Final Report Summary - SPIDIMAN (Single-Port Insulin Infusion for Improved Diabetes Management)
Executive Summary:
Executive summary
AP systems under development by the diabetes research community are built from commercial CGM systems that are wirelessly connected to a receiver that runs an algorithm to calculate the insulin infusion rate from the measured glucose concentration. The insulin infusion rate is then sent to an insulin pump that delivers the insulin. Patients using those systems need to carry 3 different devices – the sensor, the receiver and the pump. Furthermore those systems require two separate insertion sites which is cumbersome in terms of site rotation and site infection.
Exploiting a novel glucose sensor technology, SPIDIMAN aimed to develop a new coating technology to apply an optical glucose sensor onto a standard insulin infusion set cannula and incorporate this integrated glucose sensor into a single-port artificial pancreas system. The SPIDIMAN system reduces the required insertion sites and thus also the likelihood of site infections. The small dimensions of the integrated system make the SPIDIMAN concept exceptionally beneficial for children and adolescents.
The SPIDIMAN sensor is constructed by the consecutive application of 3 different layers onto the metal cannula of a commercial infusion set. The first layer is an oxygen sensitive fluorescent dye, the second layer is immobilized glucose oxidase layer and the third layer is a biocompatible protection membrane as diffusion barrier.
A miniaturized optical readout unit – the glucose reader – was developed and used for system assessment in clinical trials. The glucose reader is a two-channel phase fluorimeter that reads the signal from the glucose sensor and the reference oxygen sensor.
Within the SPIDIMAN project 3 clinical trials in adult type 1 diabetes patients were performed to assess sensor performance. Furthermore a study to assess glucose / insulin profiles in 12 children in the age group between 6-12 years was performed to get insights on the intra-patient variability in this age group which improved algorithm validation.
A second pediatric study was started with the aim to assess closed loop impact on metabolic outcome and patient satisfaction in poorly controlled adolescents. Furthermore, information on the quality and quantity of sleep was collected.
In clinical trials with type 1 diabetes patients the sensor performance of individual SPIDIMAN sensors was excellent with MARD values in the range of 8 - 15%. As a consequence of the manual sensor fabrication process the sensor to sensor variation was quite high and an overall sensor performance with MARD values of 22.5% was achieved. Till the end of the project the reproducibility of the sensor performance could be improved significantly because a new fabrication technique became available. However, in-vivo performance of this new fabrication technique could only be evaluated in preclinical trials. MARD values of 17.8 ± 3.4% were achieved in preclinical clamp studies.
Due to unforeseeable technical difficulties the ambitious goal of a fully functional single-port AP system could not be achieved. But the concept is intriguing as stated by global players in the diabetes care market during our SPIDIMAN stakeholder workshop.
Project Context and Objectives:
Summary description of project context and objectives
The SPIDIMAN consortium aimed to exploit an innovative glucose sensor concept in a new single-port device, to implement its usage, and to validate its performance. The new device combined continuous glucose measurement and insulin delivery in an artificial pancreas (AP) approach to improve diabetes management in adults and children suffering from insulin-dependent diabetes. SPIDIMAN developed a technology to coat an optical glucose sensor on standard insulin infusion set cannulas to function as a new single-port AP. The coated insulin catheter is inserted into the subcutaneous tissue and is simultaneously used for both glucose concentration measurement and insulin delivery in an integrated therapeutic device that has great potential to improve diabetes management in adults and children. The performance and applicability of this innovative device was tested in preclinical and clinical trials.
Medical concept
According to the International Diabetes Federation the number of people suffering from diabetes mellitus has risen to 425 Mio worldwide. In Europe alone 58 Mio people suffer from either type 1 or type 2 diabetes (IDF diabetes atlas 2017) resulting in health expenditures of more than €166 billion in 2017. Intensive diabetes management can lead to a better quality of life by reducing serious diabetes related complications if blood glucose concentrations are maintained within a tight specific range. Such a tight glycaemic control can reduce microvascular and macrovascular complications in the long term but carries a substantial risk of hypoglycaemia.
Current standard diabetes management used by insulin dependent diabetes patients currently involves a three step procedure: first, glucose concentrations are measured by taking a blood sample several times per day (usually from a finger prick); second, the required insulin dose is calculated; and third, insulin is delivered via injection or pump. Continuous glucose monitoring (CGM) that measures interstitial glucose levels in real time rather than at discrete time points has been developed to improve glycaemic control particularly after meals or exercise. But clinical studies showed a slight improvement of glucose levels only in adult type 1 diabetes patients but not in children and adolescents. So far, CGM display has been integrated into available insulin delivery systems (Medtronic, VEO®, Animas Vibe) but commercially available CGM systems with an integrated insulin pump still require two insertion sites (two-port system) one site for glucose monitoring, and the second site for insulin delivery. Such systems require handling of two or even three separate devices and two body-interfaces, which results in low acceptance, in particular by paediatric patients.
The latest developments in biomedical devices are aiming to provide a closed feedback system of continuous glucose monitoring (CGM) in real time, insulin dose calculation by an algorithm and continuous insulin delivery by a pump. But cumbersome technology (e.g. frequent alarms), a lack of accurate sensor technology and a lack of a fully tested and implemented algorithm for the different patient groups are the main drawbacks preventing the use as an "all-in-one" artificial pancreas (AP) system.
In order to provide diabetes patients and in particular paediatric diabetes patients with the advantages of tight glycaemic control, SPIDIMAN aimed to overcome the limitations of current strategies to manage diabetes. The project aimed to implement a novel approach for a single-port AP system employing an innovative optical sensor technology for glucose measurement that can be applied on the cannula of the infusion set. The development of the specific SPIDIMAN algorithm builds on an existing concept and is specifically adapted for the young patient population of children and adolescents. The main goal of SPIDIMAN was a fully functional single-port AP system that would offer higher tolerability and convenience for patients and insulin delivery with reduced side-effects.
Technical concept
State-of-the-art CGM techniques suffer from the limitations of electrochemical sensors which are affected by interfering substances in living tissue. In contrast to amperometric techniques optical pathways for CGM are less affected by interferents and offer high potential for miniaturization. The SPIDIMAN technology is based on the idea of using oxygen sensitive fluorescent dyes in combination with immobilized glucose oxidase as sensors to measure glucose concentrations in subcutaneous adipose tissue. The sensor signals are continuously transferred to an optical read-out system making them easier to use in-vivo. To implement wireless technology in living tissue, the fluorescent dyes are incorporated on the cannula of insulin infusion sets as carrier which are implanted and explanted at the end of sensor life. The SPIDIMAN concept circumvents the need for extended sensor life by incorporating the sensor onto standard insulin infusion sets that are exchanged after 3 days of wear time. In a preclinical glucose clamp trial a proof-of-principle for the concept of a glucose sensor on a standard insulin catheter has been shown using provisional coating technology with a fully functional fluorescent dye. In this preclinical trial subcutaneous glucose concentrations correlated well with reference glucose concentrations derived from whole blood samples and simultaneous insulin infusions did not affect the sensor readings. Independent studies using microperfusion measurements of glucose concentrations supported the finding that the accuracy of glucose measurements is not compromised by insulin delivery at the same site. But to achieve a reliable, reproducible fluorescent sensor coating of standard insulin catheters a specialised coating technology had to be developed. SPIDIMAN aimed to develop an optical sensor technology with high measurement accuracy, short response times and a stable sensor signal that measures in a wide range of glucose concentrations, responds well to low glucose levels and is particularly suitable for cost-effective high volume production.
