Применение углеродных нанотрубок в биомедицине 2 / Polizu, S., Savadogo, O., Poulin, P., & Yahia, L. (2006). Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology. Journal of Nanoscience and Nanotechnology, 6(7), 1883–1904. doi10.1166jnn.2006.197

J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

Polizu et al.	Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology
5. BIOMEDICAL APPLICATIONS OF		sheet dimension, with a minimum length corresponding to
CARBON NANOTUBES		0.5 V was observed. In fact, the mechanism for convert-
5.1. CNTs Smart Materials		ing electrical energy into mechanical energy is based on
		the double-layer charge injection and it involves the inter-
5.1.1. Artificial Muscles and Actuators		face nanotubes-solution.137 139 The actuation is due to a
		geometrical expansion of the C–C covalent bonds caused
An artificial muscle analogous to a biological muscle is		by charge injection and originates from quantum chemical
composed of an actuator material that must be able to		and double layer electrostatic effect.140 Such response,
work in a specific way in order to successfully mimic		devoid of an ionic contribution, eliminates the disadvan-
the natural one. The natural muscles are distinguished by		tages related to the faradaic conducting polymer actuators,
some characteristics: anisotropic behaviour consisting in		for which the life cycle, the discharge rate, and the energy
contraction-elongation along the fiber axis, high energy		conversion efficiency are limiting parameters.141 This new
density, fast speed and response, as well as large stroke.		mechanism is sustained by structural model of SWNT, its
With a maximum power output of 150–225 w/Kg, they can		electrical conductivity along with mechanical and charge
withstand a stress up to 150–300 KPa. The work of mus-		transfer properties.138 Since this assertion, the non-faradaic
cles is defined by three variables: the stress which they can		actuation concept has been predicted by theoretical studies
exert, the strain by which they can be shortened and the		and experimentally demonstrated using both individual and
contraction frequency.135 Actuation capacity consists in the		ropes SWNTs as well as the MWNTs.140 The first isomet-
ability to efficiently convert electrical energy into mechan-		ric measurements shows high values for elastic modulus,
ical movement and its requirements are defined in terms		of 1–2 GPa, and maximum deformation of 0.2%, corre-
of stroke and force. Generally, an actuator is composed		sponding to a stress equal to 0.75 MPa. In fact, individual
of at least three elements: two electrodes whose function		nanotubes display much better mechanical and electronic
is to apply the potential, and an interposed element.136		properties, expressed by a stress of 1 000 GPa and 1%
The ideal actuating material would operate at low voltage		actuation strain. It has been demonstrated that the struc-
and at match least performance of skeletal muscle:137 10%		tural deformation as well as the conversion of electrical
strain, 0.3% MPa stress generated and 10% s−1 strain rate.		energy into mechanical force, through radial and longitu-
Characteristics such as light, low-volume, long cycle-life,		dinal expansion or contraction, are more due to the elec-
Delivered by Publishing Technology to: University of Waterloo
large displacement, and high forcesIP:are200required.59.59.16forOn:actuTue,-		tronic structure than to the coulomb interactions. Since,
		20 Oct 2015 13:16:49

		138
	Copyright: American Scientificseveral worksPublishweres performed attempting to explain the
	ator design and some of them correspond to CNTs.		actuation performance of nanotubes and hence improve
	The nanotube’s actuation behaviour is generated by its
	good electronic and mechanical properties coupled with		these characteristics.141 They principally focus on both the
	a high surface area as well as a non-faradaic nature of		fabrication and manipulation of CNTs in order to obtain
	the electrochemical response. Owing to these properties,		suspended nanotubes.140 By manipulating these nanotubes
	the nanotube actuators perform high strain per movement		with AFM tip, and examining the change in cantilever
	and generate greater mechanical stress than any other		deflection, the measurements of both the Young’s modulus,
	materials,139 when a current of a few volts is applied. In		and actuation force are easily performed.140 142–144 More-
	this type of actuator, the nanotube acts as an active material		over, Frayse and his collaborators144 studied nanotubes
	and constitutes one of the electrodes which are immersed in		obtained by CVD growth and deposited on trenched quartz
	an electrolytic solution or solid polymer electrolyte.138 139		substrate with the NT’s ends fixed. They thus estimated
	Theoretical predictions and experimental measurements		the actuation capability under bias voltage in an electro-
	have suggested that actuators using carbon nanotubes allow		chemical cell by measuring the deformation of nanotubes
	high performances consisting in higher work densities by		with AFM cantilever.140 According to the hypothesis that a
	cycle138 and have significant contribution in term of time		limited macroscopic response arises from the building and
	and speed as well as reproducibility of its response.		entanglement of individual nanotubes at mesoand macro-
			scopic scale, the authors found the possibility of taking
	5.1.2. CNTs Actuators for Artificial Muscles		measurements at individual nanotube level. In the same
			prospect, Roth and Baughman experimented with individ-
	In 1999138 Baughman has demonstrated, for the first time,
			ual nanotubes as actuators and demonstrated that the nano-
	that carbon nanotubes can act as an actuator thus proposing		objects change their shape when electrically charged.145
	the first prototype for a bimorph actuator. The macroscopic		Since the purification level of nanotube was identified
	sheets, so called buckypapers, consisting of randomly		as a concern for the efficiency of the actuation pro-
	entangled SWNT bundles act like working electrodes,		cess, cumulated efforts contributed to the development of
	connected to a potentiostat in electrochemical cells. An		highly purified, aligned CNT, with high surface area.112–114
	axial strain of up to 0.2% was provided by using buky-		Moreover, significant improvement of actuation strain
	paper while switching the electrochemical potential from		rate was achieved by operating carbon nanotubes in an
	0.5 V to −1 0 V A roughly parabolic dependence of		organic electrolyte.146 147 For instance, the use of resistance

