Degenerative diseases and various forms of cancer are a frequent subject of research in many of Lower Normandy’s laboratories. And a number of these laboratories are located within the extremely propitious eco-system offered by the Jules Horowitz campus in Caen’s northern technology platform.

Increasingly efficient hip prostheses | Animal models renowned across Europe | Creation of the Lower Normandy Regional Cancer Institute (IRCBN)

Increasingly efficient hip prostheses
The Hérouville-based subsidiary of the American firm Stryker®, Stryker Orthopaedics Benoist Girard, designs and manufactures orthopaedic prostheses (essentially for hip replacement), together with the various instruments required for the associated surgical procedure. An average of 550,000 hip prostheses (stems and cups) are produced every year. The company has three ongoing research priorities to anticipate market changes:
• A clinical trial is currently underway to validate an innovative cup or acetabulum (the upper part of the hip), which is thin and flexible enabling micro-movements of the pelvis to be followed and to restore the patient’s own physiology. This cup is produced using a polymer which is rich in carbon fibre, a material that has never, to date, been used for this type of implant.
• A thesis is currently underway in partnership with the ENSIETA in Brest and subsidised by Europe and the Region (ERDF), for the development of a new and faster method for testing the reliability of implants before they are marketed. The results of this work should also enable manufacturing processes to be improved and more quickly validated.
• A further thesis is underway in collaboration with the UTC in Compiègne, the aim of which is to develop digital simulation tools and models capable of anticipating bone remodelling (bone regrowth) around the prosthesis. Regulatory requirements before marketing a new implant are increasingly strict, and it is essential to develop tools capable of predicting bone behaviour after hip replacement.

Animal models renowned across Europe
The “Serine Proteases and Pathophysiology of the Neurovascular Unit”  team, coordinated by Denis Vivien , is currently developing extremely innovative animal models of cerebrovascular accidents, also referred to as stroke. “The principle involves creating, in an animal that is physiologically comparable to man - such as a rat or a mouse, dysfunction that is similar to that observed in humans,” explains Denis Vivien. After having developed, on cell cultures, antibodies that are capable of fixing onto neurones and of rendering them more resistant to stroke (patent pending), we now need to control their potentially noxious effects. “Only tests on living organisms can provide an answer to that question. Given the risks involved, it’s impossible to use them directly on man. So we start by testing them on an animal model.” These models are not prone to cerebral ischaemia, so we need to provoke it. “We form a blood clot on site to obstruct the animal’s cerebral artery. The method is innovative compared to the electrocoagulation technique used to date. It enables our research to approach, even closer, the human model. And with this type of animal model, we can use the same tools as physicians do to monitor their response to treatment .” The initial results on these animal models are extremely promising. These tests, also referred to as “preclinical”, are consequently being pursued. The innovation is of interest to European teams, in particular the EUROSTROKE network, of which Denis Vivien is a member. “Our aim is to create a national platform for testing new molecules on the animal models we develop. That’s more or less the reality right now, however we would like to add IBISA* certification.” *Infrastructure in Biology, Health and Agronomy The animal models of stroke developed by Denis Vivien’s team are interesting European teams working in the same field.

Creation of the Lower Normandy Regional Cancer Institute (IRCBN)
The Lower Normandy Regional Cancer Institute (IRCBN) is gradually taking shape. The foundations have already been set in January, with the officialisation of the Groupement de Coopération Sanitaire (health cooperation group). The group reunites the University Hospital (CHU) and the François Baclesse Comprehensive Cancer Centre on joint health care and research projects. University teams working in the field of cancer will also be joining the duo. “The aim of the IRCBN is to organise the various players involved in order to achieve excellence in cancer care,” explains Khaled Meflah, director of the François Baclesse Cancer Centre. The newfound institute should reinforce exchange between these players, encourage the emergence of new projects and, in particular, offer improved national exposure for Lower Normandy’s efforts in the field.

The ARCHADE project, in particular, aims to create a European Hadrontherapy Research Centre which will be established within the grounds of the GANIL facility. Hadrontherapy is a new and particularly promising radiotherapy technique for treating certain cancers. It enables the tumour to be accurately targeted whilst safeguarding surrounding healthy tissue. “Research conducted within the framework of ARCHADE essentially involves hadrontherapy using carbon ions. This novel solution could well resolve the problem of radio-resistance that certain forms of cancer can develop,” explains Professor Jean Bourhis, the project’s scientific director. The ARCHADE centre will be relying on a partnership with the IBA Group and regional industrial firms for the construction and perfecting of a cyclotron capable of delivering protons and carbon ions, the particles that are used in hadrontherapy. The centre should be operational by 2014 and it will be the first of its kind across the globe. Consequently, the development of an associated industrial sector likely to generate many job creations throughout the region, is another of ARCHADE’s interesting development aspects.

