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NEWS 06 July 2010

www.biohellenika.gr

Biohellenika's Laboratories in Athens (TAKE EIE) are the first ministry of health licensed family cord blood bank in Greece

03 Stem Cells and Hair Loss (Alopecia)

08 New data for the use of cord blood placenta derived stem cells

09 Biohellenika's Services

10 The Advantages of Biohellenika

11 Stem cells for type I diabetes therapy

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Biohellenika's laboratories support autologous stem cell therapy CLINICAL TRIALS Biohellenika's laboratories, in collaboration with University and private sector clinics in Greece and neighboring countries are presently supporting several stem cell clinical trials that are under development. Ischemic brain injury that has been implicated in ailments, like cerebral

palsy and autism is a promising target for autologous stem cell therapy. In the case of cerebral palsy, it is presently widely accepted that autologous cord blood stem cell administration may be the only hope for cure. page 04 n

Non-haematological uses of cord blood stem cells

13 Potential role of dental stem cells in the cellular therapy of cerebral ischemia

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BIOHELLENIKA and TAK-EIE Laboratories supported the first stem cell therapy for autism in Greece The first autism stem cell therapy was possible in Greece with a collaboration of specialized doctors and the laboratory support of Biohellenika – TAK EIE. page 06 n

THE SECOND CEREBRAL PALSY CHILD WHO HAS STORED UMBILICAL CORD BLOOD STEM CELLS IN BIOHELLENIKA HAS BEEN TREATED AT DUKE UNIVERSITY HEMATOLOGY CLINIC

Athanasios is the fourth child in the family and his parents decided to store his umbilical cord blood stem cells in order to protect the future health of their growing family. Athanasios was born overweight and therefore his mother had a difficult labor. During delivery his brain became hypoxic for several minutes because the middle cerebral artery was clotted. Athanasios had early indications of cerebral palsy and his family did everything possible to cure him. page 07 n


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Biohellenika S.A. is the first Accredited by ESYD (National Accreditation Forum) Stem Cell Cryopreservation Company Biohellenika is the first company in Greece which operates under the guidelines of “ISO 15189”, and is accredited as medical laboratory on 08/02/2008 with the 410/8/2/2008 accreditation certificate by the National Accreditation Forum S.A. (ESYD), granted for procedures followed and quality testing of umbilical cord blood during the collection of stem cells. With this certification, Biohellenika is accredited according to ISO 15189:2007, special for medical laboratories, for nucleated cell measurement, hematopoietic stem cell viability and sterility testing, including aerobic, anaerobic bacteria and fungi. This certificate is valid until 2012 as long as the facility's operations comply with the above guidelines during regular ESYD inspections. Hellenic Accreditation System S.A.

ACCREDITATION CERTIFICATE Αρ. 410 The Hellenic Accreditation System S.A. (ESYD), as the national accreditation body of Greece, in accordance with the Law 3066/2002,

ACCREDITS

the

The Accreditation is recently expanded to the Molecular Diagnostics Laboratory that is established in Biohellenika's facilities and provides genetic analysis of inherited diseases, cardiovascular diseases, infertility and HPV tests. The National Accreditation Forum (ESYD) is a full member of the International Laboratory Accreditation Cooperation (ILAC) since 2004, of the European Cooperation for Accreditation – EA since 2005, and of the International Accreditation Forum (IAF-MRA) since 2006.

Laboratory

The international identity of ESYD gives the perspective of the parity and mutual recognition of accreditation between countries. Today Biohellenika is the first company in Greece whose laboratories are accredited by a national independent organization for measurements and quality control procedures followed during stem cell collection from umbilical cord blood.

of the

BIOHELLENIKA S.A. in Thessaloniki, Greece

Athens, February 8, 2008 Ν. Papaioannou Chairman of ESYD

Biohellika currently is being evaluated for the international accreditation by the American Association of Blood Banks (AABB).

NEWS Quarterly publication of Biohellenika

Biohe enika BIOTECHNOLOGY COMPANY

the biggest greek stem cell cryopreservation institution

Nr 06 65, Georgikis Scholis Avenue, 57001 Thessaloniki ZEDA building Tel.: 0030 2310.474.282, 2310.474.284, Fax: 0030 2310.474.285 E-mail: info@biohellenika.gr, www.biohellenika.gr Biohellenika S.A. is responsible for the published material in this issue. All rights reserved. No part of this issue may be reproduced without permission of the publisher.


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Biohellenika's Laboratories in Athens (TAKE EIE) ARE THE FIRST MINISTRY OF HEALTH LICENSED FAMILY CORD BLOOD BANK IN GREECE

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he laboratories of TAK EIE, a joint venture between Hellenic National Research Foundation and Biohellenika Biotechnology Applications S.A. is the first cord blood bank

that Greek Ministry of Health administered a license. TAK EIE laboratories are serving all samples Biohellenika collects from Athens, southern Greece and Aegean islands. Biohellenika owns two laboratories in Greece, one in Athens (TAKEIE) and one in Thessaloniki, in order to improve the stored stem cell quality by minimizing the time gap between birth and stem cell processing. The licensing of its laboratories will enable Biohellenika to establish medical applications locally and abroad, in collaboration with scientists, medical doctors and parents, who trusted the name Biohellenika in these countries and have already banked the precious stem cells of their children in Biohellenika.

NEW SERVICE Biohellenika has developed the technology and now provides the parents the storage of mesenchymal stem cells from the total length of the umbilical cord. With this method, all mesenchymal stem cells of the umbilical cord are collected and stored and therefore no cell cultures will be needed in the future, which would be applied if the number of stem cells is not enough, with an extra cost. This service is added to the classical collection of umbilical cord, by the puncture of the umbilical cord vein and to the placenta drainage and provides the family all the possible hematopoietic and mesenchymal stem cells that can be collected during labor. Given that, stem cells of umbilical cord and placenta are superior in quality than any other source of stem cells, Biohellenika provides the child and the family, the greatest possible quantity and quality of stem cells.

