HYbrid BIOelectronic endocrine PAnCreas Sensors (Screening and therapy in diabetes) – HY-BIOPACS

We used as a first step the development of a drug/toxicological screening device with automated signal interpretation ready for long-term and online functional exploration of islets relying on their electrical activity. This activity is measured, conditioned and processed in real time using dedicated integrated circuits. Data can be displayed online or stored for fruther processing. Low power/low cost submicronic technologiesare used for electrodes and intergated circuits. Experiments are conducted using murine primary beta cells and islets cultured on multielectrode arrays.

We have optimized the electrodes and their coating. We have established the response to glucose and to hormones and ascertained that signals can be treated by implanted algorithms. Integrated numerical circuits for spike detection have been tested. A portable system for acquisition has been developped capable to process 60 channnels in real time. Further algorithmes and on-line processing can be implemented in the system. A patent landscape has been established and a market study was conducted.

We have developped a first prototype of a embedded bioelectronic device able to process and detect glucose and hormone level out of islets electrical activity. We expect this device to allow automated insuin delivery for diabetic patients.

1 international patent «SENSOR FOR MEASURING THE ACTIVITY OF BETA-PANCREATIC CELLS OR OF
ISLETS OF LANGERHANS, MANUFACTURE AND USE OF SUCH A SENSOR«; 1 prototype device (see Illustration section); 2 conference proceedings, 1 book chapter, 1 original article; 2 original articles in preparation.

Diabetes mellitus is a serious, debilitating, currently incurable, costly disease that afflicts some 220 million persons worldwide. An alarming progression has been observed during the last decade including in the young. Diabetes implies deficient insulin secretion from pancreatic islets in type 2 diabetes mellitus (T2DM) or their destruction leading to absolute insulin deficiency in type 1 diabetes (T1DM), which counts for about 5% of all cases.

Our project addresses two major issues:
1) Functional screening of healthy or diseased beta-cells/islets is cumbersome and precludes continuous long-term observations. This represents a major obstacle in view of the considerable vulnerability of these cells and the clear need to identify new therapeutic targets.

2) Insulin therapy is mandatory for T1DM. Multiple daily injections and repetitive blood controls present a major nuisance and pose the problem of difficult dosage adapted to everyday life. Continuous glucose monitoring (CGM) linked to insulin pumps (“artificial pancreas”) improves life quality, reduces long-term complications and is cost-effective. Currently available glucose sensors measure only one parameter (glucose) and have major drawbacks in reliable detection of life-threatening hypoglycaemia, response lag-time and capacity to scope with changes in everyday life. This precludes their autonomous function as closed loop. In contrast, islet cells integrate numerous chemical and hormonal parameters in a first read-out, electrical activity resulting in action potentials. They act as real “biological sensors” for the insulin need.

Combining our expertise in pump treatment, beta-cell physiology, neuronal circuitries, cell-microelectronic interfaces and technology transfer, we propose a novel approach. As documented by our joint publications, preliminary data and patent filing, we have been able for the first time to reproducibly record and analyze tiny action potentials from b-cells for a prolonged time period and their glucose/hormone dependency. Our project will employ
- Islet as sensor, i.e. cells that have been shaped during evolution to detect precisely the need in insulin
- Smart micro-electrode arrays including conditioning and analysis on-chip functions and microfluidics implementation.

Our 3 major objectives are:
-A drug/toxicological screening device with automated signal interpretation for long-term and online functional exploration of islets. This device is marketable.
-An external closed loop sensor as a prerequisite for the second phase beyond the granting period, i.e. the development of an implantable sensor in man and overcoming important drawbacks of current sensor technologies.
-A patent licensing agreement, a know-how licensing agreement or a mixed patent/know-how licensing agreement with an industrial partner.

We propose to validate (using experiments as well as a models) and document individual items to be integrated in the final products (months 6), to optimize the processing chain by integration on low power microelectronics and real-time computation (month 12), to specify and fabricate active MEA devices (month 18) and finally to prototype the screening and glycaemia-control devices. The project is organized in tasks organized in a bottom-up approach including the TTO to optimize transfer:

Task 1 (leader IECB): Biological preparations, recordings for micro-electrode arrays:
Task 2 (leader IMS): Signal conditioning and processing, microelectronics integration of smart sensors
Task 3 (leader VALO): System integration, device prototyping, technology transfer, patent issues and qualification according to legal/regulatory framework.

Our project contains several patentable issues in addition to the two prototypes. We expect to have established within the 24 months links with an industrial partner interested in the project and its evolution. This partnership may intervene at different positions in the value chain.