european technology platform on...

Vision Paperand Basis for a Strategic Research Agenda for NanoMedicine

September 2005

European TechnologyPlatform on NanoMedicineNanotechnology for Health

For further information on NanoMedicine, please contact:Research DG

Renzo TomelliniUta FaureOliver Panzer

E-mail: [email protected]://www.cordis.lu/nanotechnology/nanomedicine.htm

Cover: © Fraunhofer IBMT, St. Ingbert

The Commission accepts no responsibility or liability whatsoever with regard to the information presented in this document.

This brochure has been produced thanks to the efforts of the stakeholders group of the European Technology Platform on NanoMedicine.

A great deal of additional information on the European Union is available on the internet.It can be accessed through the Europa server (http://europa.eu.int).

Reproduction is authorised provided the source is acknowledged.

Printed in Belgium

PRINTED ON WHITE CHLORINE-FREE PAPER

Europe Direct is a service to help you find answers to your questions about the European Union

Freephone number:

00 800 6 7 8 9 10 11

European Commission

European Technology Platform on NanoMedicine – Nanotechnology for Health

Luxembourg: Office for Official Publications of the European Communities

2005 – 37 pp. – 21.0 x 29.7 cm

ISBN 92-894-9599-5

Vision Paperand Basis for a Strategic Research Agenda for NanoMedicine

September 2005

European TechnologyPlatform on NanoMedicineNanotechnology for Health

2005

Benoît Adelus, Executive Vice President, bioMérieux

Andreas Barner, Vice Chairman of the Board of Managing Directors, Boehringer Ingelheim

Angelo Bazzari, President, Fondazione Don Carlo Gnocchi Onlus

Alfred Benninghoven, CEO, ION-TOF GmbH

Joachim Breuer, Director General, Federation of Institutions for Statutory Accident Insurance and Prevention

Lanfranco Callegaro, CEO, Fidia Advanced Biopolymers S.r.l.

Carsten Claussen, CEO, Evotec Technologies

Pilar de la Huerta, CEO, Neuropharma S.A.

Roch Doliveux, CEO, UCB

Harald Fuchs, Scientific Director, Center for Nanotechnology (CeNTech)

Eduardo Gómez-Acebo, CEO, GENOMICA S.A.U.

Roberto Gradnik, President, Assobiotec

Hans Grunicke, Rector, Medical University Innsbruck

Maris Hartmanis, Senior Vice President, GAMBRO

John Innes, New Businesses Director, SELEX Sensors and Airborne Systems

Enric Julià, Principal, Institut Químic de Sarrià

Jouko Karvinen, Member of the Group Management Committee, Royal Philips Electronicsand President and CEO, Philips Medical Systems

James Kirkpatrick, President, European Society for Biomaterials (ESB)

Emilio Mauri, Managing Director, FIDIA Farmaceutici S.p.A. and Chairman, ANTIBIOTICOS S.p.A.

Hans Jörg Meisel, Chair Department of Neurosurgery, BG-Clinic Bergmannstrost

Jörg Michaelis, President, Johannes Gutenberg-University of Mainz

2

High-Level Group ETP NanoMedicine

Helmut Mothes, Senior Vice President, Bayer Technology Services GmbH

Edmund Müller, CEO, Joanneum Research Forschungsgesellschaft mbh

Udo Oels, Member of the Board of Management, Bayer AG

Erich R. Reinhardt, Member of the Managing Board, Siemens AGand Group President, Siemens Medical Solutions

Andreas Rummelt, CEO, SANDOZ

Lino Santambrogio, CEO, Bouty S.p.A.

Ottilia Saxl, CEO, Institute of Nanotechnology

Jürgen Schmidt, Rector, Westfälische Wilhelms-Universität Münster

Günter Stock, Member of the Executive Board, Schering AG

Jean Therme, Director of technological research, Commissariat à l'énergie atomique (CEA)

Johan Vanhemelrijck, Secretary General, EuropaBio

Iacovos Vasalos, Chairman of the Board of Directors of Centre for Research and Technology - Hellas (CERTH)Chemical Process Engineering Research Institute (CPERI)

Peter Venturini, Director, National Institute of Chemistry, Slovenia

Joan-Albert Vericat, President, In Vitro Testing Industrial Platform (IVTIP)

Maurice Wagner, Director General, Eucomed

Gerhard F. Walter, Rector, Medizinische Universität Graz

David Williams, CTO, UNIPATH

Tadataka Yamada, Chairman, Research and Development, GlaxoSmithKline (GSK)

W. Henk M. Zijm, Rector Magnificus, University of Twente

3

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

2. Societal Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

3. Economic Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

4. Nanotechnology-based Diagnostics including Imaging . . . . . . . . . . . . . . . . 154.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154.2 In-vitro Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .164.3 In-vivo Nano-Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .164.4 Basis for a Strategic Research Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

5. Targeted Drug Delivery and Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .215.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .215.2 Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .215.3 Basis for a Strategic Research Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

6. Regenerative Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .276.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .276.2 A Biomimetic Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .286.3 Basis for a Strategic Research Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30

7. Regulatory Issues and Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

8. Ethical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

9. NanoMedicine: The bigger picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35

Annex 1: Drafting Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Annex 2: Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

4

Table of contents

Executive Summary

The ageing population, the high expectations for bet-ter quality of life and the changing lifestyle ofEuropean society call for improved, more efficientand affordable health care.

Our improved understanding of the functioning of thehuman body at the molecular and nanometre scaleas well as our ability to intervene at pre-symptomatic,acute or chronic stages of an illness are of utmostimportance to meet these expectations. Diseaseslike cancer, diabetes, Alzheimer’s and Parkinson’sdisease, cardiovascular problems, inflammatory andinfectious diseases and depression are serious chal-lenges to be dealt with. Nanotechnology applied tomedical problems can offer impressive solutions.Early diagnosis, ‘smart’ treatments and the trigger-ing of self-healing mechanisms are crucial targetson the way to regained health.

At present Europe has a strong position in the emerg-ing field of NanoMedicine that has a high potentialfor technological and conceptual breakthroughs,innovation and creation of employment.NanoMedicine is an area that would benefit from co-ordination at European level. Thus, close coopera-tion between industry, research centres, academia,hospitals, regulatory bodies, funding agencies,patient organisations, investors and other stakehold-ers could dramatically boost this promising field.

In response to these challenges, scientific expertsfrom industry, research centres and academia con-vened to prepare the present vision documentregarding future research priorities in NanoMedicine.In particular, the following three research areas havebeen identified as a basis of a Strategic ResearchAgenda (SRA) in this field:• Nanotechnology-based Diagnostics including

Imaging • Targeted Drug Delivery and Release• Regenerative Medicine

A key conclusion of the preparatory group that elab-orated this vision paper was the recommendation tothe EU to set up a European Technology Platform

(ETP) on NanoMedicine. This ETP will identify themajor socio-economic challenges facing Europe, inproviding high standards of healthcare across thepopulation, ensuring high quality of life, and focus-ing on breakthrough therapies, in a cost-effectiveframework.

Dissemination of knowledge, regulatory and intellec-tual property issues, ethical, environmental and tox-icological aspects as well as public perception in gen-eral have also to be addressed by the ETP.Therefore, input from other stakeholders such asinsurance companies, non-governmental organisa-tions or patient organisations will play an importantrole in shaping up the final objectives of the ETP onNanoMedicine.

This European Technology Platform addressesambitious, responsible research, developmentand innovation in Nanotechnology for Healthto strengthen the competitive scientific andindustrial position of Europe in the area ofNanoMedicine and improve the quality of lifeand health care of its citizens.

5

Crystal structure of human deoxyhaemoglobin © InformationsSekretariat Biotechnologie, 2005

6

1. Introduction

Definition: NanoMedicine, for the purpose ofthis vision document, is defined as the appli-cation of Nanotechnology to Health. It exploitsthe improved and often novel physical, chem-ical, and biological properties of materials atthe nanometric scale. NanoMedicine haspotential impact on the prevention, early andreliable diagnosis and treatment of diseases.

Artificial nanostructures, such as nanoparticles andnanodevices, being of the same size as biologicalentities, can readily interact with biomolecules on boththe cell surface and within the cell (see Figure 1).

Nanomedical developments range from nano-particles for molecular diagnostics, imaging and ther-apy to integrated medical nanosystems, which mayperform complex repair actions at the cellular levelinside the body in the future.

For the purpose of this Vision Paper, NanoMedicineencompasses the three interrelated themes of: • nanodiagnostics including imaging• targeted drug delivery and controlled release• regenerative medicine.

In nanodiagnostics, the ultimate goal is to identifydisease at the earliest stage possible, ideally at thelevel of a single cell. To achieve this goal, researchand development activities in nanotechnology needto be undertaken to improve the effectiveness of in-vivo and in-vitro diagnostics. Nanotechnology canoffer diagnostic tools of better sensitivity, specificityand reliability. It also offers the possibility to take dif-ferent measurements in parallel or to integrate sev-eral analytical steps from sample preparation todetection into a single miniaturized device. Such adevice could, thanks to nanotechnology, containenough hard wired intelligence and robustness to beused by the patient and deliver a multitude of data tothe practitioner. Furthermore, the use of nanoelec-tronics will improve the sensitivity of sensors basedon already established methods.

Improvements of microscopic and spectroscopictechniques towards ultra-high spatial resolution,molecular resolution and ultra-high sensitivity will pro-vide a better understanding of the cell’s complex“machinery” in basic research. The resulting progressshould pave the way to more innovative and power-ful in-vivo diagnostics tools. In general terms nan-otechnology will have great impact on the method-ologies available for both disease and drug discoveryand consequently impact on the scope and through-put of pharmaceutical developments.

Advancement in in-vivo diagnostics will also rely onmolecular imaging and on minimally invasive,implantable devices. In molecular imaging, the goalis to create highly sensitive, highly reliable detectionagents that can also deliver and monitor therapy. Thisis the “find, fight and follow” concept of early diagno-sis, therapy and therapy control, sometimes alsoknown as theranostics. The tissue of interest is firstlyimaged, using target-specific contrast nanostruc-tures. Then, the targeting nanostructures, combinedwith a pharmacologically active agent, can be usedfor therapy. Finally, monitoring of the results of thistherapy over time is possible by sequential imaging.Earlier and more reliable disease detection will beachieved by using better tracers and contrast agentsin combination with better detection systems - progress in which is expected to come throughcombining existing imaging techniques.

© PhotoDisc, Inc. 1996

7

Mastering Artificial Nanostructures

Scanning TunnelingMicroscopy (STM)

Scanning Force1

Microscopy (SFM)

DendrimersLiposomes

Biological Nanostructures

10-1 1 101 102 103 104

Wat

er

mo

lec

ule

Wat

er

mo

lec

ule

Electron BeamLithography

PhotoLithography

Nanoparticles (nanotubes2,fullerenes3, quantum dots, etc.)