DYNAMIC EXPANSION OF BIOHELLENIKA TO NEIGBORING COYNTRIES Biohellenika expanded its activities to Romania, through Biohellenica Ro., to Bulgaria through Biohellenika Bg. and Servia through Beo Stem. A lot of parents from the neighboring countries select Biohellenika to store their children's stem cells. Biohellenika Bulgaria announced its opening in Bulgaria with a press conference on 13th of May and participated to the Annual Meeting of Bulgaria Obstetrics-Gynecology Society. The Meeting took place in Promorie, from 24-26 Jun 2010, and Dr. Kouzi-Koliakou, the scientific director of Biohellenika, presented a topic about “Stem cells applications and the new perspectives”. Also, Dr. Koliakou on 14/5/2010 represented Biohellenika in the Annual Romanian Dentists meeting in Brasov, where she presented “The dental pulp stem cells and its applications”.


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Biohellenika's laboratories support autologous stem cell therapy CLINICAL TRIALS

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iohellenika's laboratories, in collaboration with University and private sector clinics in Greece and neighboring countries are presently supporting several stem cell clinical

trials that are under development. Ischemic brain injury that has been implicated in ailments, like cerebral palsy and autism is a promising target for autologous stem cell therapy.

In the case of cerebral palsy, it is presently widely accepted that autologous cord blood stem cell administration may be the only hope for cure. There are two known clinical trials under development, one at the University of Duke and one at the University of Georgia USA and several reports on benefited children can be found on the internet. Umbilical cord stem cell family banks are presently reviewing the costumer medical records, in order to inform the prudential parents of children with cerebral palsy for this new hope for children up to 12 years who have their umbilical cord blood stored. Two autologous samples processed and stored in Biohellenika's laboratories have been already used by children with cerebral palsy. The cells have been administered to the young patients without any complication at the Duke University Pediatric Hematology Clinic and the children have been included in the clinical trial that takes place in this university. Three months after therapy the parents reported remarkable improvement for both children. It should be noted that independent quality controls at the University of Duke verified the high quality of cells stored by Biohellenika. Cells viability after post-thaw was higher than 95% in both cases and the minimal amount of DMSO contained in the samples required no washes and was


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tolerated without any side effect by the patients. In the second case the amount of cells stored exceeded by far the required therapeutic dose and therefore one of the cryovials has been stored at Duke, for future use.

Considering cerebral palsy, Biohellenika is supporting a prospective clinical trial that has been initiated by the neonatology clinic Hipocration Hospital at the University of Thessaloniki. In this case Biohellenika will store for free the umbilical cord blood for every child born with a high possibility to develop cerebral palsy. Prognostic markers will be investigated in the blood of these children. The children will be observed for the next two years for the development of cerebral palsy and cord blood stem cells will then be administered therapeutically to the children, who will develop the disease. In the case of autism, there are several anecdotal cases and reports about children who benefitted from stem cell therapy, but no known clinical trials are under development. Biohellenika supported, free of charge, the therapy of a child, whose father, a widely respected cardiologist in Athens, insisted to try this option for his autistic son. The child was treated in Nikea General Hospital in Piraeus and was supported by TAKE IE, the joint venture Hellenic

National Research Foundation – Biohellenika's laboratories in Athens. In this case, mesenchymal stem cells derived from the child's own adipose tissue have been used. The father was enthusiastic about the results of the therapy and these results are scheduled to initiate a large official clinical trial, up on license. Currently there is no known successive cure for autism, therefore stem cell therapy may be a new hope for these children and their families. Considering adipose tissue derived stem cells, Biohellenika is supporting, free of charge, a clinical trial initiated by the Pulmonary Disease Department in Democritus University Hospital in Alexandroupolis, where autologus adipose tissue derived stem cells are used for the treatment of pulmonary fibrosis, a disease with very short life expectancy upon diagnosis and no known efficient cure. The first results indicated a marginal amelioration in gas exchange indices. Another clinical trial supported by Biohellenika is under development in the cardiovascular surgery clinic, AHEPA Hospital Aristotle University Thessaloniki. In this case, bone marrow derived stem cells are separated in the laboratories of Biohellenika and injected during an open heart operation around the infracted myocardium areas. In two patients with last stage cardiac insufficiency, a cardiac support pump has been also used to support cardiac function until recovery. Ten patients have been treated up today and no one of them had complications or side effects or arrythmias. Considerable improvement has been reported for some of the patients.

Recently one of the children that had stem cells stored in Biohellenika has been reported to suffer from acute myeloblastic leukemia (AML). This kind of leukemia is rare for the age of 18 months, where acute lymphoblastic leukaemia (ALL) is commonly expected. Examinations on bone marrow aspirate of the patient, indicated no specific mutations that could lead to leukaemia, but many chromosomes multiplications, like trisomies, among them trisomy 8, a chromosomal abnormality that can be the cause of AML. Considering this information, a small fraction of the patients' stored stem cells was examined by an independent laboratory. Stem cells were found healthy with no trisomy 8 or other chromosomic or genetic mutations that could lead to leukemia. Therefore the doctors can now consider the child's own stem cells for transplantation upon request. The examination of the patients' umbilical cord stem cells, an examination that can be done only if the stem cells have been stored privately, indicated that whatever caused leukemia was not present in hematopoietic stem cells at birth. These results are in accordance with past similar observations, indicating that cord blood stem cells stored at birth can be used for autologous hematopoietic transplantation, if needed to treat infant leukemia (Hayani et al 2007). In such cases umbilical cord blood storage can replace the expensive and apprehensive search for a “compatible” sample that, although “compatible” cannot exclude the possibility of the life threatening graft versus host disease.


