Nanomedicine, 2006

8/14/2019 Nanomedicine, 2006

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Nanomedicine

N a n o t e c h n o l o g y f o r H e a l t h

N o v e m b e r 2 0 0 6

Europ

ean

Techn

ology

Plat

form

Strategic

Research

Agenda

for

Nanom

edicine


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For further information on nanomedicine, please contact:

Research DG

Renzo Tomellini

Uta Faure

Oliver Panzer

E-mail: [email protected]

http://cordis.europa.eu/nanotechnology/nanomedicine.htm

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://ec.europa.eu).

Reproduction is authorised provided the source is acknowledged.

Photo cover: G. von Bally, Laboratory of Biophysics, Medical Centre

University of Mnster / Other pictures: B. Kleinsorge, University of Cambridge

SINTEF Materials and Chemistry 2005, Tyndall National Institute Lee Maltings

University College, Cork

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Executive Summary

1. Introduction

1.1. Nanomedicine: Answering Clinical Needs

1.2. The Impact of Nanomedicine on the Care Process

1.2.1. Preventive Medicine

1.2.2. Diagnosis

1.2.3. Therapy

1.2.4. Follow-Up Monitoring

1.3. Selected Disease Areas

1.3.1. Cardiovascular Diseases

1.3.2. Cancer

1.3.3. Musculoskeletal Disorders

1.3.4. Neurodegenerative Diseases and Psychiatric Conditions1.3.5. Diabetes

1.3.6. Bacterial and Viral Infectious Diseases

1.4. Outlook

2. Technology Development driven by Healthcare Needs

Technologies for Therapeutic Benefits

2.1. Nanotechnology based Diagnostics and Imaging

2.1.1. Introduction2.1.2. In Vitro Applications

2.1.3. In Vivo Imaging

2.1.4. Medical Devices

2.1.5. Strategic Research Priorities

2.2. Targeted Delivery

2.2.1. Introduction


2.3. Regenerative Medicine

2.3.1. Introduction

2.3.2. Intelligent Biomaterials and Smart Implants

2.3.3. Bioactive Signalling Molecules

2.3.4. Cell Based Therapies


3. Providing the Environment to Facilitate Nanomedicine

3.1. Ethical and Social Aspects of Nanomedicine

3.2. Public Acceptance of Nanomedicine

3.3. Risk Assessment

3.4. Regulatory Framework

3.5. Intellectual Property Rights

3.6. Required Research Infrastructure


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Executive Summary

Nanomedicine, the application of nanotechnology in healthcare, offers numerousvery promising possibilities to significantly improve medical diagnosis and therapy,leading to an affordable higher quality of life for everyone. At the same timenanomedicine is a strategic issue for the sustainable competitiveness of Europe.

In order to avoid that this young and very fast growing discipline suffers fromfragmentation and a lack of coordination, industry and academia together withthe European Commission have identified the need for a European initiative tointermesh the several strands of nanomedicine into a firm strategy for advancement.

The resulting European Technology Platform on NanoMedicine is an industry-ledconsortium, bringing together the key European stakeholders in the sector.In September 2005 it delivered a common vision of this technologically and

structurally multi-faceted area 1, and defines the most important objectives in thisStrategic Research Agenda (SRA).

The SRA addresses the Member States of the European Union, its CandidateCountries and Associated States to the EU Framework Programmes for researchand technological development, as well as the European Commission itself.Its main aim is to put forward a sound basis for decision making processes for policymakers and funding agencies, providing an overview of needs and challenges,

existing technologies and future opportunities in nanomedicine. The SRA also takesinto consideration education and training, ethical requirements, benefit/riskassessment, public acceptance, regulatory framework and intellectual propertyissues, thus representing a possible reference document for regulatory bodies.

The proposed disease oriented priority setting of this SRA is based on severalparameters such as mortality rate, the level of suffering that an illness imposes ona patient, the burden put on society, the prevalence of the disease and the impact

that nanotechnology might have to diagnose and overcome certain illnesses.

The scientific and technical approach is horizontal and exploits the benefits ofinterdisciplinarity and convergence of relevant technologies via breakthroughdevelopments in the areas of diagnosis, targeted delivery systems, and regenerativemedicine.


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1. Introduction

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NANOMEDICINE

1.1. Nanomedicine: AnsweringClinical Needs

Over the coming decades, the populations of many

countries around the world will age due to a declining

birth rate and an increasing life expectancy. At the same

time life-styles in developed countries have becomeincreasingly sedentary. These developments will dramati-

cally impact the healthcare system: certain diseases

related to life-style will become more prevalent earlier in

life, and the older generation wants to spend their addi-

tional years with a higher quality of life. Nevertheless,

healthcare costs should be kept affordable.

Nanomedicine, the application of nanotechnology to

healthcare, will be an essential tool to address manyunmet clinical needs of today and in the future.

This document describes the potential of nanomedicine

to address clinical needs in significant diseases. It identifies

those diseases that cause the most suffering for patients

and the highest burden on society, and for which nano-

medicine is expected to have a major impact. It describes

where in the care-process and by which technologynanomedicine could have an impact. Finally it develops a

Strategic Research Agenda, prioritising the most important

technologies, which Europe has to develop in the near future,

to realise the potential of nanomedicine for health care.

cause of death in the coming

and inflammatory diseases suc

ating impact on the quality o

medication. Neurodegener

Alzheimer's or Parkinson's are

reducing the quality of life and

dous burden on society. Diaba disease that requires consta

tion, and is expected to incre

cally. Globally, bacterial and

lives with inadequate therape

As soon as the onset of a

patient enters into a care pro

therapy, and follow-up monitocare will start before the onse

tive diagnostics devices will

risk assessment by monitor

markers. Due to its much

nanomedicine will allow an ea

treatment for many disease

understanding of diseases a

medicine holds the promise toof pharmaceutical therapy, re

drug-administration more c

regenerative medicine has the

digm shift in the healthcare sy

to trigger endogenous self-


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1.2. The Impact of Nanomedicineon the Care Process

Nanotechnology allows the manufacturing and manipu-

lation of matter at basically any scale, ranging from single

atoms and molecules to micrometer-sized objects. Thisalready enables the miniaturisation of many current

devices, resulting in faster operation or the integration of

several operations. Furthermore, at this scale, man-

made structures match typical sizes of natural functional

units in living organisms. This allows them to interact with

the biology of living organisms. Finally, nanometer sized

materials and devices often show novel properties. These

three aspects hold the promise to provide breakthroughsin nanomedicine, leading to clinical solutions within pre-

ventive medicine, diagnosis, therapy and follow-up care.

1.2.1. Preventive Medicine

New diagnostic tests making use of nanotechnology to

quantify disease-related biomarkers could offer an earlier

and more personalised risk assessment before symp-

toms show up. In general, these analyses must be cost-effective, sensitive, and reliable. The test itself should

inflict only minimal discomfort on the patient. Supported

by such an analysis and bioinformatics, health profes-

sionals could advise patients with an increased risk to

take up a personalised prevention program. People with

an increased risk for a certain disease could benefit from

regular personalised check-ups to monitor changes in the

pattern of their biomarkers.

Nanotechnology could improve in vitro diagnostic tests by

providing more sensitive detection technologies or by

providing better nano-labels that can be detected with

high sensitivity once they bind to disease-specific mole-

for their early detection. One

already is x-ray mammograph

breast cancer. Novel targeted

homing in on diseased cells, p

sitivity than today's imaging p

the detecting of cancer at an

1.2.2. Diagnosis

If a medical check-up had fo

of symptoms for a disease,

positives are excluded by

diagnostic procedures. These

expensive as they are applie

patients. In this case, molecuse of specific targeted agen

localisation and staging of

important for ascertaining th

nanotechnology could help to

specific imaging agents o

Miniaturised imaging system

perform image-based diagno

only in research centres. Audiagnostic results without an o

novel methods, combining b

advanced imaging and spec

the behaviour of single disea

environment for the individua

personalised treatment and

specific needs of a patient.

The main advantage of nano

and on costs for healthcare

disease, leading to less sev

demands, and an improved c

a disease is diagnosed, ther


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4

NANOMEDICINE

medicine will play the central role in future therapy.