By incorporating a control algorithm the gap between glucose sensing and insulin delivery was aimed to be closed into a closed-loop single-port AP system. Prandial insulin dose still has to be given prior to the meal with an insulin bolus. However, the closed-loop system will regulate postprandial glucose excursions after the meal by a variable insulin infusion regulated by the measured glucose levels. Therefore, to match current terminology the SPIDIMAN single-port device will be considered a closed-loop system.
Such a closed-loop AP system can improve adherence to self-monitoring of blood glucose levels, increase accurate insulin delivery, and increase AP acceptance for tight glycaemic control. With improved glycaemic management the risk of hypoglycaemic or hyperglycaemic episodes and subsequent micro- and macrovascular complications can be substantially reduced, leading to improved quality of life and life expectancy for diabetic patients. Results of the evaluation of the SPIDIMAN single-port AP in a preclinical as well as clinical setting with adult and paediatric patients will provide valuable data to assess the applicability and performance of a next generation AP in a clinical setting.
To provide benefits to diabetes patients through improved management of glucose levels and a reduced frequency of out-of-target glycaemic values, SPIDIMAN aimed to meet the following objectives:
Develop a comprehensive coating technology.
The new coating technology will graft an optical glucose sensing layer ("smart tattoo") onto an off-the-shelf insulin infusion catheter.
Optimise the optical glucose measurement and control algorithms.
The optical reader will be optimised to increase the accuracy of glucose concentration measurements in tissue and, based on current approaches, appropriate control algorithms will be developed that incorporate the characteristics of the glycaemic management strategy for paediatric and adult type 1 diabetes patients.
Build a new single-port AP device.
All technical components and the optimised algorithm will be combined in a new single-port AP device with innovative optical glucose sensing technology.
Validate the new single-port AP in a preclinical setting.
The performance and applicability of the single-port AP device will be evaluated and optimised in a preclinical study and the control algorithm will be additionally evaluated using a novel in-silico approach.
Validate the new single-port AP in a clinical setting.
The performance and applicability of the single-port AP device and the complete single-port AP will be tested in clinical studies in adult and paediatric type 1 diabetes mellitus patients.
Project Results:
Main results
1) Development of a comprehensive coating technology.
At the start of the project a decision matrix was set up to choose a catheter material that is suitable for the application of the sensors. Infusion sets are available with teflon cannulas and steel cannulas. The medical experts of the paediatric diabetes centre in Luxemburg advised to use steel cannulas because of safety reasons. Teflon cannulas tend to kink during insertion and get blocked more often during wear time. Also from a technical point of view steel was considered the better choice because adhesion of the sensing layers is better on steel than on teflon. Positioning of the cannula during the coating process was easier as the steel needle is rigid and does not wiggle when it is rotated.
The surface of metallic catheters was investigated by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) measurements to gain information on the surface properties of the needles. The measurements proved that metallic catheters are coated with a silicon layer which was used to enhance wettability and adhesion by different pretreatment processes e.g. chemical surface pretreatment, atmospheric plasma and low pressure plasma. Surface pretreatment using low pressure plasma has been validated on two different infusion sets and on model steel needles: Medtronic SureT infusion sets for 90° insertion and Medtronic Polyfin QR infusion sets for slanted insertion. Water contact angle measurements have been performed to investigate the surface properties. As the measurements on the round circumference of the cannulas was very difficult the contact angle needed to be measured by the picodroplet method.
Development of the coating technology and development of the sensor chemistry was done in close cooperation of the responsible partners as the results from chemistry development had a direct impact on the coating development and vice versa. As adhesion turned out to become one of the most challenging parts of the project, many designs, chemical variations and layer structures of the sensor were developed and tested to meet the criteria for sensor adhesion. Alcoxysilanes and amino silanes were incorporated as adhesion promoters into the sensor chemistry and needed to be optimized regarding adhesion and sensor functionality.
To decrease shear forces during insertion and extraction grinded recesses as cavities were tested to take up the sensor layers. These cavities were 2 mm long and 35 µm deep. The recesses helped improve sensor adhesion by reducing shear forces during insertion and extraction. But the mechanical stability of the cannulas was reduced by the recesses due to additional reduction of the thin material thickness of the cannulas. Therefore the recesses were not used for the SPIDIMAN sensors.
As a quality control a specific method to test adhesion was developed. It included immerging the sensors into human plasma through artificial skin with a defined resistance. As wear time was defined with 72 hours the sensors were kept immerged for 96 hours before the sensors were removed through the artificial skin. Sensors and artificial skin are visually inspected under the microscope to determine damaged sensor surfaces.
Sensor chemistry was continuously adapted to the fabrication process. Further improvements of the layer structure of the sensors were implemented to improve adhesion. One major result was the incorporation of the catalase layer into the enzyme layer. Before that catalase was immobilized in the diffusion barrier layer which led to layer inhomogeneity and too high permeability for glucose of the diffusion barrier.
A machine for the sensor fabrication was developed within the project. The infusion sets were placed in specially developed holders that rotate around the catheter axis during operation. A 3-axis coating deposition system is driven using a camera system to follow precisely the trajectory of the catheter needle to avoid any loss of coating. The coating dosing system is based on an electric microjack acting on a syringe. The linear displacement of the jack and the coating deposition volume are directly linked by the syringe bore. A load cell was added in order to detect the contact during the approach phase of the jack. In order to anticipate a production pace that allows producing sufficient sensors for clinical evaluation studies, 25 catheter holders have been manufactured with a dedicated support to go through the plasma surface pre-treatment. At the end, the remaining manual operation steps needed were (I) the preparation of syringes in the dedicated carousel, (II) the installation of each catheter in the dedicated holders and (III) the installation of the catheter holder in the machine.
In vitro sensor performance tests were performed continuously accompanying the development process. Linearity of the sensors was found excellent during those tests. In vivo performance of the sensors, which was initially tested in preclinical trials, pointed out that there was still a sensor performance variation from sensor to sensor and from lot to lot, although big efforts were made to define a reproducible sensor fabrication process. The sensor fabrication process could be improved significantly in the extension time of the project when the aerosol jet technique became available. With this alternative fabrication technique sensor performance variations could be reduced significantly and were demonstrated in preclinical results.
The goal of the project to turn a new and innovative sensor concept in an artificial pancreas system turned out to be too ambitious for the project lifetime. Improvements of sensor performance, system architecture and fabrication process could be achieved. Adhesion of the sensor layers onto the infusion set cannula turned out to be the crucial hurdle that consumed a big deal of resources and time that could not be compensated. Therefore the sensor did not reach the maturity to drive a closed loop AP system and to be used in clinical trials in children.