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BIOHELLENIKA and TAK-EIE Laboratories supported THE FIRST STEM CELL THERAPY FOR AUTISM IN GREECE situation. The medical team comprising a pediatrician, a pediatric surgeon, a plastic surgeon and an anesthesiologist was immediately mobilized. This team, after admission of the patient to the hospital, accomplished successfully and safely the required liposuction from the child. The collected adipose tissue was processed at the Hellenic National Research Foundation laboratories (TAK EIE) that serve Biohellenika in Athens. All required safety examinations were performed in these laboratories that are accredited by The Hellenic National Accreditation System (ESYD). After processing the cells were stored in liquid nitrogen and a part of the stored cells was administered to the child in the hospital 10 days after liposuction, upon completion of the quality control of the sample. Another part of the cells was injected after a new admission to the hospital, three months later.

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he first autism stem cell therapy was possible in Greece with a collaboration of specialized doctors and the laboratory support of Biohellenika – TAK EIE. The doctors worked in coordination and free of charge and supported a father who for 9 continuous years did not stop to strive to ameliorate his son's quality of life. As a physician as well, he enjoys a special communication approach with his colleagues and patients. Since the first communication, we were touched by his immense concern for his child's future, the vast knowledge he had acquired striving to find a solution for his problem, his easy and genuine manner describing the current

Autism and related ailments may be caused according to current scientific views by a non-satisfactory brain oxygenation. Other data support immunological origin of the disease, since autism often coexists with inflammatory bowel diseases. Adipose tissue contains a high number of cells that can contribute to angiogenesis and immunomodulation as well. Angiogenesis is attributed to progenitor endothelial cells and immunomodulation to mesenchymal stem cells. Liposuction is a medical procedure that should be performed in a hospital by specialized physicians. This is especially important for autistic children that do not easily cooperate with the doctors. The father of the child announced to a high circulation daily journal, approximately two months after the therapy, that the condition of the child was significantly ameliorated. According to him, there is an obvious socialization, behavioral control and improved communication with his family. The child will attend a regular school in the next year and is looking forward to a normal life.


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The second cerebral palsy child who has stored Umbilical Cord Blood Stem Cells IN BIOHELLENIKA HAS BEEN TREATED AT DUKE UNIVERSITY HEMATOLOGY CLINIC Biohellenika and the Hematology Clinic of Duke University began by sending the medical records and the cryopreservation file to the clinic. At last the family had the “green light” for travelling to Duke University Haematology clinic where the stem cells were administered. The family stayed in USA for four days, the administration was absolutely safe, without any side effects and finally the family came back home. The child will be followed up every three months by the Paediatric Neurology team of the clinic. Umbilical cord blood stem cells of little Athanasios were stored in three cryovials that were sent to the United States using a specific dry “voyager” type liquid nitrogen shipper. Since the number of stem cells send exceeded the number needed for therapy and the cell viability after post thaw at the site of administration was more than 97%, one of the three vials was kept for future use.

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thanasios is the fourth child in the family and his parents decided to store his umbilical cord blood stem cells in order to protect the future health of their growing family. Athanasios was born overweight and therefore his mother had a difficult labor. During delivery his brain became hypoxic for several minutes because the middle cerebral artery was clotted. Athanasios had early indications of cerebral palsy and his family did everything possible to cure him. When he was 20 months old his mother read in the news that a child with a similar problem who had stored his stem cells in Biohellenika, was treated in a United States Hospital. The mother immediately called Biohellenika and asked if her child could be treated by the same way. By that time, an exchange of scientific information between

Three months after therapy little Athanasios started communicating and participating in family life. In addition to Duke University a second American University, the University of Georgia, has recently started another clinical trial that includes children with cerebral palsy up to 12 years old, who have stored umbilical cord blood upon birth. For this type of therapy only autologous stem cells can be used, since encephalitis is a common complication of “compatible” allogenic stem cell administration. Even if stem cells of a compatible sibling are an acceptable hematopoietic graft, cannot be used in this kind of treatment.


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DIFFERENCES BETWEEN PUBLIC AND PRIVATE BANKING PUBLIC BANKING

PRIVATE BANKING

The umbilical cord blood is donated to a public bank anonymously. It belongs to the bank and is either discarded or provided by charge to a histocompatible patient. It may also be used for research.

The umbilical cord blood belongs to the family and is recorded by the name of the family and the child.

There is no charge for the donation.

The parents pay the cost for the cryopreservation and storage.

When the family is in need of stem cells, the public bank may provide them histocompatible stem cells from an unknown donor, after time consuming searching.

When the family is in need of stem cells they will receive immediately the stem cells that they have stored.

The patients pay the public bank up to 20.000 euros in the case of histocompatible stem cells are requested. Insurance companies may cover this amount, depending on the signed contract agreement.

There is no charge for the disposal of the stem cells. The family is charged in the beginning, when the stem cells are stored and the total cost of the cryopreservation and storage for 20 years is less than 2.000 euros. In case of cancer, Biohellenika offers to the family 50.000 euros financial support for autologous transplantation.

There is risk of acute or chronic rejection due to non histocompatibility.

There is no risk of rejection and higher rates of survival of the patients, due to better histocompatibility within the family.

The only medical application is for hematological diseases treatment.

Medical applications for all the diseases that are treated today or will be treated in the future with stem cells.

The time needed to find a histocompatible graft, cannot be predicted.

Immediate use.

Only for allogenic transplantations.

Use by the child and other histocompatible members of the family.