Targeted delivery agents will allow a localised therapy

which targets only the diseased cells, thereby increasing

efficacy while reducing unwanted side effects. Thanks to

nanotechnology, pluripotent stem cells and bioactive sig-

nalling factors will be essential components of smart,multi-functional implants which can react to the sur-

rounding micro-environment and facilitate site-specific,

endogenous tissue regeneration (making lifelong

immune-suppressing medication obsolete). Imaging and

biochemical assay techniques will be used to monitor

drug release or to follow the therapy progress. This thera-

peutic logic will lead to the development of novel,

disease modifying treatments that will not only signifi-cantly increase quality of life of European citizens but

also dramatically reduce societal and economic costs

related to the management of permanent disabilities.

1.2.4. Follow-Up Monitoring

Medical reasons may call for an ongoing monitoring of

the patient after completing the acute therapy. This

might be a regular check for reoccurrence, or, in the caseof chronic diseases, a frequent assessment of the actual

disease status and medication planning. Continuous

medication could be made more convenient by implants,

which release drugs in a controlled way over an extended

length of time. In vitro diagnostic techniques and molecu-

lar imaging play an important role in this part of the

care-process, as well. Biomarkers could be systema-

tically monitored to pick up early signs of reoccurrence,complemented by molecular imaging where necessary.

Oncology is one of the areas where these techniques are

already being evaluated today. Some types of tumours

can be controlled by continuous medication extending

life expectancy. However, in the case of drug resistance,

1.3.1. Cardiovascular D

Cardiovascular diseases rema

of death in the European Unio

ing to the World Health Org

infarction and stroke accou

deaths in Europe. The undecular disease is in most case

in the blood vessels. The form

a stenosis of the blood ve

decreased tissue perfusion an

cases, such as an infarct

becomes unstable and rupt

clogging of the blood vessel w

consequence. Many aspects at present, for example the

plaques, are not completely

diseases are often associate

little exercise, high choles

western life-style; howeve

indicates inherited causes.

Nanomedicine is anticipated


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minimally invasive therapeutic options that are used

today. They should be further optimised using intravas-

cular micro-navigation and image guided technologies as

well as smart materials.

In case of an infarct of the heart muscle itself, some ofthe heart tissue usually gets seriously damaged. The

regeneration potential of the heart and its ability for tissue

repair after ischemic injury has been considered limited

or nonexistent. However, recent scientific results in

regenerative medicine have radically changed this view

and thus opened the possibility of cell therapy as well as

new pharmacological concepts for the treatment of

cardiac insufficiency. New treatments will include intelligentnanobiomaterials with the ability to attract local adult

stem cells or cultured cells to the site of injury, providing

cell therapy that should improve heart function and

decrease mortality for patients with severe heart insuffi-

ciency. Early treatment in myocardial infarction with

cells/stem cell modifying drugs could improve early res-

cue of injured myocardium and thus reduce the number

of patients with severe cardiac insufficiency.

1.3.2. Cancer

Cancer is currently the second leading cause of death in

Europe, while it shows probably the highest clinical com-

plexity. Nanomedicine bears the potential to provide an

effective answer to the complexity of the disease as it

offers more therapeutic options compared to present

conventional therapy.

Especially in cancer, early diagnosis is of utmost impor-

tance. Late-stage metastatic cancer is difficult to cure

and treatment leaves severe side-effects, suffering for

the patient, and high costs. Diagnostic tests that allow

be able to reveal these inner

cedure will serve as an inpu

planning that puts higher dose

sections and lower doses o

sections, thereby reducing

neighbourhood. Chemotheradard form of therapy. Chemo

systemically which leads to

causing severe side effects

delivery schemes can be use

peutic agent specifically on

example, already in clinical

is either labelled with a rad

photon emission computed ta beta-radiation emitting iso

metastases throughout the bo

both loaded with pharmaceu

agent, are promising concep

drug release can be purely p

induced actively from outsi

ultrasound pulses or heat

waves. The combination of allows a higher control over

quantification of the treatme

tumour is monitored by com

occurs usually weeks after

imaging would allow faster as

of a patient to a therapy; m

modification of the oncol

reducing stress and pain for

Regenerative medicine offers

to deal with side effects of s

secondary immunodeficienc

may be applied to create a n


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NANOMEDICINE

1.3.3. Musculoskeletal Disorders

Musculoskeletal disorders are the most common causes

of severe long-term pain and physical disability, affecting

hundreds of millions of people across the world and

having a negative influence on the quality of life and

industrial output, inflicting an enormous cost on healthsystems. The extent of the problem and its burden on

patients and society can be illustrated by considering

that joint diseases account for half of all chronic condi-

tions in persons aged 65 and over. Back pain is the

second leading cause of sick leave, and fractures related

to osteoporosis have almost doubled in number in the

last decade. It is estimated that 40% of all women over

50 years in age will suffer from an osteoporotic fracture. The clinical symptoms are pain and functional impair-

ment that induce joint stiffness and dysfunction with sub-

sequent impaired performances in daily living and at

work. About 25% of patients cannot cope with daily

activities, often resulting in depression and social isola-

tion. In the European Union and the USA combined, over

one million joint replacements are performed each year.

cules coupled to biomaterials

locally implanted in the area

geted approach, both aiming

stimulating local stem cells

actions. Cell-based therapies

a universal donor stem cell liwith a biomaterial to modulat

inhibit inflammation. Other tre

very of nanoparticles that sel

niches and release local stimu

anti-inflammatory drugs this t

of articular cartilage and regain

Both arthritis and diabetic nepultimately a consequence of

It is expected that treatmen

well impact other inflammato

disease and psoriasis. At p

these diseases are under res

cant scope for improvemen

patients and to improve the a

1.3.4. Neurodegenerat

Psychiatric Con

Age-associated neurodege

Alzheimer's and Parkinson's d

in prevalence over the next

demographics. Neurodegener

diminution in quality of life, w

puts a financial and social aspects make this disease a

for healthcare: the diseases

difficult to detect, responsiv

depends on the individual pat

personalised, and all presentF

ig.

2


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expression level of neuro-receptors in the brain. The dis-

tribution and metabolism of relevant body-immanent

neurotransmitters could be monitored in vivo for this pur-

pose. Secondly finding the correct drug and its dosing to

treat a psychiatric condition often relies a good deal on

trial-and-error today. This is well illustrated by the exam-ple of depression where there is a growing assortment of

anti-depressives. However, it often needs many trials of

several weeks each until the symptoms of an individual

patient can be assessed; and about 25% of the patients

show no benefit. Improved positron emission tomo-

graphy of the brain could allow an earlier recognition of

patients, who don't respond to a certain medication.

Getting more information about the patient's individualresponse by imaging in connection with genomic and

proteomic analysis, opens the long-term opportunity to

a treatment tuned to the individual patient's needs.

Furthermore, the very same methods could clarify the

underlying specific defect mechanisms of several neuro-

degenerative and psychiatric conditions, which manifest

with the same symptoms.

Treating the symptoms and slo

ration is often all that can b

findings have shown that

retrieved from many kinds of h

differentiation stages, and th

in vitro to de-differentiate or dof cells, including neuronal

sensory cells. There are seve

central nervous system, wh

dously from safe and affordab

regenerate tissue. Some maj

nervous system are characte

of specific types of cells, an

inter alia the level of neurotrA therapy for advanced stage

consist of regenerating cells s

metabolites in order to keep s

al. In addition, it would requir

that had killed the cells pri

which today are unknown in

measures for the regenerate

matrices, or matrices, incluthose factors, or modified cel

tors. The ultimate goal would

tion of the cells inside the hum

integration, even in nerve tiss

earlier development steps wo

expansion in vitro.

1.3.5. DiabetesDiabetes presents an increas

48 million patients in Europ

effects which require costly lo

the major cause of blindness

and of renal dysfunction, wheF

ig.

3


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Nanotechnology may in the first instance not come up

with novel, more effective drugs; however, it may

certainly help to administer vaccines or current drugs in

a more effective way.

