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Nano Today (2010) 5, 282—295
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nanotoday
REVIEW
Silicon nanostructures for bioapplications
Yao He a, Chunhai Fan c, Shuit-Tong Lee b,∗
a
Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-based Functional Materials &
Devices, Soochow University, Suzhou, Jiangsu 215123, China
b
Center of Super-Diamond & Advanced Films (COSDAF) and Department of Physics & Materials Science, City University of Hong
Kong, 83 Tat Chee Avenue, Kowloon Tong, Hong Kong SAR, Hong Kong, China
c
Laboratory of Physical Biology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China
Received 6 May 2010; received in revised form 10 June 2010; accepted 28 June 2010
Available online 27 July 2010
KEYWORDS
Silicon;
Quantum dots;
Nanowires;
Bioimaging;
SERS;
Biosensor
Summary
There has been rapidly increasing interest in design and synthesis of siliconbased nanostructured materials for bioapplications. In this review, we focus on recent
research progress in design, synthesis and bioapplications of two silicon-based nanostructures, zero-dimensional silicon quantum dots and one-dimensional silicon nanowires. These
two low-dimensional silicon nanomaterials have found important applications in ultrasensitive
biomolecular detection and ﬂuorescent cellular imaging. We further highlight major challenges
and promises in this area.
© 2010 Elsevier Ltd. All rights reserved.
Introduction
Nano-biotechnology is a promising and interdisciplinary
research involving chemistry, physics, biology and medicine
[1,2]. Particularly, the utilization of nanostructured materials in biology and biomedicine is recognized as one
of the fast moving and exciting interfaces in nanobiotechnology, and has been extensively explored [3—7].
It is critically important to develop and fabricate novel
functional nanomaterials with well-deﬁned structures for
nano-biotechnology [5—7]. During the past decade, a great
number of nanomaterials and nanofabrication techniques
have been elegantly developed, imparting momentum to
∗
Corresponding author. Tel.: +852 2784 4209; fax: +852 2784 4696.
E-mail addresses: [email protected] (Y. He), [email protected]
(C. Fan), [email protected] (S.-T. Lee).
the development of nano-biotechnology and opening up
new avenues in biological and biomedical studies [1—4]. To
date, many interesting nanomaterials, such as ﬂuorescent
quantum dots [5], magnetic nanoparticles [6] and carbon
nanotubes [7], have been studied and utilized in widespread
nano-bioapplications (e.g., biological imaging, biosensor,
disease diagnosis and therapy). Their attractive optical,
magnetic and mechanical properties provide new platforms
for studying complicated biological processes that are difﬁcult to access with conventional techniques [3—7].
Silicon nanomaterials are a type of important nanomaterials with attractive properties including excellent
electronic/mechanical properties, favorable biocompatibility, huge surface-to-volume ratios, surface tailorability,
improved multifunctionality, as well as their compatibility
with conventional silicon technology [8—11]. Consequently,
there has been great interest in developing functional silicon nanomaterials for various applications ranging from
electronics to biology. To meet increasing demands of
1748-0132/$ — see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.nantod.2010.06.008
Silicon nanostructures for bioapplications
silicon-based applications, silicon materials of various
nanostructures (e.g., nanodot [12,13], nanowire [14,15],
nanorod [16,17] and nanoribbon [18,19]) have been developed, among which silicon quantum dots (SiQDs) and
silicon nanowire (SiNWs) are of our primary interest
[12—15,20—24]. Quantum conﬁnement phenomenon in
SiQDs can increase the probability of irradiative recombination via direct band gap transition [15,26], leading to
improvement of ﬂuorescent intensity and the prospect of
optical applications. Due to their excellent biocompatibility and noncytotoxic property, SiQDs are also considered as
promising ﬂuorescent biological probes for in vivo and in
vitro imaging [27—31]. On the other hand, SiNWs could act as
a general platform for greatly enhanced surface-enhanced
Raman scattering (SERS) studies. Signiﬁcantly, SiNWs decorated with metal nanoparticles, e.g. silver nanoparticles,
possess high enhancement factor (EF) of up to 107 —109 .
Such SiNWs-based highly efﬁcient SERS-active substrates
could be utilized as biosensors for ultrasensitive detection
of biomolecules (e.g., DNA and protein) [32—36].