DN

A1

Proteins Typicalvirus2,3,4

Hu

ma

n c

ell

nu

cle

us

Sta

ph

ylo

co

cc

us

Lym

ph

ocy

te,

Re

d b

loo

d c

ell5

Fib

rob

last

ce

ll6

Ha

em

og

lob

in

Lip

id b

ilaye

r su

rro

un

din

g c

ells

Size, nm

Figure 1. Artificial (top) and biological (bottom) nanostructures

1

2

3

1 3 4 5 62

Carbon nanotube© Chris Ewels

Fullerene

Scanning Force Microscopy(SFM)

Marburg virus© H. Oberleithner,

University of Münster

Ebola virus© Digital Stock 1996

DNA© PhotoDisc Inc 1996

Influenza virus© Roche, 2005

Red blood cell Fibroblast cell© Roche, 2005

1. INTRODUCTION

The long-term objective of drug delivery systems isthe ability to target selected cells and/or receptorswithin the body. At present, the development of newdrug delivery techniques is driven by the need on theone hand to more effectively target drugs to the siteof disease, to increase patient acceptability and reducehealthcare costs; and on the other hand, to identifynovel ways to deliver new classes of pharmaceuticalsthat cannot be effectively delivered by conventionalmeans. Nanotechnology is critical in reaching thesegoals. Already now nanoparticle formulations makeuse of the fact that an enlarged surface/volume ratioresults in enhanced activity. Nanoparticles are alsouseful as drug carriers for the effective transport ofpoorly soluble therapeutics. When a drug is suitablyencapsulated, in nanoparticulate form, it can be deliv-ered to the appropriate site, released in a controlledway and protected from undergoing premature degra-dation. This results in higher efficacy and dramaticallyminimises undesirable side effects. Such nano-particulate delivery systems can be used to more effec-tively treat cancer and a wide range of other diseases,which call for drugs of high potency.

Drug-delivering microchip technology, resulting fromthe convergence of controlled release and fabricationtechnologies evolved for the electronics industry, isalso benefiting from the application of nanotechnol-ogy. Further miniaturization and the ability to storeand release chemicals on demand offer new treat-ment options in the fight against disease. A futurevision is that nanoparticles will carry therapeutic pay-loads or genetic content into diseased cells, minimis-ing side effects as the nanoparticles will only becomeactive upon reaching their ultimate destination. Theymay even check for overdosage before becomingactive, thus preventing drug-related poisoning. In thepast three decades, the number and variety of con-trolled release systems for drug delivery applicationshas increased dramatically. Many utilize polymers thathave particular physical or chemical characteristics,such as biodegradability, biocompatibility or respon-siveness to pH or temperature changes. In spite ofmany successful examples, the notion of combiningpolymer science with concepts from structural biologyto provide new strategies and opportunities in thedesign of novel drug delivery systems adapted to

8

Droplets (50nl) dispensing robot © P. Stroppa, CEA

1. INTRODUCTION

today’s demands, has not been fully embraced. Inpart progress has been slowed by regulatory submis-sions. It is critical for all nanoparticulates that drugsafety is considered in parallel with efficacy.

The focus of regenerative medicine is to work withthe body’s own repair mechanisms to prevent andtreat disabling chronic diseases such as diabetes,osteoarthritis, and degenerative disorders of the car-diovascular and central nervous system and to helpvictims of disabling injuries. Thanks to nanotechnol-ogy, a cellular and molecular basis has been estab-lished for the development of innovative disease-mod-ifying therapies for in-situ tissue regeneration andrepair, requiring only minimally invasive surgery.Rather than targeting the symptoms or attempting todelay the progress of these diseases, future therapieswill be designed to rectify chronic conditions usingthe body’s own healing mechanisms. To name someexamples: facilitating the regeneration of healthy car-tilage in an osteoathritic joint, re-establishing a phys-iological release profile in diabetic pancreatic islets,or promoting self-repair mechanisms in areas of thecentral nervous system and of the heart.Nanotechnology can play a pivotal role in the devel-opment of cost-effective therapies for in-situ tissueregeneration. This involves not only a deeper under-standing of the basic biology of tissue regeneration,but also identifying effective ways to initiate and con-trol the regenerative process. This ‘nanobiomimetic’strategy depends on three basic elements: intelligentbiomaterials, bioactive signalling molecules, and cells.

By ‘tailoring’ resorbable polymers at the molecularlevel for specific cellular responses, nanotechnologycan assist in the development of biomimetic, intelli-gent biomaterials. These biomaterials are designedto react positively to changes in the immediate envi-ronment, stimulating specific regenerative events atthe molecular level, directing cell proliferation, celldifferentiation, and extracellular matrix productionand organization. The sequential signalling of bioac-tive molecules, which triggers regenerative events atthe cellular level, is necessary for the fabrication andrepair of tissues. Nano-assisted technologies shouldenable the sequential delivery of proteins, peptidesand genes to mimic nature’s signalling cascade. Asa result, bioactive materials are produced, whichrelease signalling molecules at controlled rates thatin turn activate the cells in contact with the stimuli.

Finally, a major focus of ongoing and future efforts inregenerative medicine will be to effectively exploitthe enormous self-repair potential that has beenobserved in adult stem cells. Nano-assisted tech-nologies will aid in achieving two main objectives –to identify signalling systems, in order to leveragethe self-healing potential of endogenous adult stemcells; and to develop efficient targeting systems forstem cell therapies. Of huge impact would also bethe ability to implant cell-free, intelligent bioactivematerials that would effectively provide signalling tostimulate the self-healing potential of the patient’sown stem cells.

9

Tissue engineered epithelium © Fidia Advanced Biopolymers

Fibroblast cell on nanostructured substrate © Fraunhofer IBMT, St. Ingbert

1. INTRODUCTION

10

Multimodal cameras formedical imaging

Implantable device forcontinuous measurementof blood markers

Transfection nanodevicefor therapeutic use

Encapsulating contrastagents

Biomimetic sensors

Clinical cameras forwhole-body images

Multifunctionalnanoparticles for drugrelease and imaging

Integrative lab-on-chip forin vitro diagnostics (incl.sample preparation)

Point of care analyticaldevice

Quantum dots formolecular diagnostics andimaging

20

05

20

10

20

15

20

20

20

05

20

10

20

20

20

05

20

10

20

15

20

15

20

20

Biomimetic polymers

Carbon nanotubes

Polymeric nanocapsulesfor drug delivery

On-command deliverysystems

Self-regulating deliverysystems interacting withthe body

Bio-engineered virusesand bacteria

Therapeutic magneticand paramagneticnanoparticles

Therapeutic dendrimers

Delivery systems oftherapeutic peptides andproteins (biopharmaceutics)

Nanoparticles forimplantable devices andtissue engineering

Cell and gene targetingsystems

Combined therapy andmedical imagingsystems

Multi-reservoir drugdelivery microchips

In vitro engineered skin, cartilage

In vitro engineered bone

Cell therapy formyocardial regeneration

Cartilage self-regenerating treatmentfor osteoarthritis

In vitro engineered organpatches

Intelligent biomaterialsfor in situ regeneration ofbone

Anti-cancer vaccines

Langerhans’ isletregenerating therapyfor diabetes

Intelligent biomaterials forin situ myocardialregeneration

Disease modifyingtreatment for Alzheimer’s,Parkinson’s disease

Nerve regeneration forspinal and limb repair

Nanodiagnostics timeline Targeted drug delivery timelineRegenerative Medicine timeline

11

Disease areas which can be expected to benefit mostfrom nanotechnology within the next 10 years arecancer, diseases of the cardiovascular system, thelungs, blood, neurological (especially neuro-degenerative) diseases, diabetes, inflammatory/infectious diseases and orthopaedic problems.

Cancer is a complex disease involving a multitude ofmolecular and cellular processes, arising as theresult of a gradual accumulation of genetic changesin specific cells. Nanotechnology-based highly effi-cient markers and precise, quantitative detectiondevices for early diagnosis and for therapy monitor-ing will have a wide influence in patient management,in improving patient’s quality of life and in loweringmortality rates. Devices capable of bypassing bio-logical barriers to deliver therapeutic agents withaccurate timing and at locally high concentrationsdirectly to cancer cells will play a critical role in thedevelopment of novel therapeutics.

Applications of nanotechnology to diseases of thecardiovascular system include the non-invasive diag-nosis and targeted therapy of atherosclerotic plaque.Devices to monitor thrombotic and haemorrhagicevents can have a high impact, e.g. in the diagnosisand treatment of stroke and embolisms.Multifunctional devices could detect events, transmit

real-time biological data externally, and deliver anti-coagulants or clotting factors while the patient seeksfurther treatment.

Nanotechnology could also have a large impact in thearea of blood purification/decontamination, based onintelligent sorbents and hemocompatible andimmuno-tolerated implantable nanodevices, or onnovel separation techniques using for example mag-netic nanoparticles or carbon nanotubes.

Tissue repair and regeneration are other areas wherenanotechnology could have great impact. For exam-ple, biodegradable nanoparticles which releaseappropriate growth factors and angiogenic factorscould improve the bioengineering of heart or lung tis-sue or the production of vascular grafts to build func-tional tissue.

Lung inflammatory disease represents anotherlikely target for diagnosis and therapy utilizingnanotechnology. Therapeutic nanoparticles capa-ble of sensing alveolar function could release drugsonly when needed, restricting drug delivery to dis-ease-affected areas.

The brain represents one of the most complex sys-tems in biomedicine. With an improved understand-ing of brain function, nanotechnology offers better

2. Societal Impact

Fluorescence microscopy of labeled chromosomes © P. Stroppa, CEA

Engineered tendon © Fidia Advanced Biopolymers

12

diagnosis and treatment for neurodegenerative dis-eases like multiple sclerosis, Alzheimer’s diseaseand Parkinson’s disease.

The risks and challenges of NanoMedicine compriseissues of toxicity and carcinogenicity, as well as long-term stability and excretion pathways for artifi-cial nanostructures, and technological challenges inmolecular manufacturing, quality assurance andeventually, the programmability of nanodevices.There are challenges in managing the interdiscipli-nary requirements that span traditional industries.The experts identified regulatory challenges in theareas of approval times, intellectual property protec-tion and harmonization. As medical technologyadvances in general, many legal and ethicalchallenges will also need to be addressed.

2. SOCIETAL IMPACT

Membrane Proteins, imaged by Scanning Force Microscopy© H. Oberleithner, University of Münster

Human Immunodeficiency Viruses budding out of T-cells, which play a large role in the immune response.Transmission electron microscopy. © Roche, 2005

13

NanoMedicine is not only important to Europe fromthe social and welfare aspects, but also for its eco-nomic potential. It includes all products that can bedefined as ‘systems and technologies for healthcare,aimed at prevention, diagnosis or therapy’. Little mar-ket data is published specifically about NanoMedicineat present. However, an analysis of the market seg-ments for medical devices and drugs & pharma-ceuticals gives an idea about the leverage ofNanoMedicine on the markets. These two marketsegments represented in 2003 an end-user value of€ 535 billion, of which the drugs segment is the mostimportant, with a value of € 390 billion. Globally thismarket has been growing at a 7 to 9% annual rate,with variations according to country, technologiesand market segments.