1893

Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology		Polizu et al.
compensation resulted in a higher rate, of 0.6% s−1	addition reaction on nanotube external surfaces and its sol-
[148] with an increasing pulse amplitude and more nega-	ubilisation in aqueous media. At the same time, an exhaus-
tive potential limit. Thus, a strain amplitude of 0.3%	tive work on solubilization of SWNT has been directed
in 0.5 s was attained which is considerably better than	towards the assembly of coated peptides.119
0.5% in 1 s, previously reported. Despite a small dis-	Nanotube-based supramolecular structures have been
placement of nanotubes, these results sustain the unde-	prepared by controlling the factors that influence peptide-
niable actuation capacity of advanced carbon nanotube	peptide interactions.159 Based on both molecular modeling
structure and forecast their promising potential149 for actu-	and experimental data, an amphiphilic -helical peptide
ators with a performance similar, in some respects, to that	model was developed with the aim to predict the self
of a biological muscle. This CNTs resource to emulate	assembly function. This construction is the first step
artificial muscles opens the door for nanoscale devices150	towards a new architectural arranging of carbon nanotubes
with various applications. Other actuating designs, such	for molecular sensing mechanisms. Thus, a recent identi-
implants for tissue stimulation151 152 or electrical stimula-	fication of polypeptides with selectivity for nanotubes160
tor capable of encouraging ostoeogenezis are envisaged.153	announces a new method for the manipulation and use of
In combination with biopolymers, such as collagen,154 or	CNTs in the biological and medical area. These peptide
functionalized,155 carbon nanotubes are processed as mate-	sequences, with specific affinity for nanotubes, naturally
rial for the creation of engineered tissue or as component	bind to the surface of carbon nanotubes, in a selective man-
for other devises. Although our focus is not the presen-	ner; this ability is owed to the flexibility and conformation
tation of carbon nanotubes as macroscopic material, we	of their chains. It seems that peptidic chains act as symmet-
mention that, the advantages coming from this avenue are	ric detergents, with hydrophobic sequence in the middle
very enriching for the design of biocompatible biomateri-	and hydrophilic ones at the ends. Their inherent selectivity
als. Indeed it has been proven that the insertion of func-	enables them to discriminate between different nanotube
tionalized CNTs in a collagen scaffold induce positive	structures, according to their chirality and diameter, and
effects155 in terms of physiology, electrical conductivity,	thus facilitates the CNTs manipulation for biosensors.
and mechanical behaviour.	The multifunctionalization of CNTs finds application in
With regard to the macroscopic formulation of the	the design of systems for delivery of antibiotics to different
CNTs, it is important to note that composite structure is	type of cells. Using selective transport through the mem-
Delivered by Publishing Technology to: University of Waterloo

another alternative of material whichIP: 200could.59improve.59.16 On:actu-Tue,brane,20 Octa 2015new approach13:16:49is proposed for the modulation of

ator performance. In this context SWNT-Nafion composite	the therapeutic actions.		Such strategy was experimented
Copyright: Amer can Sci ntific Publishers		161
actuators were created and tested.156 The results qualify the	in the last year and demonstrated, in vitro, the aptitude
system as promising potential for MEMS switches con-	of oxidized MWNTs to conjugate with both fluorescin
struction. Moreover, combinatory actuator effect of both	and amphotericin (AmB) molecules. Even though AmB is
carbon nanotubes and conductor polymer, such as polyani-	known to be the most effective antibiotic for cronical fun-
line, are in exploration.157 Film composites were tested in	gal infection, a high toxicity risk appears when in contact
order to evaluate the actuation synergism of two compo-	with mammalian cells. Consequently, the advantage of this
nents in a new actuator material. The influence of elec-	new conjugated system consists in its capacity to partially
trolyte has also been evaluated by using both salt and basic	avoid the molecules aggregation resulting in more aque-
solutions. Thus, the contribution of redox process was evi-	ous solubility for AmB and internationalization capacity
denced while demonstrating the increase in conductivity	of CNTs, which finally improve antibiotic activity.
of composite by participation of CNTs, leading to more	The influence of interfacing of carbon nanotubes with
electrochemical efficiency. It is more evident that mate-	biomolecules is various162 and could be extended to certain
rial processing offers a diversification of smart materials	reactions which they influence. Indeed, an investigation of
for actuators. Indeed, the experimental work on nanotube-	effects generated by addition of SWNT to the polymerase
epoxy layered actuator is promising for the development of	chain reaction163 illustrate an increase in efficiency of poly-
dry nanocomposites actuator material.158 In spite of man-	merase mechanism, proving the capacity of nanotubes to
ufacturing challenge, it appears that these composites may	act as catalysts in a variety of biochemical reactions as elec-
become a new smart material for structural application,	tron/donor receptors. With regards to biologic cells, carbon
which could promote the development of dry actuator, as	nanotubes showed excellent proliferation164 for cell culture.
component of active prostheses.	These effects can be accommodating for exploitation of
	carbon nanotubes as scaffold for regenerative medicine.

