Bioencapsulation of Living Cells for Diverse Medical Applications


by

Eva Maria Brandtner, John Austin Dangerfield

DOI: 10.2174/97816080572071130101
eISBN: 978-1-60805-720-7, 2013
ISBN: 978-1-60805-721-4

  
  




Bioencapsulation (or microencapsulation) of cells and their implantation into a body of immunoprotected cells allows resear...[view complete introduction]
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Table of Contents

Foreword , Pp. i-iii (3)

Brian Salmons
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Preface , Pp. iv-v (2)

Eva Maria Brandtner and John Austin Dangerfield
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List of Contributors , Pp. vi-viii (3)

Eva Maria Brandtner and John Austin Dangerfield
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Particular Challenges in Microencapsulation of Insulin-Producing Cells for the Treatment of Diabetes Mellitus , Pp. 3-39 (37)


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Human Trials with Microencapsulated Insulin-Producing Cells: Past, Present and Future , Pp. 40-69 (30)

Bernard Tuch, Vijayaganapathy Vaithilingam and Jayne Foster
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The Diversity of Uses for Cellulose Sulphate Encapsulation , Pp. 70-92 (23)

John A. Dangerfield, Brian Salmons, Randolph Corteling, Jean-Pierre Abastado, John Sinden, Walter H. Gunzburg and Eva M. Brandtner
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Inducible Systems for Cell Therapy and Encapsulation Approaches , Pp. 93-101 (9)

Viktoria Ortner, Cornelius Kaspar and Thomas Czerny
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Cell Encapsulation Technology: An Alternative Biotechnological Platform for the Treatment of Central Nervous System Diseases , Pp. 102-152 (51)

Tania López-Méndez, Ainhoa Murua, José L. Pedraz, Rosa M. Hernández and Gorka Orive
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Production of Cell-Enclosing Microparticles and Microcapsules Using a Water-Immiscible Fluid Under Laminar Flow and Its Applications in Cell Therapy , Pp. 153-177 (25)

Shinji Sakai, Shinji Tanaka, Koei Kawakami and Shigeki Arii
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Index , Pp. 178-184 (7)

Eva Maria Brandtner and John Austin Dangerfield
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Foreword

It is almost 60 years since the first successful organ transplantation, which took place in 1954, revolutionised medicine. Since then, the idea of implanting living cells, tissues and organs into the body has been pursued as a strategy for the treatment of a variety of diseases. Microencapsulation of cells and their implantation into the body can be viewed as an extension or specialised form of organ transplantation in that it allows cells to take over a missing or defective function in the body. However, unlike organ transplantation, microencapsulation has the advantage that immunosuppression is not needed due to the immunoprotective effects of the encapsulation material, which also acts as a safety device. Microencapsulation of cells can be achieved using a number of different polymers, most notably alginate, cellulose sulphate and agarose, all of which are included in the various chapters that comprise this eBook. Excitingly, microencapsulated cells are already more than living up to their potential in that they have been shown to be safe and efficacious in numerous clinical trials, and this is regardless of the encapsulation material used. Our major contribution to this field was the first clinical trial that employed cellulose sulphate encapsulated cells for the treatment of pancreatic cancer.

The editors of this timely eBook and my dear colleagues and friends, Dr. Eva Maria Brandtner and Dr. John Dangerfield, have brought together contributions from some of the leading research in the field of cell encapsulation with the aim of providing an overview of the status of the latest exciting developments. The use of implanted, microencapsulated cells has long been proposed as a means to treat a variety of diseases but has historically mainly focussed on diabetes which is still a major focus for many academic groups and companies (as is reviewed in this eBook in the chapters by Tuch and Vaithilingam as well as that by Bilodeau and Halle). However, encapsulated cells are being used to treat a wide variety of diseases and now are even being used to improve on stem cell therapies which have generally been proposed as a cell based, cure all. Here the capsule material functions as both a safety device, as well as a means to localise cells to the site where they are needed. Encapsulation may help cells survive longer as well as prevent immune rejection and/or Graft vs. Host Disease, the most common adverse event seen in stem cell clinical trials. As evidenced by the chapters in this exciting new eBook, great progress has been made in improving the survival of encapsulated cells as well as moving these novel therapies into the clinic.

As well as use in cancer therapy to improve on existing chemotherapies by reducing the dose and thus side effects while increasing efficacy (see chapters by Dangerfield and colleagues and also by Sakai and co-workers), encapsulated cells can be used to produce antibodies. These can be tumoricidal antibodies or virus neutralising activities. The advantages to using encapsulated cells rather than more conventional injections as a delivery means include the long term stable and steady state levels that result from production of antibodies by implanted encapsulated cells.