The medical devices market is expected to grow invalue by about 9% annually at present. The introduc-tion of novel nanotechnologies can be expected togive rise to a much higher rate, by providing innova-tive solutions and more precise care and new infor-mation for preventive medicine. The market can befurther segmented into areas where NanoMedicinemight have the highest potential of penetration, suchas in-vitro diagnostic products, patient monitoring sys-tems, imaging systems or imaging contrast agents.

In a medical devices market of € 145 billion in 2003,in-vitro diagnostic systems represented € 18 billion,or 13% of the total. It can be expected that nanotech-nology will have an impact on this expanding marketin the coming years, as it offers the potential of fasterand more accurate analyses of smaller and smallersamples.

Medical imaging systems represent € 14.5 billion, or8% of the total devices market. Imaging tools andimaging agents (including contrast media and radio-pharmaceuticals) represent € 4 billion, or 3%. Thesesegments will benefit from the application of tech-niques developed from an understanding both ofmaterials and cellular activities at the nanoscale.Already the sale of tools dedicated to molecular clin-ical and preclinical imaging represents € 0.8 billion

out of the € 14.5 billion total, and the patient moni-toring market represents € 1.5 billion.

NanoMedicine can also potentially affect aspects ofall medical devices, for example new materials forsurgical implants, nanometric systems for monitor-ing cardiac activities or minimally invasive surgerysensors.

The worldwide market for pharmaceutical drugshas been growing at a rate of 7% in 2004. The drugmarket can be segmented, with the global market foradvanced drug delivery systems accounting for€ 42.9 billion or 11% of the total. Approximately halfof this market is in controlled release systems, withneedle-less injection, injectable/implantable polymersystems, transmucosal, rectal, liposomal drug deliv-ery and cell/gene therapy responsible for the rest,and is estimated to reach € 75 billion in 2005.Developments in this market are rapid; especially inthe sector of alternatives to injected macromolecules,as drug formulations seek to cash in on the € 6.2 bil-lion worldwide market for engineered protein andpeptide drugs and other biological therapeutics.

When reviewing the economic potential ofNanoMedicine, all the biotech companies must beconsidered as they are directly involved in the devel-opment of new molecules, and also in the develop-ment of new tools for accelerating the discovery of

3. Economic Impact

Camera for magnetic resonance imaging.© C. Boulze, CEA

14

appropriate molecules. Today half of the new mole-cules discovered worldwide come from biotech com-panies. There are more than 4,000 worldwide, withover 300 companies in the US actively working ondeveloping drug-delivery platforms, including thera-pies targeted to the site of the disease, as well asdrug-containing implants, patches and gels.

Europe has acknowledged strengths particularly inmedical devices development and in drug deliveryresearch, and these are clearly areas where theestablishment of a European NanoMedicine Platformwould contribute to maintaining and improvingEuropean competitiveness.

Drugs and Medical Devices Market (€ billions)

Pharmaceutical drugs (€ 390 billion) and Medical devices (€ 145 billion)Controlled release systemsOther advanced drug delivery systemsOther pharmaceutical drugsMedical devices

Other medical imaging systemsMolecular pre-clinical and clinical imagingPatient monitoring marketImaging tools and imaging agentsMedical devices other than imaging

145.00

21.45

21.45

126.50

12.20

0.80

1.50

4.00

347.10

3. ECONOMIC IMPACT

15

4.1 Introduction

The application of micro- and nanobiotechnology inmedical diagnostics can be grouped into two areas, in-vitro (biosensors and integrated devices) and in-vivo(implantable devices, medical imaging) applications.

The basis of modern medicine was laid already in themiddle of the 19th century by the recognition that thecell is the source of health and disease. It followedthat basic research to provide a better understandingof the highly complex working of cells is mandatoryfor medicine. Improvement and combination of meth-ods to characterize cells or cell compartments in-vitro(like novel optical microscopy, scanning probemicroscopy, electron microscopy and imaging mass-spectrometry) will be of importance for NanoMedicine.

In-vitro diagnosis for medical applications has tradi-tionally been a laborious task; blood and other bodyfluids or tissue samples are sent to a laboratory foran analysis, which could take hours, days or weeks,depending on the technique used, and be highlylabour intensive. The many disadvantages includesample deterioration, cost, lengthy waiting times(even for urgent cases), inaccurate results for smallsample quantities, difficulties in integrating parame-ters obtained by a wide variety of methods, and poorstandardisation of sample collection. Steadily, minia-turisation, parallelisation and integration of differentfunctions on a single device, based on techniquesderived from the electronics industry, have led to the

development of a new generation of devices that aresmaller, faster and cheaper, do not require specialskills, and provide accurate readings. These analyt-ical devices require much smaller samples and willdeliver more complete (and more accurate) biologi-cal data from a single measurement.

The requirement for smaller samples also meansless invasive and less traumatic methods of extrac-tion. Nanotechnology enables further refinement ofdiagnostic techniques, leading to high throughputscreening (to test one sample for numerous dis-eases, or screen large numbers of samples for onedisease) and ultimately point-of-care diagnostics.These technological advancements pave the waytowards major changes in the way drugs can be pre-scribed in future, by enabling the goal of personalisedmedicine that is tailored to individual needs.

It is interesting to note that many new in-vitrotechniques developed for medical testing are alsofinding important diverse applications, such as inenvironmental monitoring and security.

Medical imaging has advanced from a marginal role inhealthcare to become an essential tool of diagnosticsover the last 25 years. Molecular imaging and image-guided therapy is now a basic tool for monitoring dis-ease and in developing almost all the applications ofin-vivo NanoMedicine. Originally, imaging techniquescould only detect changes in the appearance of tis-sues when the symptoms were relatively advanced.Later, contrast agents were introduced to more easilyidentify and map the locus of disease. Today, throughthe application of nanotechnology, both imaging toolsand marker/contrast agents are being dramaticallyrefined towards the end goals of detecting disease asearly as possible, eventually at the level of a single cell,and monitoring the effectiveness of therapy.

The convergence of nanotechnology and medicalimaging opens the doors to a revolution in molecularimaging (also called nano-imaging) in the foreseeablefuture, leading to the detection of a single molecule ora single cell in a complex biological environment.

4. Nanotechnology-based Diagnostics

including Imaging

Brain pictures with PET (Positron Emission Tomography)and NMR (Nuclear Magnetic Resonance). © CEA

One of the challenges has been to define researchpartnerships between the imaging industry and thecontrast agent industry, which bring different, com-plementing competencies to the table. The proposedEuropean Technology Platform in NanoMedicinewould be timely to accelerate their integration.

4.2 In-vitro Diagnostics

An in-vitro diagnostic tool can be a single biosensor,or an integrated device containing many biosensors.Abiosensor is a sensor that contains a biological ele-ment, such as an enzyme, capable of recognisingand ‘signalling’ (through some biochemical change)the presence, activity or concentration of a specificbiological molecule in solution. A transducer is usedto convert the biochemical signal into a quantifiablesignal. Key attributes of biosensors are their speci-ficity and sensitivity. Nanoanalytical tools like scan-ning probe microscopy or imaging mass spectrome-try offer new opportunities for in-vitro diagnostics,like molecular pathology or reading out highlyintegrated ultra-sensitive biochips.

Techniques derived from the electronics industryhave enabled the miniaturisation of biosensors,allowing for smaller samples and highly integratedsensor arrays, which take different measurements inparallel from a single sample. Higher specificityreduces the invasiveness of the diagnostic tools and

simultaneously increases their effectiveness signifi-cantly in terms of providing biological informationsuch as phenotypes, genotypes or proteomes.Several complex preparation and analytical stepscan be incorporated into ‘lab-on-a-chip’ devices,which can mix, process and separate fluids, realis-ing sample analysis and identification. Integrateddevices can measure tens to thousands of signalsfrom one sample, thus providing the general practi-tioner or the surgeon with much more complemen-tary data from his patient’s sample. Some nanobiode-vices for diagnostics have been developed tomeasure parts of the genome or proteome usingDNA fragments or antibodies as sensing elementsand are thus called gene or protein chips. ‘Cells–on-chips’ use cells as their sensing elements, employedin many cases for pathogen or toxicology screening.

Integrated devices can be used in the early diagno-sis of disease and for monitoring the progress of ther-apy. New advancements in microfluidic technologiesshow great promise towards the realisation of a fullyintegrated device that directly delivers full data for amedical diagnosis from a single sample. Recentdevelopments aim at developing in-vitro diagnostictools to be used in a standard clinical environmentor e.g. as ‘point-of-care’ devices.

4.3 In-vivo Nano-Imaging

In-vivo diagnostics refers in general to imaging tech-niques, but also covers implantable devices. Nano-imaging includes several approaches using tech-niques for the study of molecular events in-vivo andfor manipulation of molecules. Imaging techniquescover advanced optical imaging and spectroscopy,nuclear imaging with radioactive tracers, magneticresonance imaging, ultrasound, optical and X-rayimaging, all of which depend on identifying tracers orcontrast agents that have been introduced into thebody to mark the disease site

Targeted molecular imaging is important for a widerange of diagnostic purposes, such as the identifica-

16

Scanning force micrograph of amyloid fibrils formed fromthe Parkinson’s disease-related protein alpha-synuclein. © V. Subramaniam, Biophysical Engineering, University ofTwente

4. NANOTECHNOLOGY-BASED DIAGNOSTICS INCLUDING IMAGING

17

tion of the locus of inflammation, the visualisation ofvascular structures or specific disease states and theexamination of anatomy. It is also important forresearch on controlled drug release, in assessing thedistribution of a drug, and for the early detection ofunexpected and potentially dangerous drug accumu-lations. The ability to trace the distribution of a drugleads to the possibility of activating it only whereneeded, thus reducing the potential for toxicity (seechapter on Targeted Drug Delivery and Release).

A wide range of particles or molecules is currentlyused for medical imaging. Some recent develop-ments focus on using nanoparticles as tracers or con-trast agents. Fluorescent nanocrystals such as quan-tum dots are nanoparticles which, depending on theircoating and their physical and chemical properties,can target a specific tissue or cell and be made tofluoresce for imaging purposes. They offer a moreintense fluorescent light emission, longer fluores-cence lifetimes and increased multiplexing capabili-ties compared to conventional materials. Quantumdots are expected to be particularly useful for imag-ing in living tissues, where signals can be obscuredby scattering. Toxicological studies are being under-taken to precisely study their impact on humans, ani-mals and the environment. New developments arefocusing on the nanoparticle coating, to improve itsefficiency of targeting and biocompatibility.

The main benefits of nano-imaging for in-vivo diag-nostics are the early detection of disease, the mon-itoring of disease stages (e.g. in cancer metastasis),in patient selection leading to individualised medi-cine and in the real-time assessment of therapeuticand surgical efficacy.