2) Optimise the optical glucose measurement and control algorithms.
The first generation glucose reader was developed to perform in vitro sensor tests and system optimization. It was successfully used in preclinical studies for first in-vivo tests. Initial problems with hardware and software could be solved and a convenient analysis software was written. Additionally, non-sequential optical ray tracing was employed to estimate effects of catheter thickness, material and insertion mode on the sensor readout with the aim to facilitate the decision for a catheter type for the project. Experiments with laser diode excitation instead of LEDs were carried out but stopped, because space and energy requirements of laser diodes would be too high.
Figure 1: scheme of the measurement concept (left) and first generation glucose reader with 2€ coin for size comparison
Emission filters were used to selectively read out each indicator dye with one of the photodiodes. The glucose channel had a filter combination with band pass characteristics, transmitting between 725nm and 840nm while the reference channel was equipped with a long pass filter, transmitting above 840nm. The optoelectronic was enclosed in a cylindrical, black anodized aluminium body. The housing served as optical bench to align LEDs, filters and photodiodes and prevented unwanted tunnelling of light. It shielded against ambient light and protected the electronics. A Mini-USB connector was used to connect the device to the readout PC and to supply it with power.
The second generation glucose reader was a complete re-design based on the experience gained with the first generation reader and the requirements for the clinical use of the system. Additionally, features requested by the project partners responsible for system integration were incorporated for easy integration with existing insulin infusion sets. The second generation glucose reader was significantly reduced in size and weight (25mm diameter, 7mm thickness and approximately 5g) for convenient wearing by the patients in the clinical studies. To actualise this reduction in size, the digital part of the electronics was moved in a separate small housing and only the analogue optoelectronics were placed above the sensors on the skin. Slanted catheters and 90° catheters could both be used with the new design. The optics of the reader was of prime importance for the proper operation of the system. The two channels needed to be separated spectrally. In order to achieve this, excitation was done with two different LEDs, matching the absorption peaks of the two indicators as close as possible. The LED of channel 1 was equipped with a short pass filter that limits the excitation of the reference dye. The emission filter of channel 2 was equipped with a band pass that likewise reduces the excitation of the glucose dye. These filters were custom made interference filters on 4 x 4 x 0.5mm glass substrates. The emission filters were color glass filters with 4.5mm diameter and 2mm thickness which were custom coated with interference layers. In case of the glucose channel, the resulting filter had narrow band pass characteristics while the reference channel was a long pass filter.
Figure 2: second generation glucose reader and size comparison for first generation reader and 1€ coin (inset)
The PC software to operate the glucose readers was based on LabView®. It handled the communication of the device via the USB Port, allowed to change all relevant measurement settings e.g. measurement interval, LED intensities, photo current amplification, background correction etc. Measurement results were displayed graphically and logged to a text file. The user had access to all raw data for validation purposes. One instance of the software was used for each optical reader. Channel 1 and Channel 2 represented glucose and oxygen, respectively. In addition, the readers could be accessed directly via virtual COM Ports over the USB interface, using a simple set of ASCII commands. This allowed easy integration into custom software.
The housing was precision-milled out of aluminium. Optical filters were specified and custom build for improved spectral discrimination between the glucose channel and the reference oxygen channel. The electronical, optical and mechanical design allowed reading out both, 90° and slanted inserted sensors. Ex vivo tests with prototypes showed sufficient signal intensities with 90° inserted sensors, which is the preferred configuration for clinicians and also for the system integration. However, the slanted insertion remains an alternative if higher signal intensitiess or better discrimination between the channels would be necessary. The spectral separation of the two channels was investigated in a setup that allowed positioning a sensor spot symmetrically between the channels. By exchanging the sensor material, the cross talk between the two channels could be quantified and compared to similar measurements with the 1st Generation Reader. The main issue causing the cross-talk was the relatively broad emission spectrum of the channel 1 dye and the close absorption maxima of both dyes. The LED of channel 2 therefore also excited dye 1 and the emission of dye 1 was not fully blocked by the emission filter of channel 2. In the 1st Generation Readers, unacceptably high cross talk was the result. More than 70% of the signal in channel 1 could be seen in Channel 2. In the 2nd Generation Readers, the crosstalk from channel 1 to channel 2 could be reduced below 30%. The crosstalk from channel 2 to channel 1 is negligible with values between 1% and 2% in both reader generations.
Figure 3: concept of second generation glucose reader for readout of slanted (left) and straight inserted sensors (right).
3) Build a new single-port AP device.
In the first paediatric trial data was collected for the in silico modelling of the control algorithm that allowed adapting the algorithm to the young population. The participating children have been exposed to the use of a closed loop system, in the clinic (CRC) and at home. The outcome of this study was that more time was spent in target at home while using the closed loop compared to the open loop, and no major adverse events were observed in either group. A tendency for lower blood insulin levels and lower frequency of hypoglycaemia were observed when using the closed loop. The study clearly demonstrated that the use of the closed loop system in children between 6-12 years was feasible and well perceived by the patients and their family.
In order to combine glucose measurement and insulin infusion a software was created that calculated the glucose concentration from the raw data measured by the glucose reader, fed the information into the control algorithm that calculated the insulin infusion rate, and displayed measured glucose values and insulin infusion rate. Due to the technical issues faced in the sensor development part of the project a complete AP device could not be built because the sensor did not reach the maturity to drive a closed loop control algorithm.
4) Validate the new single-port AP in a preclinical setting.
The performance and applicability of the SPIDIMAN sensor was evaluated and optimised in preclinical experiments in pigs. The experiments performed included in-vivo sensor performance tests of the different sensor designs in clamp studies, assessment of the influence of insulin infusion and tissue oxygen variations on the glucose measurement. System usability topics like fixation of the sensor and the glucose reader, insertion and extraction of sensors and influence of insertion depth on sensor signal intensities were evaluated.
Figure 4: Preclinical sensor results: MARD 17.8 ± 3.4%
Beside the sensor tests in animals the control algorithm was evaluated using a novel in-silico approach. Numerical simulation tests were carried out to assess the effect of a subcutaneous continuous glucose sensor error on the performance and safety of the closed loop control algorithm. A compartment model was used to study pharmacokinetics of insulin Aspart during closed loop insulin delivery and utilised the obtained results in the development of the SPIDIMAN algorithm for the paediatric population. The model was used to measure time-to-peak of insulin concentration, insulin metabolic clearance rate and background insulin concentration. The findings from this study suggested that insulin dilution has no effect on its pharmacokinetics but may result in less variable insulin absorption. We concluded that diluted insulin could be used in children undergoing closed loop insulin delivery. The results from this study were used to improve our simulation model of glucose regulation in children with type 1 diabetes and the development of a synthetic population of children with type 1 diabetes.
5) Validate the new single-port AP in a clinical setting.