1.4. Outlook

Nanomedicine will be important to improve healthcare in

all phases of the care process. New in vitro diagnostic

tests will shift diagnosis to an earlier stage, hopefully

before symptoms really develop and allow pre-emptive

therapeutic measures. in vivo diagnosis will become

more sensitive and precise thanks to new imagingtechniques and nano-sized targeted agents. Therapy as

well could be greatly improved in efficacy by new systems

that allow targeted delivery of therapeutic agents to the

diseased site, ideally avoiding conventional parenteral

delivery. Regenerative medicine may provide a therapeu-

tic solution to revitalise tissue or organs, which may

make life-long medication unnecessary.

While the diseases vary in their pathways, and often

demand very different levels of maturity from the pro-

posed technologies, they also share some common clin-

ical needs. Those activities which could be applied

broadly should have top priority. For example, in all dis-

eases new in vitro diagnostic

that allow rapid, sensitive abroad set of disease indicative

of disease-specific biomarker

of nanomedicine and should

research. Following the same

on multi-tasking agents for i

regenerative medicine that co

in different diseases should

research is needed on clinicato one disease. For example

invasive measurement of bl

need for agents that cross t

unique aspects to diabete

diseases respectively.

Seamlessly connecting D

Targeted Delivery and Re

Diagnostics, targeted delivconstitute the core discipline

Technology Platform on Nwishes to actively support reits three science areas. It activities as theranostics, wdiagnostic devices and tha real benefit to patients.


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NANOMEDICINE

Technologies for Therapeutic Benefits

This Strategic Research Agenda addresses a choice of

diseases, selected by their impact on patients, their

prevalence and burden to society, and by the expected

beneficial impact nanomedicine is likely to have on

them in the near future.

Consideration has been given to the prospects from

more conventional approaches as well as the industrial

progress made to date with nanomedicines. All three

research areas diagnostics, targeted delivery and

regenerative medicine have different priorities on

different diseases but they can significantly impact

virtually all of the chosen disease areas.

2.1. Nanotechnology basedDiagnostics and Imaging

2.1.1. Introduction

The application of micro- and nanobiotechnology in

medical diagnostics can be subdivided into three areas:

in vitro diagnostics, in vivo diagnostics and medicaldevices. The development of these applications relies

on a common ground of enabling technologies.

The basis of modern medicine was laid already in the

middle of the 19th century by the recognition that the

device, based on techniques d

industry, have led to the devel

of devices that are smaller, f

require special skills, and p

These analytical devices req

and will deliver more comple

logical data from a single me

The requirement for smaller

invasive and traumatic meth

Nanotechnology enables furth

techniques, leading to high th

one sample for numerous dise

bers of samples for one disea

care diagnostics. These tepave the way towards major

can be prescribed in future,

medicine tailored to individua

Many new in vitro techniqu

medical testing often find di

important areas later, such as

and security.

Medical imaging has advanc

healthcare to become an es

over the last 25 years. Mole

guided therapy are now b

2. Technology Developme

driven by Healthcare N


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between the imaging industry and the contrast agent indus-

try, which bring complementing competencies to the table.

The convergence of nanotechnology and medical imaging

opens the doors to a revolution in molecular imaging

(also called nano-imaging) in the foreseeable future,leading to the detection of a single molecule or a single

cell in a complex biological environment.

2.1.2. In Vitro Applications

An in vitro diagnostic tool can be a single chemo- or

biosensor, or an integrated device containing many

sensors. A sensor contains an element, capable of

recognising and 'signalling' through some biochemicalchange, the presence, activity or concentration of a

specific molecule of biological importance in solution.

A transducer is used to convert the biochemical signal

into a quantifiable signal. Key attributes of theses types

of sensors are their specificity, sensitivity, and robustness.

Techniques derived from the electronics industry have

made possible the miniaturisation of sensors, allowingfor smaller samples and highly integrated sensor arrays,

which take different measurements in parallel from a sin-

gle sample. Higher sensitivity and specificity reduce the

invasiveness of the diagnostic tools and simultaneously

increase their effectiveness significantly in terms of pro-

viding biological information such as phenotypes, geno-

types or proteomes. Several complex preparation and

analytical steps can be incorporated into lab-on-a-chipdevices, which can mix, process and separate fluids

before carrying out sample identification and quantification.

Integrated devices can measure tens to thousands of

signals from one sample, thus providing the general

practitioner or the surgeon with much more extensive

2.1.3. In Vivo Imaging

In vivo diagnostics refers in

niques, but also covers implan

or molecular imaging includes

molecular events in vivo and

The main benefits of moldiagnostics are the early det

monitoring of disease stages

leading to individualised med

ment of therapeutic and surg

Imaging techniques cover adv

cence imaging and spectros

radioactive tracers, magnetispectroscopy, ultrasound, an

which depend on targeting ag

have been introduced into th

site. In vivo molecular diagnos

positron emission tomograph

advanced applications of m

niques such as magnetic

(MRS), magnetic resonanc(MRSI), diffusion spectrosco

magnetic resonance (f-MRI)

study human biochemical pro

in vivo, opening up new hor

nostic medicine.

However, in order to avoid po

toxicity and patient safety, optical nano-imaging method

tives. This holds true espec

capabilities for quantitative m

(imaging) analysis and qua

engineered implants or self-


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NANOMEDICINE

A wide range of particles or molecules is currently used

for medical imaging. Some recent developments in optical

imaging focus on using nanoparticles as tracers or con-

trast agents. Fluorescent nanoparticles such as quantum

dots and dye-doped silica nanoparticles are systems that,

depending on their coating and their physical and chem-ical properties, can target a specific tissue or cell. Their

fluorescence can easily be tuned for specific

imaging purposes. They offer a more intense fluorescent

light emission, longer fluorescence lifetimes and a much

broader spectrum of colours than conventional fluo-

rophores. They are expected to be particularly useful for

imaging in living tissues, where scattering can obscure

signals. Toxicological studies are underway to preciselystudy their impact on humans, animals and the environ-

ment. New developments are focusing on the nano-

particle coating, to improve its efficiency of targeting and

biocompatibility. Other agents are based on liposomes,

emulsions, dendrimers or other macromolecular

constructs.

Besides the use of nano-agents for in vivo imaging of

grouped into four blocks conc

mally invasive surgery, heart

demand and finally pain thera

Medical devices can be use

latter case their developmetheir invasiveness.

Nanotechnology has applicat

for therapeutic uses. An exam

would be the development of

logical barriers, like the bloo

multiple therapeutic agents a

directly to cancer cells and tothat play a critical role in the

Nanotechnology also has ma

diagnostic devices such as

diagnostic and therapeutic

instruments. Monitoring of ci

of great interest for some ch

betes or HIV. Continuous, smaor blood markers of infectio

market for implantable device

invasiveness, combined with

and the 'biologicalisation' of

increase their acceptance by t

image guided therapy using n

advanced multi-modal imagin

outcome of therapy. Autonomremote control and external

other considerations in the de

Nanosensors, for example th

also provide data to surgeons

F

ig.

5


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Data-acquisition and -prnanobiosystems requires s

mining, data integration an

Tools are required for mgene expression levels a

enable detection of new tynetworking.

Production of accurate, valtitative results will require n

data analysis and interpret

The management of datashould also be integrated w

the patient coming from ot

Modelling and computation

improve the design and man

molecular constituents such

acids. Computer simulation r

technological investigation. C

and nano-biosystems are tun

the fundamental characterist

potently, they allow quantitatand also allow the reconstru

basis of a set of responses to

should simulate the interact

biological constituents.

In parallel to technological de

markers specific to diseases h

in vitro diagnostic techniquespersonalised diagnosis for pati

technology-based tools for re

will provide accurate diagnosis

stage, but also before onset

nosis is the first step in treat

pathologies. Nevertheless, centralised analytical labora-

tories require reliable, cheap, fast and multiplexed highly

sensitive detectors providing high content results from a

single sample, with fewer constraints in terms of minia-

turisation. While the precise specifications will depend on

the target users of the diagnostic devices, whether theanalysis is centralised or decentralised, operated by the

patient or by trained medical staff, the following are

examples of envisaged improvements in the new gener-

ations of diagnostic devices:

Pre-test non-destructive, minimally invasive or non-invasive sampling for biopsy material should be possible

with painless collection of bio-samples usually from

body fluids or tissue.Sample preparation should no longer be a bottleneck

for routine applications of micro- and nanobio-

diagnostic devices, based on integration of sample

preparation with analysis devices, enabling secure and

user friendly sample preparation by laboratory personnel.