5.2. Biomolecules and Carbon Nanotubes Assemblies

The first step towards the synthesis of peptides based carbon nanotubes started a few years ago with the achievement of derivatives of SWNTs and MWNTs with n-protected aminoacids.118 The method is based on the

5.3. CNT Neural Biomaterial

Neural prostheses provide the means to apply and monitor electrical signals in neural tissues. The development of systems able to restore the nerve function does not strictly

1894	J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

1895

	Polizu et al.				Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology
	lie in the realm of neuroscience, medicine and engineer-					(ii) small particle size minimizes possible irritant reactions
	ing; new possibilities arise at the interface of all three and					at the injection site;
	demand the use of advanced biomaterials. Carbon nano-					(iii) miniaturised size allows the penetration of carriers in
	tubes possess excellent electrical properties which have					the membrane of the sicken cells, thus providing a way
	been proven useful in the area of neural prostheses. The					to selectively deliver the drug to cancerous tumours, while
	pertinence of nanotube fibers as neural prosthetic biomate-					avoiding the healthy cells.
	rial has been demonstrated by McKenzie and his collabora-					As presented in the section about functionalization, well
	tors.165 Thanks to their capacity to minimize the astrocites
						functionalized nanotubes and their derivatives are destined
	function, the CNTs possessing high surface energy become
						for biomedical and biotechnological applications. Indeed,
	interesting			biomaterials for a new	generation of neural
						the organic modification		of nanotubes creates multiple
	prosthesis. Haddon and his colleagues reported the appli-
						attachment sites for bioactive molecules and hence facili-
	cation of carbon nanotube in neural research and estab-
						tates the assembly in complex nanodevices. A very recent
	lished the			function of nanotubes as	a support for nerve
						study demonstrated the capacity of nanotubes to serve as
	cell growth as well as substrates for probes with neu-
						vehicles for the administration of vaccines84 85				by devel-
	ronal function at nanometer scale.166 Using nanotubes of					oping new and	effective	delivery	approaches	of protec-
	diameters similar to those of small nerve fibers, they devel-
						tive antigens. They offer the possibility to effectively use
	oped methods for growing embryonic rat-brain neurons
						the antigens while enhancing and modulating the immune
	on MWNT. The chemically modified MWNT coated with
						response. The	potential	of CNTs	to present	a biologi-
	4-hydroxynonenal bioactive molecules stimulated neurite
						cally important	epitope,	with the	appropriate	conforma-
	growth with extensive branching. A similarity between the
						tion, in vitro and in vivo tests, enables them to be used in
	diameter of nanotubes, ranging from 1 nm for SWNT and
						vaccine delivery. The peptide-carbon nanotube conjugated
	10–100		nm for MWNT, and those		of neurites, favours
						system, integrating aminoderivatized nanotubes selectively
	localized molecular interactions, necessary for the forma-
						bonded to a peptide, provides the peptide bis-adducts.85.
	tion of a neuronal circuit. Furthermore, the conductivity					This conjugated system elicited strong anti-peptide anti-
	of nanotubes renders them a valuable candidate for elec-
						body response and retains the antigen conformation, which
	trophysiological analysis of neuronal micro circuitry. It is
						fulfills the main requirements for the induction of an anti-
	known that neural development is based on a complex
				Delivered by Publishing Technology to: University of Waterloo
						body response, with the accurate specificity. Since nano-
	phenomenon that requires, amongIP:others,200the.59.outgrowth59.16 On:ofTue, 20 Oct 2015 13:16:49
						tubes do not have any detectable immunogeneicity, the
	neurites.	167			Copyright: American Scientific Publishers
				The investigation of CNTs as neural biomate-		system is very appropriate for the delivery of a vaccine
	rials directly requires biocompatibility studies. Investigat-
						antigen. More	specifically, new structures are designed
	ing the in vitro cytocompatibility of CNTs,168 the authors
						using water soluble SWNT derivatives which are able to
	demonstrated the beneficial effects of carbon nanofibers
						cross the cell membrane;84 they can be accumulated in the
	to limit		astrocyte functions, leading		to a decreased glial	cytoplasm or reach the nucleus without being toxic up to
	scar tissue formation and further established a relationship
						a quantity/concentration of 10 pm; their investigation as
	between fiber characteristics and astrocyte interactions.
						delivery systems in targeting therapy171 demonstrated that
	These investigations promote the development of minia-					the absence of immunogenicity of nanotubes increases the
	turized devices in which the nanotubes play a role in the
						efficacy of their function.
	formation of a nerve cell network with an active func-
	tion, possibly to contribute to the restoration of a damaged					5.5. Miniaturized Devices and Nanorobotics
	neuronal		circuit. These encouraging results recommend
						for Nanomedicine
	CNTs as promising neural biomaterial for the innova-
	tion of implant devices for the central nervous system.					5.5.1. CNTs Electrodes and Biosensors
	Today this area is limited by the use of silicon material					CNT Electrode: Carbon nanotube is a better electrode
	which shows the capacity to induce significant glial scar
	tissue formation169 which is known as a common diffi-					material than the classical carbon and its development
	culty in the field of neural prosthetics. Indeed very recent					becomes a relatively new topic in electrochemical stud-
	results demonstrating the biocompatibility of native and					ies. The useful electrochemical properties combined with
	functionalized single-walled carbon nanotubes for neural					its high surface area provide some advantage to the field.
	applications170 promote the CNTs potential for regenera-					Although the CNTs inertness is evident, it has been proven
	tive medicine.					that the chemical environment to which the nanotubes are
						exposed influences their conducting capacity and thus cre-
	5.4. CNTs for Delivery Systems					ates an additional transduction mechanism. It				has been
						demonstrated that CNTs can enhance the electron transfer
	Three characteristics of nanostructured materials recom-					when used as an electrode in electrochemical reactions.9 11
	mend them for the design delivery system:					An important advantage lies in the fact that these materials
	(i) nanoscale size enables intravenous injection;					are very sensitive to various molecules with the reactivity