In the first period of the project a study to assess glucose / insulin profiles in children in the age group between 6-12 years was performed with an available closed loop system. It was discussed with the parent group of the Luxembourg Diabetes Association (ALD) and included two 17h afternoon-overnight profiles to increase insights on the intra-patient variability in this patient group which will help to improve algorithm validation for this age group. Not only venous samples for glucose and insulin will be used for the algorithm development, but also the obtained sensor data (interstitial glucose values) and the insulin pump data.
Sensor performance tests were performed in 3 clinical trials to assess sensor accuracy.
i) In the first clinical trial the SPIDIMAN sensors were applied on Medtronic Sure-T infusion sets which were inserted straight into the subcutaneous tissue. 12 patients with type 1 diabetes wore 2 SPIDMAN sensors each in the abdominal region. The patients received a standardized breakfast (60g carbohydrates) and an increased dose of their usual rapid-acting insulin analogue (180% of the patients’ calculated mealtime dose) was administered to cover breakfast (8:30) with the aim of inducing a period of minor hypoglycemia. The patients received a standardized lunch (60g carbohydrates) and again an increased dose of their usual rapid-acting insulin analogue (180% of the patients’ calculated mealtime dose) Patients performed an exercise test consisting of two 15 min session of cycling on a home trainer at 50% of individual VO2max separated by a 5 min rest. Individual sensors achieved excellent performance with MARD values between 7.9% and 14.7%. Taking all sensors into account an overall MARD of 22.5% was achieved.
Figure 5: Glucose profiles from clinical trial: reference blood glucose (red) and two sensors per subject sensor1 (blue) and sensor2 (green).
Figure 6: Error grid analysis of the corresponding sensor glucose profiles shown in Figure 5.
ii) In the second clinical trial the SPIDIMAN sensors were applied on Dana Superliner infusion sets which were inserted slanted into the subcutaneous tissue. 16 patients with type 1 diabetes wore 4 SPIDMAN sensors each in the abdominal region. Sensor analysis time was extended to 24 hours, glucose dynamics were induced by high glycaemic index food and increased dose of insulin (180% of the patients’ calculated mealtime dose). Patients performed an exercise test consisting of two 15 min session of cycling on a home trainer at 50% of individual VO2max separated by a 5 min rest. Again single sensors achieved excellent performance with MARD values below 10% during daytime. An overall MARD of 25.7% was achieved. Movement artifacts, especially during the night-time, were observed in this trial and prevented better results.
iii) In the third clinical trial the SPIDIMAN sensors were used on infusion sets for straight as well as for slanted insertion. Furthermore glucose concentrations were calculated online based on a two point calibration. 4 patients with type 1 diabetes wore 4 SPIDMAN sensors each, 3 in the abdominal region and one slanted inserted sensor on the upper arm. Sensor analysis time was 24 hours, glucose dynamics were again induced by high glycaemic index food and increased dose of insulin (180% of the patients’ calculated mealtime dose). Patients performed an exercise test consisting of two 15 min session of cycling on a home trainer at 50% of individual VO2max separated by a 5 min rest. Single sensors independent of the insertion type achieved excellent performance with MARD values below 10% during daytime. Slanted inserted sensors achieved an overall MARD of 22.4%, while straight inserted sensors achieved an overall MARD of 21.5%.
Figure 7: Comparison of slanted (green line) and straight (blue line) inserted sensors in one participant.
Figure 8: Comparison of glucose profiles calculated with retrospective (green line) and prospective (brown line) sensor calibration in one participant.
iv) A pediatric clinical trial with the SPIDIMAN single-port device was planned but could not be performed due to the insufficient maturity of the new sensor technology. Therefore the aim of the pediatric clinical trial was changed with the aim to build up the best knowledge about closed loop use in the population of young and adolescent diabetes patients. The study included data collection on the impact of the closed loop on metabolic outcome as well as on patient satisfaction in the poorly controlled adolescent population. Furthermore, we included information on the quality and quantity of sleep in this population.
Potential Impact:
Potential impact
The SPIDIMAN project will have a potential impact on type 1 diabetes patients, especially in the paediatric age group, on the industrial competitiveness of the participating SMEs and on European research networks between academic centers and research intensive companies.
1) Impact on type 1 diabetes patients
Although we did not reach our ambitious goal to develop a fully functional closed loop single-port artificial pancreas device, the SPIDIMAN project demonstrated an alternative sensor technology to the commercial electrochemical glucose sensors. The single-port concept combines continuous glucose monitoring and insulin delivery in one single device and needs only one access site to the patients´ subcutaneous tissue. Therefore the concept is still intriguing and will have a major impact on quality of life of type 1 diabetes patients. Comfort for the patients is increased by the reduced number of insertion sites and the familiar handling as patients can set and exchange the sensor just like a regular insulin infusion set which will in turn increase acceptance of the new technology. The improved acceptability of a single-port AP device will lead to improved compliance and, consequently, to better glycaemic control and improved quality of life. Assuming that the development of the SPIDIMAN system will continue and the necessary maturity will be achieved the SPIDIMAN concept could be especially suitable for children suffering from diabetes. It could offer an excellent treatment option for very young children due to the reduced number of tissue access sites and reduced size and number to be carried by the patients. This, in turn, could have an impact on minimising short- and long- term diabetes complications and the general wellbeing of the diabetic paediatric population.
2) Impact on industrial competitiveness
Most commercially available sensors for continuous glucose monitoring are currently developed and manufactured in the USA. The innovative new sensor developed in SPIDIMAN could dramatically increase industrial competitiveness in the biomedical sector in the area of diabetes management for European industries and could boost innovative leadership and competitiveness in an area dominated by US companies. Rescoll, as a service company developing and improving products for its customers, will be able to expand its network of contacts to receive interesting offers in the field of specialised coatings involving complex interface technologies, particularly in the field of medical device industry. Akira’s business has so far been focused on electro-mechanical engineering for the aerospace industry, the automotive industry and research laboratories. By participating in the SPIDIMAN project Akira will be able to apply its technical know-how to the new field of medical R&D in the biomedical sector. Pyroscience will be able to gain new expertise in adapting its existing optical oxygen sensing technology to the new analyte glucose. Pyroscience will gain valuable experience in adapting its current optical measurement techniques to several completely new application areas. The project might open very attractive business possibilities in the medical sector. Altogether, the outcome of the project should provide substantial opportunities for Pyroscience to increase its turnover and to create more jobs.
3) Impact on European networks
The SPIDIMAN project strengthened the link of academic and SME research and established new collaborations especially between Joanneum Research and the companies located in France. Also SPIDIMAN created a new partnership between the Centre Hospitalier de Luxembourg and the University of Cambridge for further development of the closed loop algorithm for the peadiatric age group. Those networks will stay alive after the end of the project and will strengthen European collaborations conducting multidisciplinary biomedical research.
