Claire Masalski |Communication officer
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The Defymed SME
The Univercell-Biosolutions SME
The Laboratory of experimental surgery of the Université Catholique de Louvain (UCL)
June 2017 |
Study Center (for Centre européen d’étude du Diabète or CeeD) and initiated by a CeeD spin-off, the
start-up Defymed (developer of the MAILPAN® bioartificial pancreas). The BIOSID consortium, which
brings together five other expert bodies, has culminated in a positive outcome thanks to results
which will soon be possible to put into use.
Funded by the European Commission via the 7
Framework Programme for Research and
progress for the bioartifical pancreas MAILPAN®, thus speeding up its development.
MAILPAN® is now on track to achieve its primary goal: application in humans. Something that
could see the hopes of more than 40 million insulin-dependent diabetics across the world become
Type 1 diabetes: treatments to be improved
Despite constant scientific and medical advances, today diabetes is still incurable. To take care of
themselves, type 1 diabetes patients are forced to inject themselves each day with the insulin they
need to regulate their blood sugar properly (since their body no longer produces it), either by
injection (syringe or pen) or by pump – and this for lifetime.
Although whole pancreas transplant and pancreatic islets transplantation (or islets of Langerhans)
allows these patients to receive a more physiological treatment (in the short or medium term), these
pancreas donors, but also to potentially toxic anti-rejection treatments, these procedures are
reserved for extreme and unstable cases of type 1 diabetes, which represent only about 100 people
in France for example. But nearly 40 million people worldwide currently suffer from this type of
The MAILPAN® device, an alternative that carries hope for patients
Smaller than a CD, the MAILPAN® takes the form of a pouch or pocket designed to be implanted into
a patient's abdomen. This is designed to contain insulin-secreting cells in order to replace the
patient’s pancreatic islets and respond autonomously to their body's insulin needs.
If the MAILPAN® project is successful, patients would find themselves significantly or even
completely freed from the constraints of multiple daily insulin injections: their everyday life would
BIOSID has a track record of more than 15 years of research relating to the MAILPAN®: At the
beginning of this project the CeeD developed and piloted two initial European programmes, FP4 and
FP6, which were also funded by the European Commission. This led to the creation of the Defymed
Starting in 1996, the prototype was developed by the CeeD in a series of stages that led to the
creation of the Defymed SME in 2011.
To ensure all the chances of success of this project, the CeeD and its spin-off Defymed, two French
complementary fields of expertise. In this case:
the Department of Endocrinology, Diabetes and Nutrition from the University Hospital
AvantiCell (ACS), a Scottish SME- UK
The consortium’s expertise includes encapsulation techniques, islet isolation, cell engineering, islet
transplantation, islet preconditioning, surgical implantation, and medium formulation; items that are
complementary and essential for the implementation of the present project.
Positive results that it will soon be possible to put into use
With over 5 million euros of funding from the European Commission (FP7) over 4 years, BIOSID has
animals in preparation for proceeding to the clinical phase with this device in humans.
BIOSID has made it possible to better understand physical and chemical conditions present inside
the MAILPAN® device while developing various strategies aimed at reducing harmful effects on the
cells, such as inflammation or hypoxia. These have included formulating a novel culture medium,
BIOSID has also made it possible to develop a new generation of insulin-producing human cell lines.
Several fields of applications have already been identified for the future commercial exploitation of
these various products.
At the same time, studies have helped to support and confirm preclinical data on biocompatibility,
safety and functioning of the MAILPAN® in small and large animals. This is done in order to meet
regulatory requirements in force for this type of medical device and thus ensure that the first
implantation is without risk for the patient.
Finally, the BIOSID project has made it possible to optimise the development of the MAILPAN®, as
a future physiological solution for type 1 diabetes patients. Defymed continues to test insulin-
secreting cells from different sources (supplied by international partners) in combination with the
MAILPAN® on animals, in order to select the most suitable cells for the device. At the same time,
the start-up will also go through all the regulatory steps to obtain an authorisation to proceed to
the clinical phase with this combination.
In 2014, diabetes affected 422 million people worldwide, compared with only 108 million patients
240 million people by 2025 ... The forecasts from these two bodies are all the more worrying because
they predict 550 million diabetic patients for 2025 and 642 for 2040: in the very near future, one in
10 adults will be affected by diabetes – and this without taking into account the fact that almost
50% of diabetics worldwide are not diagnosed (40% in Europe).