Stem Cells and Hair Loss (Alopecia) Alopecia is most common in men and presents with hair thinning or total hair loss. Stem cells have been proposed as a cure for alopecia with various combinations. In fact hair follicle contains stem cells that can regenerate hair and the reimplantation of these stem cells gives rise to new hairs. Hair follicle stem cells have been characterised as pluripotent because these can be transformed into cells of other tissues such as neuron cells. In order to ameliorate hair loss and hair thinning, mesenchymal stem cells have been used. Adipose tissue is considered to be the richest tissue in mesenchymal stem cells that can be collected safely and with minimum pain. These stem cells have been characterised as safe stem cells, because these are adult type stem cells. Adipose tissue derived stem cells can be collected with

liposuction from the subcutaneous fat that is accumulated at the abdominal area of the body. Liposuction can be performed under local anesthesia and the separation of mesenchymal stem cells should be done at a specialized laboratory. Stem cells can be administered to the affected area of the head and a part of these cells can be banked in order to be administered at a later time, if necessary. In certain cases of severe alopecia, adipose derived stem cells can be used for supporting follicular transplantation. The results indicate significant decrease of the hair loss rate, increase of the hair growth rate and thickening of the hair. Today, Biohellenika supports with its laboratories the plastic surgeons that use stem cell for alopecia therapies.


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New data for the use of cord blood and placenta derived stem cells TH

AS WERE PRESENTED AT THE 8 INTERNATIONAL SYMPOSIUM FOR CORD BLOOD TRANSPLANTATIONS THAT TOOK PLACE IN SAN FRANCISCO BETWEEN 3RD AND 5TH OF JUNE 2010

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he new advancements in the use of placenta derived stem cells, presented at the 8th Annual International Symposium for Cord Blood Transplantations, are impressive. The symposium took place between the 3rd and the 5th of June in San Francisco, USA and was supported by the United States Ministry of Health. The presentations focused on the autologous uses in the Regenerative Medicine field and the improvement of methods for the search of better histocopatible transplants for allogeneic uses in hematological diseases. The Scientific Director of Biohellenika, Dr. K. Kouzi 窶適oliakou, attended the symposium and presented a study that refers to a special method of acquiring stem cells from the placenta, a method that provides a large number of hematopoietic and mesenchymal stem cells, sufficient for adults' treatment. The storage benefits of placenta derived stem cells are widely known and accepted in every society. Successful applications rely on the administration of high quality stem cell samples. Placenta blood, apart from primary hematopoietic cells, contains pluripotent cells that can be transformed into cells of other tissues, with special attention to neurons. For this reason in Duke University stem cells derived from placenta blood are successfully administered to children with cerebral palsy and traumatic injury of the

brain. Cerebral palsy may occur due to prematurity of the infant, low endouterus oxygenation and perinatal hypoxia. For these uses only the child's own stem cells are used. Many children have benefited from this therapy that is performed during the first months of the child's life, when there are signs of cerebral palsy, or during the fist years when the condition is verified clinically. International studies use placenta derived stem cells for the therapy of spinal cord injuries and stroke. The presentation of patients with severe stroke that had total recovery and were able a year after inter cerebral administration of placenta derived stem cells, to go back to their normal lives, was spectacular. Presentations of gene therapy of stem cells in cases of sickle cell anemia and thalassemias that aimed to their re-administration to patients, was also very impressive. Already many patients suffering from inherited hemoglopathies in USA and Japan, 16 years old and more, have been cured by gene therapy of their own stem cells and have stopped blood transfusions. Efforts are made in order younger children to take part in this study, in order to prevent side effects from long term transfusions. Today, two grafts of histocompatible placenta blood derived stem cells are used for the treatment of adult patients suffering from leukemia and the reason for this, is to ensure a

large number of cells, adequate for the weight of the adult patient. In allogeneic transplantations, it is very important to prevent the rejection of the graft. For this reason the efficiency of public banks relies on the finding and administration of the best possible histocompatible grafts. Public banks target their research towards the finding of new antigens of histocompatibility that will allow the recognition of the best compatible grafts, minimizing the possibilities of rejection. New scientific data open a new era in autologous stem cell therapies of Regenerative Medicine and for this reason classical hematologists in USA, pioneers in allogeneic transplantations and basic research scientists, participate in international private family cord blood stem cells banks.


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Biohellenika's Services Biohellenika, pioneer in the provision of high quality services in the stem cells field, has the know-how to offer all potential methods for stem cells collection during birth and secure the maximum amount of stem cells that can be collected. Thus, except the classic method of the puncture of the umbilical cord, Biohellenika is the first company that proceeds to another two extra collection methods, straining of the placenta and stem cells from Wharton's Jelly. The increased amount of stem cells is necessary for patients with excess of body mass, for whom the classic stem cells collection may not be enough. Collection of umbilical cord blood stem cells The procedure is simple, lasts 5 minutes and is safe for both child and mother as it is performed after the birth. The umbilical cord blood is taken only after the child is born and the umbilical cord is cut. The special isolation method that Biohellenika uses, permits the utilization of small volume samples, so the final criteria for the acceptance of one sample are the number of cells and not its volume. Collection of stem cells by straining the placenta This collection method concerns the isolation of stem cells that remain inside the placenta after the classic umbilical cord puncture. For this purpose, the whole placenta is transferred to the laboratory, under sterilized conditions. Following Biohellenika's special published method, the cells trapped inside the placenta are collected and added to the initial collection ensuring almost the double amount of stem cells. This method was published at the international journal Transplantation Proceedings 2007, 39 (10):3380-4, received an award at the 15th Hellenic Transplant Congress at Thessaloniki at December 2007 and was mentioned in the internet till February 2008 as one of the most interesting recent medical publications. Biohellenika is the only company in European Union and one of the three companies worldwide that has the knowhow to offer this unique service. Stem cells collection from the umbilical cord tissue (wharton's jelly) This method concerns the collection of mesenchymal cells that are found outside and around the umbilical cord vessels. The cells are collected from a 15cm part of the umbilical cord, cut by the obstetrician, which is send to the laboratories inside a sterilized kit. The collection of mesenchymal cells increases the histocompatibility into the family. Today Biohellenika offer the storage of this type of stem cells from the total length of the umbilical cord.