Improvements in micro- and nanofluidics should helpachieve significant reductions in the volumes of bio-

logical samples and reagents, gaining speed in reactiontimes.

Miniaturisation should deliver faster and more costeffective systems with higher performance in terms of

resolution, sensitivity, specificity, reliability, robustness

(stability of the analytical process in a single laboratory,

independent of the laboratory personnel), reproducibility

(from laboratory to laboratory) and integration (all

operations in a single device).The detection process should enable multiplex analysis

of a complete bio-pattern including genes, peptides,

and small molecules in a complex, non-amplified and

preferably unlabelled sample.

A broad range of detection sensitivity is needed, such


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14

NANOMEDICINE

Scanning probes/near field methodsHybrid microscopies like combinations of scanning

probe/optics, scanning probe/force, magnetic manipu-

lation and optical microscopy, vibrational and fluores-

cence imaging, scanning probe nanography and

electrophysiologyCombinations of the above with spectroscopies like

spectrally resolved photo-acoustic imaging.

Investment in enabling basic science such as physics

and engineering is needed to support this kind of techno-

logical development.

In Vivo Imaging

The ultimate objective of in vivo imaging is to get highly

sensitive, highly reliable imaging techniques usable for

diagnosis in personalised medicine for delivering drugs,

following their distribution, and monitoring therapy. Thisconcept is called theranostics (therapy and diagnostics),

and is based on the find, fight and follow approach.

Research priorities for in vivo imaging should address

simultaneously each step of the analytical process:

Positron emission tomograMagnetic resonance imaginUltrasoundOptics/biophotonicsPhoto-acoustic.

Existing detectors should alarchitectures and materials.

New probes with enhanced ca

should be developed specific

techniques including:

An ability to penetrate into The ability to crossover

blood-brain barrierCompatibility with external a

radio frequency, ultrasound

the therapeutic activity

Non-toxicFree from any immune or i Therefore, ADME-Tox1 studie

most probably needed as for

The development of multspecific multi-modal probes, w

active drug release on the site

on the efficacy of the thera

ments on particle design, o

sation, and on adequate lab

extensively elaborated in chap

Both the use of labels, and labased on physical propertie

analysing in vivo target molec

respect, improvements in th

technologies will benefit in viv

Magnetic resonance spectr

F

ig.

6


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of signals from detectors should be implemented. Efforts

in 3D, 4D, and 5D reconstruction (multiple parameters)

in 3D space and time, or real time intracellular tomogra-

phy are needed to get a dynamic analysis of biological

events. Of course, this would require computer aided

detection and diagnosis for facilitating the extraction ofinformation.

In general, the development of all new in vivo techniques

will need better (small) animal models for translational

research and adapted imaging techniques to be used

on these animal models for a more accurate probe

development. This need is valid in general for all new

development of drugs as well (see chapter 2.2 ontargeted delivery).

Medical Devices

Medical devices can be classified according to their inva-

siveness. Envisaged improvements from nanotechnology

will yield enhanced:

Catheters

EndoscopesNeedles for electro-stimulationSmart stentsGene or cell transfection systemsSyringes for less traumatic sampling Local delivery of therapeutic agentsOn-line monitoring sensors for detection of circulating

molecules with low concentration.

These minimally invasive instruments should get an abilityto cross biological barriers like the blood-brain barrier or

on the contrary prevent crossing of biological barriers.

By reducing the size of the active components or the

components interacting with the biological samples,

2.2 Targeted DelivMulti-Tasking

2.2.1 Introduction

This area deals with synthet

systems for therapeutic agedrug products, consisting of at

of which is the active comp

nanotechnology encompasses

ceuticals or other therapeut

utilities for diagnostics an

areas where research is at a

Therapeutic systems in this ccal drugs like aspirin up to a

larger there is more scope fo

which makes their descriptio

and their delivery more diffi

plexity, however, gives these s

tackle more challenging disea

the complexity of technology

aspects of our daily life. Thetargeted delivery, and regene

of multi-tasking and can eve

diagnosis and therapy lea

theranostics.

It should be noted that, as wit

the timescale for developing

point where they are approvedto a decade. For society, patie

and regulatory bodies this tim

in the regulatory process and

public and patients, to facilit

ness, acceptance and patien


20/45

16

NANOMEDICINE

the patient for them to get to the market. An early

research focus should be moving the most advanced

therapeutic modalities into the clinic. These include:

LiposomesMicellular and micro-emulsion Systems

Liquid crystal based formulationsNanocrystalsAntibodies and conjugatesNaturally occurring proteins as delivery systemsPolymer conjugates and bio-conjugates based on the

conjugation of polypeptides and polymers, which can

be hierarchically self-assembled into well-defined ter-

tiary and quaternary structures

Biodegradable nanoparticles/nanocapsules. Thisincludes systems, which dissemble in vivo for targeting

or clearance

Virus-like particles for gene delivery. These still presentmajor problems in vivo but offer an alternative and

probably longer term approach

Delivery of small nucleic acids or mimeticsDelivery of vaccines

Synthetic biomimetics to induce physiologicalmechanisms, for example they may activate eitherimmune stimulatory or immune regulatory cascades.

Besides development of approaches with a clear intrinsic

therapeutic activity, targeted nano-delivery systems that

facilitate other medical interventions should be subject of

study, e.g., those that facilitate external radiotherapy

planning, monitoring, and radioimmunotherapy thatcombines diagnostic and therapeutic potential.

Exploring the more novel nanomedicines should focus on

measuring critically their efficacy and safety in vitro and

in vivo as well as potential scale-up issues. These broadly

Such systems have to be cap

towards clinical application. To

to have appropriate DMPK

Pharmaco-Kinetics) and toxic

pharmaceutics liabilities shou

also have a realistic prospect chosen disease area, base

including perhaps biomarker s

Improving Targeting Ag

Targeted delivery systems c

a key one is their ability to re

implicated in disease which c

membrane of target cells, o

within the cell. Research effoand particularly to reduce prod

the benefits of this approach a

identification of such molecule

by high throughput screening o

the two.


21/45

Interactions between Biological Systems

and Artificial Nanostructures

The potential of targeted delivery will only be realised with

a much better understanding of how such structures

interact with the body and its components in vitro,

ex vivo and in vivo. Very few studies are in the publicdomain on how potential nanomedicines are transported

and eliminated in vivo, and what the possible serious

consequences such as immunogenicity will mean for

body homeostasis. Areas of priority are:

Design of nanostructures with stealth properties thatprevent them from being opsonised or cleared before

reaching the target cells

Fundamental studies on the interaction of nano-structures with plasma proteins and the relationbetween protein adsorption and removal of nano-

structures from the circulation by the reticulo-

endothelial system

Absorption of nanostructures to cells (with emphasison relation to the surface chemical characteristics,

size and shape of the nanostructures)

Uptake and recycling of nanostructuresTrans-endocytosis of nanostructures Endosomal escape of nanostructures Safety evaluation. In vitro/in vivo cytotoxicity, haemo-

compatibility, immunogenicity and genotoxicity testing.

Immunogenicity is an expensive function to evaluate in

the clinic and other non-in vivo methodologies should

be evaluated and validated, it is recognised that this

is a challenging objective In vivo carrier biodistribution and degradation.

Pharmaceutics Formulation and Stability

There are many basic problems associated with nano-

particles, before they can become therapeutic agents

parenterally, but both the m

prefer other routes such as ora

Getting such large molecules t

challenging and requires an u

cular transport. This is difficult

decade ago and should be an Success would fundamental

technology-based drugs were

The oral route continues to be

one for drug administration.

the ability on nano-formulat

intestinal tract epithelium o

permeability barriers. Pulmoninvasive method of delivery

focused on aerodynamic c

systems and their ability to d

bioavailability. There are seve

drugs to the lungs. These incl

of delivery, a large surface ar

thin alveolar epithelium, perm

absence of first-pass metabo

The ability of delivery system

barrier should also be asse

diseases of the central nerv

high throughput screening

to transport through biologi

entity to a specific location is

issue. There is early data sfruitful area.

The use of Nano-Devices

Cutting across many therapeut

devices for targeted delivery.