One person dies of diabetes in the world every 6 seconds: the number of deaths attributable to
diabetes is 3.7 million a year worldwide (43% of which before the age of 70) and this figure is
expected to reach 5 million by 2025. By way of comparison, in the same year AIDS will have been
responsible for 1.5 million deaths and malaria for 600,000 deaths. Furthermore, a recent study
published in the journal Plos One
showed that the mortality statistics associated with diabetes were
this disease now accounts for the cause of death in 12% of cases in the United States, which is to say
three times what was previously estimated.
It should also be taken into account that diabetes exposes patients to complications: it multiplies
myocardial infarction or stroke by 2. Diabetes remains the leading cause of acquired blindness in
adults and can have a dramatic impact on the quality of life of diabetics, especially in cases of severe
The financial impact
Diabetes also has indirect consequences on the national health care systems and economy through:
the loss of earnings associated with decreased productivity;
the degenerative complications caused by diabetes, such as blindness, kidney failure or
general state of health is usually severely impaired.
The cost of diabetes to society naturally reflects the seriousness of this chronic disease. It accounts
for between 5 and 20% of the health budgets of the developed countries (on average, 12.5%).
Resolution 66/2. Policy statement of the General Assembly High-level Meeting on prevention and control of
Deaths Attributable to Diabetes in the United States-Comparison of Data Sources and Estimation Approach,
Currently estimated at $673 billion worldwide, it is forecast to cost $802 billion in 2040 ($156 and
To be fully effective, the treatment used by a diabetic has to be complemented by high-quality
dietary and general health management measures, in the form of a balanced diet and regular
physical activity. For the most part, patients find that implementing and above all maintaining these
measures over time is a very negative experience, and one in which the doctor often gives only very
More and more medicines, including but not restricted to insulin, require self-injection by pen or
precisely according to their needs- which is not the case when a diabetic receives the same hormone
as a treatment. The patient therefore has to monitor their capillary blood glucose by taking sample
drops of blood, which is also essential in order to give advance warning of any complications.
A diabetic who treats himself for 20 years, with 3-4 insulin injections and the same number of
glucose checks every day, will have jabbed himself with a needle nearly 50,000 times.
Diabetes can lead the diabetic - like many patients with a chronic condition - to become veritably de-
experience deterioration in their quality of life due to difficulties with social and professional
Hence the specifications of what is to become the treatment for diabetics in years to come, namely
a treatment that is the most automated possible:
Finally making it possible to have a high quality social, professional and family life.
A disease on the rise
For nearly 20 years now, the prevalence of type 1 diabetes has been increasing by 3 to 4% a year
worldwide. It has also been found that the onset of this disease is occurring earlier and earlier,
particularly in children under 5 years of age; in fact it is one of the most common endocrine and
metabolic disorders in children. In 2015, figures from the International Diabetes Federation (IDF)
indicated that children with type 1 diabetes numbered over half a million worldwide. Various reasons
for this increase have been suggested, such as diet, exposure to endocrine disruptors, increased
maternal age etc. The main cause of this exponential increase is thought to be environmental
changes interacting with the genome.
progressive destruction of the islets of Langerhans (pancreatic cells) which are responsible for the
secretion of insulin. It is this hormone, insulin, which regulates blood sugar levels. As their body no
longer manufactures it, patients are thus forced to inject themselves with insulin throughout their
life in order to control their blood glucose. Without insulin, patients cannot survive their illness. They
must also monitor their blood sugar, keep to a healthy diet and practice physical activity. Failure to
continuously monitor and control diabetes most often leads to the development of complications
(affecting the heart, blood vessels, nerves, eyes and kidneys) in the medium and long term, which
places a heavy burden patients and those around them.
It affects people of any age, this disease most commonly develops before the age of 20. Symptoms
fatigue, abundant urine etc.
The BIOSID consortium has made it possible to speed up the development of the MAILPAN® and to
ensure that this treatment – that offers such hope – could have every chance of success.
In comparison with current treatments for type 1 diabetes, the MAILPAN® bioartificial pancreas is
thought to be able to offer numerous advantages that could significantly improve the quality of life
of many diabetic patients.
Three functions are essential for the bioartificial pancreas:
Protect the transplanted cells from the recipient's immune system
Protect the recipient from the transplanted cells
Maximize the function of the transplanted cells
The development of a bioartificial pancreas would be based on an effective immuno-isolation of
insulin-secreting cells based primarily on their encapsulation using artificial membranes
impermeable to molecules involved in the rejection but permeable to glucose, insulin, oxygen
Therefore, no immunosuppressive therapy would be required. This physiological solution would
allow cellular therapy to become a widely deployed reality.
The MAILPAN® would control the patient’s blood glucose physiologically: the patient no longer
needs external insulin input.