Collection of stem cells from deciduous teeth This service of cryopreserving stem cells from the deciduous teeth pulp is a new service worldwide. Aim and purpose of this service is the collection of the valuable biological resource of dental pulp stem cells – as a second chance – from children, 5-6 years old, that didn't collect their stem cells at birth or have used them for therapeutic applications. Also, this service concerns adults that want to use their wisdom teeth or any other permanent teeth that is extracted for orthodontic reasons. Collection of stem cells from adult adipose tissue Biohellenika offers the exclusive opportunity of preserving stem cells from adipose tissue. Biohellenika has established the first Isolation and Cryopreservation Laboratory of Stem Cells from Adipose Tissue in Europe. With no further inconvenience, stem cells can be collected by the adipose tissue that is taken during a liposuction for cosmetic reasons or any other scheduled surgery. Limited liposuction aiming to the stem cells collection is a simple and rather painless procedure that is worth to be done as long as we are young and healthy in order to shield our future health. Biohellenika supports many clinical trials in Greece and abroad in collaboration with University Hospitals, for esthetic and plastic surgery applications. Also, supports clinical trials for neurodegenerative diseases, cerebral palsy, autism, cardiac failure and chronic pulmonary obstruction. For all these cases adipose tissue stem cells are used. Molecular Analysis of Inherited Diseases Biohellenika offers the services of a full functioned and certified molecular analysis lab for inherited diseases diagnosis. Specialized genetists give advice to parents who suffer from inherited diseases or they search for mutations in their genes. Infertility tests in blood, smears and amniotic fluid related to bacteria or virus infections and thrombophilia are provided. RT-PCR methods are applied to each test, that gives the most safe and reliable results.


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The Advantages of Biohellenika Biohellenika, the most respectable Greek Stem Cells Bank, was founded and operates under the strict surveillance of scientists, academic professors, Dr. Koliakos, Assoc. Professor of Biochemistry and Dr. Kouzi-Koliakou, Assoc. Professor of Histology-Embryology. Biohellenika's innovative services are scientifically proven and are the result of the long-term experience of the scientists in academic research and medical practice. Approved Banking Method: Biohellenika is one of the companies in Europe that the quality of its services has been judged in action, with the successful administration of cryopreserved cord blood stem cells to two patients at Duke University, Hematopoietic Clinic, USA and also by the daily therapeutic applications in Greece.

Certificate No 362306/2002 and it is the first stem cells bank that renewed the certification according to ISO 9001:2008 for the processing, quality test and preservation of autologous cells populations (hematopoietic autologous transplants from umbilical cord blood, mesenchymal autologous transplants from deciduous teeth pulp, wisdom teeth and adipose tissue).

Double Security: The cryopreservation takes place at two independent locations, at company's accredited laboratories in Athens and Thessaloniki.

Accreditation: Biohellenika is the first company accredited with the certificate (No.410/8-2-2008 and No.618/2-10-2009) by the National Accreditation System, the liable public organization according to Law 3066/2020 for the quality tests performed at its laboratories, including the nucleated and hematopoietic cells count and tests for bacteria and viruses detection.

Guarantee: The collaboration with the National Hellenic Research Foundation is the guarantee for the unhindered preservation of your child's stem cells. Biohellenika is the only company that collaborates with a public organization in order to secure the banking of your stem cells for the whole duration of the agreement, even in the case the company is forced to terminate its operations. Financial Support: Biohellenika supports the family with 50.000 euro in case of cancer or leukemia of the child whose stem cells are banked at the company, until the expiration of the contract agreement. Scientific Board: The scientific board consists of Professors from the Aristotle University of Thessaloniki and specialized scientists with PhD, postgraduate studies and long-term experience in cell lines' cryopreservation. Know-how: The laboratories are fully equipped with the most reliable and updated systems that follow the international guidelines of GMP. The equipments in use bear the CE sign, while all materials are certified for human therapeutic application (EOF). The operation of the laboratories concerning the isolation and cryopreservation is adjusted to the demands of Greek Legislation, European guidelines, AABB regulations, JACIE and Netcord, and ISO 9001, 13485, 14644, 15189 and 27001. Certification of Operation: Since the first days of its operation, Biohellenika is certified by ISO 9001:2000 from Lloyd's Register Quality Assurance with the

Laboratories' Certification: Today, Biohellenika owns 8 clean rooms, 5 at Thessaloniki and 3 at Athens, specially designed for the stem cells processing and are certified according to the standards of ISO 14644-5 and VDI 2089 by the German Company BSR. The company recently was certified according to ISO 13485 for medical devices. Hellenic Data Protection Authority: The Company applied and obtained license from the Hellenic Data Protection Authority from its foundation. Freedom of Choice: Biohellenika informs the parents about the two methods of cryopreservation (cryobag or cryovials). Exclusive Collaborations: The scientific collaborations with the National Hellenic Research Foundation, the Molecular Targeting Network of Aristotle University of Thessaloniki, the Regenerative Medicine and Cell Therapy Research Organisation and the biggest maternity clinics in Greece, reflect company's care about the future and the best of quality services. Cost: There are favourable financial terms with monthly installments for paying or in full the total amount. All financial transactions start after the birth and no deposit is needed before the end of the service. In case of small amount of stem cells, the cryopreservation is free of charge.