List of Websites:
www.spidiman.eu
JOANNEUM RESEARCH – HEALTH
Institute for Biomedicine and Health Sciences
Project Coordinator Univ.-Prof. Dr. Thomas Pieber
Neue Stiftingtalstrasse 2
8010 Graz
Phone: +43 316 876-4000
Fax: +43 316 8769-4000
Leonhardstraße 59, A 8010 Graz
info@spidiman.eu
Executive summary
AP systems under development by the diabetes research community are built from commercial CGM systems that are wirelessly connected to a receiver that runs an algorithm to calculate the insulin infusion rate from the measured glucose concentration. The insulin infusion rate is then sent to an insulin pump that delivers the insulin. Patients using those systems need to carry 3 different devices – the sensor, the receiver and the pump. Furthermore those systems require two separate insertion sites which is cumbersome in terms of site rotation and site infection.
Exploiting a novel glucose sensor technology, SPIDIMAN aimed to develop a new coating technology to apply an optical glucose sensor onto a standard insulin infusion set cannula and incorporate this integrated glucose sensor into a single-port artificial pancreas system. The SPIDIMAN system reduces the required insertion sites and thus also the likelihood of site infections. The small dimensions of the integrated system make the SPIDIMAN concept exceptionally beneficial for children and adolescents.
The SPIDIMAN sensor is constructed by the consecutive application of 3 different layers onto the metal cannula of a commercial infusion set. The first layer is an oxygen sensitive fluorescent dye, the second layer is immobilized glucose oxidase layer and the third layer is a biocompatible protection membrane as diffusion barrier.
A miniaturized optical readout unit – the glucose reader – was developed and used for system assessment in clinical trials. The glucose reader is a two-channel phase fluorimeter that reads the signal from the glucose sensor and the reference oxygen sensor.
Within the SPIDIMAN project 3 clinical trials in adult type 1 diabetes patients were performed to assess sensor performance. Furthermore a study to assess glucose / insulin profiles in 12 children in the age group between 6-12 years was performed to get insights on the intra-patient variability in this age group which improved algorithm validation.
A second pediatric study was started with the aim to assess closed loop impact on metabolic outcome and patient satisfaction in poorly controlled adolescents. Furthermore, information on the quality and quantity of sleep was collected.
In clinical trials with type 1 diabetes patients the sensor performance of individual SPIDIMAN sensors was excellent with MARD values in the range of 8 - 15%. As a consequence of the manual sensor fabrication process the sensor to sensor variation was quite high and an overall sensor performance with MARD values of 22.5% was achieved. Till the end of the project the reproducibility of the sensor performance could be improved significantly because a new fabrication technique became available. However, in-vivo performance of this new fabrication technique could only be evaluated in preclinical trials. MARD values of 17.8 ± 3.4% were achieved in preclinical clamp studies.
Due to unforeseeable technical difficulties the ambitious goal of a fully functional single-port AP system could not be achieved. But the concept is intriguing as stated by global players in the diabetes care market during our SPIDIMAN stakeholder workshop.
Project Context and Objectives:
Summary description of project context and objectives
The SPIDIMAN consortium aimed to exploit an innovative glucose sensor concept in a new single-port device, to implement its usage, and to validate its performance. The new device combined continuous glucose measurement and insulin delivery in an artificial pancreas (AP) approach to improve diabetes management in adults and children suffering from insulin-dependent diabetes. SPIDIMAN developed a technology to coat an optical glucose sensor on standard insulin infusion set cannulas to function as a new single-port AP. The coated insulin catheter is inserted into the subcutaneous tissue and is simultaneously used for both glucose concentration measurement and insulin delivery in an integrated therapeutic device that has great potential to improve diabetes management in adults and children. The performance and applicability of this innovative device was tested in preclinical and clinical trials.
Medical concept
According to the International Diabetes Federation the number of people suffering from diabetes mellitus has risen to 425 Mio worldwide. In Europe alone 58 Mio people suffer from either type 1 or type 2 diabetes (IDF diabetes atlas 2017) resulting in health expenditures of more than €166 billion in 2017. Intensive diabetes management can lead to a better quality of life by reducing serious diabetes related complications if blood glucose concentrations are maintained within a tight specific range. Such a tight glycaemic control can reduce microvascular and macrovascular complications in the long term but carries a substantial risk of hypoglycaemia.
Current standard diabetes management used by insulin dependent diabetes patients currently involves a three step procedure: first, glucose concentrations are measured by taking a blood sample several times per day (usually from a finger prick); second, the required insulin dose is calculated; and third, insulin is delivered via injection or pump. Continuous glucose monitoring (CGM) that measures interstitial glucose levels in real time rather than at discrete time points has been developed to improve glycaemic control particularly after meals or exercise. But clinical studies showed a slight improvement of glucose levels only in adult type 1 diabetes patients but not in children and adolescents. So far, CGM display has been integrated into available insulin delivery systems (Medtronic, VEO®, Animas Vibe) but commercially available CGM systems with an integrated insulin pump still require two insertion sites (two-port system) one site for glucose monitoring, and the second site for insulin delivery. Such systems require handling of two or even three separate devices and two body-interfaces, which results in low acceptance, in particular by paediatric patients.
The latest developments in biomedical devices are aiming to provide a closed feedback system of continuous glucose monitoring (CGM) in real time, insulin dose calculation by an algorithm and continuous insulin delivery by a pump. But cumbersome technology (e.g. frequent alarms), a lack of accurate sensor technology and a lack of a fully tested and implemented algorithm for the different patient groups are the main drawbacks preventing the use as an "all-in-one" artificial pancreas (AP) system.
In order to provide diabetes patients and in particular paediatric diabetes patients with the advantages of tight glycaemic control, SPIDIMAN aimed to overcome the limitations of current strategies to manage diabetes. The project aimed to implement a novel approach for a single-port AP system employing an innovative optical sensor technology for glucose measurement that can be applied on the cannula of the infusion set. The development of the specific SPIDIMAN algorithm builds on an existing concept and is specifically adapted for the young patient population of children and adolescents. The main goal of SPIDIMAN was a fully functional single-port AP system that would offer higher tolerability and convenience for patients and insulin delivery with reduced side-effects.
Technical concept
State-of-the-art CGM techniques suffer from the limitations of electrochemical sensors which are affected by interfering substances in living tissue. In contrast to amperometric techniques optical pathways for CGM are less affected by interferents and offer high potential for miniaturization. The SPIDIMAN technology is based on the idea of using oxygen sensitive fluorescent dyes in combination with immobilized glucose oxidase as sensors to measure glucose concentrations in subcutaneous adipose tissue. The sensor signals are continuously transferred to an optical read-out system making them easier to use in-vivo. To implement wireless technology in living tissue, the fluorescent dyes are incorporated on the cannula of insulin infusion sets as carrier which are implanted and explanted at the end of sensor life. The SPIDIMAN concept circumvents the need for extended sensor life by incorporating the sensor onto standard insulin infusion sets that are exchanged after 3 days of wear time. In a preclinical glucose clamp trial a proof-of-principle for the concept of a glucose sensor on a standard insulin catheter has been shown using provisional coating technology with a fully functional fluorescent dye. In this preclinical trial subcutaneous glucose concentrations correlated well with reference glucose concentrations derived from whole blood samples and simultaneous insulin infusions did not affect the sensor readings. Independent studies using microperfusion measurements of glucose concentrations supported the finding that the accuracy of glucose measurements is not compromised by insulin delivery at the same site. But to achieve a reliable, reproducible fluorescent sensor coating of standard insulin catheters a specialised coating technology had to be developed. SPIDIMAN aimed to develop an optical sensor technology with high measurement accuracy, short response times and a stable sensor signal that measures in a wide range of glucose concentrations, responds well to low glucose levels and is particularly suitable for cost-effective high volume production.