J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

These macromolecular biological compounds are properly attached to the transducer surface through immobilization processes which do not only enable the fixation of the receptor to the surface but also improve the stabilisation of biological materials. Research efforts pursued in the last few years mainly focus on the development of new techniques involving bio-nanosensors effective at the single cell level, where the detection mechanisms involve chemical interactions between nanotube surface atoms and the absorbed molecules119 175

1896

Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology

Polizu et al.

controlled by the redox system. Moreover, due to its highly

CNTs provide an excellent platform for biosensors and

specific capacitance, the CNTs can be used as electro-

even for integrated systems, able to analyse the chemical

chemical devices. The well-aligned MWNTs based elec-

and biological environment. Owing to their high surface

trodes have demonstrated their successful application for

area and outstanding electrical properties, the nanotubes

the detection of uric acid in urine samples with excel-

performance is superior when compared to conventional

lent sensitivity and selectivity.172 When employed as an

materials. Experimental results clearly demonstrate that

electrode, the relationship between structure-topology and

electrical conductivity changes as the carbon nanotubes

properties enables the use of the enzyme-immobilized

are exposed to a minuscule amount of a certain gas

CNTs for biomolecular sensing or as a miniaturised sensor

molecules.10 16 Thus, SWNT based chemical sensors183

in gas environmental analysis. These chemically modified

display a dramatic change in their electrical resistance

CNTs enhance the electrode sensitivity and selectivity.173

when exposed to gaseous molecules such as N, O2, and

Therefore, using layer-by-layer methodology, the nano-

NH3.184–186 Recent achievements have confirmed the apti-

scale biosensors were constructed. These electrodes enable

tude of individual SWNTs to detect the smallest concen-

to generate an electrochemical signal as function of sub-

trations of toxic gas molecules, such as NO2 and NH3, as

strate concentration, resulting in very good detection

documented by Dai and his group.187 In fact, this molec-

limit.174

ular wire benefits from the full exposure of nanotube sur-

CNTs Biosensors: One of the most important and far

face to chemical environment, thus conducting to a fast

reaching applications of nanotubes is in the biosensors

response and sensitivity as high as 103.

field where their biorecognition function is combined with

Moreover, the capacity of CNTs to detect ppm-level

signal transduction. Combining biological selectivity with

compounds at room temperature allows the development

the electronic process, the biosensors provide direct infor-

of nanotube sensor at physiological temperatures because,

mation about the chemical composition of their biological

once fully immersed in water, the SWNT still maintains

environment. They constantly screen the presence, absence

its intrinsic electronic properties.

Such ability

propels nanotubes towards the design

or concentration of organic or inorganic substances with

of

miniaturized

implantable devices such

as,

biomedi-

a rapid time of response, thus allowing a continuous real

cal nanosensors with high impact on nanomedecine;187–189

time monitoring of analysts. The biosensors not only have

these nanodevices will further promote innovation in early

a stand–alone identity butDeliveredthey also actby Publishingas part of mediTechnology-

to: University of Waterloo

175 176

detection diagnostic techniques. More specifically, the sen-

cal

devices for the

IP: 200.59.59.16 On: Tue, 20 Oct 2015 13:16:49

detection of

toxic substances

or therapeutic drug

monitoring.

177 178Copyright: American ScsitiveentificdetectionPublishersof nanotubes-based probes in conjunction

Several biological

with the modulation of mechanical or electrical character-

events such as genotoxicity, immunotoxicity, biotoxin, and

istics favours the interactions with a biologic host, i.e., the

endocrine effects are measured using biosensors.179–182

The sensing process is divided in two parts: recogni-

deposited cellular materials on the surface.190–192

Endowed with a high specificity, these devices are dedi-

tion, which results in selectivity and amplification which

cated to accurate control performance of environment193–195

increases the power of weak signals to a level at which

and even for in vivo and in vitro evaluation.196–198 Thus,

it can be conveniently manipulated by electronic devices.

a drastically

change

in

nanotube electrical properties,

The multiplicity in transduction mechanisms and amplifi-

in

response

to

the

surrounding

environment,

is con-

cation, processing variety along with its suppleness in ele-

verted in

high

specific, sensitive

signal

as

predicted by

ments recognition create a wide range of biosensors. Five

theoretical

studies199

and

demonstrated

by

experimental

principal groups of biologically sensitive materials can be

measurements.200 201

used for selective recognition:

In fact,

the potential of nanotube as

electrodes for in

(i) enzymes;

vitro and in vivo investigation was experimented, for the

(ii)

antibodies;

first time,

in

1996 when

the Ajayan’s

group

construc-

(iii)

nucleic acid;

ted

a nanotube-electrode

for neurotransmitters

involving

(iv)

receptors;

dopamine, using bromophorm as binder.198 The voltamo-

(v)

intact cells.

grame profile, corresponding to the oxidation of active molecules, such dopamine, has demonstrated the superiority of the CNT electrode, versus the untreated one. This new attainment of the electrode has been attributed to the carbon nanotubes size, as well as to their electronic structure combined with their topological parameters.