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Stem cells for type I diabetes therapy

A recent review article published by Harvard University scientists at Nature Rev Endocrin, summarized recent advances towards a cure for type 1 diabetes (T1DM) using stem cells. The authors state that novel stem-cellbased therapies for T1DM should address to two targets, the replacement of insulin secreting cells and the control of the autoimmune destruction of the already existing insulin secreting cells. Pluripotent cells from diverse sources have been used to generate insulin secreting cells, however in order to be usable these cells should respond to high glucose concentrations. Mesenchymal stromal and umbilical cord blood cells have been used in clinical trials in order to modulate the destruction of insulin secreting cells by immune response. Definitive results of these trials are

pending. Although mesenchymal stem cells have been transformed in vitro to insulin secreted cells, the scientists can not found the optimal conditions under those the cells could be engrafted to pancreas or elsewhere in human body. Few days later the cells are prompt to apoptosis, because they can not develop vasculature to connect with the systemic blood circulation.

Aquayo-Mazzucato at al 2010. Nat Rev Endocrinol 6 (3): 139-48


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Non-haematological uses of cord blood stem cells

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mbilical cord blood stem cells have been safely used for the last 20 years to treat blood diseases and more. Placenta blood comprises in addition to hematopoietic multipotent stem cells as well. These stem cells are capable of differentiation into hematopoietic, epithelial, endothelial and neural cells. Thus, umbilical cord blood stem cells can be used to treat diseases of the cardiovascular, ophthalmic, muscle-skeletal, as well as neurological and endocrine diseases. Recently umbilical cord blood stem cells have been used in children with cerebral palsy and type I diabetes. The number of individuals affected by each of these diseases is estimated at 10.000 infants diagnosed with cerebral palsy annually and 15.000 young persons diagnosed with type 1 diabetes annually. Harris DT 2009. Br J Hematology 147(2): 177-84.

NEW TYPE OF HUMAN BLOOD STEM CELL CAN BE USE FOR THE TYPE I DIABETES TREATMENT Type 1 diabetes (T1D) is an autoimmune disease caused by an autoimmune destruction of pancreatic islet insulin-producing cells. Autoimmunity and shortage of insulin-producing cells are two key issues for the treatment of T1D. To cure T1D in a comprehensive manner, both issues need to be addressed simultaneously. Not only the islet cells must be replaced, the patient's immune system also must be dealt with. Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and selftolerance through their inhibitory impacts on autoreactive effector T cells. Scientists identified a novel type of stem cells from human umbilical cord

blood, which may be able to address immune modulation of the autoimmune process and allow for beta-cell replacement. Simultaneously, treatment with this novel type of stem cells and Tregs from cord blood is effective on immunomodulation and beta cell regeneration. These data open new ways to treat autoimmune diseases and especially type I diabetes. Zhao et al. Transl Res 2010; May 155(5):211-6


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NEWS

Wharton's jelly mesenchymal cells can be used as potential delivery vehicles for cancer therapeutics

CELL THERAPY FOR NEONATAL HYPOXIC-ISCHEMIC ENCEPHALOPATHY (HIE) Perinatal hypoxia can often lead to cerebral palsy and neurological disability. There is not yet a known effective cure that can prevent or ameliorate the adverse development in these neonates. Despite advances in supportive care, no treatments for HIE are available at present. The role of stem cells in neuroprotection or regeneration of the damaged neural tissues has been evaluated in several preclinical studies. Recently umbilical cord blood and Wharton jelly derived stem cells are systematically evaluated in large clinical trials for the treatment of perinatal hypoxia, with promising results. The combination of mesenchymal and hematopoietic stem cells from placenta may offer a more complete cure for brain damage because this combination can support angiogenesis and neurogenesis and have an antiiflamatory action. Pimentel-Coelho PM et al, 2009. Stem cells Dev 19 (3):299-310.

Scientists from Kansas University underline accumulating evidence indicating that stem cells isolated from the Wharton's jelly of the umbilical cord can be used as gene therapy delivery cells. These type of cells can be isolated from the umbilical cord after birth in large numbers and because of the mesenchymal origin can penetrate into organs. However these cells do not form tumours themselves. Wharton jelly mesenchymal cells have been engineered to secrete tumour killing cytokines and anticancer proteins and have shown to exert a potent anticancer effect in preclinical animal models. Also can be conjugated with chemotherapeutics, radioactive molecules or virus and directed to organ tumours for local action. By this technology, side effects are avoided, common in systemic administration of chemotherapeutics, and due to increased local concentration in organs the antitumor effect is better.

HUMAN UMBILICAL CORD WHARTON'S JELLY-DERIVED MESENCHYMAL STEM CELLS CAN BE DIFFERENTIATED INTO GERM-LIKE CELLS IN VITRO Recent studies have demonstrated that mesenchymal stem cells could differentiate into germ cells under appropriate conditions. These results may provide a new route for reproductive therapy involving mesenchymal stem cells as already had been proved by dental pulp stem cells. Huang P et al 2010. J Cell. Biochem. (c) 1;109(4):747-54.

Rachakatla RS, Troyer D. Future Oncol 2009 Oct; 5 (8):1237-44


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MESENCHYMAL STEM CELLS DERIVED FROM HUMAN UMBILICAL CORD AMELIORATE ISCHEMIA / REPERFUSION – INDUCED ACUTE RENAL FAILURE IN RATS Mesenchymal stem cells are candidates for cell therapy of kidney diseases. Until today there is no available data on the effect of stem cells on renal failure. Mesenchymal stem cells were transplanted via the left carotid artery into acute renal failure rats which was established by clamping bilateral pedicles for 60 min and reperfusing. Serum creatinine and urea decreased notably into treated animals in comparison to control groups. The rate of cell proliferation into kidneys of treated animals was higher than that in the control groups. In addition, the transplanted mesenchymal stem cells could reside in local injury sites, leading to the relief of hyperemia and inflammation, but no obvious transdifferentiation into renal-like cells. Cao et al. Biotechnol Letter 2010 May; 32(5): 725-32

