay for the packaging material of the continuous glucose measurement system is necessary to evaluate the toxicity, cell activity changes, ability to suppress tumor cell growth before the animal experiment and in-vivo application stage.
  • The most direct way to measure living cells is to measure the number of surviving cells with a microscope and a hemocytometer after staining cells by treating trypan blue. However, it takes a lot of time and effort to measure and it can be inaccurate when the number of samples is large. Therefore, Tetrazolium salt assay is performed as an alternative method since it is difficult to use a direct method.
  • Tetrazolium salt is a generic name for a heterocyclic compound in which three aromatic rings are connected, and it is easily reduced by a reduced compound or enzyme such as dehydrogenase to form formazan and causes color reaction. The solubility and absorbance of the aqueous solution vary depending on the type of aromatic ring structure bonded to the basic structure of tetrazolium salt. Cells that are metabolically active produce energy necessary for survival through the electron transport system process of mitochondria. The assay using tetrazolium salt demonstrates the principle that dehydrogenases present in the electron transfer system decompose tetrazolium salt to produce formazan. It can be used to quantitatively evaluate living cells.
  • The absorbance is measured at 540 nm with an ELISA plate reader (VERSAmax, Molecular Devices), and the percentage value of the absorbance for the test substance-treated group is calculated and biocompatibility is evaluated by comparing the proportion of living cells.

그림5Figure 5. Sensor interface SoC configuration diagram for driving Model-1 sensor

Analysis of biocompatible packaging materials for subcutaneous insertion

  • Packaging that ensures the stability of the Mode-1 sensor including SoC in the body is essential in order to suppress the immune response caused by the implant sensor. It is important to select a package material that is suitable for toxicity evaluation and at the same time does not block electromagnetic waves. It is also essential to have waterproof function in order to protect electric circuit of SoC.
  • According to preliminary analysis of materials for suppressing the human immune response, COC (Cyclic Olefin Copolymer) can be used as a material that satisfies all these conditions, and Dextran-based polymers that can reduce reaction with fat or cholesterol in the interstitial fluid.
  • We developed a packaging by analyzing membrane structures that can be manufactured with composite materials. It also increases specificity for glucose at the same time have good water-proof performance. It ensures stable performance in the body without shielding electromagnetic waves (Figure 6).
  • It is possible to use Boronic acid derivatives that have excellent body compatibility and can reversibly detect glucose without enzymes or reagents to distinguish similarly sized ascorbic acid and acetaminophen among glucose-like substances.

그림6Figure 6. Sensor implant condition inside body

Comparison with other products

Scroll left and right
Company M Company D Company E SB solutions
Measurement type minimally invasive minimally invasive Subcutaneous Implant Subcutaneous Implant
price/year USD 5,199 USD 6,600 USD 4,200 USD 900
Accuracy (MARD) 10.55 9 8.5 8.5
Measuring Technique Finger prick with microneedle Finger prick with microneedle Sensor implanted just under the skin Implantable sensor under the skin and an external sensor*
sensor life 6 days 7 days 90 days 2-5 years (semi-permanent)
Calibration cycle Every 12 hour Every 12 hour Every 12 hour Once-a-day then automatic correction function
transmitter position above the sensor above the sensor above the sensor around the sensor
Power supply method battery battery IPT wireless power transfer MR wireless power transmission

CGMS for pets

As the demand for quality medical services increases for companion animals, it is expanding to treat diseases and early diagnosis of diseases for companion animals.

Trends in Diabetes Incidence of Pets
  • 고양이당뇨발병률
  • 강아지당뇨발병률

Reference : https://www.banfield.com/Banfield/media/PDF/Downloads/soph/Banfield-State-of-Pet-Health-Report-2016.pdf