4.4 Basis for a StrategicResearch Agenda

In-vitro diagnosticsThe ultimate goal is the fast, reliable, specific andcost-effective detection of a few molecules (or evena single molecule) in a complex, non amplified and


Novel diagnostic approaches: cell surface characterizationof pancreatic tumor cell lines with complementary methods © J. Schnekenburger, Department of Medicine B, University of Münster

Digital Holography © Gert von Bally, University of Münster

Scanning-Electron-Micoscopy © Marcus Schäfer, University of Münster

Digital Instruments NanoScopeScan size 5.000 μmScan rate 1.001 HzNumber of samples 1.512Image Data HeightData scale 1.117 μm

Scanning Force Microscopy © Boris Anczykowski, nanoAnalytics GmbH

unlabelled biological sample. The improvement of in-vitro diagnostics towards this goal requires:• nanoanalytical instruments of the highest spatial

resolution, sensitivity and range of information, andintegrated, combined instruments;

• better sensitivity of screening methods, enablingthe sample size to be decreased, or for the earlydetection of low concentrations of disease markers;

• higher specificity, for quantitative detection of mark-ers in complex samples,

• stronger reliability, simplicity of use and robustness;• faster analysis;• integration of different technologies to provide data

for complementary multi-parameter analyses.

The commercialization of low cost, user-friendly lab-on-a-chip devices for point-of-care and disease pre-vention and control at home is driving research intoareas of:• user-friendly sample preparation techniques,

enabling the detection of minute amounts of diseasemarker in a fairly concentrated blood drop and alsominute quantities diluted in a relatively huge samplevolume, e.g. 5 to 10 cancer cells in 100 ml of urine;

• ultra-sensitive and label-free detection techniquesaiming at a faster and more compact direct detec-tion, using for example, cantilevers or conductingpolymers;

• synthetic recognition elements as sensors, in orderto increase the sensitivity, specificity and rugged-ness of recognition. This requires advancement indeposition techniques and surface chemistry includ-ing self assembly of biomolecules, hybrid conju-gates of biomaterials with nanoparticles orMolecularly Imprinted Polymers;

• integrated, complex devices based on advancedmicro- and nanofluidics, using for example activefunctionalised channel walls, and complex analysisprotocols;

• biomimetic sensors using molecules as sensors.

In-vivo nano-imagingThe goal of in-vivo diagnostics research is to cre-ate highly sensitive, highly reliable detection agentsthat can also deliver and monitor therapy. This is the

‘find, fight and follow’ concept of early diagnosis,therapy and therapy control, that is encompassedin the concept of theranostics. With this strategy, thetissue of interest can firstly be imaged, using tar-get-specific contrast nanostructures. Then, com-bined with a pharmacologically active agent, thesame targeting strategy can be used for applyingtherapy. Finally, monitoring of treatment effects ispossible by sequential imaging. All developmentsrelated to the drug release and drug targetingaspect can be found in Chapter 5: Targeted DrugDelivery and Release.

Improved DetectionResearch is needed to improve the efficiency and reli-ability of detection systems. A major objective for thecoming years is to develop efficient, reasonably pricedclinical cameras capable of acquiring whole-bodyimages in one step and undertaking multi-isotopestudies. The benefit would be a drastic increase in thethroughput of whole body imaging, particularly impor-tant for cancer screening. Developments in nuclear

imaging (which remains an expensive technology)require new detector architectures and new crystalgrowing methods to reduce manufacturing costs.

Combining different imaging modalities is a prom-ising approach; for example, positron emissiontomography with magnetic resonance imaging,

18

Brain pictures with PET (Positron Emission Tomography)and NMR (Nuclear Magnetic Resonance).© LABORATOIRE CYCERON, CEA


19

magnetic resonance imaging with ultrasound orwith electroencephalogram-based brain mapping,ultrasound with optical technologies, and will leadto the possibility of benefiting from the advantagesof each system. The fusion of magnetic resonanceimaging and optical imaging modalities remains achallenge. In principle, this will require use of flu-orescent nanoparticles as signal emitters, whichfunction in both paramagnetic and infrared modes.Once this is achieved, nanotechnology may leadto the miniaturisation of detection devices or theremote transduction of signals.

In high-resolution measurements of electromagneticfields, the development of new interfaces with nano-structured and/or biological functionalised surfaces,would improve continuous monitoring of biologicalparameters dramatically. Research is also requiredto improve methods of image analysis and visualisa-tion, such as 3-D optical reconstruction, real-timeintracellular tomography, stereo-imaging, virtual andaugmented reality, holography, in-vivo imaging fromoptical catheters, and better endoscopic tools.

Furthermore, the ability to measure small local vari-ations in temperature using radio frequency detec-tors has applications in identifying the onset andlocus of many diseases, especially cancer.

Several other research issues are to be taken intoconsideration if molecular imaging is to become areality. When dealing with the identification of tinychanges, achieving gains in the signal-to-noise ratiois critical, so also is the validation of the delicate meas-urements that images appear to provide for drug andtherapy developments, as well as improvements tomeasurement techniques and data processing soft-ware. Lastly, effort has to be dedicated to the man-agement of large amounts of data in order to fully gainadvantage of nano-imaging results.

Nano ProbesThe development of probes is an extremely activefield where the miniaturization of complex reportingdevices adapted to in-vivo imaging would beextremely beneficial. The major issues are specificityand the ability to penetrate the cell.

The very earliest manifestations of disease in the bodyare indicated by changes in living cells, including defec-tive cell adhesion, cell mis-signalling, mitotic errors,intercellular communication errors, and abnormal cyto-plasmic changes. Major benefits are envisaged frombeing able to image and identify these changed states.Different imaging techniques require different reportingdevices; for example, quantum dots may ‘report back’by fluorescing on contact with diseased cells. It is notdifficult to make the leap from a reporter device to adevice that not only indicates the locus of the disease,but also delivers a cure; for example nanomagneticparticles ‘report back’ by providing increased contrastand also take part in the therapeutic process (in addi-tion, this concept underpins the need for research intogene and cellular therapy and drug delivery).

To improve reporting, research is required into thedesign and composition of nanoparticles, enablingthem to better target diseased cells, including those sit-uated behind barriers such as epithelial tissues. Furtherresearch is required into the creation of an ‘all-purposenanoparticle’ that can be imaged by the variety of exist-ing instruments (e.g. optical, acoustic, magnetic, etc.).Apart from identifying disease and delivering therapy,


Scanning Force Microscopy analysis of chromosomes,which were processed with a laser as a tool fornanosurgery. © Fraunhofer IBMT, St. Ingbert

the non-toxic labelling of specific cell types is impor-tant for the imaging of intracellular trafficking.

Work is also urgently required to improve the biocom-patibility of reporter devices and for minimising anypotential toxicity, allergic or inflammatory response,taking into account natural elimination to prevent pos-sible long lasting effects. Research is also requiredon encapsulating contrast agents to facilitate theirdelivery to the target site, or on attaching specific link-ers to provide new properties.

Essentially, the development of new probes formolecular imaging requires a multidisciplinaryapproach, with the transfer of discoveries in materialscience (new nanostructures such as particles,tubes, capsules, fullerenes, dendrimers, newpolymer structures, etc.).

Combined TechniquesNanobiotechnology offers significant inputs to theimprovement of detection devices and in the taggingof disease indicators administered in-vivo, which willlead to advancement in imaging. Potent driving forcesinclude synergies, such as those between in-vitro diag-nostics (probes and markers) and in-vivo imaging; andbetween contrast / probe development (in drug deliv-ery and/or toxicology studies) and imaging technology(medical instrumentation). The combination of in-vitrodiagnostics and in-vivo nano-imaging could lead to tar-geted tumor disruption or removal: Tagging tumor cellswith functionalized nanoparticles, which react to exter-nal stimuli, allows for in-situ, localized ‘surgery’ (break-ing up or heating of particles by laser, magnetic fields,microwaves, etc.) without invasiveness within thehuman body.

SurgeryIn the clinic, the use of nanoparticles for diagnosis andmanipulation may lead to an improvement of surgicaltechniques. This may be achieved, for example,through cancer distribution mapping using near-infrared quantum dots, and applying thermotherapyor heat treatment, the characterisation and non-destructive removal of cells or tissue in a specific area,the tracking of specific cell types used in therapy, aswell as the visualisation of bio-therapeutic agents.

Nanotechnology has further application in transfec-tion devices for therapeutic uses. An example wouldbe the development of devices that can cross biolog-ical barriers (like the blood-brain barrier) to deliver mul-tiple therapeutic agents at high local concentrationsdirectly to cancer cells and the neighbouring tissuesthat play a critical role in the spread of the disease.

Implantable devices for in-vivo diagnosticsImplantable devices for in-vivo diagnosticsNanotechnology also has many implications for in-vivo diagnostic devices such as the swallowableimaging ‘pill’ and new endoscopic instruments.Monitoring of circulating molecules is of great inter-est for some chronic diseases such as diabetes orAIDS. Continuous, smart measurement of glucose orblood markers of infection constitutes a real marketfor implantable devices. Miniaturisation for lower inva-siveness, combined with surface functionalisation andthe ‘biologicalisation’ of instruments will help increasetheir acceptance in the body. Autonomous power, self-diagnosis, remote control and external transmissionof data are other considerations in the developmentof these devices.

Nanosensors, for example used in catheters, will alsoprovide data to surgeons. Nanoscale entities couldidentify pathology/defects; and the subsequent removalor correction of lesions by nanomanipulation could alsoset a future vision.

20

Localisation of benzodia receptors by Positron EmissionTomography (PET). © LABORATOIRE CYCERON, CEA


21

5.1 Introduction

The very slow progress in the treatment of severediseases has led to the adoption of a multidisciplinaryapproach to the targeted delivery and release ofdrugs, underpinned by nanoscience and nanotech-nology. New drug delivery systems (DDS) combinepolymer science, pharmaceutics, bioconjugate chem-istry and molecular biology. The aim is to better con-trol drug pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity and biorecognition ofsystems in the quest for improved efficacy.

Drug delivery and targeting systems under develop-ment aim to minimize drug degradation and loss, pre-vent harmful side effects and increase the availabil-ity of the drug at the disease site. Drug carriersinclude micro and nanoparticles, micro and nanocap-sules, lipoproteins, liposomes, and micelles, whichcan be engineered to slowly degrade, react to stim-uli and be site-specific. Targeting mechanisms canalso be either passive or active. An example of pas-sive targeting is the preferential accumulation ofchemotherapeutic agents in solid tumors as a resultof the differences in the vascularization of the tumor

tissue compared with healthy tissue. Active target-ing involves the chemical ‘decorating’ of the surfaceof drug carriers with molecules enabling them to beselectively attached to diseased cells.

The controlled release of drugs is also important fortherapeutic success. Controlled release can be sus-tained or pulsatile. Sustained (or continuous) releaseof a drug involves polymers that release the drug ata controlled rate, by diffusion out of the polymer orby degradation of the polymer over time. Pulsatilerelease is often preferred, as it closely mimics theway by which the body naturally produces hormonessuch as insulin. It is achieved by using drug-carryingpolymers that respond to specific stimuli (e.g. expo-sure to light, changes in pH or temperature).