CNS diseases such as epilepsy, neurodegenerative disorders like Parkinson's disease, Alzheimer, Amyotrophic lateral sclerosis, Huntington's disease but also pathologies caused by trauma and/or ischemic processes and brain tumors are ideal candidates for treatment using encapsulated cells producing neuron nurturing factors and this is the focus of the chapter by López-Méndez and colleagues.

Cell types that have been encapsulated for therapeutic purposes include islet cells, stem cells and "platform" cell lines such as HEK293 and CHO cells. Stem cells are of particular interest. Two of the chapters discuss the use of encapsulated stem cells. Tuch and Vaithilingam discuss the use of pancreatic progenitors from pluripotent human embryonic stem cells as a much more reliable and larger source of surrogate cells for encapsulation and transplantation than human or porcine islets which are in limited supply and more likely to be contaminated with adventitious agents.

Inducible expression and expression control may or may not be required, depending on the disease and whether there are dosing issues. Islet cells have the intrinsic ability to sense glucose levels and to respond by producing insulin when glucose levels are high or not when levels are low. Genetic engineering of cells can allow control of expression of biotherapeutic products from encapsulated cells. Ortner, Kaspar and Czerny review some of the methods used to achieve inducible or controllable gene expression, including a novel system that they have pioneered using heat as the inducer of expression.

While I am sure this will not be the last word (or eBook) on this exciting and fast moving field of cell microencapsulation, I think this eBook will be much more than a useful resource for all researchers, clinicians and those interested in the future of biomedicine. Well done Lilli, John and the various colleagues and friends who have contributed to this excellent eBook.

Brian Salmons
SG Austria / Austrianova Singapore
Singapore


Preface

The encapsulation of cells into a biocompatible shell has three main purposes: 1) Protection of the cells from the immunity of the living system where they are applied 2) Physical localisation of the cells, and hence the biomolecule they produce, at the therapeutic target site (in contrast to single cells which would in most cases migrate or move away at some point) and 3) The opportunity to remove the cells after treatment is completed if required.

The concept of encapsulation to allow implantation of foreign cells into a patient is not new, but is something that has still not been successfully developed to the point at which a licensed medical product exists on the market. In times when allogeneic cell therapy is considered to be potentially big business and encapsulation allows an easy way to make a “one-for-all” product, this is surprising. This is most likely due to the complex challenges of generating a GMP (Good Manufacturing Practice) grade of off-the-shelf living cell product in addition to the challenges of combining this with an encapsulation device. Several research laboratories and small companies are however currently working to achieve this with some varying levels of success. An Australian based company named Living Cell Technologies has achieved small scale GMP production and is undertaking clinical trials for the treatment of diabetes and has encouraging pre-clinical work for a number of other neurodegenerative applications. The US based company Novocell also has a focus on stem cell encapsulation for diabetes treatment and a clinical trial has been undertaken. The now Singapore based company, SG Austria (Austrianova Singapore), could show safety and efficacy of encapsulated cells producing a prodrug converting enzyme in a clinical phase I/II trial for pancreatic cancer (Lohr et al., 2001). Subsequently, orphan drug status was granted and a large-scale GMP facility with production license was established, showing for the first time that it could be done (Salmons et al., 2007). More recently in 2012, they presented similar positive results for a second phase II trial in the same indication.

Proof of principle has been shown for several different encapsulation techniques and materials (and combinations thereof). Predominantly, biocompatible and non-toxic polymers such as sodium cellulose sulphate, alginate, agarose or polyethylene glycol are used. The speed and sterility of the process and the quality and purity of the encapsulation agents are critical for success and reproducibility of the procedure and further viability of the cells, i.e., that they continue to produce and/or secrete their therapeutically relevant biomolecules and remain bio-inert when implanted into animals or patients.

A huge variety of cells with proven or potential therapeutic activity exist in research laboratories and companies alike and because many of these cells cannot be brought into the patient directly such groups are networking hard with encapsulation specialists. A prominent example is the use of pig islet cells, or other forms of insulin producing cells, for the treatment of diabetes. In immune deficient animal models such cells can react to blood sugar levels and produce insulin on demand, and encapsulation offers the perfect way to bring such cells into a patient.

This eBook describes the details and pros and cons of the currently most used and most promising types of encapsulation methods and materials as well as the currently most focused-on cells, biomolecules and disease areas. Authored by leading scientists and company executives, it gives relevant examples, reviews published data and describes the projects closest to commercialisation. Several chapters also include easy-to-follow lab protocols making it a useful laboratory handbook for researchers and students alike.