Moreover, in 1998, the foremost demonstration of the CNTs potential for protein immobilization202 has proven that small proteins are not only immobilised at the nanotube surface, but they can also be readily placed within the interior cavity of the opened nanotube. This assertion

J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

1897

	Polizu et al.					Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology
	reveals the capability of SWNTs to act as a benign host							involves the use of purely electrical transducers in pro-
	for the selective encapsulation of proteins inside the tube,							teomic applications with the aim to detect different pro-
	which is a real potential for biosensors. At the same							teins without labelling them.
	time, Gao has researched the possibility of deposing DNA							On the other hand, the nanotubes compound with a
	molecules on robust nanotubes, thus proving the nanotubes							polymer resulting in the production of composite material
	capacity to recognize different biomolecules as a function							for the construction of electrochemiluminescence-sensing
	of their diameter and helicity.203 These progresses con-							device.211 Adapted for immobilization of streptavidin, they
	tributed to a better comprehension of the interactions bet-							are attractive for the realization of a nanotube based quan-
	ween nanotubes and molecular species, in addition to their							titative biosensor, capable for wide range measurements
	sensing mechanisms. Furthermore, a relationship between							of biological analytes, with application in areas of med-
	electronic properties and the absorption of gas molecules							ical diagnoses, drug discovery, etc. Moreover, the con-
	was formulated.204							struction of a 3D electrode for a stable, very sensitive
	Theoretical calculations indicate that the molecule abs-							and high selective glucose sensor was realised by using
	orption on the surface or inside the nanotube bundle is							aligned CNT coated with conducting polymer favouring
	stronger than that on an individual tube. In addition, the							enzymes accessibility, thus increasing efficiency.172 The
	impressive properties of nanotubes, such as nanometer							use of CNTs facilitates the development of single enz-
	size, large surface area, and chirality—dependent on elec-							yme biosensors, with activity toward thiocoline, without
	trical conductivity, have been exploited for building the							the use of mediating redox species. A surface modifica-
	nano-arrays, functioning as biosensors or double layer							tion of MWNT electrode makes possible immobilization
	capacitor, with higher resolution. Hence, the use MWNT							of the enzyme213 in a simple construction which per-
	arrays as an immobilization matrix for the development of							forms with good precision and excellent limit of detec-
	amperometric biosensor have been reported by Sotiropoulu							tion whilst ensuring good stability and reproducibility.
	and Chaniotakis.10 Using oxidation for opening and func-							Therefore, significant advancements are attempted in clin-
	tionalizing of the nanotube array leads to an efficient							ical medicine, enabling direct electrical detection of bio-
	immobilization of glucose oxidaze enzyme. In this system,							logical and chemical agents. In fact the preparation of
	a platinum substrate acts as direct transduction platform							polymeric nanocomposite from nanotubes and PVA214 and
	for signal monitoring, whereas the nanotubes play a dual							CNTs/nickel hexacyanoferrate nanocomposite215 resulted
		Delivered by Publishing Technology to: University of Waterloo
	role, as an immobilization matrice as well as a mediator.							in significantly improved electrical conductivity and elec-
				IP: 200.59.59.16 On: Tue, 20 Oct 2015 13:16:49
	The reported results are very promisingCopyright:for the thirdAmericangener-							tro catalytic activity resulting in good electrochemical per-
								Scientific Publishers
	ation of biosensors. The SWNT capability to act as a build-							formance for glucose detection when used as an electrode.
	ing block for nanobiosensors, dedicated to the sub-cellular							Moreover, using the bio-composite principle, a CNT epoxy
	kinetic studies, has been investigated by Guisepi-Elie and							composite biosensor was built which offers an excellent
	collaborators.205 It seems that the nanotubes can perform							sensitivity and stable electrochemical properties combined
	as a benign host enables to trap and support biological							with a reliable calibration profile.216
	molecules while the acidic sites present at the surface							5.5.2. CNTs Flow Sensors
	enhance molecule binding. This resulting proximity facili-
	tates the redox process of proteins and enzymes from a							The excellent sensing capacity of nanotubes was extended
	kinetic and energetic point		of view. Thus, coupling the
								to the flow conditions resulting in systems for flow envi-
	SWNTs with redox active enzymes favours nanobiosen-
								ronment. Gosh and his collaborators reported the experi-
	sors development, i.e., the		evolution		of	glucose biosen-
								mental observation of the voltage generated by the flow of
	sors.206–210	This functional	enrichment,			resulting from
								a polar liquid over SWNT bundles. The magnitude of volt-
	nanoscale	surface modification		of implantable			devices,
								age induced along the nanotube significantly depends on
	triggers many surface interactions with biological host tis-
								the ionic strength and polar nature of the liquid.217 A high
	sue, in order to either evade the host’s immune system or							sensitivity along with a fast response time was detected at
	to successfully engage it in a mutual reaction.211
								low velocities, following the direction of the current ver-
	Noncovalent functionalization			of SWNTs212			has also
								sus the fluid flow. These results demonstrate the ability of
	been considered for the development				of	highly	specific
								nanotubes to act as flow sensors for small volumes, in a
	electronic	biomolecule detectors,		with	a	selective recog-
								flowing liquid environment, which is ideal for biomedical
	nition, enable to target proteins			by the		conjugation of
								applications.
	their specific receptors.195 These biosensors easily work in
	the clinical detection of biomolecules, such as antibodies,							5.5.3. CNTs Nanosensors and Probes
	associated with human autoimmune diseases. Two princi-
	pal applications have been found for this array system: the							Carbon nanotubes are considered the primarily building
	first brings into play the selective detection of proteins in							materials for nanosensors because they function both as
	solution and considers the detecting serum protein after a							sensor elements and as electrical contacts.173 An innovative,
	vaccination or a therapeutic intervention. The second one							alternative method for the fabrication of nanowire sensor