Other nano-based approaches to drug delivery arefocused on crossing a particular physical barrier,such as the blood-brain barrier; or on finding alter-native and acceptable routes for the delivery of anew generation of protein-based drugs other thanvia the gastro-intestinal tract, where degradation canoccur. Nanoscience and nanotechnology are thusthe basis of innovative delivery techniques that offergreat potential benefits to patients and new marketsto pharmaceutical and drug delivery companies.

For over 20 years, researchers in Europe have usednanoscale technology as the basis of vast improve-ments in drug delivery and targeting, and Europe isnow well placed to build on this body of knowledge.

5.2 Drug Delivery Systems

Drug CarriersA successful drug carrier system needs to demon-strate optimal drug loading and release properties,long shelf-life and low toxicity. Colloidal systems,such as micellar solutions, vesicle and liquid crystaldispersions, as well as nanoparticle dispersions con-sisting of small particles of 10 - 400 nm diametershow great promise as carriers in drug deliverysystems.

5 Targeted Drug Delivery and Release

Zoom on a virus head, computer model. © E. Hewat, IBS-CEA

22

Micelles: Drugs can be trapped in the core of a micelleand transported at concentrations even greater thantheir intrinsic water solubility. A hydrophilic shell canform around the micelle, effectively protecting the con-tents. In addition, the outer chemistry of the shell mayprevent recognition by the reticuloendothelial system,and therefore early elimination from the bloodstream.A further feature that makes micelles attractive is thattheir size and shape can be changed. Chemical tech-niques using crosslinking molecules can improve thestability of the micelles and their temporal control.Micelles may also be chemically altered to selectivelytarget a broad range of disease sites.

Liposomes are vesicles that consist of one to several,chemically-active lipid bilayers. Drug molecules can beencapsulated and solubilised within the bilayers.Certain (channel) proteins can be incorporated in themembrane of the liposome, which act as size-selec-tive filters only allowing the diffusion of small solutessuch as ions, nutrients and antibiotics. Thus, drugsencapsulated within a liposome ‘nanocage’ that hasbeen functionalized with channel proteins, are effec-tively protected from premature degradation. The drugmolecule, however, is able to diffuse through the chan-nel, driven by the concentration difference between theinterior and the exterior of the ‘nanocage’.

Dendrimers are nanometre-sized, polymer macro-molecules. They consist of a central core, branchingunits and terminal functional groups. The core chem-istry determines the solubilizing properties of the

cavity within the core, whereas external chemicalgroups determine the solubility and chemicalbehavior of the dendrimer itself. Targeting is achievedby attaching specific linkers to the external surfaceof the dendrimer which enable it to bind to a diseasesite, while its stability and protection from phagocytesis achieved by ‘decorating’ the dendrimers withpolyethylene glycol chains.

Liquid Crystals combine the properties of both liq-uid and solid states. Liquid crystals can be made toform different geometries, with alternate polar andnon-polar layers (i.e., lamellar phases), within whichaqueous drug solutions can be incorporated.

Nanoparticles, including nanospheres and nanocap-sules, can be amorphous or crystalline. They are ableto adsorb and/or encapsulate a drug, thus protectingit against chemical and enzymatic degradation. Innanocapsules, the drug is confined to a cavity sur-rounded by a polymer membrane, while nanospheresare matrix systems within which the drug is physicallyand uniformly dispersed. In recent years, biodegrad-able polymeric nanoparticles have attracted consid-erable attention in the controlled release of drugs intargeting particular organs/tissues, as carriers of DNAin gene therapy and in their ability to deliver proteins,peptides and genes by the oral route.

Hydrogels are three-dimensional polymer networks thatswell but do not dissolve in aqueous media. They areused to regulate drug release in reservoir-based

Gene delivery using ultrasound. The presence of gas in the gene-filled microbubbles allows ultrasound to burst them. © Unger et al. Therapeutic Applications of Microbubbles

5. TARGETED DRUG DELIVERY AND RELEASE

23

systems or as carriers in swelling-controlled releasedevices. On the forefront of controlled drug delivery,hydrogels, as enviro-intelligent and stimuli-sensitive gelsystems, can modulate drug release in response to pH,temperature, ionic strength, electric field, or specific ana-lyte concentration differences. Release can be designedto occur within specific areas of the body. Hydrogels asdrug delivery systems are very promising if combinedwith the technique of molecular imprinting.

Molecularly imprinted polymers have an enor-mous potential for drug delivery systems. Examplesinclude: rate-programmed drug delivery, where drugdiffusion from the system has to follow a specific rateprofile; activation-modulated drug delivery, where therelease is activated by some physical, chemical orbiochemical processes; and feedback-regulated drugdelivery, where the rate of drug release is regulatedby the concentration of a triggering agent, which isactivated by the drug concentration in the body.

Despite already-developed applications, the incor-poration of the molecular imprinting approach for thedevelopment of drug delivery systems is at an earlystage. It can be expected that in the next few yearssignificant progress will occur, taking advantage ofthe improvements in this technology in other areas.

The conjugation of biological molecules (pep-tides/proteins) and synthetic polymers is an effi-cient means of improving control over the nanoscalestructure formation of synthetic polymers that can be

used as drug delivery systems. The conjugation ofsuitable synthetic polymers to peptides or proteinscan reduce toxicity, prevent immunogenic or anti-genic side reactions, enhance blood circulation timesand improve drug solubility. Modification of syntheticpolymers with peptide sequences, which can act asantibodies to specific epitopes, can also prevent ran-dom distribution of drugs throughout a patient’s bodyby active targeting. The functionalisation of syntheticpolymers with peptide sequences derived from extra-cellular matrix proteins is an efficient way to mediatecell adhesion, for example. In addition the ability ofcationic peptide sequences to complex DNA andoligonucleotides offers prospects for the develop-ment of non-viral vectors for gene delivery, based onsynthetic polymeric hybrid materials.

The field of in-situ forming implants has grownexponentially in recent years. Liquid formulationsgenerating a (semi-) solid depot after subcutaneousinjection are attractive delivery systems for par-enteral (non-oral) application because they are lessinvasive and painful compared to implants. Theyenable drugs to be delivered locally or systemicallyover prolonged periods of time, typically up to sev-eral months. These depot systems could minimizeside effects by achieving constant, ‘infusion-like’drug profiles, especially important for delivering pro-teins with narrow therapeutic indices. They also offerthe advantage of being relatively simple and cost-effective to manufacture.

Left to right:• Schematic of nanofabricated biomimetic drug delivery vehicle. The surface of a hollow polystyrene bead containing

the desired payload is functionalized for specific targeting. The payload is released through the membrane lipid bilayercovering the hole nanofabricated in the scaffold.

• Transmission electron microscopy image of a hollow polystyrene bead with a nanofabricated hole. • Transmission electron microscopy image of the cross-section of an “artificial cell”. © A. Dudia and V. Subramaniam, University of Twente, The Netherlands


The ultimate goal in controlled release is the devel-opment of a microfabricated device with the ability tostore and release multiple chemical substances ondemand. Recent advancement in microelectro-mechanical systems (MEMS) have enabled thefabrication of controlled-release microchips, whichhave the following advantages: • Multiple chemicals in any form (e.g. solid, liquid or

gel) can be stored and released; • Chemical release is initiated by the disintegration

of the barrier membrane by applying an electricpotential;

• A variety of highly potent drugs can potentially bedelivered accurately and safely;

• Complex release patterns (e.g. simultaneous con-stant and pulsatile release) can be achieved;

• Local delivery is possible, achieving high concen-trations of drug where needed, while keeping thesystemic concentration of the drug at a low level;

• Water penetration into the reservoirs is avoided bya barrier membrane and thus the stability of protein-based drugs with limited shelf-life is enhanced.

Administration RoutesThe choice of drug is often influenced by the way itis administered, as this can make the differencebetween a drug’s success and failure. So the choiceof a delivery route can be driven by patient accept-

ability, important properties of the drug (e.g. solubil-ity), the ability to target the disease location, or effec-tiveness in dealing with the specific disease.

The most important drug delivery route is the peroralroute. An increasing number of drugs are protein-and peptide-based. They offer the greatest potentialfor more effective therapeutics, but they do not eas-ily cross mucosal surfaces and biological membranes,they are easily denatured or degraded, they are proneto rapid clearance in the liver and other body tissuesand they require precise dosing. At present, proteindrugs are usually administered by injection, but thisroute is less accepted by patients and also posesproblems of oscillating blood drug concentrations. So,despite the barriers to successful drug delivery thatexist in the gastrointestinal tract (e.g. acid-inducedhydrolysis in the stomach, enzymatic degradationthroughout the gastrointestinal tract, bacterial fermen-tation in the colon), the peroral route is still the mostintensively investigated as it offers advantages of con-venience, cheapness of administration and manufac-turing cost savings.

Parenteral routes (e.g. intravenous, intramuscularor subcutaneous) are very important. The onlynanosystems presently on the market, liposomes,are administered intravenously. Nanoscale drug car-riers have a great potential for improving the deliv-ery of drugs through nasal and sublingual routes,both of which avoid first-pass metabolism; and for dif-ficult-access ocular, brain and intra-articular cavities.It has been possible to deliver peptides and vaccinessystemically using the nasal route through theassociation of active drug macromolecules withnanoparticles. In addition, there is the possibility ofimproving the ocular bioavailability of drugs ifadministered in a colloidal drug carrier.

Pulmonary delivery is also important and is effectedin a variety of ways - via aerosols, metered doseinhaler systems, powders (dry powder inhalers) andsolutions (nebulizers), which may contain nanostruc-tures such as liposomes, micelles, nanoparticles anddendrimers. Aerosol products for pulmonary delivery

24

Microchromatographic column. © P. Stroppa, CEA


25

comprise more than 30% of the global drug deliverymarket. Research into lung delivery is driven by thepotential for successful protein and peptide drug deliv-ery by this route and by the promise of an effectivedelivery mechanism for gene therapy (e.g. in the treat-ment of cystic fibrosis), as well as the need to replacechlorofluorocarbon propellants in metered doseinhaler systems. Pulmonary drug delivery offers localtargeting for the treatment of respiratory diseases andincreasingly appears to be a viable option for the deliv-ery of drugs systemically. However, the success ofpulmonary delivery of protein drugs is diminished byproteases in the lung, which reduce their overallbioavailability, and by the barrier between capillaryblood and alveolar air (the air-blood barrier).

Transdermal drug delivery avoids problems suchas gastrointestinal irritation, metabolism, variationsin delivery rates and interference due to the presenceof food. It is also suitable for unconscious patients.The technique is generally non-invasive, wellaccepted by patients and can be used to providelocal delivery over several days. Limitations includeslow penetration rates, lack of dosage flexibilityand/or precision, and a restriction to relatively lowdosage drugs.

Trans-tissue and local delivery systems are sys-tems that require to be tightly fixed to resected tissueduring surgery. The aim is to produce an elevatedpharmacological effect, while minimizing systemic,administration-associated toxicity. Trans-tissue sys-tems include: drug-loaded gelatinous gels, which areformed in-situ and adhere to resected tissues releas-ing drugs, proteins or gene-encoding adenoviruses;antibody-fixed gelatinous gels (cytokine barrier) thatform a barrier that on a target tissue could prevent thepermeation of cytokines into that tissue; cell-baseddelivery, which involves a gene-transduced oralmucosal epithelial cell-implanted sheet; device-directed delivery - a rechargeable drug infusion devicethat can be attached to the resected site.