22/45

18

NANOMEDICINE

Microelectromechanical systems (MEMS) in or morelikely on the skin

Temporal/sequential release of multiple drugs Gels, patches, sensor-pump systems, e.g. integrated

glucose sensor and insulin release for diabetics

Implantable biochips/microfluidics Nanosized devices or components on devices e.g. pillon a chip type technology

Carriers for therapeutic agents, in particular advancedpolymeric carriers. These have to contain sufficient

amounts of the agent for a therapeutically useful

effect; biocompatibility and solubility must be good.

Smart carriers, such as polymersomes or liposomes

that release drugs, induced by pH, temperature, light,local metabolite/analytes, enzyme action

Physical stimuli, e.g. electric or ultrasonic, by externalor implantable nanodevices to specific sites in organs

to increase transiently the penetration of the released

drugs into the intracellular compartment

Nanodevices possessing a sensor for a specific meta-bolite/entity with a feedback action for drug release,

e.g. glucose sensor and insulin release.

2.3. Regenerative

2.3.1. Introduction

Perhaps uniquely this area ha

change the way some dise

future, as this is a new therapThe last decade has seen the

the start of nanomedicines

Regenerative medicine is a fa

for the area to be comme

progress has to be seen. This

a large field with the need to

patients as soon as possible

By leveraging novel cell culture

of bio-resorbable polymers, ti

have recently emerged as the

option presently available in r

Tissue engineering encompa

their molecules in artificial c

for lost or impaired body fuscaffold-guided tissue regen

seeding of porous, biodegra

cells, which differentiate and

tissues. These tissue-engine

implanted into the patient to re

tissues. With time, the sc

replaced by host tissues that i

and nerves. Current clinicaengineered constructs incl

cartilage and bone for autolo

advancement in therapeutic

engineering and includes the

source of regenerative cells, aF

ig.

8


23/45

modifying benefits of tissue-engineered products to a

wide patient population. Thus, the vision for nano-assisted

regenerative medicine is the development of cost-effec-

tive disease-modifying therapies for in situ tissue regen-

eration. The implementation of this approach involves not

only a deeper understanding of the basic biology of tissueregeneration wound healing, in its widest sense but

also the development of effective strategies and tools to

initiate and control the regenerative process.

In the field of biomaterials and biotechnology, the term

biomimesis has been established to describe the

process of simulating what occurs in nature. The bio-

mimetic philosophy can be condensed into three basicelements: intelligent biomaterials, bioactive signalling

molecules and cells.

2.3.2. Intelligent Biomaterials and Smart

Implants

Artificial biomaterial scaffolds designed to support cell

and tissue growth have traditionally aimed, at a macro-

scopic level, to match the properties of the organs theyare to replace without recreating the intricate and essen-

tial nanoscale detail observed in real organs. In the body,

the nanoscale structure of the extra-cellular matrix pro-

vides a natural web of intricate nanofibers to support

cells and present an instructive background to guide their

behaviour. Unwinding the fibers of the extra-cellular

matrix reveals a level of detail unmatched outside the

biological world. Each hides clues that pave the way forcells to form tissue as complex as bone, liver, heart, and

kidney. The ability to engineer materials to a similar level

of complexity is fast becoming a reality.

Engineering extra-cellular matrix ligands, such as the

immediate environment and t

responses at the molecular lev

of resorbable polymer system

with cells and direct cell proli

extracellular matrix producti

example, new generations being developed which can

conformation in response to

pH, electrical, physical stimul

Access to nanotechnology ha

perspective to the material sc

types of extra-cellular mat

Techniques are now availablemolecular structures of nano

trolled composition and a

polymer chemistry, combined

such as electrospinning,

patterning and self-assembly

facture a range of structures

ferent and well defined

morphologies, nanofibrousnanowires and nanocues, n

(e.g. dendrimers), nano-com

molecular structures. Nano

developed allowing for integr

nanofibre-matrices with high

connectivity, and controlled a

cell orientation and migration

Given the diversity of tissue-s

(parallel and aligned in te

in bone, orthogonal lattices i

skin), this latter feature is

In addition, it is also possib


24/45

20

NANOMEDICINE

it may be possible to surround implanted tissue with a

nanofabricated barrier that would prevent activation of

the rejection mechanisms of the host, allowing a wider

utilisation of donated organs. Nanomaterials and/or

nanocomposites with enhanced mechanical properties

could replace the materials that undergo fatigue failuredue to crack initiation and propagation during physiological

loading conditions. Nanomaterials with enhanced electrical

properties that remain functional for the duration of

implantation could replace the conventional materials

utilised for neural prostheses, whose performance dete-

riorates over time. Third-generation bioactive glasses and

macroporous foams can be designed to activate genes

that stimulate regeneration of living tissues. Nano andmicro engineered biocompatible membranes may be

used e.g. for cell seeding, cell growth or cell encapsulation.

By understanding the fundamental contractile and

propulsive properties of tissues, biomaterials can be

fabricated that will have nanometer-scale patterns repre-

senting the imprinted features of specific proteins.

Biomimetic membranes can provide cell specific adhesion

sites (integrins) for cells and incorporation of membrane-bound, cell signalling molecules can potentially be stimuli

for specific proliferation of adhered cells. Finally, nano-

technology has enabled the development of a new gen-

eration of so-called nanowire sensors functionalised with

specific receptor layers, capable of monitoring the presence

of e.g. small organic molecules, proteins, cancer cells,

viruses, etc. - the advantage of these sensors is that they

offer direct, real time measurement of captured ligandsand are therefore well suited for use as a sensor device

inside a small implant.

fundamental matrix biology,

molecular self-assembly, reco

and printing technologies wi

materials that can provide en

maps of molecular and struct

2.3.3. Bioactive Signa

Bioactive signalling molecules

cules, which are naturally p

growth factors, receptors, seco

regenerative events at the ce

able therapies based on signa

uncontrolled delivery of a sing

obvious oversimplification, inassociated with the healing

especially in chronic patholog

obligatory in the fabricatio

Therefore, the developmen

sequential delivery of protein

crucial.

The provision of the correctcules to initiate and direct t

being pursued, by designing b

biological signals able to trigge

mary goal is to develop extrac

by either combining natural po

tures starting from synthetic

matricellular cues. By imm

peptides and other biomolecpossible to mimic the extrac

and provide a multifunctional

specific recognition factors ca

resorbable polymer surface,

teins, fibronectin or functiona


25/45

Bioactive molecules as therapeutic agents could be

incorporated in the degradable tailored scaffolds to be

delivered in a controlled manner. In addition, bioactive

signalling may also be effected by biomimetics capable

of modulating body systems through the interaction with

specific cells and receptors. Such biomimetics aredesigned to induce physiological mechanisms, for example

they may activate either immune stimulatory or immune

regulatory cascades.

Finally, drug and gene delivery methodologies could be

coupled to provide in a temporal and spatial manner the

physiological concentrations of signalling molecules

required for tissue regeneration. Incorporation of suchsystems into the biomaterial scaffold, whether permanent

or biodegradable, will be essential for clinical success.

In conclusion, nano-assisted technologies will enable the

development of bioactive materials which release

signalling molecules at controlled rates by diffusion or

network breakdown that in turn activate the cells in contact

with the stimuli. The cells then produce additional growthfactors that will stimulate multiple generations of growing

cells to self-assemble into the required tissues in situ.

2.3.4. Cell Based Therapies

Cellular differentiation occurs in mammals as part of the

embryological development and continues in adult life as

part of the normal cell turnover or repair following injury.

Growth, from the cellular aspect, means a continuousprocess of cellular turnover that is dependent on the

presence of self-renewing tissue stem cells that give rise

to progenitor and mature cells. Cellular turnover is known

to be fast in certain tissues, such as intestinal epithe-

lium, blood and epidermis, and slow in others, such as

cells, next generation therapi

progress made with tissue en

the huge potential for cell-ba

undifferentiated cells. Nanote

ing two main objectives: 1. id

in order to leverage the selfgenous adult stem cells, a

targeting systems for adult st

One possible application for fu

strategies is to avoid having

tured biomaterial scaffold or m

cells, but rather to have the

essential signalling moleculescells in the implant site. Thu

cells react to such nanostruct

of tissue regeneration will be

specific applications.