Turning placenta into brain: placental mesenchymal stem cells differentiate into neurons and oligodendrocytes Stroke and generally brain injury can cause permanent disability to the patients and a lot of efforts are put in order to restore the patients' health. Umbilical cord blood contains stem cells that already have been transformed to neuron and glial cells and proposed to treat damaged areas of the brain. Placenta itself also contains huge number of mesenchymal stem cells that have the same abilities with cord blood and can be differentiated into neural progenitors. It is obvious that

HUMAN UMBILICAL CORD MESENCHYMAL STEM CELLS REDUCE FIBROSIS OF BLEOMYCIN-INDUCED LUNG INJURY Acute respiratory distress syndrome is characterized by alveolar loss as a result of inflammation and fibrosis. Wharton's jelly derived mesenchymal stem cells have been successfully used for the cure of lung devastation in an experimental model of bleomicin induced lung injury. Stem cell administration reduced inflammation response, attraction of immune system cells and oxidative stress and resulted into a reduction of pulmonary fibrosis and amelioration of pulmonary function. Biohellenika currently supports a clinical trial conducted in the University Pulmonology clinic of Alexandroupolis Hospital considering the treatment of autoimmune pulmonary fibrosis. Moodley Y, et al 2009. Am J Pathol 175(1):303-13.

cryopreserving the cord blood we do not exhaust all the possibilities to collect the total amount of stem cells during the birth of a child, since placenta contains the same or even greater amount of stem cells that will end to the wasting material in case we do not collect. This type of stem cells is useful to treat organs or generally in regenerative medicine. Biohellenika already has established the method to collect stem cells from placenta, through a specific procedure and this method's results were presented in the 8th International Congress on Cord Blood Transplantations in San Francisco USA this year. Placenta perfusion collected stem cells already in our labs have been transformed into osteocytes and adipocytes.

Portmann R et al 2010. Am J Obstet Gynecol. Mar;202(3):294.e1-294.e1.


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Dental pulp regeneration with stem cells Experimentally, dental pulp stem cells transplantation into the pulp chamber after pulp necrosis, resulted in regeneration and new pulp development. Within 14 days full dental pulp regeneration was observed with new vessels and neural branches. Iohara K et al 2009. Regen Med;4(3):377-385

DENTAL PULP STEM CELLS IN AN ARTERIAL OBSTRUCTION Dental pulp stem cells were injected into the muscles of the animal extremities after experimentally obstruction by ligation of the femoral artery. In the areas where stem cells were injected, an increase in the blood supply and the number of vessels was observed. The results showed the ability of dental pulp stem cells to neoagiogenesis and tissue regeneration after arterial occlusion. Iohara K., et al., Stem Cells 2008; 26(9):2408-2418

DENTAL PULP STEM CELLS RESTORE THE LOWER JAW BONE DEFICITS Dental pulp stem cells have been used for the first

POTENTIAL ROLE OF DENTAL STEM CELLS IN THE CELLULAR THERAPY OF CEREBRAL ISCHEMIA Dental pulp derived stem cells can be transformed into neural tissue cells under the appropriate conditions. These stem cells take the form of neural cells and express specific receptors that are characteristic for neural cells. Accordingly it may be suggested that dental pulp derived stem cells can be used in the future as a stem cell source for the cure of neurodegenerative diseases including Parkinson and Alzheimer disease as well as stroke. Arthur A. et al., J Dent Res 2009; 88(9):829-834

time in patients in order to fill the bone cavitiy after the third mollar extraction. These patients would have ended to lose the second mollars too, because the background of the bone after extraction was not very solid. Transplantation of dental pulp stem cells of the third mollars into the remained cavity resulted in bone recovery after three months. This data gives new perspectives in bone or other tissue regenaration. D' Aquino R. et al., Eur Cell. Mater, 2009.12:18:75-83


NEWS 17

CAROTID REPAIR AFTER ATHERECTOMY AND STENT APPLICATION, USING AUTOLOGOUS ADIPOSE-DERIVED ENDOTHELIAL CELLS Adipose tissue is a rich source of pre-endothelial cells that can repopulate the damaged endothelium in experimental models. Carotids are big blood vessels that are some times obstructed by atheromatic lesions. Atheromas can be removed by atherectomy and the lumen can be kept open by placing a stent. The delayed endothelium reconstitution is a serious factor for the development of new atheromatic lesions. Intra-arterial administration of adipose derived stem cells within 48 hours after the operation can lead to a progressive reconstitution of the endothelium and prevent later complications. Adipose tissue is an important source of primitive endothelial cells able to reconstitute epithelia of blood vessels after angioplasty preventing thickening of the tunica intima. Froehlich H et al 2009. Stroke, 40(5):1886-91.

ADIPOSE DERIVED STEM CELLS BONE GENERATION Adipose tissue contains stem cells that can be used for the regeneration of bone, cartilage and intervertebral fibrocartilage. Adipose derived stem cells can be mixed with osteogenetic factors and applied onto specific scaffolds that can be then utilised to cover bone deficit or bone fissure areas. The importance of the use of scaffolds is profound because these can assure the viability and functionality of stem cells. Scaffold technology in combination with stem cells is less invasive for the patient, can omit large orthopaedic operations, shorten hospitalisation time and minimise postoperative complications. 1. Ahn HH et al 2009. Tissue Eng part A. 15(7):1821-32.

ADIPOSE DERIVED STEM CELLS HAVE BEEN TRANSFORMED INTO BEATING HEART CELLS Human adipose-derived stem cells may differentiate ex vivo into beating cardiomyocytes, as they show spontaneous contractions like in normal positions in heart. The ability of adipose tissue derived stem cells to transform into cardiac functioning cells opens new perspectives in cardiac cell therapy or tissue engineering after infarction or cardiac failure generally. Choi YS et al 2010. J cell Mol Med 14(4):878-79.