Gene delivery is a challenging task in the treatmentof genetic disorders. Plasmid DNA has to be intro-duced into the target cells. It then needs to be tran-scribed, and the genetic information ultimately trans-lated into the corresponding protein. To achieve this,a number of hurdles have to be overcome. The genedelivery system has to be targeted to the target cell,transported through the cell membrane, taken up anddegraded in the endolysosomes, and the plasmidDNA trafficked intracellularly to the nucleus.


For all delivery routes formulation is essential andpresents new challenges. Research into novel waysto introduce nanomedicines into the body is as impor-tant as the drug itself. Formulation research addsvalue in a competitive marketplace where change isnow rapid. Present paradigms may not hold; anexample is the increasing market share now occu-pied by needleless injections.

Nanoparticles and nanoformulations have alreadybeen used as drug delivery systems with great suc-cess, and nanoparticulate drug delivery systemshave still greater potential for many applications,including anti-tumour therapy, gene therapy, AIDS

Pulmonary delivery© StockbyteTM, 2000


therapy, radiotherapy, in the delivery of proteins,antibiotics, virostatics, vaccines, and as vesicles topass the blood-brain barrier.

Nanoparticles provide massive advantages regard-ing drug targeting, delivery and release, and withtheir additional potential to combine diagnosis andtherapy, will emerge as one of the major tools inNanoMedicine. The main goals are to improve theirstability in the biological environment, to mediate thebio-distribution of active compounds, to improve drugloading, targeting, transport, release and interactionwith biological barriers. The cytotoxicity of nanopar-ticles or their degradation products remains a majorproblem and improvements in biocompatibility obvi-ously are a main concern of future research.

The European Technology Platform on NanoMedicineneeds to reflect on European strengths in this area inorder to be competitive. In drug delivery, these are inpolymer therapeutics, non-viral gene delivery, biolog-ical models for cells and tissues for in-vitro testingand in cancer targeting and therapy.

These form the basis for further developments,such as:• Nano-drug delivery systems that deliver large but

highly localized quantities of drugs to specific areas,to be released in controlled ways;

• Controllable release profiles, especially for sensi-tive drugs;

• Materials for nanoparticles that are biocompatible,biodegradable and non-toxic;

• Architectures/structures, such as biomimetic poly-mers and nanotubes;

• Technologies for self-assembly; • New functions (active drug targeting, on-command

delivery, intell igent drug release devices/bioresponsive triggered systems, self-regulateddelivery systems, smart delivery);

• Virus-like systems for intracellular delivery; • Nanoparticles to improve implantable devices; • MEMS (improved by nanotechnology) for nanopar-

ticle release and multi-reservoir drug delivery sys-tems;

• Nanoparticles for tissue engineering, e.g. for thedelivery of cytokines to control cellular growth anddifferentiation and to stimulate regeneration;

• Biodegradable layered coatings on implants for sus-tained release of active molecules;

• Advanced polymeric carriers for the delivery of ther-apeutic peptide/proteins (biopharmaceutics).

And also in the development of:• Combined therapy and medical imaging, for exam-

ple, nanoparticles for diagnosis and manipulationduring surgery (e.g. thermotherapy with magneticparticles);

• Universal formulation schemes that can be used asintravenous, intramuscular or peroral drugs;

• Cell and gene targeting systems;• Devices for detecting changes in magnetic or phys-

ical properties after specific binding of ligands onparamagnetic nanoparticles that can correlate withthe amount of ligands;

• Better disease markers in terms of sensitivity andspecificity;

• nanoanalytical instrumentation for improved under-standing, engineering, and control of drug deliverysystems;

• High throughput in-vitro and in-vivo test systemsfor immunological and toxicological screening ofnanoparticles and nanoformulations.

26

Stereographic pictures of pseudo-virus © CEA


27

6.1 Introduction

In the 1960s and 1970s, the first generation of mate-rials was developed for use inside the human body.A common feature of most of these materials wastheir biological inertness. The clinical success ofbioinert, bioactive and resorbable implants was animportant response to the medical needs of a rapidlyageing population. The field of biomaterials subse-quently began to shift in emphasis from a bioinert tis-sue response, to instead producing bioactive com-ponents that could elicit controlled actions andreactions within the body. By the mid-1980s, bioac-tive materials had reached the clinic in a variety oforthopaedic and dental applications. They includedvarious compositions of bioactive glasses, ceramics,glass-ceramics and composites, as well as a rangeof bioresorbable polymers. Whereas second-gener-ation biomaterials were designed to be eitherresorbable or bioactive, more advanced therapeuticapproaches are now being followed to combine thesetwo properties to develop implants, which will inducea regenerative-like healing modality. In other words,help the body to heal itself.

By leveraging novel cell culture techniques and syn-thesis and the design of bio-resorbable polymers,tissue engineering strategies have recently emergedas the most advanced therapeutic option presentlyavailable in regenerative medicine.

Tissue engineering encompasses the use of cellsand their molecules in artificial constructs that com-pensate for body functions that have been lost orimpaired as a result of disease or accidents. It isbased upon scaffold-guided tissue regeneration andinvolves the seeding of porous, biodegradable scaf-folds with donor cells, which become differentiatedand mimic naturally occurring tissues. These tissue-engineered constructs are then implanted into thepatient to replace diseased or damaged tissues. Withtime, the scaffolds are resorbed and replaced by hosttissues that include viable blood supplies and nerves.Current clinical applications of tissue-engineeredconstructs include engineering of skin, cartilage andbone for autologous implantation. Recent advance-ment in therapeutic strategies involving tissueengineering include the use of adult stem cellsas a source of regenerative cells, and the use of cell-signalling molecules as a source of molecularregeneration messengers.

Acomplex and uneven European regulatory and fund-ing environment has limited, to date, the extensivetherapeutic use of tissue-engineered treatments inaddressing different clinical needs, despite the signif-icant advancements that have been made. The highcost, together with a limited space for significanteconomies of scale in the mass-production of tissue-engineered products, has hindered widespread clin-ical application. In addition, presently available tis-sue-engineered products still share some of theconcepts of substitution medicine, where a labora-tory grown ‘spare part’ is implanted in the body tocompensate for lost tissue. Despite these limitations,the clinical availability of therapies based on tissueengineering represents a tremendous step forward inregenerative medicine. By building on the pioneeringachievements of tissue engineering, advanced ther-apies in regenerative medicine can therefore addresseven more challenging objectives - to initiate and con-trol the regeneration of pathological tissue, and totreat, modify and prevent disabling chronic disorderssuch as diabetes, osteoarthritis, diseases of the car-diovascular and central nervous system. Given thedynamics of Europe’s societal growth and the need

6. Regenerative Medicine

Engineered adipose tissue © Fidia Advanced Biopolymers

28

to provide advanced and cost-effective therapies toan ageing population, it is a further challenge forregenerative medicine to deliver the disease modify-ing benefits of tissue-engineered products to a widepatient population, in a cost-effective way.

6.2 A Biomimetic Strategy

The vision for nano-assisted regenerative medicineis the development of cost-effective disease-modi-fying therapies that will allow for in-situ tissue regen-eration. The implementation of this approachinvolves not only a deeper understanding of thebasic biology of tissue regeneration – wound heal-ing, in its widest sense – but also the developmentof effective strategies and tools to initiate and con-trol the regenerative process.

In the field of biomaterials and biotechnology, theterm ‘biomimetics’ has been established to describethe process of simulating what occurs in nature. Thebiomimetic philosophy can be condensed into threebasic elements: intelligent biomaterials, bioactive sig-nalling molecules and cells.

Intelligent biomaterials and smart implantsThird-generation biomaterials that involve tailoringof resorbable polymers at the molecular level to elicitspecific cellular responses show great promise as

scaffolds or matrices in tissue regeneration. These‘intelligent’ biomaterials are designed to react tochanges in the immediate environment and to stim-ulate specific cellular responses at the molecularlevel. Molecular modifications of resorbable polymersystems elicit specific interactions with cells anddirect cell proliferation, differentiation and extracel-lular matrix production and organization. For exam-ple, new generations of synthetic polymers are beingdeveloped which can change their molecular confor-mation in response to changes in temperature, pH,electrical stimuli or energetic status.

Access to nanotechnology has offered a completelynew perspective to the material scientist to mimic thedifferent types of extra-cellular matrices present in tis-sues. Techniques are now available which can pro-duce macromolecular structures of nanometre size,with finely controlled composition and architecture.Conventional polymer chemistry, combined withnovel methodologies such as electrospinning, phaseseparation, direct patterning and self-assembly, havebeen used to manufacture a range of structures, suchas nanofibres of different and well defined diametersand surface morphologies, nanofibrous and porousscaffolds, nanowires and nanoguides, nanospheres,nano ‘trees’ (e.g. dendrimers), nano-composites andother macromolecular structures.

Nanotechnology also improves non-resorbable bioma-terials and effective manipulation of biological interac-tions at the nanometre level, which will dramaticallyimprove the functionality and longevity of implantedmaterials. By applying bioactive nanoparticle coatingson the surface of implants, it will be possible to bondthe implant more naturally to the adjoining tissue andsignificantly prolong the implant lifetime. Similarly, itmay be possible to surround implanted tissue with ananofabricated barrier that would prevent activation ofthe rejection mechanisms of the host, allowing a widerutilization of donated organs. Nanomaterials and/ornanocomposites with enhanced mechanical proper-ties could replace the materials that fatigue-fail due tocrack initiation and propagation during physiologicalloading conditions. Nanomaterials with enhanced elec-

Growth cone of an immature hippocampal neuron devel-oping in vitro. Fluorescence microscopy. © Roche, 2005

6. REGENERATIVE MEDICINE

29

trical properties that remain functional for the durationof implantation could replace the conventional materi-als utilised for neural prostheses, whose performancedeteriorates over time. Third-generation bioactiveglasses and macroporous foams can be designed toactivate genes that stimulate regeneration of living tis-sues. By understanding the fundamental contractileand propulsive properties of tissues, biomaterials canbe fabricated that will have nanometre-scale featuresrepresenting the imprinted features of specific proteins.

In conclusion, nanotechnology can assist in thedevelopment of biomimetic, intelligent biomaterials,which are designed to positively react to changes intheir immediate environment and stimulate specificregenerative events at the molecular level in orderto generate healthy tissues.

Bioactive signalling moleculesBioactive signalling molecules are defined as thosemolecules which are naturally present in cells(cytokines, growth factors, receptors, second mes-sengers) and trigger regenerative events at the cel-lular level. Recently available therapies based on sig-nalling molecules involve the uncontrolled delivery ofa single growth factor - which is an obvious oversim-plification, in light of the complexities associated withthe healing cascades of living tissues, especially inchronic pathologies. Sequential signalling is obliga-tory in the fabrication and repair of tissues; therefore

the development of technologies for the sequentialdelivery of proteins, peptides and genes is critical.