J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

	Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology				Polizu et al.
	arrays was developed using an electrodeposition technique.			Topics regarding structural and mechanical character-
	The main advantages are related to the effectiveness of this			istics, fabrication methods along with tip characteristics,
	process to produce individually or addressable nanowire			resolution as well as functional imaging, are featured. The
	sensor arrays with multi-chemical sensing capabilities,			tips obtained by different methods,227 provide images of
	thus stimulating the evolution of carbon nanotube based			biomolecules or bio-assemblies, with a very high lateral
	nanosensors.218 Such versed sensors are capable of fitting			resolution owing to nanotubes robustness.222 New triple-
	inside single cells thus capturing information related to the			probe atomic force microscope, consisting in an AFM sys-
	concentration of proteins in living cells during the body’s			tem coupled to carbon nanotube nanotweezers, was tested
	normal operation; they play a major role in the development			for the first time with the aim to measure the electric
	of miniaturized, implantable devices for full-time detec-			properties of a tri-terminal single DNA molecule device.228
	tion of medical problems. Hence, the construction of nan-			Hence, the operation of a single DNA molecule as a
	otube based probes offers new possibilities for the sensitive			three-terminal device has been demonstrated, leading to
	detection of single particles and single molecules.219 The			new opportunities for DNA electronics. Moreover, cur-
	SWNTs are very hopeful for conducting probe techniques			rently works demonstrated that changes in electronic char-
	as AFM or STM, endowed with high lateral resolution,			acteristics of carbon nanotube FET can be correlated with
	high aspect ratio and good resistance. Through function-			DNA detection, demonstrating that DNA adosorption and
	alization, the nanotube becomes an ideal tip for biologi-			hybridization were selective for nanotubes.229 This design,
	cal molecule probes220 221 and opens up the possibility of			with certain modifications, could serve as nanosensor for
	inserting a nanoscale electrode into the small pore struc-			discrimination of DNA in a milliliter of blood.
	ture. These devices have the capacity to measure the length			5.5.4. CNTs-FET Devices
	dependence of electrical transport.		222
	Interfacing nanotechnology with biology enables the			Field Effect Transistors (FETs) have been fabricated by
	integration of carbon into highly aligned and water stable
				using semi conducting single wall nanotubes. Their exten-
	process resulting in electrically-conductive probes.223 With
				sive study confirmed that they are extremely sensitive to
	several hundreds microns in length, the CNT probes have
				the chemical or biological environment (oxygen) surround-
	the ability to easily penetrate the cell membrane of epithe-
				ing them.174 The capacity of proteins to crystallise in a
	Deliv		ed by Publishing Te hnology to: University of Waterloo		favours the
	lial cells. Such local probes operate in a manner which			helical configuration on the nanotube surface104
		IP: 200.59.59.16 On: Tue, 20 Oct 2015 13:16:49
	preserves cells viability; this is a new promising technique			topological compatibility between nanotubes and confor-
			Copyright: American Scientific Publishers
	for nanoassembly of nano-devices and nano-tools. More-			mation of organic products, such as proteins. On the other
	over, new instruments for performing cell-level surgical
				hand, the carboxylic open ends of nanotubes, possessing
	operation has been performed by using AFM and fabri-
				an important hydrophilic behaviour, are not attractive for
	cated probes shaped as ultrathin needles.224 This technique
				hydrophobic proteins; they thus permit a specific reaction
	enables the extended of AFM principle to analyses and
				with analyte, leading to its identification.219
	surgery of living cells. In fact the needle enables to pen-			A new technique for the electronic detection of proteins
	etrate the cell membrane and could be easily insert into
				was recently experimented using CNTs as a conducting
	a nucleus with highly accurate positioning. Furthermore,
				channel. Taking advantage of the capacity of biotin-strep-
	recent theoretical studies demonstrated the possibility to
				tavidin to bind to CNTs, the authors produced a specific
	obtain the arrangements as DNA-CNT arrays which could			architecture that uses the nanotube field effect transducer
	perform as functioning device.225 This complex system can			and polymer functionalization to obtain a supramolecular
	be used as an electronic switch or as device for DNA			assembly.45 The application of a conducting polymer coat-
	sequencing.			ing leads to the conversion of nanotube from p- to n-type
	Announcing a promising function for CNT as neuron-			conductor, thus preventing non-specific attachment of pro-
	probes, the recent results reveal the CNTs capacity to offer			teins. However, the coating with a hydrophilic polymer
	a high spatial resolution required for probing neurons.15			results in a reduction of the affinity of nanotube for pro-
	Endowed with high electrical conductance, the small and			teins. Such modifications enhance the activity of a minia-
	flexible nanotube enables the	detection of the electri-		turized device, acting as a rapid sensor within individually
	cal signal from neuron to neuron. Since the concept of			detect proteins or virus.
	nanotube bio-nanoprobe has been proven, several studies			The recent works reported a selective reaction path-
	have been performed in order to evaluate the detection			way of SWNTs, in which chemical functionalization is
	and discrimination capacities of CNT probes towards pat-			controlled by the difference in the nanotube’s electronic
	terned samples, using molecular interactions and forces			structure.220 The authors anticipate the extension of this
	in bimolecular interactions.222 Thus, the use of nanotubes			concept to cell-based electronic sensing devices for the
	as probes has gained great interest in the recent years. A			measurement of electronic responses to living systems,
	review paper covering the most important aspects related			with in vivo applications. For instance, the construction of
	to this application has been presented.226			a complex architecture coupling SWNT to peptide nucleic