And although emblematic, it is not the only example of technological innovation in Lower Normandy. Several research teams from public institutions ⁽¹⁾ and private laboratories develop and use innovative processes, both to enhance our knowledge on disease and to implement new therapeutic modalities.

Innovating to understand disease

Radiotracers
The “Positron Emission Tomography Methodology Development Group”, coordinated by Louisa Barré, develops “new generation” radiotracers. The American firm AVID was looking for French imaging centres likely to use one of their molecules, recently developed as a diagnostic tool in Alzheimer’s disease. Centres in Caen, Tours and Toulouse were selected. “We have adapted our molecule to suit European regulations so that it can be used on humans. Contrary to the PIB (Pittsburgh Compound-B), marked with carbon 11 and widely used for this disease, AV45 is marked with fluorine-18, has a longer lifespan and can be distributed and used in hospitals,” adds Louisa Barré. The development of this radiotracer has recently led to support granted within the framework of two national research programmes.

Image analysis software
Another innovative technology associated with understanding disease: image analysis software. Five years ago, the GINLANG or “LANGuage Neurofunctional Imaging Group”, managed by Nathalie Tzourio-Mazoyer, produced the AAL (Anatomical Automatic Labelling) software package. It enables an accurate representation of the anatomical structure of a specifically targeted zone within the brain. A development that has led to the publication of several scientific papers. Another software package, entitled WHALE (White matter Hyperintensignal Automated Longitudinal Evaluation) was finalised early 2009, after 15 years of research, by Bernard Mazoyer and the GINDECO or “Conscious States Neurofunctional Imaging Group”, managed by Marc Joliot. The aim of the application is to detect lesions within the brain’s white matter, for they are markers of age-related diseases. “This application also offers the opportunity to monitor how these lesions evolve over time,” explains Bernard Mazoyer, Director of the Ci-Naps and Professor at Caen University. The “U923 INSERM unit, mixed INSERM-UCBN-EPHE research team in Cognitive Neuropsychology and Functional Neuroanatomy of the Human Memory” managed by Francis Eustache, is also involved in the development of image analysis techniques. “Several members of my team are currently working on a procedure for the medical image registration of MRI and PET images, or for the correction of image deformations observed during functional MRI,” explains Francis Eustache. Tools that contribute towards improving the diagnosis and the analysis of neurodegenerative diseases.

Therapeutic research

Transcranial magnetic stimulation
On the therapeutic research front, the “Schizophrenia Neurofunctional Imaging Group”, managed by Sonia Dollfus, has been developing over the past four years, in partnership with the Esquirol psychiatric centre and the CHU’s department of functional exploration of the nervous system, a therapy aimed at treating auditory hallucinations in schizophrenic patients. “We use high frequency repetitive Transcranial Magnetic Stimulation (rTMS) guided by anatomofunctional imaging and neuronavigation. It is a totally pain-free and straightforward technique, consisting in stimulating neuronal circuits by creating a magnetic field around the stimulated zone, which is detected via cerebral imaging.” Neuronavigation-guided transcranial magnetic stimulation is, as yet, not widely used in France, but it is an established technique in many other countries. However, to date, only low frequencies have been used. The choice of using high frequencies is a genuine innovation in the field. “The man behind the idea is Olivier Etard, a UCBN lecturer and hospital practitioner at the CHU in Caen. He considers that the common belief that high frequencies excite, whereas low frequencies inhibit cannot be generalised to all zones of the human brain.” Since October 2009, the project has been the subject of a controlled study aimed at validating its therapeutic efficacy. Over two years, a total of 72 patients will be treated with these new methods, throughout seven French health care centres. And to help pursue its efforts, the team has already been granted a budget of €250,000 by the French Ministry of Health within the framework of its hospital clinical research programme (PHRC). “We obtained encouraging results in eleven patients during a recent pilot study. Two of them were cured from persistent hallucinations thanks to high frequency rTMS,” notes Sonia Dollfus.

Neuroprotective gases
Other therapeutic strategies, other technological innovations: gases used as neuroprotectors in the treatment of cerebral ischaemia. “They are essentially noble gases which are present in the natural atmosphere and offer the advantage of being metabolically inert and devoid of adverse effects,” explains Jacques Abraimi, in charge of the “Pharmacology and Formulation of Gaseous Drugs” ERT 1063 - Technological Research Team (a label awarded by the Directorate General for Research and Innovation). In 2001, the neuroprotective properties of these gases was demonstrated on cell cultures in vitro. Then in 2003, Jacques Abraini’s team was the first to demonstrate the same properties in vivo on a cerebrally ischaemic animal model; a joint discovery with a competing American team. Since, “we have not only demonstrated that xenon has a neuroprotective effect but, furthermore, that it can block the noxious effects of thrombolytic agents ⁽²⁾ which can favour cerebral haemorrhage.” The team has also, more recently, demonstrated the neuroprotective effects of helium. “We are now working on the possibility of combining xenon and helium to obtain an optimal neuroprotective effect,” details Jacques Abraini. And the team’s research is also benefiting from industrial support, “We have been working in partnership with the Canadian biotech firm NNOXe Pharmaceuticals, since 2003, and the French Health Service of the Armies with which we are planning the creation of a joint research unit.”