By incorporating a control algorithm the gap between glucose sensing and insulin delivery was aimed to be closed into a closed-loop single-port AP system. Prandial insulin dose still has to be given prior to the meal with an insulin bolus. However, the closed-loop system will regulate postprandial glucose excursions after the meal by a variable insulin infusion regulated by the measured glucose levels. Therefore, to match current terminology the SPIDIMAN single-port device will be considered a closed-loop system.
Such a closed-loop AP system can improve adherence to self-monitoring of blood glucose levels, increase accurate insulin delivery, and increase AP acceptance for tight glycaemic control. With improved glycaemic management the risk of hypoglycaemic or hyperglycaemic episodes and subsequent micro- and macrovascular complications can be substantially reduced, leading to improved quality of life and life expectancy for diabetic patients. Results of the evaluation of the SPIDIMAN single-port AP in a preclinical as well as clinical setting with adult and paediatric patients will provide valuable data to assess the applicability and performance of a next generation AP in a clinical setting.
To provide benefits to diabetes patients through improved management of glucose levels and a reduced frequency of out-of-target glycaemic values, SPIDIMAN aimed to meet the following objectives:
Develop a comprehensive coating technology.
The new coating technology will graft an optical glucose sensing layer ("smart tattoo") onto an off-the-shelf insulin infusion catheter.
Optimise the optical glucose measurement and control algorithms.
The optical reader will be optimised to increase the accuracy of glucose concentration measurements in tissue and, based on current approaches, appropriate control algorithms will be developed that incorporate the characteristics of the glycaemic management strategy for paediatric and adult type 1 diabetes patients.
Build a new single-port AP device.
All technical components and the optimised algorithm will be combined in a new single-port AP device with innovative optical glucose sensing technology.
Validate the new single-port AP in a preclinical setting.
The performance and applicability of the single-port AP device will be evaluated and optimised in a preclinical study and the control algorithm will be additionally evaluated using a novel in-silico approach.
Validate the new single-port AP in a clinical setting.
The performance and applicability of the single-port AP device and the complete single-port AP will be tested in clinical studies in adult and paediatric type 1 diabetes mellitus patients.
Project Results:
Main results
1) Development of a comprehensive coating technology.
At the start of the project a decision matrix was set up to choose a catheter material that is suitable for the application of the sensors. Infusion sets are available with teflon cannulas and steel cannulas. The medical experts of the paediatric diabetes centre in Luxemburg advised to use steel cannulas because of safety reasons. Teflon cannulas tend to kink during insertion and get blocked more often during wear time. Also from a technical point of view steel was considered the better choice because adhesion of the sensing layers is better on steel than on teflon. Positioning of the cannula during the coating process was easier as the steel needle is rigid and does not wiggle when it is rotated.
The surface of metallic catheters was investigated by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) measurements to gain information on the surface properties of the needles. The measurements proved that metallic catheters are coated with a silicon layer which was used to enhance wettability and adhesion by different pretreatment processes e.g. chemical surface pretreatment, atmospheric plasma and low pressure plasma. Surface pretreatment using low pressure plasma has been validated on two different infusion sets and on model steel needles: Medtronic SureT infusion sets for 90° insertion and Medtronic Polyfin QR infusion sets for slanted insertion. Water contact angle measurements have been performed to investigate the surface properties. As the measurements on the round circumference of the cannulas was very difficult the contact angle needed to be measured by the picodroplet method.
Development of the coating technology and development of the sensor chemistry was done in close cooperation of the responsible partners as the results from chemistry development had a direct impact on the coating development and vice versa. As adhesion turned out to become one of the most challenging parts of the project, many designs, chemical variations and layer structures of the sensor were developed and tested to meet the criteria for sensor adhesion. Alcoxysilanes and amino silanes were incorporated as adhesion promoters into the sensor chemistry and needed to be optimized regarding adhesion and sensor functionality.
To decrease shear forces during insertion and extraction grinded recesses as cavities were tested to take up the sensor layers. These cavities were 2 mm long and 35 µm deep. The recesses helped improve sensor adhesion by reducing shear forces during insertion and extraction. But the mechanical stability of the cannulas was reduced by the recesses due to additional reduction of the thin material thickness of the cannulas. Therefore the recesses were not used for the SPIDIMAN sensors.
As a quality control a specific method to test adhesion was developed. It included immerging the sensors into human plasma through artificial skin with a defined resistance. As wear time was defined with 72 hours the sensors were kept immerged for 96 hours before the sensors were removed through the artificial skin. Sensors and artificial skin are visually inspected under the microscope to determine damaged sensor surfaces.
Sensor chemistry was continuously adapted to the fabrication process. Further improvements of the layer structure of the sensors were implemented to improve adhesion. One major result was the incorporation of the catalase layer into the enzyme layer. Before that catalase was immobilized in the diffusion barrier layer which led to layer inhomogeneity and too high permeability for glucose of the diffusion barrier.
A machine for the sensor fabrication was developed within the project. The infusion sets were placed in specially developed holders that rotate around the catheter axis during operation. A 3-axis coating deposition system is driven using a camera system to follow precisely the trajectory of the catheter needle to avoid any loss of coating. The coating dosing system is based on an electric microjack acting on a syringe. The linear displacement of the jack and the coating deposition volume are directly linked by the syringe bore. A load cell was added in order to detect the contact during the approach phase of the jack. In order to anticipate a production pace that allows producing sufficient sensors for clinical evaluation studies, 25 catheter holders have been manufactured with a dedicated support to go through the plasma surface pre-treatment. At the end, the remaining manual operation steps needed were (I) the preparation of syringes in the dedicated carousel, (II) the installation of each catheter in the dedicated holders and (III) the installation of the catheter holder in the machine.
In vitro sensor performance tests were performed continuously accompanying the development process. Linearity of the sensors was found excellent during those tests. In vivo performance of the sensors, which was initially tested in preclinical trials, pointed out that there was still a sensor performance variation from sensor to sensor and from lot to lot, although big efforts were made to define a reproducible sensor fabrication process. The sensor fabrication process could be improved significantly in the extension time of the project when the aerosol jet technique became available. With this alternative fabrication technique sensor performance variations could be reduced significantly and were demonstrated in preclinical results.
The goal of the project to turn a new and innovative sensor concept in an artificial pancreas system turned out to be too ambitious for the project lifetime. Improvements of sensor performance, system architecture and fabrication process could be achieved. Adhesion of the sensor layers onto the infusion set cannula turned out to be the crucial hurdle that consumed a big deal of resources and time that could not be compensated. Therefore the sensor did not reach the maturity to drive a closed loop AP system and to be used in clinical trials in children.
