1. The need for rules and
regulations
In recent years there has been increasing
interest in the impact of engineered
nanoparticles on human health and
the environment. At the same time
it has become clear that some of the
most exciting opportunities presented
by nanotechnology are in the field
of nanomedicine. However, for
nanotechnology to make a real impact in
medicine, it will be necessary to have a
clear regulatory framework for approving
new nano-enabled medical products and
treatments. Until these new frameworks
for the regulation of nanomedicine are
available, the uncertainty of the approval
process will impede the development
of innovative therapies by pharma and
device companies, and also decrease
public acceptance of nano-enabled
medical therapies.
The therapeutic applications
of nanomaterials are illustrated in
Fig. 1 for four main types of material.
Nanoparticles are well suited for targeted
drug delivery, molecular diagnostics and
imaging applications (both magnetic
resonance imaging (MRI) and
X-ray imaging). Nanoporous materials
will have applications in implants, as
membranes (for example, for dialysis
machines) and also in drug delivery.
Nanostructured materials can enhance
the biocompatibility of medical devices,
whereas drugs and nanostructured
polymers can be combined to control
the rate at which the drug is released in
yet another drug delivery application.
The unique mechanical properties of
nanostructured and nanocomposite
materials (such as high strength and
shape-memory properties) are
also invaluable for implants and
catheter devices.
Nanomaterials for medical
applications can be synthetic (such
as polymeric, metallic or ceramic
materials) or have a biological origin
(such as proteins, DNA, tissue and so
on). In the United States, three centres
at the Food and Drug Administration
(FDA) are responsible for regulating
medical therapeutics: the Center for
Drug Evaluation and Research (CDER),
the Center for Biologics Evaluation and
Research, and the Center for Devices
and Radiological Health. Responsibility
for the regulation of nano-enabled
therapies will also fall on one or more of
these centres1
. In Europe the European
Commission has laws that regulate
medical devices and pharmaceuticals,
and nano-enabled therapies will
be regulated within the existing
regulatory framework2,3
.
Many nanotherapies are likely to
combine nanoparticulate drugs with
devices. A well-known example is the
drug-eluting stent: originally stents
were passive objects that kept blood
vessels and other structures in the
body, such as the trachea, open. In the
late 1990s, however, it was realized
that drugs could be released from
nanostructured stents, greatly reducing
the need for surgery. The drug-eluting
stent is an example of a drug–device
combination, but it is also possible to
have biologic–device combinations
(such as a nanoporous stent delivering
an endothelial cell growth factor) and
drug–biologic combinations (such as a
monoclonal antibody combined with
a chemotherapeutic drug). The Office
of Combination Products at the FDA
regulates such products jointly with one
or more of the three centres listed above.
Nano-enabled pharmaceuticals are
finding their way into the clinic: Feridex,
for example, which is a combination
of superparamagnetic iron oxide
nanoparticles (which are MRI imaging
agents) and Dextran (a sugar-based
carrier for the particles). The CDER
guidelines that cover imaging agents were
not specifically written for nanoparticles.
However, unless or until it becomes clear
that additional tests are required, the
safety testing required for nanoparticles
will be similar to the tests outlined in
the existing guidelines. The full range of
safety tests will be required, including
ADME (absorption, distribution,
metabolism, excretion), pharmacology,
genotoxicity, developmental toxicity,
irritation studies, immunotoxicology
and carcinogenicity4
. Additional tests
will most likely be required if it becomes
clear that the nanoparticles deposit in a
particular tissue or organ, or if they have
specific interactions with cell receptors
or cellular organelles.
Just as nanomaterials have unique
chemical and physical properties courtesy
of surface-area and quantum effects,
they can also have unique biological
properties that must be considered in
safety evaluations. Nanoparticles can, for
instance, cross the blood–brain barrier
and various cell membranes, allowing
them to target tissues and cellular
structures that are beyond the reach of
conventional materials. For instance,
fullerene molecules can induce necrotic
cell death or apoptosis depending on
the physical and chemical properties
of the particles5
, and quantum dots can
contain heavy metals, which are often
toxic. Coating potentially dangerous
nanoparticles and quantum dots with
biocompatible materials could create a
barrier to prevent adverse responses, but
there is still much research to do. One
Nanotechnology could have an enormous impact on medicine but, says Michael Helmus,
the regulations that govern new drugs and medical devices need to be updated before
nanomedicine can be commercialized.