Technologies for health care

Technological innovation is not a privilege reserved for public research. Private laboratories and businesses are also investing in the field.

Intraocular pressure sensor
Ophtimalia is a brand new NXP spin-off, currently accommodated with the Incubateur de Basse-Normandie and is working on electronic solutions for the diagnosis and treatment of eye diseases. Its first innovation: an intraocular pressure sensor “The aim is to improve the diagnosis and treatment of glaucoma. High and fluctuating ocular pressure is a characteristic of this disease. By measuring it over time, the device facilitates the detection of such pressure. The sensor should also facilitate the adaptation of treatment, which is often a lengthy affair,” explains Peter Biermans, the company’s director. The system involves a sensor which is integrated within a contact lens, and a receiver located on the arms of glasses. “The particularity of our technology lies in its affordable price. It’s an important aspect since our ultimate aim is to organise screening campaigns,” explains Peter Biermans. The idea of developing this system truly emerged following a request from the director of the Institut de la Vision in Paris. “We then conducted a market study, which confirmed a high demand.” Developed in close collaboration with the Institut de la Vision, the project is currently in its development phase. The preclinical validation phase should be complete by late 2010.

Hearing aids
Laboratoire Cotral, located in Condé-sur-Noireau, is also innovating, but in a different field. And rather than treatment, the laboratory is investing in prevention. Alone, it represents 50% of the French market in tailor-made hearing aids. “Our aim is to develop products that are comfortable, so that they can be worn on a permanent basis, which is the key to their efficiency,” explains Gwenolé Nexer, Cotral’s technical director. And with that goal in mind, the laboratory has been working on new Cyrlit© aids, which are digitally modelled based on an ear impression. “3D manufacturing offers a product that is almost a perfect replica of the ear. We have also been working on standardising the frequency of the acoustic filters inside our hearing aids.” These filters, which are integrated within the ear plug , enable the sound level to be adjusted as required. The project is now in its certification phase and the product is due to be marketed in the near future.

Glucotep
Concurrently, the Caen-based pharmaceutical laboratory Cyclopharma is shortly due to launch production of GLUCOTEP - (18F)-fluorodeoxyglucose. “GLUCOTEP is a radiopharmaceutical capable of detecting, via a TEP camera (Positron Emission Tomography) energy-consuming cells, in particular cancerous cells,” explains El Amine Chentouf, Cyclophrama’s production pharmacist. Nuclear physicians have been familiar with (18F)-fluorodeoxyglucose for several years now, for it offers adequate image resolution for the diagnosis of certain cancers. A vast array of innovative technologies developed and used throughout Lower Normandy and offering the region excellent exposure on the national and European scene.

(1) The research teams presented in this report are all from the Ci-Naps - Centre for Imaging - Neuroscience and Applications in Pathology (CEA-CNRS-UCBN-University of Paris Descartes).
(2) Injected to destroy the blood clot responsible for cerebral ischaemia.

Jean Bourhis
Scientific Director for the ARCHADE project
Tél. : 06 83 81 53 98

Khaled Meflah
Director of the François Baclesse Cancer Centre
Tél. : 02 31 45 50 50

Pascal Collet
Manager for STRYKER ORTHOPAEDICS
Benoist Girard
Tél : 02 31 46 34 00

El Amine Chentouf
Production Pharmacist for Cyclopharma
Tél : 02 31 53 23 00

Gwenolé Nexer
Technical Director for Cotral
Tél. : 02 31 69 36 36

Peter Biermans
Director of Ophtimalia
Tél. : 06 27 21 16 15

Denis Vivien
Manager of the “Serine Proteases and Pathophysiology of the Neurovascular Unit” team
Tél. : 02 31 47 01 66

Louisa Barré
In charge of the “Positron Emission Tomography Methodology Development Group”.
Tél. : 02 31 47 02 24

Jacques Abraini
In charge of the “Pharmacology and Formulation of Gaseous Drugs” team
Tél. : 02 31 47 01 02

Sonia Dollfus
In charge of the “Schizophrenia Neurofunctional Imaging Group” team
Tél. : 02 31 06 50 18

Bernard Mazoyer
Director of the Ci-Naps and Professor at the University of Caen
Tél. : 02 31 47 02 71

Francis Eustache
In charge of the INSERM- UCBN-EPHE “Cognitive Neuropsychology and Functional Neuroanatomy of the Human Memory” joint research team
Tél. : 02 31 47 02 25

Send post as PDF to