spidiman

Project summary

  • EU FP7 Programme
  • Grant Agreement number: 305343
  • Project Full Title: SPIDIMAN - Single-Port Insulin Infusion for Improved Diabetes Management
  • Project start: November 1st, 2012
  • Duration:60 months
  • Total Budget: € 6.378.035,70
  • EU Contribution: € 4.941.739,00
  • Coordination: JOANNEUM RESEARCH  HEALTH – Institute for Biomedicine and Health Sciences 

Existing therapeutic devices for diabetic patients suffer from bulky size, inaccurate measurements and the difficulties of handling two body interfaces. Suboptimal control of blood glucose levels in type 1 or type 2 diabetes mellitus patients results in periods of hypo- and hyperglycaemia leading to severe and life-threatening complications. Exploiting a novel glucose sensor technology, SPIDIMAN aims to improve glycaemic management for better quality of life and healthier aging. The consortium will develop a new coating technology to apply a glucose-sensitive fluorescent dye onto a standard insulin catheter and incorporate this integrated glucose sensor into a single-port artificial pancreas system. Advanced optical continuous glucose monitoring technology (smart tattoos) with improved sensor accuracy, faster response times, wider dynamic range and higher signal stability will advance diabetes management by reducing hypo- and hyperglycaemic episodes. Within SPIDIMAN, research-intensive European SMEs will develop an innovative artificial pancreas approach, and experienced participants will perform clinical validation in a European network of specialized diabetes centres. SPIDIMAN will thus pave the way for a single-port device that integrates improved glucose measurement and more accurate insulin delivery to provide better glycaemic management in patients with insulin-dependent diabetes. The new device is expected to be particularly suitable for patients in childhood and adolescence, who will form a special focus group of the project.

 

SPIDIMAN objectives

The SPIDIMAN consortium aims 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 will integrate advanced glucose measurement and accurate insulin delivery in an artificial pancreas (AP) approach to improve diabetes management in adults and children suffering from insulin-dependent diabetes. To improve on continuous glucose monitoring, research at four European SMEs will develop a standard insulin catheter coated with a glucose-sensitive fluorescent dye to function as a new single-port AP. The coated insulin catheter is inserted into the subcutaneous tissue and will simultaneously be 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 will be tested in preclinical and clinical trials in a European network of specialised diabetes centres to improve glycaemic management of type 1 and type 2 diabetes patients as soon as possible.

To provide benefits to diabetes patients through improved management of glucose levels and a reduced frequency of out-of-target glycaemic values, SPIDIMAN will 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.

 

Medical concept

According to the WHO the number of people suffering from diabetes mellitus has risen to 346 Mio worldwide (WHO August 2011). In Europe alone 55.4 Mio people suffer from either type 1 or type 2 diabetes (IDF diabetes atlas 2010) resulting in health expenditures of more than €78 billion in 2010. 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 widely used by 90% of the 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 (1). But clinical studies showed a slight improvement of glucose levels only in adult type 1 diabetes patients but not in children and adolescents (2). 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 body-interface sites (two-port system) one port for glucose monitoring, and the second port for insulin delivery (Fig. 1). Such systems require handling of two devices and two body-interfaces, which results in low acceptance, in particular by paediatric patients.

Figure 1: The SPIDIMAN approach (left) will integrate an optical sensor for continuous glucose monitoring onto a standard insulin catheter and close the loop with a control algorithm to function as a single-port artificial pancreas to go beyond state-of-the-art CGM approaches (below).

The latest development 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 pump (3) but cumbersome technology (e.g. frequent alarms), a lack of accurate sensor technology and a lack of a fully tested and implemented algorithms are the main drawbacks preventing the use as an "all-in-one" artificial pancreas (AP) system. All systems currently employ amperometric CGM sensors that still suffer from limited sensor accuracy and insufficient dynamic range at low glucose levels due to electrochemical interferences of other substances being oxidised at the same working potential as hydrogen peroxide.

In order to provide diabetes patients and in particular paediatric diabetes patients with the advantages of tight glycaemic control, SPIDIMAN will overcome the limitations of current strategies to manage diabetes. The project aims to implement a novel approach for a single-port AP system employing an innovative optical sensor technology for glucose measurement that offers improved accuracy to control, via a specifically developed algorithm, an insulin delivery system with an improved safety profile at the hypoglycaemic range (Fig. 1, 2). This strategy builds on existing concepts wherever possible and will take full account of all safety, biocompatibility, interoperability and regulatory aspects. The fully functional SPIDIMAN single-port AP will offer higher tolerability and convenience for patients, more accurate glucose concentration measurements and insulin delivery with reduced side-effects.

Therefore, SPIDIMAN will clinically validate improved management of glycaemia by providing a convenient device that should be much more acceptable to patients of all ages and will accurately restore blood-glucose to near-normal levels. This will result in improved glycaemic control on the basis of CGM, and effective treatment to target glucose levels with a lower incidence of hyper- and hypoglycaemic events. This innovative approach to manage diabetes has therefore the potential to significantly reduce the burden diabetes imposes on patients by improving the quality of life and reducing vascular complications associated with this disease.

Figure 2: Schematic drawing showing the single-port SPIDIMAN device (left) compared to dual-port AP approach (right).

Figure 2: Schematic drawing showing the single-port SPIDIMAN device (left) compared to dual-port AP approach (right).

 

Technical concept

 

State-of-the-art CGM techniques suffer from the limitations of electrochemical signals which are affected by interfering substances in living tissue. In contrast to amperometric techniques optical pathways for CGM are less error-prone and more accurate over a wider range of glucose concentrations and in particular during a hypoglycaemic event when the signal-to-noise ratio is low. Innovative “smart tattoo” technology is based on the idea of using glucose sensitive fluorescent dyes in subcutaneous adipose tissue as sensors to measure glucose concentrations which are continuously transferred to an optical read-out system making "smart tattoo"-based sensors easier to use in-vivo. To implement wireless “smart tattoo” technology in living tissue, the fluorescent dyes have to be incorporated on some form of carrier which has to be implanted and explanted at the end of sensor life(4). SPIDIMAN will circumvent the need for long sensor life and sensor explantation by incorporating glucose sensitive dyes onto standard insulin catheters integrating the sensor into the disposable part of the AP system. In a preclinical glucose clamp trial at the Medical University of Graz, a proof-of-principle for a “smart tattoo” 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 support the finding that the accuracy of glucose measurements is not compromised by insulin delivery at the same site (5, 6). Sensor integration onto the insulin catheter also achieves thesingle-port approach as intended for the SPIDIMAN device. But to achieve a reliable, reproducible fluorescent sensor coating of standard insulin catheters a specialised coating technology has to be developed. SPIDIMAN will develop the new coating technology to apply a “smart tattoo” fluorescent dye on a standard insulin catheter and create an integrated “smart tattoo” glucose sensor with improved 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 can be closed into a closed-loop single-port AP system. All current closed-loop systems are in fact only semi-closed loops as the algorithms are only able to respond to existing glucose levels. Prandial insulin dose still have 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 glucose levels. Therefore, to match current terminology the SPIDIMAN single-port device will be considered a closed-loop system.

Such a closed-loop AP 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.