THESIS
nature nanotechnology | VOL 2 | JUNE 2007 | www.nature.com/naturenanotechnology 333
Risks to safety will be
minimized by the use of
meticulous pre-clinical
experimental protocols and
peer review by experts in the
interactions of nanomaterials
with biological systems.

2. THESIS
334 nature nanotechnology | VOL 2 | JUNE 2007 | www.nature.com/naturenanotechnology
potential problem is that of nanoparticles
being deposited in tissue rather than
being excreted.
Antimicrobial coatings containing
silver nanoparticles and hydroxyapaptites
that are used for bone repair have
both been through the FDA regulatory
process6–8
. In general, the usual
biocompatibility tests will be adequate
for these types of materials, but it would
be prudent to study them in more detail
and keep a watchful eye on possible side
effects. With new materials there are
always concerns about potential adverse
long-term biological consequences,
and issues such as carcinogenicity
must be addressed as part of regulatory
submissions. Meticulous animal studies
that examine cellular responses over
longer periods of time will mitigate
the risk. However, historical studies of
traditional implants have shown that these
events are extremely rare in humans9
.
Do regulatory agencies have the
wherewithal to deal with these new
technologies? If the current science
of evaluating safety is adequate and
robust, the answer to this question
is yes. However, small incidences of
adverse effects in clinical trials of new
materials, whether they are nano-enabled
or not, may not be statistically clear
until there are a large number of users.
The development of new models and
methodologies that ‘red-flag’ statistical
trends of adverse events will help
to reduce risk. However, if there are
data that demonstrate unique cellular
interactions and accumulation in specific
tissues and/or organs, it would be
prudent to require further testing in vitro
and in vivo as needed.
Last year Michael Taylor, former
deputy commissioner for policy at the
FDA, published a report10
that identified
the limitations in its regulatory authority.
Risks to safety will be minimized, he
wrote, by the use of meticulous pre-
clinical experimental protocols and peer
review by experts in the interactions
of nanomaterials with biological
systems. The development of standards
for definitions, characterization,
methodologies, cytotoxicity and
safety testing will also be necessary,
reported Taylor, and bodies such
as the International Organization
for Standardization, the American
National Standards Institute and other
agencies are already working on these.
Institutional review boards — groups of
professionals and lay people who approve
experimental clinical protocols within
hospital settings — will also have an
important role to play.
Although the potential benefits of
nanomedicine are enormous, they will
not be realized unless the necessary
framework — the regulations, standards
characterization and safety testing — are
in place.
References
1. www.fda.gov/nanotechnology
2. www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_
PAGE&nodeId=208
3. www.emea.europa.eu/pdfs/human/genetherapy/7976906en.pdf
4. www.fda.gov/nanotechnology/ChBSA-nanotech-
presentation06-04.ppt
5. Isakovic, I. et al. Toxicol. Sci. 91, 173–183 (2006).
6. www.acrymed.com
7. www.spirecorp.com/spire-biomedical/surface-treatment/spi-
argent/index.php
8. www.angstrommedica.com/images/NanOss%20Clearance.htm
9. Brand, K. G. & Brand, I. Plast. Reconstr. Surg. 66, 591–955 (1980).
10. www.nanotechproject.org/82/10506-regulating-the-products-
of-nanotechnology
Michael N. Helmus is senior vice president
for Biopharma at Advance Nanotech.
e-mail: michael.helmus@Advancenanotech.com
In Thesis next month:
Chris Toumey on outreach
Figure 1 Nanomaterials for medical therapies can
be categorized as nanoporous, nanostructured,
nanoparticles and nanocomposites. These different
categories of materials are used for different
applications, as shown above. Many applications
require combinations of more than one category of
material. For instance, drugs can be delivered by
nanoparticles, but the addition of a biocompatible
coating (courtesy of a nanostructured material) will
improve performance.
Nanoporous
Membranes
Drug depots
Biomimetic
Bioactive
Nanoparticles
Targeted drug delivery
Molecular diagnostics
Imaging (MRI, X-ray)
Nanocomposites
Implants
Catheters
Nanostructured
Implants
Catheters
Biocompatible coatings
Drug depots
Biomimetic
Bioactive