The fulfilment of these vision

ledge of the localisation and

niches for each specific tissuof cell isolation and culture te

of critical signalling mechanis

as well as the identification

that could be potential targe

or particles aimed for local st

In conclusion, cell-based the

the efficient harvesting of adubrief pre-implantation, cultivat

immediate intra-operative adm

gent biomaterial as a bio-inte

huge impact would also be th

intelligent, bioactive materia


26/45

22

NANOMEDICINE

opportunities here for European small and middle-sized

enterprises, in particular. This is an emerging market sec-

tor where the European Research Area can gain prestige

and an early share of the world market in the develop-ment, production and marketing of such intelligent bio-

materials.

Thanks to nanotechnology, a cellular and molecular basis

has been established for the development of third-

generation biomaterials that will provide the scientific

foundation for the design of scaffolds for tissue engi-

neering, and for in situ tissue regeneration and repair,needing only minimally-invasive surgery. It is strongly

recommended that future planning policy, attention and

resources should be focused on developing these bio-

materials.

Projects will also need to be highly focused towards

clearly identified clinical applications, not being confined

to basic research on the optimisation of generic cell/arti-ficial matrix constructs. They must be rooted in the spe-

cific characteristics of the tissue to be regenerated, and

in the economic advantage of one approach over another.

Emphasis should be given to projects designed with the

objective of developing disease-modifying, cost-effective

treatments for chronic disabilities that mostly affect the

elderly, such as osteoarthritis, cardiovascular and centralnervous system degenerative disorders.

The following is a list of recommended research topics in

nano-assisted regenerative medicine:

Control of the topographicmaterials at the micro an

the design of intelligent sca

tissue engineering. This wthe fields of micro- and

creation of structures tha

adhesion, and orientation,

Research on modalities to

genesis will also be relevan

Design and production of have the ability to attract

by their differentiation to thBiomimetic membranes

which can mimic real ce

cell attachment and/or

differentiation)

Technologies for the develoof synthetic polymers that

conformation in response

stimuli (mechanical, tempeenergetic status)

Technologies for the dnano-structured coatings

Projects which include electcomponents in forms of

(or their equivalents) for the

of cells within an artificial m

Sensor technology for the aactivity and the progress functional state

Sensors for precise genduring cell and tissue grow

Development of appropr


27/45

Bioactive Signalling Molecules

Design, synthesis and characterisation of extracellular-matrix analogues

Identification, design, synthesis and characterisationof bioactive signalling factors Identification, design, synthesis and characterisation

of small molecules triggering stem cell recruitment and

activation

Novel technologies that enable the development ofbiomaterials for the sequential delivery of actives

and/or chemo-attractants for the triggering of endoge-

nous self-repair mechanisms Technologies for controlled release of stem cell

signalling factors

In vitro and in vivo toxicity testing of engineerednanoparticles

Application of nanotechnologies to promote rapidvascularisation in targeted tissues

Incorporation of drug and gene delivery systems into

biomaterial scaffoldsBiodegradable biomaterials where the by-products are

bioactive agents

Alternative bioactive molecules (e.g. plant bioactiveprinciples) which can replace the use of expensive

growth factors and drugs in tissue engineering

constructs

Matrices for integrating cells in tissue and developing

macroscopic functionalityCombination of drugs and delivery technologies, usinge.g. vesicles or micelles, with cell therapies

Matrices resorbing and releasing cytokines passively oractively.

Research aiming to generacentred on the nanoscale in

types of cells and their imm

Monitoring tissue regeneraStudy and construction of and/or precursor cells to b

differentiated

Study of the life cycle of nespecimen with their short-

in the biological environme

Human adult progenitor cel

nanostructured biomaterial Identification and characte

in different tissues

Stem cell homing and migrStem cell phenotype i.e.

specific gene expression

Methods for isolation andpopulations

Methods for culturing stempluripotent state Induction and control of diff

and space resolved)

Methods of stem cell delivovercoming the probl

Rationalised database pro

scientific community about

and differentiation pathwatissue biochemistry

Minimally invasive methoisolation of progenitor cells

Environment for storing ansingle cells


28/45

3. Providing the Environm

to Facilitate Nanomedi

24

NANOMEDICINE

3.1. Ethical and Social Aspectsof Nanomedicine

The potential impact that nanotechnology will have on

diagnostics, regenerative medicine, and targeted delivery

raises the question, which ethical, legal, and social

aspects have to be addressed to create an environmentfor the socially acceptable and economically successful

development of nanomedical applications. The enabling

character of nanotechnology generates familiar bio-

medical ethics like the gap between diagnostics and

therapy or sensitivity of genetic information. This means

we build on a familiar pool of ethical and social discus-

sions, from principles of human dignity to generic

questions of science ethics.

Nanotechnology may also add a new dimension to the bio

(human) and non-bio (machine) interface such as retina

implants due to improved biocompatibility, or nanoelec-

tronics. This latter example shows that new inventions

might add new horizons to ethical, legal, and social

considerations. For example where do we draw the line

between medical treatment and enhancement or whendo we call a person ill (genetic disposition to get a dis-

ease, detection of a single cancer cell vs. tumour, etc.)?

Regardless of the question, whether new normative

issues arise or known aspects have to be adapted, an

Non-instrumentalisation: Tnever defining individuals

always as an end of their o

Enhancement: The improvwithout a medical indicatio

Human dignity and integ

respect human dignity andPrecautionary principle: Th

risk assessment with rega

impact of new technologies

of novel implants in the hu

Besides the effect on ethic

will also have a large impact

Reduced healthcare expenssensitive diagnostics togethe Increased costs of soci

to ageing of population

Unequal access to nanomenationally)

Shift of responsibility forto patient due to point of c

Impact on health care sshift from current acute thto future earlier diagnosis b


29/45

These issues call for a proactive round table approach

involving scientists, experts in ethical, legal, and social

aspects, patient groups, regulatory agencies, health

insurances, national healthcare systems representatives,

policy makers and company representatives to forecast

the impact on healthcare and social security systems.This round table will help that new nanomedical innova-

tions will meet the requirements of the health insurance

systems and regulatory frameworks, which will be essen-

tial for introducing new nanomedical innovations into the

market.

The broad scope and the speed of nanotechnological

innovations in the medical sector make it extremely diffi-cult for experts in ethical, legal, and social aspects to

understand the technological background and impact of

these innovations. To overcome this problem it is

suggested:

To involve experts in ethical, legal, and social aspectsin prospective studies and technology assessments

To involve experts in ethical, legal, and social aspects

in research projects where it is appropriate, to getadvice on possible emerging issues

To develop tutorials for experts in ethical, legal,and social aspects on nanotechnologies in medical

applications to build up expertise for informed moni-

toring of research projects and for basic academic

discussions and evaluation of the ethical, legal, and

social aspects of nanomedicine.

A close collaboration between technology developers and

ethics and social specialists will support the socially and

ethically acceptable development of innovative tools and

devices in nanomedicine.

The fascination about nanotec

technical achievements lik

scratch resistant paintings o

which are not directly related

the environment. The impo

areas for the public acceptademonstrated by the emergi

risks related to certain nanop

some nanoparticles have be

decade. To prevent an ove

negative opinion to nano

transparent dialogue with the

supported by communicatio

Special needs are:Media training of scientists,

the public and especially w

Workshops with journalistsrepresentatives to discuss

developments

To speak from the pe(instead of nanotechnology

be important for this field tits own in the public opinio

To use experts in ethical, lneutral mediators

Tutorials for groups like patwell trusted by the public an

mediators

Public engagement such

consensus conferences, citabout public opinion and d

Lectures on ethical, legascientific conferences

Material for teaching, both Other creative forms of out


30/45

26

NANOMEDICINE

2. What are the mechanism

tation? This is an essent

and targeted delivery it

whether the nanoparticle

barrier or are able to cross

air-blood barrier in the lun

Such scientific considerations

1. Development of suitable

nanobiology, e.g. how n

cells, especially of human

2. Search for suitable cell

parameters, which could

of nanoparticles in differe3. Which animal models ar

biology and how can they

4. Comparison of in vivo and

3.4. Regulatory Fr

The possibility to work at the nand nanotechnology has alre

tions in medicine both in th

medical devices area.