1898	J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

	Polizu et al.	Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology
	acid (PNA) was performed.221 This structure intermedi-		of exposure. Functionalized nanotubes are tested for new
	ates the attachment to DNA, by hybridization at room		applications in cell immobilization and transport meas-
	temperature. Moreover, the incorporation of SWNTs into		urement232 able to ensure biological recognition.
	larger devices by interfacing nanotube ends with PAN		5.5.7. CNTs Nanopipettes
	enables the creation of highly selective nanotube sensors,
	offering a new approach for complex devices, with selec-		The nanopipettes, as new shaping of nanotubes, are based
	tive recognition of target proteins in conjugation with their
			on a new morphological manifestation of carbon nano-
	specific receptors.
			structure, characterised by a hollow conical structure.
	5.5.5. CNTs-Cathode for Imaging X-ray Radiation		This 1–3 nm hollowness remains constant throughout
			the length of the structure,234 while the shape grow up,
	The high performance CNT-based field emission cathode		thanks to the simultaneous growth of nanotubes during
	for the design of X-ray tubes has been reported230 by using		the chemical vapour deposition process, with the atypi-
	CNT film with optimized morphology. This device read-		cal composition for gas phase. These whiskers with some
	ily produces both continuous and pulsed X-rays in a pro-		minor faceting on the surface have a pointed tip in the
	grammable wave form and with a finite repetition rate.		shape of pipette and the base at submicron size. These
	The tubes are constructed using purified SWNT bundles		new carbon nanotube pipettes could be ideal candidates
	created by laser ablation; they produce focused electron		for simultaneous drug delivery and in vivo detection of
	beams with small energy spread which is potentially used		neurotransmitters.234
	as X-ray energy tubes, for high resolution imaging with
	ultrafine focal spots. This CNT cathode X-ray technology		5.5.8. CNTs Components for Medical Nanorobots
	can potentially lead to portable miniature X-ray sources		Nanorobotics is concerned with the interaction between
	for specific medical	applications. Recent works,231 pre-
	sented the development of a dynamic radiography system		atomicand molecular-sized objects and mainly deals with
			their controlled manipulation.235 Nanorobots are nanodevi-
	with CNT based microfocus X-ray tube that can generate
			ces which, in a futuristic vision, will be used for maintain-
	pulsed X-ray radiation with a temporal resolution as short
			ing the human body and protecting it against pathogenic
	as 50 ns, significantly better than thermionic X-ray tubes.
			agents. Having a diameter of about 0.5 to 3 microns,
		Delivered by Publishing Technology to: Uni ersity of Wa erloo
	In spite of some limitations which could be overcome, this
		IP: 200.59.59.16 On: Tue, nanorobots20 Oct 2015could13:16:49be constructed out of parts with dimen-
	compact and versatile system is promising for non-invasive
		Copyright: American Sc e tific Publishers
	imaging devices for biomedical research, as proven by the		sions in the range of 1 to 100 nanometers. They will allow
			doctors to perform direct in vivo surgery on individual
	first results.231
			human cells;235 the powering of nanorobots can be sup-
	5.5.6. CNTs Nanotweezers for Biological Applications		plied by metabolising local glucose and oxygen for energy,
			or external energy. In spite of the complexity requirements
	The nanotweezers, a powerful tool for manipulation and		for the design and development of nanorobots, theoretical
	performing electric measurements at nanoscale level, fully		and simulation studies are on going. This first step aims
	exploit the actuation effect of single nanotubes. Their con-		to explain the role of nanorobot behaviour and to further
	struction is based on individually connected, free-standing		propose new approaches and strategies236 for future devel-
	carbon nanotubes sitting on two metal terminals separated		opments. In the light of properties and functions presented
	by a 50 nm gap.232 The application of a voltage to two		herein, it becomes visible that carbon nanotubes are a very
	electrodes causes an electrostatic attraction of the nano-		promising support for some nanorobots components.237
	tubes, thus closing the two ends. Such nanoscale elec-		Generally, the objectives of nanomanipulation refer to
	tromechanical system was realised, for the first time in		the 3D manoeuvring of chemical compounds for molecule
	1999 by Kim and Lieber;233 the electrically conducing and		building which will be further assembled into larger
	mechanically robust nanotubes were attached to indepen-		devices. Thus, in living bodies, nanomanipulation involves
	dent electrodes made of pulled glass micropipettes. The		nano-scale biological entities such as DNA and proteins
	free ends of nanotubes alternatively open and close, while		for the clinical and scientific analysis. This requires mate-
	applying a voltage to the electrode. These nanotweez-		rials for the fabrication of nano-devices or components for
	ers enable the manipulation of individual nanostructures,		integrated systems, with very specific properties. Indeed,
	and their electrical properties can be harnessed in sev-		by manipulating carbon nanotubes at both the atomic and
	eral manners.233 One of them finds application in the bio-		molecular scale, the biological assemblies integrating car-
	logical field, for manipulations/modifications within a cell.		bon nanotubes are more accessible.235
	The construction of dual mechanical/chemical nanotweez-		On the other side, nanorobots could assist the immune
	ers is based on the self assembly principle, through bio-		system by finding and disabling unwanted bacteria or
	recognition on the molecular level.232 The resulting tubes		viruses. When an invader is identified it can be punc-
	have 50 nm in diameter and quite uniform length, with		tured, letting its content spill out and thus ending its
	the possibility of being quantitative control by the time		efficiency.238 By following a predetermined search pattern,