2) Optimise the optical glucose measurement and control algorithms.
The first generation glucose reader was developed to perform in vitro sensor tests and system optimization. It was successfully used in preclinical studies for first in-vivo tests. Initial problems with hardware and software could be solved and a convenient analysis software was written. Additionally, non-sequential optical ray tracing was employed to estimate effects of catheter thickness, material and insertion mode on the sensor readout with the aim to facilitate the decision for a catheter type for the project. Experiments with laser diode excitation instead of LEDs were carried out but stopped, because space and energy requirements of laser diodes would be too high.
Figure 1: scheme of the measurement concept (left) and first generation glucose reader with 2€ coin for size comparison
Emission filters were used to selectively read out each indicator dye with one of the photodiodes. The glucose channel had a filter combination with band pass characteristics, transmitting between 725nm and 840nm while the reference channel was equipped with a long pass filter, transmitting above 840nm. The optoelectronic was enclosed in a cylindrical, black anodized aluminium body. The housing served as optical bench to align LEDs, filters and photodiodes and prevented unwanted tunnelling of light. It shielded against ambient light and protected the electronics. A Mini-USB connector was used to connect the device to the readout PC and to supply it with power.
The second generation glucose reader was a complete re-design based on the experience gained with the first generation reader and the requirements for the clinical use of the system. Additionally, features requested by the project partners responsible for system integration were incorporated for easy integration with existing insulin infusion sets. The second generation glucose reader was significantly reduced in size and weight (25mm diameter, 7mm thickness and approximately 5g) for convenient wearing by the patients in the clinical studies. To actualise this reduction in size, the digital part of the electronics was moved in a separate small housing and only the analogue optoelectronics were placed above the sensors on the skin. Slanted catheters and 90° catheters could both be used with the new design. The optics of the reader was of prime importance for the proper operation of the system. The two channels needed to be separated spectrally. In order to achieve this, excitation was done with two different LEDs, matching the absorption peaks of the two indicators as close as possible. The LED of channel 1 was equipped with a short pass filter that limits the excitation of the reference dye. The emission filter of channel 2 was equipped with a band pass that likewise reduces the excitation of the glucose dye. These filters were custom made interference filters on 4 x 4 x 0.5mm glass substrates. The emission filters were color glass filters with 4.5mm diameter and 2mm thickness which were custom coated with interference layers. In case of the glucose channel, the resulting filter had narrow band pass characteristics while the reference channel was a long pass filter.
Figure 2: second generation glucose reader and size comparison for first generation reader and 1€ coin (inset)
The PC software to operate the glucose readers was based on LabView®. It handled the communication of the device via the USB Port, allowed to change all relevant measurement settings e.g. measurement interval, LED intensities, photo current amplification, background correction etc. Measurement results were displayed graphically and logged to a text file. The user had access to all raw data for validation purposes. One instance of the software was used for each optical reader. Channel 1 and Channel 2 represented glucose and oxygen, respectively. In addition, the readers could be accessed directly via virtual COM Ports over the USB interface, using a simple set of ASCII commands. This allowed easy integration into custom software.
The housing was precision-milled out of aluminium. Optical filters were specified and custom build for improved spectral discrimination between the glucose channel and the reference oxygen channel. The electronical, optical and mechanical design allowed reading out both, 90° and slanted inserted sensors. Ex vivo tests with prototypes showed sufficient signal intensities with 90° inserted sensors, which is the preferred configuration for clinicians and also for the system integration. However, the slanted insertion remains an alternative if higher signal intensitiess or better discrimination between the channels would be necessary. The spectral separation of the two channels was investigated in a setup that allowed positioning a sensor spot symmetrically between the channels. By exchanging the sensor material, the cross talk between the two channels could be quantified and compared to similar measurements with the 1st Generation Reader. The main issue causing the cross-talk was the relatively broad emission spectrum of the channel 1 dye and the close absorption maxima of both dyes. The LED of channel 2 therefore also excited dye 1 and the emission of dye 1 was not fully blocked by the emission filter of channel 2. In the 1st Generation Readers, unacceptably high cross talk was the result. More than 70% of the signal in channel 1 could be seen in Channel 2. In the 2nd Generation Readers, the crosstalk from channel 1 to channel 2 could be reduced below 30%. The crosstalk from channel 2 to channel 1 is negligible with values between 1% and 2% in both reader generations.
Figure 3: concept of second generation glucose reader for readout of slanted (left) and straight inserted sensors (right).
3) Build a new single-port AP device.
In the first paediatric trial data was collected for the in silico modelling of the control algorithm that allowed adapting the algorithm to the young population. The participating children have been exposed to the use of a closed loop system, in the clinic (CRC) and at home. The outcome of this study was that more time was spent in target at home while using the closed loop compared to the open loop, and no major adverse events were observed in either group. A tendency for lower blood insulin levels and lower frequency of hypoglycaemia were observed when using the closed loop. The study clearly demonstrated that the use of the closed loop system in children between 6-12 years was feasible and well perceived by the patients and their family.
In order to combine glucose measurement and insulin infusion a software was created that calculated the glucose concentration from the raw data measured by the glucose reader, fed the information into the control algorithm that calculated the insulin infusion rate, and displayed measured glucose values and insulin infusion rate. Due to the technical issues faced in the sensor development part of the project a complete AP device could not be built because the sensor did not reach the maturity to drive a closed loop control algorithm.
4) Validate the new single-port AP in a preclinical setting.
The performance and applicability of the SPIDIMAN sensor was evaluated and optimised in preclinical experiments in pigs. The experiments performed included in-vivo sensor performance tests of the different sensor designs in clamp studies, assessment of the influence of insulin infusion and tissue oxygen variations on the glucose measurement. System usability topics like fixation of the sensor and the glucose reader, insertion and extraction of sensors and influence of insertion depth on sensor signal intensities were evaluated.
Figure 4: Preclinical sensor results: MARD 17.8 ± 3.4%
Beside the sensor tests in animals the control algorithm was evaluated using a novel in-silico approach. Numerical simulation tests were carried out to assess the effect of a subcutaneous continuous glucose sensor error on the performance and safety of the closed loop control algorithm. A compartment model was used to study pharmacokinetics of insulin Aspart during closed loop insulin delivery and utilised the obtained results in the development of the SPIDIMAN algorithm for the paediatric population. The model was used to measure time-to-peak of insulin concentration, insulin metabolic clearance rate and background insulin concentration. The findings from this study suggested that insulin dilution has no effect on its pharmacokinetics but may result in less variable insulin absorption. We concluded that diluted insulin could be used in children undergoing closed loop insulin delivery. The results from this study were used to improve our simulation model of glucose regulation in children with type 1 diabetes and the development of a synthetic population of children with type 1 diabetes.
5) Validate the new single-port AP in a clinical setting.