For some time there has been

ateness and adequacy of th

work to cope with the cha

presence of nanoparticles in tnology at nano level may brin

First of all it is important to u

is not a new category of heal

a new enabling technology u

3.3. Risk Assessment

In the three areas of nanomedicine (nanotechnology-

based diagnostics, including imaging, targeted delivery

and release, and regenerative medicine) possible side

effects have to be considered. Although there is no reasonfrom our present perspective to think that a nano-

structured surface on say an implant should represent

any increase in risk compared with a non-nanostructured

surface, the unknown properties of certain nanostruc-

tures call for careful attention regarding their reliability

and potential side effects.

For medical applications based on free nanostructures aswith any new medicine the following safety issues are

important:

1. Systemic distribution: kinetics, variation depending

on route of administration

2. Accumulation phenomena: dose-response, tissue/

organs involved

3. Ability to disturb cellular metabolism

4. Ability to cause protein conformational change5. Ability to promote tumour formation.

Coupled with these questions there are various basic

scientific questions which arise:

1. How do cells interact with nanoparticles and is this

similar to or different from the reaction to micro-

particles?

- Mechanisms of cellular uptake- Is there sub-cellular compartmentalisation?

- What determines intracellular accumulation?

- Relative importance of size, shape and chemistry

of nanoparticles.


31/45

management procedure. In conducting the analysis of

the risks related to the product, the manufacturer has to

take into account all relevant information he can gather

on the technology and on the product at stake. This task

is facilitated by the reference to harmonised standards

for current and well-established technologies. For inno-vative technologies, the manufacturer has to be aware of

the latest scientific data. Further products classified in

class III, IIb or IIa shall be examined by an independent

third party (Notified Body), which, under the control of

the authorities of the Member State in which it is located,

will confirm or challenge the conclusions of the manu-

facturer. The structure of the system seems to be appro-

priate to cope with any new emerging technologiesincorporated into or applied to medical devices. This

assessment has recently been recognised by an ad-hoc

Working Group hosted by the European Commission,

which has clearly indicated that the medical devices reg-

ulatory system is an appropriate framework to deal with

nanotech-based medical devices. Nevertheless, the

Commission is analysing if there is a need for specific

guidance or supporting instruments, particularly concerningthe classification of medical devices, for new technolo-

gies including products based on nanotechnology.

Medicinal Products: The legislative framework for

medicinal products can be prescriptive both in terms of

technical requirements and in terms of manufacturing,

but flexibility is embedded provided that the applicant

has scientifically sound justifications. The system isbased on evaluation of the quality, safety and efficacy of

the product, leading to a risk/benefit assessment and

related risks minimization and management. Risk man-

agement may also be required in the post authorisation

phase. Whenever a new technology is applied, the regu-

devices and medicinal produc

coping with the challenges of

the medical devices system

with it effectively with relativ

short time, the system for

might require more extensive not delay patients' access to

there are procedures in place

from the early stages of the

ducts even in absence of spe

improved collaboration betw

for Medical Devices and Me

perceived, as integration o

required for complex nanotec

Imaging Agents: Imaging a

pharmaceuticals under the

Directives and Regulations), w

under the MDD (Medical De

potential risks associated wi

are administered and used s

necessary series of laboratorwith different phases take

approval than the tests of m

material that is intended for

trials (MPD Article 3.3) is n

the MPD.

In the USA, where the resp

oversight of clinical trials is cDrug Administration (FDA), ch

to speed up the developm

agents. Recently the FDA h

first-in-man assessments of

exploratory Investigational Ne


32/45

3.5. Intellectual Property Rights

Within the general rules on intellectual property for the

Seventh Framework Programme, an intellectual property

model will be developed by the European Technology

Platform on NanoMedicine.

This model aims to achieve a large participation in the

initiative and a fair allocation of rights on generated intel-

lectual property. The basic principle of the ownership and

exploitation of intellectual property will include:

The foreground will be owned by the party that is theemployer of the inventor(s). The employer will ensure,

that it claims all rights to the invention. In case ofremuneration obligations, the employer will be respon-

sible for remuneration. Where several participants

have jointly carried out work generating foreground

and where their respective share of the work cannot

be ascertained, they shall agree among themselves on

the allocation and the terms of exercising the owner-

ship of the joint foreground in accordance with the

provisions of the Seventh Framework Programmeregulations. Parties will try to reach a common agree-

ment on ideally one applicant per patent case to

reduce administrative burden. In case joint owners do

not come to agreement on territorial scope, each

owner will be allowed to file in all countries the other

owners are not interested in. He shall then be the sole

owner in such country and shall bear all costs. The

other co-owners of an invention retain a royalty freeright to use the same also in such country for their

own purposes.

Use of foreground rights for research purposes,including clinical trials will be royalty free for at least

the project members of the related specific project of

A working group composed

industry, academia, and pub

established to further elabo

intellectual property policy of

Platform on NanoMedicine.

3.6. Required ResInfrastructure

Nanomedicine is a very spec

because:

It is an extremely large fie

in vitro diagnostics to thdelivery and regenerative m

It has to interface nanomaetc.) or analytical instrum

material (cells, tissue, body

It creates new tools ansignificantly existing conser

In the near future, the secrepresent the biggest ch

nanomedical tools and dev

novelty of the field no infrast

have evolved yet, which cr

proximity between experts

areas. This is essential for in

to create the condition o

research results to the clinicthis problem a distributed in

28

NANOMEDICINE


33/45

European poles of excellence of complementary expertise

is a necessary first step like nanotechnologies in

cancer. Each centre or node should already have:

excellence in one area of nano-technology (surfaces,

particles, analytics, integrated systems, etc.), a biolog-

ical and/or medical research centre and hospital, and(most importantly) companies, which have access to

and knowledge of the relevant markets. The missing

expertise should be quickly and very easily accessible

within this network of distributed infrastructures and

experts pools. Dedicated clinics or hospital units

developing and testing nanotechnology based tools,

devices and protocols should be supported in

the key places across Europe. In fact, a few techno-logical/clinical centres will have to specialise on the

transfer of nanomedical systems from the bench to the

patient's bed the clinicalisation of the nanomedical

devices to take into account its specificities. Testing

patient's bio-samples on nanobio-analytical systems,

implanting an in vivo nanobio device or injecting a nano-

tech based drug carrier require a specific environment

in dedicated clinics as close as possible to nanotechno-logy centres, which is not currently found in the usual

university hospitals. These places will also be key sup-

port facilities for joint training of medical doctors and

technology developers.

A European infrastructure based on such places with

complementary nanotechnological and biomedical excel-

lences will have the capacity to build up scientific andtechnical expertise at the interface between nano and

bio to speed up the development of tools and devices

for the market. Upgrading and combining these places

therefore is crucial for effective market oriented develop-

ments in nanobiotechnology, because speed is the most

exception of a few regional in

need for qualified personnel

or three major disciplines

Therefore, it is necessary t

develop regional education sc

comprehensive education procan get credits in the most c

Europe in the framework of

hensive curriculum. The edu

first concentrate on gradua

degree in one of the basi

chemistry, physics, material

long run programmes at all le

e.g. by exchange of expericommon standards for Euro

of dissemination and dis

towards the new Member Sta

one important tool at the Eu

E-learning programme, jointl

of European nanomedicine c

Besides education of studenclinical personnel is needed

to the physicians or the surg

practical training are essentia

nanotechnology into medica

purpose physicians, pharmac

be trained in nanomedici

research whereas physicists

engineers have to be trained inTraining of medical personne

good way to facilitate the

routine operation in hospital

The education and training e


34/45

The European Technology Platform on NanoMedicine

addresses ambitious, responsible research, development

and innovation in nanotechnology for health to

strengthen the competitive scientific and industrial

position of Europe in the area of nanomedicine and

improve the quality of life and healthcare of its citizens.

The European Technology Platform on NanoMedicine

identifies the most important socio-economic challenges

facing Europe in this area, focusing on some major

diseases with main economic impact. It aims to improve

the standard of healthcare across the population,

enhancing quality of life, and focusing on breakthrough

therapies, in a cost effective framework.

As well as dissemination of knowledge, regulatory and

intellectual property issues, the European Technology

Platform in general addresses ethical, environmental and

toxicological aspects as well as public perception.