The provision of the correct bioactive signalling mol-ecules to initiate and direct the regenerative processis being pursued by designing bioactive materialsand encoding biological signals able to trigger bio-logical events. The primary goal is to develop extra-cellular, matrix-like materials, by either combiningnatural polymers or developing structures startingfrom synthetic molecules combined with matricel-lular cues. By immobilizing specific proteins, pep-tides and other biomolecules onto a material, it ispossible to mimic the extracellular matrix (ECM)environment and provide a multifunctional cell-adhesive surface. Cell-specific recognition factorscan be incorporated into the resorbable polymersurface, including the adhesive proteins, fibronectinor functional domains of ECM components. Polymersurfaces can be tailored with proteins that influenceinteractions with endothelium, synaptic develop-ment and neurite stimulation.

To achieve any advancement it is essential to under-stand those molecular interactions that lead to regen-erative pathways, and the development of technolo-gies for the sequential delivery of proteins, peptidesand genes to mimic the signalling cascade. The useof nanotechnologies is advocated in assisting in thedevelopment of therapies involving the activation andspatio-temporal control of in-vivo tissue regeneration.

In conclusion, nano-assisted technologies will enablethe development of bioactive materials which releasesignalling molecules at controlled rates by diffusionor network breakdown that in turn activate the cellsin contact with the stimuli. The cells then produceadditional growth factors that will stimulate multiplegenerations of growing cells to self-assemble intothe required tissues in-situ.

Cell based therapiesCellular differentiation occurs in mammals as part ofthe embryological development and continues inadult life as part of the normal cell turnover or repair


Spontaneous stem cell differentiation © Fraunhofer IBMT, St. Ingbert

following injury. Growth, from the cellular aspect,means a continuous process of cellular turnover thatis dependent on the presence of self-renewing tis-sue stem cells that give rise to progenitor and maturecells. Cellular turnover is known to be fast in certaintissues, such as intestinal epithelium, blood and epi-dermis, and slow in others, such as bone and carti-lage, while it has been considered limited or non-existent in tissues such as the brain and the heart.However, scientific results in recent years have rad-ically changed the view of the ability of even thesetissues to regenerate after ischaemic injury. Thisparadigm shift will refocus research into the under-standing of mechanisms for stem cell recruitment,activation, control and homing.

The major focus of ongoing and future efforts in regen-erative medicine will be to effectively exploit the enor-mous self-repair potential that has been observed inadult stem cells. Given the logistical complexities andthe costs associated with today’s tissue engineering

therapies, which are based on the autologous reim-plantation of culture-expanded differentiated cells, nextgeneration therapies will need to build on the progressmade with tissue engineering in understanding thehuge potential for cell based therapies which involveundifferentiated cells. Nanotechnology will help in pur-suing two main objectives – identifying signalling sys-tems in order to leverage the self-healing potential ofendogenous adult stem cells, and developing efficienttargeting systems for adult stem cell therapies.

In conclusion, cell-based therapies should be aimedat the efficient harvesting of adult stem cells, toallow for a brief pre-implantation, cultivation stage,or, preferably, for immediate intra-operative admin-istration using an intelligent biomaterial as a bio-interactive delivery vehicle. Of huge impact wouldalso be the ability to implant cell-free, intelligent,bioactive materials that would effectively providesignalling to leverage the self-healing potential ofthe patient’s own stem cells.

30


MESODERMAL

Adult Stem Cells(ASC)

hematopoetic cellschondrocyte

muscle celladipocyteosteoclast

endothelial/vascular

nerve cell

ENDODERMAL ECTODERMAL

31


Careful consideration of the high-potential for regen-erative medicine leads to the conclusion that muchbasic and applied research must be undertaken, notonly in developmental biology and stem cell research,but also in the field of biomaterials. As numerousEuropean groups are amongst the world leaders inbiomaterials and cell therapies, there are great oppor-tunities here for European small and medium enter-prises. This is a niche where the European ResearchArea can gain prestige and a corresponding share ofthe world market in the development, production andmarketing of such ‘intelligent’ biomaterials.

These complex challenges can be addressed onlyby an interdisciplinary approach using internationalspecialists, with both academic and industrial back-grounds. This will require enlarging the number, facil-ities and staffing of the relevant laboratories withinEurope, with an emphasis on nanotechnology expert-ise and capability. It will be essential to set up multi-disciplinary research groups which bring togetherchemistry and biochemistry, molecular and cell biol-ogy, materials science and engineering, as well asensuring an adequate balance of academic andindustrial researchers.

Thanks to nanotechnology, a cellular and molecularbasis has been established for the development of

third-generation biomaterials that will provide the sci-entific foundation for the design of scaffolds for tis-sue engineering, and for in-situ tissue regenerationand repair, needing only minimally-invasive surgery.It is strongly recommended that in future planning pol-icy, attention and resources be focused on develop-ing these biomaterials.

Projects will also need to be highly focused towardsa clearly identified clinical application, not being lim-ited to basic research on the optimisation of ‘generic’cell/artificial matrix constructs. They must be rootedin the specific characteristics of the tissue to beregenerated, and in the economic advantage of oneapproach over another.

It should be feasible to design a new generation ofgene-activating biomaterials tailored for specificpatients and disease states. Emphasis should begiven to projects designed with the objective of devel-oping disease-modifying, cost-effective treatments forchronic disabilities that mostly affect the elderly, suchas diabetes, osteoarthritis, cardiovascular and centralnervous system degenerative disorders.

To this end, the following research activities will needto be promoted:• The development of ‘intelligent’, multi-functional bio-

materials; • Control of the structure of materials at the micro-

and nanoscale - mandatory in the design of intelli-gent scaffolds. This will also require research in the

Chondrocyte on Hyaluronan-derivative fiber imaged byscanning electron microscopy © Fidia Advanced Biopolymers

Left: intervertebral disc, 12 months after treatment withautologous disc chondrocytesRight: untreated intervertebral discRegenerated discs mimic native disc morphology; autologous treatment promotes tissue regeneration.© T. Ganey, co.don AG


fields of micro- and nanofabrication for the creationof structures that differentially control cell adhesion,proliferation and function;

• Technologies for the development of new genera-tions of synthetic polymers that can change theirmolecular conformation in response to changes inexternal stimuli (temperature, pH, electric field orenergetic status);

• Technologies for the development of bioactivenanocoatings;

• Projects which include electronic and/or communi-cation components in forms of nanowires andnanopores (or their equivalents) for the stimulationand biosensing of cells within an artificial matrix;

• Sensor technology for the assessment of theinterface activity and the progress of implantintegration;

• Novel technologies that enable the development ofbiomaterials for the sequential delivery of activesand/or chemo-attractants for the triggering ofendogenous self-repair mechanisms;

• Stem cell research, aimed at understanding mainlythe potential and plasticity of adult stem cells;

• The development of technologies for minimally-invasive, site-specific cell therapy;

• Research aiming to generate knowledge and productscentred on the nanoscale interactions between differ-ent types of cells and their immediate environment;

• Monitoring tissue regeneration;• Sensors for precise gene activation and control

during cell and tissue growth; • In-vitro and in-vivo toxicity testing of engineered

nanoparticles.

Finally, a future goal for regenerative medicine is thepossibility of using bioactive stimuli to activate genesas a preventative treatment; maintaining the healthof tissues as they age. Only a few years ago this con-cept would have seemed unimaginable. But we needto remember that only 30 years ago the concept ofa material that would not be rejected by living tissuesalso seemed unimaginable!

32

Engineered epithelium © Fidia Advanced Biopolymers

Gliacells on substrate with electrodes © Fraunhofer IBMT, St. Ingbert


33

The acceptance of NanoMedicine necessitates trans-parent and timely information of all stakeholders,including the general public. Safety aspects ofNanoMedicine have to be properly and systemati-cally addressed, and there has to be a clear positivebenefit-to-risk ratio that will accompany the clinicalimplementation of products and procedures based onnanotechnology. This will be achieved by a combi-nation of evidence-based public awareness pro-grammes and the development of science-basedregulatory processes, which have to take risk man-agement into account, e.g. by adopting a system,which identifies and assesses risks at every stageof the product or process cycle from the concept topost-treatment.

All medical products in Europe are currently regu-lated according to well-established Directives relat-ing to medicinal products or to medical devices,according to their principal mode of action.Discussions are also underway to provide a regula-tory framework for human tissue engineered prod-ucts and their associated processes. It is extremelyimportant that any new risks that may be associatedwith the introduction of nanotechnology into clinicalmedicine are evaluated, and that the details of newrisk management procedures identified as being

relevant to this assessment are properly incorporatedinto the existing regulatory frameworks and are fullyintegrated into any new regulatory developments thatmay emerge in the future as being necessary tocomplement existing European legislation.

It is necessary to put into place measures that iden-tify the hazards associated with novel nanotechnol-ogy-based therapies, characterize the associatedrisks, reduce those risks as far as reasonably prac-ticable, establish a positive risk/benefit balance, andcommunicate the nature of any residual risks andother relevant safety information to doctors, patientsand other key stakeholders. These risks could relateto, for example, patients, medical personnel andthose working in production. There is a possible rolefor standards in this process. A harmonized system-atic risk management standard already exists formedical technology products and could form thebasis for a risk management protocol for medicalnanotechnology. In addition, existing harmonizedstandards relating to biological safety could bereviewed and revised as necessary to take accountof the specific characteristics of medical nanotech-nology products.

An approach to the safe, integrated and responsibleintroduction of nanotechnology into medical practiceshould thus be included at a fundamental scientificlevel, to assess all aspects of risk and to contributeto appropriate regulations for this new technology, sothat safety for patients and others is maximisedwhilst, at the same time enabling the benefits ofNanoMedicine to be realised in a timely manner andin a way that encourages innovation and technolog-ical development. This approach is fully in line withthe Commission’s European strategy for nanotech-nology set out in the Communication “Towards aEuropean Strategy for Nanotechnology” and itsassociated Action Plan.

7. Regulatory Issues and Risk Assessment

Technician at a robot producing oligonucleotides © P. Stroppa, CEA

8. Ethical Issues

Nanotechnology offers great promise for medicine,but much of this lies in the future. This future orien-tation has made nanotechnologies vulnerable to thecurrent zeitgeist of over claiming in science, eitherthe potential benefit or harm. There is a need to becareful about placing premature weight on specula-tive hopes or concerns about nanotechnologiesraised ahead of evidence. Foresighting of break-through technologies is notoriously difficult, and car-ries the risk that early public engagement may pro-mote either public assurance or public panic over thewrong issues.