In the first period of the project a study to assess glucose / insulin profiles in children in the age group between 6-12 years was performed with an available closed loop system. It was discussed with the parent group of the Luxembourg Diabetes Association (ALD) and included two 17h afternoon-overnight profiles to increase insights on the intra-patient variability in this patient group which will help to improve algorithm validation for this age group. Not only venous samples for glucose and insulin will be used for the algorithm development, but also the obtained sensor data (interstitial glucose values) and the insulin pump data.
Sensor performance tests were performed in 3 clinical trials to assess sensor accuracy.
i) In the first clinical trial the SPIDIMAN sensors were applied on Medtronic Sure-T infusion sets which were inserted straight into the subcutaneous tissue. 12 patients with type 1 diabetes wore 2 SPIDMAN sensors each in the abdominal region. The patients received a standardized breakfast (60g carbohydrates) and an increased dose of their usual rapid-acting insulin analogue (180% of the patients’ calculated mealtime dose) was administered to cover breakfast (8:30) with the aim of inducing a period of minor hypoglycemia. The patients received a standardized lunch (60g carbohydrates) and again an increased dose of their usual rapid-acting insulin analogue (180% of the patients’ calculated mealtime dose) Patients performed an exercise test consisting of two 15 min session of cycling on a home trainer at 50% of individual VO2max separated by a 5 min rest. Individual sensors achieved excellent performance with MARD values between 7.9% and 14.7%. Taking all sensors into account an overall MARD of 22.5% was achieved.
Figure 5: Glucose profiles from clinical trial: reference blood glucose (red) and two sensors per subject sensor1 (blue) and sensor2 (green).
Figure 6: Error grid analysis of the corresponding sensor glucose profiles shown in Figure 5.
ii) In the second clinical trial the SPIDIMAN sensors were applied on Dana Superliner infusion sets which were inserted slanted into the subcutaneous tissue. 16 patients with type 1 diabetes wore 4 SPIDMAN sensors each in the abdominal region. Sensor analysis time was extended to 24 hours, glucose dynamics were induced by high glycaemic index food and increased dose of insulin (180% of the patients’ calculated mealtime dose). Patients performed an exercise test consisting of two 15 min session of cycling on a home trainer at 50% of individual VO2max separated by a 5 min rest. Again single sensors achieved excellent performance with MARD values below 10% during daytime. An overall MARD of 25.7% was achieved. Movement artifacts, especially during the night-time, were observed in this trial and prevented better results.
iii) In the third clinical trial the SPIDIMAN sensors were used on infusion sets for straight as well as for slanted insertion. Furthermore glucose concentrations were calculated online based on a two point calibration. 4 patients with type 1 diabetes wore 4 SPIDMAN sensors each, 3 in the abdominal region and one slanted inserted sensor on the upper arm. Sensor analysis time was 24 hours, glucose dynamics were again induced by high glycaemic index food and increased dose of insulin (180% of the patients’ calculated mealtime dose). Patients performed an exercise test consisting of two 15 min session of cycling on a home trainer at 50% of individual VO2max separated by a 5 min rest. Single sensors independent of the insertion type achieved excellent performance with MARD values below 10% during daytime. Slanted inserted sensors achieved an overall MARD of 22.4%, while straight inserted sensors achieved an overall MARD of 21.5%.
Figure 7: Comparison of slanted (green line) and straight (blue line) inserted sensors in one participant.
Figure 8: Comparison of glucose profiles calculated with retrospective (green line) and prospective (brown line) sensor calibration in one participant.
iv) A pediatric clinical trial with the SPIDIMAN single-port device was planned but could not be performed due to the insufficient maturity of the new sensor technology. Therefore the aim of the pediatric clinical trial was changed with the aim to build up the best knowledge about closed loop use in the population of young and adolescent diabetes patients. The study included data collection on the impact of the closed loop on metabolic outcome as well as on patient satisfaction in the poorly controlled adolescent population. Furthermore, we included information on the quality and quantity of sleep in this population.
Potential Impact:
Potential impact
The SPIDIMAN project will have a potential impact on type 1 diabetes patients, especially in the paediatric age group, on the industrial competitiveness of the participating SMEs and on European research networks between academic centers and research intensive companies.
1) Impact on type 1 diabetes patients
Although we did not reach our ambitious goal to develop a fully functional closed loop single-port artificial pancreas device, the SPIDIMAN project demonstrated an alternative sensor technology to the commercial electrochemical glucose sensors. The single-port concept combines continuous glucose monitoring and insulin delivery in one single device and needs only one access site to the patients´ subcutaneous tissue. Therefore the concept is still intriguing and will have a major impact on quality of life of type 1 diabetes patients. Comfort for the patients is increased by the reduced number of insertion sites and the familiar handling as patients can set and exchange the sensor just like a regular insulin infusion set which will in turn increase acceptance of the new technology. The improved acceptability of a single-port AP device will lead to improved compliance and, consequently, to better glycaemic control and improved quality of life. Assuming that the development of the SPIDIMAN system will continue and the necessary maturity will be achieved the SPIDIMAN concept could be especially suitable for children suffering from diabetes. It could offer an excellent treatment option for very young children due to the reduced number of tissue access sites and reduced size and number to be carried by the patients. This, in turn, could have an impact on minimising short- and long- term diabetes complications and the general wellbeing of the diabetic paediatric population.
2) Impact on industrial competitiveness
Most commercially available sensors for continuous glucose monitoring are currently developed and manufactured in the USA. The innovative new sensor developed in SPIDIMAN could dramatically increase industrial competitiveness in the biomedical sector in the area of diabetes management for European industries and could boost innovative leadership and competitiveness in an area dominated by US companies. Rescoll, as a service company developing and improving products for its customers, will be able to expand its network of contacts to receive interesting offers in the field of specialised coatings involving complex interface technologies, particularly in the field of medical device industry. Akira’s business has so far been focused on electro-mechanical engineering for the aerospace industry, the automotive industry and research laboratories. By participating in the SPIDIMAN project Akira will be able to apply its technical know-how to the new field of medical R&D in the biomedical sector. Pyroscience will be able to gain new expertise in adapting its existing optical oxygen sensing technology to the new analyte glucose. Pyroscience will gain valuable experience in adapting its current optical measurement techniques to several completely new application areas. The project might open very attractive business possibilities in the medical sector. Altogether, the outcome of the project should provide substantial opportunities for Pyroscience to increase its turnover and to create more jobs.
3) Impact on European networks
The SPIDIMAN project strengthened the link of academic and SME research and established new collaborations especially between Joanneum Research and the companies located in France. Also SPIDIMAN created a new partnership between the Centre Hospitalier de Luxembourg and the University of Cambridge for further development of the closed loop algorithm for the peadiatric age group. Those networks will stay alive after the end of the project and will strengthen European collaborations conducting multidisciplinary biomedical research.
List of Websites:
www.spidiman.eu
JOANNEUM RESEARCH – HEALTH
Institute for Biomedicine and Health Sciences
Project Coordinator Univ.-Prof. Dr. Thomas Pieber
Neue Stiftingtalstrasse 2
8010 Graz
Phone: +43 316 876-4000
Fax: +43 316 8769-4000
Leonhardstraße 59, A 8010 Graz
info@spidiman.eu