ADIPOSE DERIVED STEM CELLS CAN RECONSTITUTE LIVER DEGENERATION Hepatic cirrhosis1, hepatic fibrosis2 and hepatocellular cancer are severe and life threatening liver diseases that need immediate care. The only effective treatment today is liver transplantation, limited by donor availability and immune-rejection. Regenerative medicine is a promising medical field, developing cell-based therapies that can enable hepatic regeneration. Transplantation of adipose tissue-derived mesenchymal stem cells can be today used for regenerating liver cells. When compared with embryonic stem cells or induced pluripotent stem (iPS) cells, adipose derived stem cells provide advantages considering ethical and safety issues. Adipose derived stem cells can be used without ex vivo culture, are immuno-compatible, exhibit controlled differentiation and multi-functional abilities and do not undergo post-transplantation rejection or unwanted differentiation such as formation of teratomas. In the future adipose tissue derived stem cell therapies will be the first choice for the confrontation of currently incurable liver disease.

2. Tapp H et al 2008. Arthritis Res Ther 10(4): R89

1. Ishikawa T et al 2010. Curr Stem Cell Res Ther 5 (2):182-189.

3. Tapp H, et al 2009. Exp Biol Med (Maywood). 2009 Jan;234(1):1-9.

2. Tsai PC et al 2009. Liver Transpl 15(5):484-495.


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Biohe enika ΕΤΑΙΡΕΙΑ ΒΙΟΤΕΧΝΟΛΟΓΙΑΣ

Preservation and Safety at the Maternity Clinic “Genesis”

Special Care and Safety program for Biohellenika's Children

The successful collaboration between Biohellenika and the private maternity clinic “Genesis” of Thessaloniki continues. The program “Care and Safety” offers today to the parents who choose to have their child at the maternity clinic “Genesis”, the most complete umbilical cord stem cells cryopreservation service. For the parents who choose to give labor at the clinic it is not necessary to carry the collection bag, among their other belongings during entry. The clinic will ensure it is provided at the delivery room. Upon entry of the parents to the Maternity Clinic they express their wish to collect stem cells and the clinic in collaboration with Biohellenika ensures that the stem cells collection procedure is completed without an added burden to the parents.

The special Care and Safety of Biohellenika is

The Maternity Clinic “Genesis” guarantees the

reinforced by the cover of hospitalization fees

preservation for the next 20 years as described in a

up to the amount of 50.000€ in case of using

special article in the Private Contract.

the stem cells for the autologous treatment of cancer or leukemia in Greece or abroad for the duration of the Private Contract.


CRETE - CHANIA

40-42 Tzanakaki Str. Ă”: +30 28210.58758 +30 6976 977.384

clinical trials Accreditation Number 410

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Biohe enika BIOTECHNOLOGY COMPANY

the biggest greek stem cell cryopreservation institution

clinical trials Accreditation Number 410

1

THESSALONIKI Laboratories - Offices 65, Georgikis Scholis Avenue, 57001 Thessaloniki, ZEDA building T: 0030 2310.474.282, 2310.474.284, F: 0030 2310.474.285 Mobile: 0030 6944.677.746 E-mail: info@biohellenika.gr

ATHENS Offices 2 Mesogion Str, Athens Tower, Building A’ T: 0030 210.77.08.882, 210.77.08.218, F: 0030 210.77.90.788 M: 0030 6973.346.704 email: info@biollenikasa.gr Laboratories NATIONAL HELLENIC RESEARCH FOUNDATION 48 Vasileos Konstantinou Str. 11635 Athens Τ: 0030 210.72.73.700, F: 0030 210.72.46.618 TAK.EIE 28A Archelaou Str., 11635 Athens, T: 0030 210 7299140, F: 0030 210.72.99.140

LARISSA 3 Megalou Alexandrou Str. 6th floor, 41222 T: 0030 2410.535.603, F: 0030 2410.535.664, M: 0030 6973.984.260

PATRA Kos 18 & Panepistimiou 3 Τ: 0030 2610.437.436, F: 0030 2610.431.339, M: 0030 6978.483.170

IOANNINA Technological Park, Pedini Τ: 0030 26510.97.667, F: 0030 26510.97.673, M: 0030 6970.267.540

IRAKLION - CRETE 17 Amaltheias & Katechaki Str., 71201 Τ: 0030 2810.229.351, M: 0030 6970.803.497

CHANIA - CRETE 40-42 Tzanakaki Str., 1st Floor, Office A6, 73134 Τ: 0030 2821058758, M: 0030 6976.977.384

17th November Str., Pilea, MB 16513, PC 54301,Thessaloniki Tel.: 0030 2310.984.000, Fax: 0030 2310.984.469 E-mail: info@genesis.org.gr

CYPRUS 55 Alekos Constantine Street Τel.: +357 22028208, 77776001, Fax: +357 22028210

BULGARIA - SOFIA 66 Exarch Joseph Str., Τel.: 0700 10 804

SKOPJE Frenklin Ruzvelt 4, Lokal 5 1000, Τel.: 0038 923111114

801.11.99299 OPEN LINE (Calls only from line phone)

ROMANIA - BUCHAREST 69 Union Avenue, Grand Floor, Τel.: 004 0213203029, Fax: 004 0213203031 Mobile: 004 0730078930

www.biohellenika.gr

SCIENTIFIC CONSULTANTS: G. Koliakos, MD, PhD Associate Professor of Biochemistry K. Kouzi, MD, PhD Associate Professor Histology – Embryology, Cell phone: +30 6944 677746


Biohellenika news 6