Research on nanomedicine is unusually spread across

industrial, clinical and academic sectors. For real clinical

progress improved communication is required betweenall three parties; as ultimately only those teams able to

manage clinical studies through phases 1-3, regulatory

submissions and marketing will be able to provide

benefits for patients. Depending on the stage of the

research, it will be advisable for proposals to show that

through the clinic. Resea

ultimately this is a regulated

of scientific evidence required

higher than that required for

Due to the major importance

issue is covered by various oPlatforms. Besides the Europe

NanoMedicine, three othe

Platforms are addressing d

applications:

The scope of most European

identify and describe core tren

that benefit the citizen in the l

such as an ageing populatiocare as well as to focus up

impact industry.

European Technology P

Innovative Medicines

The overall policy objective of

Innovative Medicines is to en

development process of medmost rapid application of sc

approved new medicines. This

lating integrated forms of co

development, in particular

private partnerships, with

4. Making it Happen

30

NANOMEDICINE


35/45

with a time horizon on developments beyond existing

product roadmaps. http://www.smart-systems-integra-

tion.org/public

European Technology Platform on

Photonics (Photonics 21)This European Technology Platform is paving the way for

Europe's scientific, technological and economic leader-

ship in photonics. Life science and healthcare are areas

where photonic technologies are expected to bring

benefits. www.photonics21.org

The European Technology Platform on NanoMedicine will

be connected with its three sister European TechnologyPlatforms to prevent duplication, double funding of

projects and ensure better use of knowledge. For

instance, generic development in photonics under

Photonics 21 can be then

Technology Platform for Na

device or application. The

envisaged with the two ot

Platforms.

The European Technology P

has developed the follow

Priorities. They are addresse

the European Union, its C

Associated States to the EU

for research and technologic

the European Commission.

basis for and encourage thnanomedical research pro

national and regional level,

cooperation of multisectorial

Strategic Research Priorities


36/45

32

NANOMEDICINE

1-2 years

Non- and minimal invasive dynamicfunctional 3D imaging techniques (i.e.tissue elasticity, blood flow)in the cardiovascular system

Surface nanostructured bioelectricalsensors for continuous monitoring

3-in-1 smart in vivo nanodiagnosticssystem for combined diagnostics,therapy and therapy monitoring

Smart probes with reduced toxicity fordrug targeting, contrast carrier forimaging, local activation and con-trolled activity

Integrated nanotechnology devices forcancer related proteomic, metabolomicand epigenomic molecular serum

pattern detectionIdentification of biomarkers orpatterns for predisposition and earlyscreening in body fluids

Intelligent blood filtration devicesdetecting/removing inflammationrelated molecules (e.g. interleukines)

Identification of biomarkers or pat-terns for predisposition and earlyscreening

Probes than can cross blood-brainbarrier for imaging (like amyloidplaque in vivo), and delivering therapy

Imaging/spectroscopy strategies forrapid identification of protein aggre-gates relevant for neurodegenerativedisease

Dynamic optical imaging tools for 3Dneurotissue engineering

Non- and minimal-invasive diagnostictools to measure glycemia

In vivo characterisation of glucose

Activities should start in:

Cardiovascular

Diseases

Cancer

Musculoskeletal& InflammatoryDiseases

NeurodegenerativeDiseases

Diabetes

3-5 years

Intracorporal robotics for heart diag-nostic and therapy

Nanostructured surfaces as specific invivo and in vitro biosensors for cancerrelated molecular markers

Minimal invasive endoscope/cathederfor diagnostics and therapy

Imaging of labelled white cells

In vivo drug delivery probes coupled tosensors in autonomous systems

Image guided implatantation ofadvanced neurostimulators

Minimally invasive, combined glucosesensor/insulin delivery systems fordaily home-care

DIAGNOSTICS

Strategic Research Priorities


37/45

1-2 years

Identification of markers on plaqueor infarcted area

Theranostic programme for cardiovas-cular diseases, especially ischaemicheart disease

Critically evaluating existing nano-

medicines in a pre-clinical contextprior to validation in the clinic.Of particular importance is under-standing the science behind thepharmaceutics of these complexand multi-tasking entities

Researching new and low cost targetingagents. Multi-target approaches

Research into novel Nanomedicinesto critically explore their potential in a

non-clinical context. The interaction ofnanoparticles with biological systemsrequires much more critical and indepth studies

Research into new types of lower costtargeting agents to reduce the costof goods for such nanomedicinesRheumatoid Arthritis and Crohn'sdisease should be a therapeutic focus

Design and synthesis of nanomedi-cines capable of crossing the bloodbrain barrier with Alzheimer'sDisease/Parkinson's as the longerterm targets

Treatment of vascular inflammatoryprocesses in diabetes types 1 and 2,

diet related nephropathy and auto-immune disease induced vascularinflammation

Development of inhalable forms ofinsulin or other drugs capable ofmodifying blood glucose levels.High bioavailability is a priority


CardiovascularDiseases

Cancer



Diabetes

3-5 years

Research into theranostics for CVDespecially cerebrovascular disease

Clinical trials for Cancer nanomedicines

Exploring easier routes of administratione.g. not with a conventional needle

Nanomedicines to facilitate boneregeneration or the treatment ofOsteoporosis. Perhaps includingaspects of regenerative medicine.

Semi-invasive programmablenano-devices to deliver drugs withParkinson's as the target disease

Treatment of diabetes by insulindelivery by a responsive nano-enabled

device (e.g. capable of detectingglucose levels)

TARGETED DELIVERY


38/45

34

NANOMEDICINE

1-2 years

Cell based therapies for treatment ofcardiovascular diseases

Advanced biomaterials for site specificcell therapy

Biomimetic biomaterials for vascularreplacement

Cell based therapies for managementof cancer related immunodeficiencies

Cell based therapies for treatment ofosteoarthritis

Bioactive coatings of orthopaedicimplants for cell attraction,Nanostructures stimulating bonedeposition

Advanced biomaterials for treatmentof spinal disorders

Advanced nanomaterials as neuralprostheses

Methodologies for cell therapies intissues of the adult central nervoussystem

Bioengineered pancreatic cells inthe management of diabetes

Identification of mechanisms foractivation and control of tissue-specific progenitor cells

Identification and synthesis of bio


CardiovascularDiseases

Cancer



Diabetes

EnablingTechnologies

3-5 years

Bioactive signalling factors triggeringregenerative events in the heart

Advanced biomaterials for site specificdelivery of bioactive signalling factors

Advanced biomaterials as targets fostem cell therapies

Technologies for mass production ofimmune cells

Advanced biomaterials for site specificdelivery of bioactive signalling factor

Identification of bioactive signallingfactors stimulating bone remodelling

Advanced bioactive biomaterialsdesigned for disease-modifyingtreatments of osteoarthritis

Cell based therapies for disorders ofthe central nervous system

Bioactive signalling factors triggeringregenerative events in the centralnervous system

Biomimetic biomaterials for site-specific cell therapy

Development of glucose sensitivedevices for controlled delivery ofinsulin/insulin analogues

Advanced biomaterials for deliverybioengineered pancreatic cells

Advanced biomaterials for site specific

delivery of bioactive signalling factorsin healing of diabetic wounds

Identification of signalling systems forleveraging regenerative potential ofprogenitor cells

Associations of biomaterial and bio

REGENERATIVE MEDICINE


39/45

CHAIRS

KARVINEN, Jouko A., President and CEO, Philips Medical

Systems, The Netherlands

SMIT, Paul, Vice-Chair, Philips Medical Systems,The Netherlands

REINHARDT, Erich R., Member of the Managing Board

Siemens AG, CEO and President Medical Solutions, Germany

SCHMITT, Karl-Jrgen, Vice-Chair, Siemens Medical Solutions,

Public Relations & Health Policy, Germany

WORKING GROUP NANODIAGNOSTICS

Chair and Main Section Author:

BOISSEAU, Patrick, CEA-Lti, France

Members and Contributors:

BENNINGHOVEN, Alfred, ION-TOF, Germany

BRIEL, Andreas, Schering, Germany

CLEUZIAT, Philippe, BioMrieux, France

DEACON, Julie, MN

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Nanomedicine, 2006

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