Eva Maria Brandtner
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT)
Austria

&

John Austin Dangerfield
SG Austria / Austrianova Singapore
Singapore

List of Contributors

Editor(s):
Eva Maria Brandtner
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT)
Austria


John Austin Dangerfield
SG Austria / Austrianova Singapore
Singapore




Contributor(s):
Jean-Pierre Abastado
Singapore Immunology Network (SIgN)
8A Biomedical Grove, Immunos Building, Level 4
Singapore


Shigeki. Arii
Department of Hepato-Biliary-Pancreatic Surgery
Graduate School of Medicine, Tokyo Medical and Dental University
1-5-45 Yushima, Bunkyo-ku
Tokyo, 113-8519
Japan


Stéphanie Bilodeau
Université de Montréal / Centre de Recherche de l’Hôpital Maisonneuve-Rosemont
Research Laboratory on Bio-artificial Therapies
5415 boul. L’Assomption
Montréal (Québec), H1T 2M4
Canada


Eva Maria Brandtner
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT)
Molecular Biology Laboratory
Stadtstrasse 33
Dornbirn, A-6850
Austria


Randolph Corteling
ReNeuron Limited
10 Nugent Road, Surrey Research Park, Guildford
Surrey, GU2 7AF
UK


Thomas Czerny
Department for Applied Life Sciences
University of Applied Sciences, FH Campus Wien
Helmut-Qualtinger-Gasse 2
Vienna, A-1030
Austria


John Austin Dangerfield
SG Austria / Austrianova Singapore
20 Biopolis Way, #05-518 Centros
Singapore


Jayne Foster
Former Diabetes Transplant Unit
Prince of Wales Hospital & University of New South Wales
Sydney
Australia


Walter Gunzburg
Institute of Virology in the Department of Pathobiology
SG Austria / Austrianova Singapore
20 Biopolis Way, #05-518 Centros
Vienna, 138668
Singapore


Jean-Pierre Hallé
Université de Montréal / Centre de Recherche de l’Hôpital Maisonneuve-Rosemont / Research Laboratory on Bio-artificial Therapies
5415 boul. L’Assomption
Montréal (Québec), H1T 2M4
Canada


Rosa Martin Hernández
NanoBioCel Group, Laboratory of Pharmaceutics
University of the Basque Country, School of Pharmacy
Vitoria-Gasteiz
Spain


Cornelius Kaspar
Department for Pathobiology
Institute of Virology, University of Veterinary Medicine
Veterinärplatz 1
Vienna, A-1210
Austria


Koei Kawakami
Department of Chemical Engineering
Faculty of Engineering, Kyushu University
744 Motooka, Nishi-ku
Fukuoka, 819-0395
Japan


Tania López-Méndez
NanoBioCel Group, Laboratory of Pharmaceutics
University of the Basque Country, School of Pharmacy
Vitoria-Gasteiz
Spain


Ainhoa Murua
NanoBioCel Group, Laboratory of Pharmaceutics
University of the Basque Country, School of Pharmacy
Paseo de la Universidad street 7
Vitoria-Gasteiz, 01006
Spain


Gorka Arroyo Orive
NanoBioCel Group, Laboratory of Pharmaceutics,
University of the Basque Country, School of Pharmacy
Vitoria-Gasteiz
Spain


Viktoria Ortner
Department for Applied Life Sciences
University of Applied Sciences, FH Campus Wien
Helmut-Qualtinger-Gasse 2
Vienna, A-1030
Austria


José Luis Pedraz Muñoz
NanoBioCel Group, Laboratory of Pharmaceutics
University of the Basque Country, School of Pharmacy
Vitoria-Gasteiz
Spain


Brian Salmons
SG Austria / Austrianova Singapore
20 Biopolis Way, #05-518 Centros
Singapore


Sakai Shinji
Department of Materials Science and Engineering,
Graduate School of Engineering Science, Osaka University
1-3 Machikaneyama-cho, Toyonaka
Osaka, 560-8531
Japan


John Sinden
ReNeuron Limited
10 Nugent Road, Surrey Research Park, Guildford
Surrey, GU2 7AF
UK


Shinji Tanaka
Department of Hepato-Biliary-Pancreatic Surgery
Graduate School of Medicine, Tokyo Medical and Dental University
1-5-45 Yushima, Bunkyo-ku
Tokyo, 113-8519
Japan


Bernard Tuch
Biomedical Materials & Devices, Materials
Science & Engineering, Commonwealth Scientific & Industrial Research Organization (CSIRO)
Riverside, Life Science Centre
11 Julius Avenue
North Ryde, NSW 2113
Australia


Vijayaganapathy Vaithilingam
Biomedical Materials & Devices, Materials
Science & Engineering, Commonwealth Scientific & Industrial Research Organization (CSIRO)
Riverside, Life Science Centre
11 Julius Avenue
North Ryde, NSW 2113
Australia




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