Nanotechnology as an enabling technology for manyfuture medical applications touches on issues suchas sensitivity of genetic information, the gap betweendiagnosis and therapy, health care resources andtensions between holistic and functional medicine.On the other hand nanotechnology will add a newdimension to the bio (human) and non-bio (machine)interface such as brain chips or implants, which even-tually might raise new ethical issues specific toNanoMedicine. This requires careful analysis of eth-ical aspects in view of existing standards and regu-lations by ethics committees at the European scale.At the same time new nanomedical inventions haveto be evaluated for new ethical aspects by ethical,legal and social aspects - specialists. The most cru-cial point in this regard is an early proactive analysisof new technological developments to identify anddiscuss possible issues as soon as possible. Thisrequires a close collaboration and co-learning oftechnology developers and ethics specialistsassisted by communication experts to ensure openand efficient information of the public about ethicalaspects related to nanomedicine. This co-evolutionwill ensure a socially and ethically accepted devel-opment of innovative diagnostic and therapeutic toolsin NanoMedicine.

From the above it is clear that an in-depth ethicalanalysis is necessary in this field. Such an analysisshould be based on the following principles.

Human Dignity and the derived ethical principles of:• Non-instrumentalisation: The ethical requirement

of not using individuals merely as a means butalways as an end of their own.

• Privacy: The ethical principle of not invading aperson’s right to privacy.

• Non-discrimination: People deserve equal treat-ment, unless there are reasons that justify differ-ence in treatment. It is a widely accepted principleand in this context it primarily relates to the distri-bution of health care resources.

• Informed Consent: The ethical principle thatpatients are not exposed to treatment or researchwithout their free and informed consent.

• Equity: The ethical principle that everybody shouldhave fair access to the benefits under considera-tion.

• The Precautionary Principle: This principle entailsthe moral duty of continuous risk assessment withregard to the not fully foreseeable impact of newtechnologies as in the case of ICT implants in thehuman body.

The last of these principles (the PrecautionaryPrinciple) is particularly important in this particularcontext.

The ethical analysis should also examine valueconflictsThere could be conflict between the personal free-dom to use one’s economic resources to obtainadvanced treatment such as NanoMedicine and whatsociety at large considers desirable or ethicallyacceptable. Freedom of researchers may conflict withthe obligation to safeguard the health of researchsubjects. Concern for economic competitiveness andother economic values (economic growth) may comeinto conflict with respect for human dignity. The unre-stricted freedom of some may endanger the healthand safety of others. Therefore a balance has to bestruck between values that are all legitimate in ourculture.

34

35

Future techniques in medical diagnosis and treat-ment have often been the subject of science fictionliterature and cinema. What was once the stuff of sci-ence fiction is now closer to becoming reality. Natureoperates at the nanoscale, and today we are acquir-ing an increasingly profound understanding of natu-ral processes at this scale, enabled by a new gener-ation of scientific instruments. From this knowledge,we are able to design devices that can either directlyinteract with, or influence, the behaviour of livingcells. As with any nascent and rapidly developingfield, there are research, technological, and ethicalchallenges to be considered, and the approaches tothese constitute an integral part of the vision.

Nanotechnology has a trump card to play whenapplied to medicine. At the nanometre scale, mate-rials often exhibit surprisingly different physical,chemical and biological properties, compared to thevery same material in bulk form. The properties ofnanoparticles, such as increased chemical activityand the ability to cross tissue barriers, are leading tonew drug targeting and delivery techniques. In thefuture, a nanoparticle or a set of nanoparticles maybe designed to search for, find and destroy a singlediseased cell, taking us even closer to realising theultimate goal of disease prevention.

Nanotechnology is also making possible the stimu-lation of the body’s own mechanisms to successfullyrepair diseased or damaged tissues, replacing theneed for transplants and artificial organs. In the fore-seeable future, nanotechnology as applied to medi-cine, will lead to advancement in remote monitoringand care, where a patient may be treated at home -a less expensive option, and one that is moreconducive to a successful medical outcome thantreatment in a surgery or hospital.

Continued research into disease processes at themolecular level is essential for the development ofNanoMedicine, and involves teams of scientists fromacross ‘conventional’ disciplines, such as physics,chemistry, surgery and mathematics, as well as thosefrom the ‘new’ fields of genomics, proteomics,metabolomics, pharmacokinetic modeling andmicroscope design.

Europe has already established key strengths inthose nanomedical technologies which will form thebasis of some future medical breakthroughs. TheEuropean Technology Platform on NanoMedicine willbring together the key stakeholders to ensure thislead is maintained, and that technologies are quicklydeveloped to address the health needs of its citizens.

9. NanoMedicine: The bigger picture

Filling channels with a mix for PCR analysis © P. Stroppa, CEA

Plasma membrane with proteins, Scanning ForceMicroscopy © H. Oberleithner, University of Münster

Main Section AuthorsPatrick Boisseau, CEA-LETI, FranceCostas Kiparissides, CERTH/CPERI & Aristotle University of Thessaloniki, Greece Alessandra Pavesio, FAB, Abano Terme, Italy Ottilia Saxl, Institute of Nanotechnology, UK

Contributing AuthorsLuigi Ambrosio, ICBM-CNR, Naples, Italy Alfred Benninghoven, IONTOF GmbH, Münster, GermanyClaire-Noël Bigay, CEA-LETI, FranceSalvador Borros, Institut Quimic de Sarrià-Universidad Ramon Llull, SpainAndreas Briel, Schering, GermanyDonald Bruce, Society, Religion and Technology Project, Church of Scotland, Edinburgh, UKJean Chabbal, CEA-LETI, FranceFrançoise Charbit, CEA-LETI, FrancePhillip Cleuziat, BioMérieux, Grenoble, FranceThierry Coche, GlaxoSmithKline, BelgiumJulie Deacon, MNT Network, UKPaul Debbage, Innsbruck Medical University, AustriaMike Eaton, UCB Group, Slough, UKHarald Fuchs, University of Münster & CeNTech, GermanyGuenter Fuhr, Fraunhofer IBMT, Germany John Goossens, Bayer Technology Services GmbH, GermanyFurio Gramatica, Fondazione Don Gnocchi, Milano, ItalyRolf Guenther, Evotec Technologies, GermanyMarko Hawlina, University Medical Center, Ljubljana, SloveniaAnton Hofmeister, ST Micro, ItalyBengt Kasemo, Chalmers University, SwedenJames Kirkpatrick, Johannes Gutenberg University, Mainz, Germany and European Society for BiomaterialsMichael H. Kuhn, Philips Medical Systems, The NetherlandsPatrice Marche, INSERM, FranceHans Jörg Meisel, BG-Clinic Bergmannstrost, Halle, Germany Corinne Mestais, CEA-LETI, FranceRichard Moore, Eucomed, Belgium Bozidar Ogorevc, National Institute of Chemistry, Ljubljana, SloveniaChristine Peponnet, CEA-LETI, FranceThomas Pieber, Medical University of Graz, AustriaDario Pirovano, Eucomed, Brussels, BelgiumPierre Puget, CEA-LETI, FranceMeike Reinmann, Fraunhofer-IBMT, GermanyJuan Riese, Genomica, SpainJesus Rueda Rodriguez, European Diagnostics Manufacturers Association, Brussels, BelgiumJosep Samitier, Barcelona Science Park, PCB, SpainHeinrich Scherfler, Sandoz, AustriaChristoph Schild, Bayer Technology Services GmbH, GermanySebastian Schmidt, Siemens, GermanySven Schreder, Boehringer Ingelheim Pharma GmbH & Co KG, GermanyJacques Souquet, Philips Medical Systems, The NetherlandsVinod Subramaniam, University of Twente/MESA+ & BMTI, Enschede, NetherlandsBertrand Tavitian, CEA-DSV, FrancePeter Venturini, National Institute of Chemistry, Ljubljana, SloveniaJoan Albert Vericat, Neuropharma, SpainGert von Bally, Medical Centre, University of Münster, Germany Klaus-Michael Weltring, bioanalytik-muenster, Germany David Williams, UNIPATH, UKMarko Zivin, Faculty of Medicine, University of Ljubljana, Slovenia36

Annex 1: Drafting Authors

Molecular ImagingRalph Weissleder, MD, PhD and Umar Mahmood, MD, PhDRadiology. 2001;219:316-333.

PET: the merging of biology and imaging into molecular imaging.Phelps ME. J. Nucl. Med. 2000; 41:661-681

Nanobiotechnology: Concepts, Applications and Perspectivesby Christof M. Niemeyer (Editor), Chad A. Mirkin (Editor)John Wiley & Sons (March 26, 2004)

Springer Handbook of Nanotechnologyby Bharat Bhushan (Editor)Springer; 1 edition (February 17, 2004)

Ultrathin electrochemical chemo- and biosensors. Technology and performance.Springer series on chemical sensors and biosensors 02Series editor O.S. Wolfbeis, Volume editor V.M. MirskySpringer

Physicochemical characterization of colloidal drug delivery systems such as reverse micelles,vesicles, liquid crystals and nanoparticles for topical administrationC.C. Muller-GoymannEuropean Journal of Pharmaceutics and Biopharmaceutics 2004; 58:343-56

Peptide/Protein Hybrid Materials: Enhanced Control of Structure and Improved Performance throughConjugation of Biological and Synthetic PolymersGuido W.M.Vandermeulen, Harm-Anton KlokMacromolecular Bioscience 2004; 4:383-98

Advanced drug delivery devices via self-assembly of amphiphilic block copolymersAnnette Rosler, Guuido W.M. Vandermeulen, Harm-Anton KlokAdvanced Drug Delivery Reviews 2001; 53:95-108

Molecularly imprinted polymers for drug deliveryCarmen Alvarez-Lorenzo, Angel ConcheiroJournal of Chromatography B 2004; 804:231-45

Peroral Route: An Opportunity for Protein and Peptide Drug DeliveryAnurag Sood and Ramesh PanchagnulaChemical Reviews 2001; 101:3275-303

Tissue-Engineering: An Evolving 21st-Century Science to Provide Biologic Replacementfor Reconstruction and TransplantationB.A.Nasseri, K.Ogawa, J.P. VacantiSurgery 2001; 130:781-4

Tissue Engineering Designs for the Future: New Logics, Old MoleculesA.I. CaplanTissue Engineering 2000; 6:17-33

Third-Generation Biomedical MaterialsL.L. Hench and J. M. PolakScience 2002; 295:917-1180

Adult Stem Cells for Tissue Repair- a New Therapeutic Concept?M. Korbling and Zeev Estrov. New England Journal of Medicine 2003; 349:570-82

Bone engineering by controlled delivery of osteoinductive molecules and cells.Leach JK, Mooney DJ.Expert Opin Biol Ther. 2004; 4(7):1015-27

37

Annex 2: Key References

KI-67-05-937-E

N-C

The ageing population, the high expectations for better quality of life and the changing lifestyleof European society call for improved, more efficient and affordable health care.

Nanotechnology can offer impressive resolutions, when applied to medical challenges like cancer, diabetes, Parkinson's or Alzheimer's disease, cardiovascular problems, inflammatoryor infectious diseases.

Experts of the highest level from industry, research centers and academia convened to preparethe present vision regarding future research priorities in NanoMedicine. A key conclusion was therecommendation to set up a European Technology Platform on NanoMedicine designed tostrengthen Europe's competitive position and improve the quality of life and health care of its citizens.

european technology platform on...

Documents