Choosing to implant the MAILPAN® into the patient’s abdomen would make it possible to render
Thanks to the MAILPAN® in case of success, the patient would need only simple, routine visits to
emptying/re-filling procedure carried out through the input and output ports placed under the
Moreover, this device would have no electronic components and would have the advantage of
isolated from human donors, porcine islets or even stem cells) some of which are available in
a medical device.
pancreas, called MAILPAN® (macro-encapsulation of pancreatic islets) to design an implantable device for
macro-encapsulation of insulin-secreting cells in humans. This work was conducted in partnership with
STATICE (Besancon) and with the Centre de Transfert de Technologie du Mans (CTTM).
This project involved the validation and integration of multiple technological steps, of which the first two
encapsulation using semi-permeable artificial membranes.
The BARP+ project developed within the 6
OCRD framework (2004-2007) which defined
expected features: filling capacity, biocompatibility, implantation and function.
At this stage, it was then necessary to change the system for a qualified medical device for its placement
Since its foundation, Defymed was rewarded several times, receiving in particular:
The national competition award for the creation of innovative technology companies in the
"Emergence" category and the Innovation Award for the Alsace Region (2010)
The national competition award for the creation of innovative technology companies in the
"Creation-Development" category of the Ministry of Higher Education and Research (2011)
First prize winner of the “Tremplin Entreprise” contest of the French Senate in the category “Life
Laureate of the “Universal Biotech” contest (2011)
Winner of the “Fond’Action Alsace” price in the category “Talent of the future”
“Innovative companies” label obtained of the French Bioclusters (2012)
Winner of the Fast 50 Deloitte-In Extenso prize (2014)
First laureate of the « Inventer demain » Award (2015)
Special award from INPI and gold medal with the jury mention at the 44th international
inventions tradeshow in Geneva (2016)
Winner of the Medstartup- Galien Awards 2016 – Category ” Best Innovative trial design leading
to quicker and better therapeutic outcome” (2016)
The European Diabetes Study Center (in French, Centre européen
Structure of translational research, the CeeD combines physicians and researchers to respond via
Its main objectives are to:
develop new prevention and treatment models for patients;
initiate and drive innovative projects alongside the best European research
BIOSID project coordinator, the CeeD has extensive coordination experience through the 2 European
projects, BARP (4th FPRD) and BARP+ (6th FPRD), which gave rise to the current MAILPAN®
bioartificial pancreas prototype. The BARP+ project was recognized as a "Success Story" by the
European Commission. During these two projects, 3 patents protecting the MAILPAN® were filed and
numerous scientific publications in international journals.
In addition to coordinating the project, the CeeD worked on understanding the needs of the islets in
terms of viability and function. Thus, the CeeD mobilized its research teams in order to study the
behavior of islets in the MAILPAN®.
take advantage of ACS processes for additive manufacture of 3D cell culture models, and Cryotix™
cryopreservation technology which will allow advanced cell systems to be delivered to customers in
user-friendly “plug and play” formats.
Role in the BIOSID project
secreting cells within the bioartificial pancreas, and to maintain their secretory function. ACS
systematically tested a range of medium formulations, using its cell-based analysis platforms to
evaluate effect on pancreatic islet ß-cell viability and glucose-dependent insulin secretion of media
containing different combinations of protective agents. Cell-based analysis was performed under
hypoxic conditions likely to reflect initial cell filling of the MAILPAN® device. The ultimate formulation
arrived at through a series of incremental improvements was then used to commission the first
commercial manufacture of culture medium customised for MAILPAN® use, creating the opportunity
for scalable manufacture to industry-compliant quality standards.
This work was performed in close collaboration with project partners, and took advantage of the ACS
network of collaborations built through participation in multiple European programmes, which gave
access to other valuable, leading-edge cell-based technologies.
department contributes to a collaborative group for innovative technologies in drug infusion with the
Association for Helping Patients Treated by Drug Infusion (AMTIM) dedicated to the clinical trials of
innovative medical devices for the treatment of diabetes (implantable and external pumps and the
artificial pancreas). The UHC of Montpellier is also experienced in the isolation of human pancreatic
islets and in the study of mechanisms involved in the survival of islets, before and after
transplantation in humans. The UHC of Montpellier has participated from 2003 in the GRAGIL
network (Rhine-Rhone-Alps Geneva Group for the transplantation of islets of Langerhans). The UHC
has been involved in several European programs (7th FPRD and others) and its experience in the
conduct of such projects is a great advantage for BIOSID.
Its role in BIOSID will mainly focus on following tasks:
the isolation of human pancreatic islets from donors,
the understanding of the needs of insulin-secreting cells in the bioartificial pancreas, in
islets in the MAILPAN®.
of the most developed. Their work on the isolation of pancreatic islets began in the 80s, for
applications in research, while clinical application began in the 90s. This department has access to
unique facilities for the isolation of human pancreatic islets under GMP conditions, with
transplantation success that exceeds 70% of transplant patients.