1899

Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology

Polizu et al.

the nanorobots can ingest and destroy harmful bacteria

imaging and in perspective, a constitutive element for

they encounter by using mechanical and chemical phago-

nanorobots.221

cytosis. Such devices enable to distinguish every cell type

by checking their surface antigen by

chemotactic

sen-

6. TRENDS FOR THE FUTURE:

sors

keyed to specific antigens

target

cells. Nanorobots

CHALLENGES AND OPORTUNITIES

would even work in the bloodstream where they could nib-

ble away at arterisclerotic deposits, widening the diseased

The

CNTs

contribution to biomaterials

appears to

be

blood vessels.239 240

fascinating

and they are of a

major significance

for

Carbon nanotubes and their nanocomposites offer sup-

the medicine and biomedical applications. However, the

port

for

nanoelectromechanical

systems

(NEMS)

and

scientists’ preoccupation concerning the potential risk of

microand nano-robots; endowed with high strength and

nanostructures to human health raises an uncertainty. Inter-

chemical inertness they can thus avoid an attack by the

pretation of information regarding the toxicological effects

host’s immune system. Recently, new methods have been

generated by

inhalation and handling of

carbon nano-

developed in order to construct, at the nanometer scale,

tubes suggest that a policy of industrial hygiene measures

building blocks

of carbon nanotubes with

these desired

must be elaborated. Additional confusions relating to the

features. These

3D assemblies,

built

with great accu-

effects of their surface area and geometric parameters are

racy, could be functionalized using biological specimens.

pulling alarm trigger about the potential risks and there-

Indeed, based on controlled nanostructure interactions and

fore, necessitate precise requirements for the use of nano-

complexity, nanoassemblies can posses

a

higher density

tubes into the body. Therefore, a sensible research able to

and

thus

become better electrical conductors,

faster

cir-

answer the growing concern regarding unintended negative

cuits as with more complex functions and with reduced

impacts would be of a great value for the enormous inter-

power consummation.241 Such sophisticated architectures

est generated by the use of carbon nanotubes in engineered

are in reality quite similar to biological entities with nano-

nano-biomaterials with advanced functions for biomedical

scale

organization. This resemblance facilitates the

sys-

applications.

tem’s integration to the living body, resulting in the estab-

From

molecular-scale components of

nanoelectronic

lishment of much more natural interactions, thus offering

devices to nanoactuators and nanorobots, the nanotubes

a greater

control and highDeliveredresolutionbymonitoringPublishingofTechnologythe

to: University of Waterloo

235 240

will be the support of a revolutionizing class of devices

phenomena, without secondary

IP: 200.59.59.16 On: Tue, 20 Oct 2015 13:16:49

effects.

Moreover,

with diagnostic and therapeutic aims. Moreover, the in-

Copyright: American Scientific Publishers

building a high level programming system for their manip-

progress nanoscale

research enhances nanotechnology’s

ulation is a big challenge since it involves the integration

contribution to medicine and thus new prototype devices

of various components.241

will be able to overcome most of the limits of modern

In fact, the design of CNTs based SPM is currently in

medicine. Theoretical models and experimental research

progress and will play an important role in the advance-

demonstrated

there

bewildering

potential. The chemical

ment

of

nanorobotics.242 Some

representative develop-

inertness of

CNTs

along with

their nanoscale dimen-

ment’s elements are:

sions renders them perfect candidates

for

biological

(i) substrate that serves as nanofixture;

and

biotechnological applications.84 85 171

Their intrin-

(ii)

tips, probes, and molecules that serve as grippers or

sic properties enable their bioconjugation for biosensing

end-effectors;

applications.16 187 188

Moreover, the remarkable combina-

(iii)

chemical and physical nanoassembly processes;

tion

of

electronic and mechanical

properties

of CNTs

(iv)

primal nanoasssembly operation for insertion;

makes

them

a potential building

block

of

revolution-

(v)

methods exploiting selfassembly thus eliminating spa-

ary

electronic

devices and nano-electromechanical sys-

tial uncertainty;

tems with applications in the biological and biomedical

(vi)

adequate hardware for building nanostructure;

fields.137 144 232 234 240

(vii)

algorithms and software for sensory interpretation;

As biocompatible support for biological assemblies or

(viii)

motion planning;

nanomechanical part in integrated

systems,

these new

(ix)

SPM driving.

materials become components for implants, artificial org-

In response, CNTs obviously exert a multiplicity of

ans and other prosthetic devices.153 156 157 They contribute

functions243 in nanoelectronics, and other nanodevices.

to the advancement of medical applications and promote

Even though the fabrication of a complete circuit at

a new approach to nanomedecine, with safer, more effi-

the molecular level remains a challenge, the realisation

cient and ultimately, more powerful tools. Biosensors offer

of CNT based nano electronic devices is presently in

a wide range of new biotechnological enhancements; they

progress and hence, paves the way to nanorobot produc-

are the key to a number of major projects in medical

tion. As presented in a previous section, a complex sys-

technology such as the development of artificial organs

tem has been manufactured using CNT probe tip.189 This

that mimic the function of real organs more accurately.

system is

the precursor of tips

for molecular

resolution

Biosensoring technology, based on carbon nanotubes will

1900	J. Nanosci. Nanotechnol. 6, 1883–1904, 2006

Polizu et al. Applications of Carbon Nanotubes-Based Biomaterials in Biomedical Nanotechnology

be unique due to its high sensitivity, selectivity, stability,

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