NDS worked closely with the CeeD to understand the needs of insulin-secreting cells in the
bioartificial pancreas and provided the answers necessary for their survival in it. In addition, this
public department intervened in the supply of MAILPAN® with human pancreatic islets for clinical
trials and performed a part of these tests, at Oxford.
The first product designed by Defymed is a bioartificial pancreas intended to be implanted in diabetic
MAILPAN (macro-encapsulation of pancreatic islets) is in the form of a pocket having functions of a
bioartificial pancreas, which once implanted will be filled with insulin-secreting cells. Defymed’s
strength is based on its network of national and international partners, including historical partners
such as the CTTM (Centre de Transfert de Technologie du Mans) and STATICE. Defymed has a unique
technology which enables it to shape these medical devices to respond to other therapeutic
As owner of the bioartificial pancreas MAILPAN®, on which the BIOSID project is based, Defymed is
responsible for managing the exploitation and dissemination of the BIOSID project. The team from
the start-up also investigated the biocompatibility and function of the MAILPAN® device in preclinical
phases in small and large animals, with a particular focus on the regulatory aspects related to these
studies. Finally, Defymed was responsible for the design and manufacture of MAILPAN® adapted to
the model used (small or large animals and humans) for the BIOSID partners.
Univercell-Biosolutions, a pioneer in human cell differentiation and maturation technologies from
stem cells and foetal cells, provides innovative cell models for drug development and enables the
exploitation of these ground-breaking technologies by setting new standards for industrial
production. Founded in 2010, UB introduced EndoC-βH1 cell line, the first ever available human β-
cell line. UB’s mission is to exploit the potential of stem cells (induced pluripotent stem cells and
embryonic stem cells) and design functional human cell models for fundamental research and drug
Role in the BIOSID project
The Univercell-Biosolutions team has optimized culture conditions of the human Beta cell line Endoc-
BH1 to understand for improving the functional robustness but also viability when coupled with the
MAILPAN® device. This remarkable job has been done in close and efficient partnership with
Defymed et UCL .To this end, Univercell-Biosolutions studied Endoc-BH1 cell line behavior and
mortality yield during the preclinical phase. Furthermore, the Endoc-BH1 cells effectiveness and
safety has also been deeply investigated by BIOSID partners using animal models.
The laboratory of experimental surgery of the UCL (Université Catholique de
Directed by Professor Pierre Gianello, this laboratory is specialized in the encapsulation of insulin-
laboratory of an area over 600m
, it provides the best conditions and equipment for experimental
The UCL team intervened in the preclinical validation of the MAILPAN® device on large animals, in
close collaboration with Defymed, as well as the isolation of insulin-secreting cells of animal and
human origin. The preclinical validation allowed understanding the function of MAILPAN® associated
with different cells, its integration, immune responses within and around the device, in order to
obtain permission to enter clinical trials, via the European regulatory authorities. UCL developed its
own large diabetic animal models which had been used for the implementation of the MAILPAN®.
Understand the internal environment of MAILPAN® and develop new strategies in order to ensure
study of the environment of the cells in the MAILPAN® had been conducted in years 1 and 2. The
ultimate goal was to formulate an innovative culture medium for cells, incorporating beneficial
molecules for their survival and function in the MAILPAN®. The effect of this new culture medium has
been tested for the survival and function of the encapsulated cells, in years 3 and 4. These various
tasks will be carried out primarily by CEED, NDS, ACS, CHU and Univercells-Biosolutions, in close
collaboration with Defymed.
Testing in parallel, from year 1, the existing MAILPAN® prototype (developed in the 6th FPRD), in the
to enter into the human clinical phase. Among the encapsulated cells in the MAILPAN® are animal
pancreatic islets or even genetically modified human cells. Thus, the MAILPAN®’s capacity, combined
with the cells, to restore normal and stable blood sugar levels had been investigated. Finally, in order
to obtain permission to enter human clinical phases, the MAILPAN®’s biocompatibility and safety had
been validated in preclinical phases, in large animals. The various tasks of this component had been
conducted mostly by the UCL, Defymed and Univercells-Biosolutions in close collaboration with CHU
meetings and media. We have noted:
more than 28 press releases/interviews
participation in 20 congresses (40 presentations), where BIOSID partners have
reviewed scientific journals.
Furthermore, the project results will allow obtaining a short- or mid-term exploitation to
Therefore, taken all together, the BIOSID project was considered by all project partners as a
largely deployed reality to patients, such as Type 1 diabetic patients.