In this review article, by paying particular attention
to the SiQDs and SiNWs, we summarize recent research
progress in synthesis and bioapplications of these lowdimensional silicon nanomaterials, based particularly on
recent progress of our laboratory. In brief, in the following
sections, we ﬁrst introduce methods for preparing SiQDs and
SiNWs, and categorize representative synthesis strategies.
Then we summarize typical examples of SiQDs/SiNWs-based
bioapplications that were reported recently, and describe
in detail about the biological applications of SiQDs or SiNWs
as ﬂuorescent bioprobes or biosensors, respectively. In the
ﬁnal section, we discuss challenges and perspectives for
the silicon-relative biological applications in the future.
This review intends to take SiQDs and SiNWs as models
and discuss topics ranging from their synthesis to their
biological applications, with the hope to outline these exciting achievements as the starting points in the realm of
silicon-based nano-biotechnology. Due to page limitation,
this review will not discuss the applications of silicon nanostructures in other important areas, such as energy, catalysis
and optoelectronics.
Synthesis of SiQDs and SiNWs
Synthesis of SiQDs
Bulk silicon is considered as one of the most important
materials in semiconductor microelectronics industry; nevertheless, its optical properties are poor because of its
indirect band gap, leading to the slow electron-hole radiative recombination [37]. Notably, intense room temperature
photoluminescence could be observed from nanocrystalline
silicon, which is generally believed to result from a combination of quantum conﬁnement effects. For examples,
recombination rates of electrons and holes are distinctively
enhanced due to the increased overlap of the electron and
hole wave functions conﬁned in nanodots with diameters
smaller than 5 nm [25,26]. Such observations have intrigued
intense studies on this ﬂuorescent SiQDs-relative ﬁeld, since
the ﬁrst reports of room temperature light emission from
porous silicon in the early 1990s [38,39].
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Over the past decade, a variety of fabrication techniques have been developed for preparation of silicon
quantum dots, including solution-phase reductive [40,41],
plasma-assisted aerosol precipitation [42,43], microemulsion [44], mechanochemical [45], laser ablation [46] and
sonochemical synthesis [47]. Particularly, the solution-phase
reduction synthesis strategy was developed by Kauzlarich’s
group in 1990s [40], involving reduction of silicon halides
(e.g., SiCl4 ) in organic solution. This strategy has been
well-established for producing silicon quantum dots, which
could be readily prepared under mild reaction conditions
(e.g., room temperature and low pressures) [40,41]. Moreover, this method leads to silicon nanoparticles terminated
with alkyl groups, hydrogen or other chemical species. The
ability for facile surface chemical modiﬁcation provides a
new way to study the relationship between surface effects
and optical properties of the SiQDs, and more importantly,
offers opportunity to functionalize the SiQDs according to
different requirements [40]. Alternatively, plasma-assisted
aerosol precipitation provides a way to production of silicon nanoparticles with high efﬁciency and yield [42,43]. This
method is also very rapid as compared to the relatively timeconsuming liquid-phase approaches (e.g., solution-phase
reductive, microemulsion and sonochemical synthesis). Typically, luminescent silicon nanocrystals of 2—8 nm can be
synthesized via a single-step continuous ﬂow nonthermal
plasma process within milliseconds [42].
While luminescent intensity of silicon is enhanced at the
nanoscale, SiQDs usually possess inferior optical properties
(quantum yield <10%) to semiconductor II—VI and III—V QDs
(e.g. CdSe, CdSe/ZnS QDs) with direct band gaps (quantum yield 80—90%) [48,49]. Recent theoretical studies reveal
that optical properties of SiQDs are signiﬁcantly inﬂuenced
by surface oxidation. Particularly, oxygen bonded to the surface of silicon quantum dots often reduces the band gap and
limits luminescent emission, resulting in low quantum yield
[20—22,50,51]. Consequently, it is essential to avoid surface
oxidation to improve the quantum yields of SiQDs [50—52].
Indeed, Kortshagen and co-workers recently reported successful preparation of SiQDs with remarkably high ensemble
quantum yields exceeding 60% by using plasma-assisted synthesis with strict removal of oxygen and elaborate surface
passivation [43], which provides an excellent example. It
demonstrates that SiQDs could possess quantum yields as
high as II—VI QDs under optimum conditions.
Our group recently developed a polyoxometalateassisted electrochemical etching method for synthesizing
SiQDs with controllable luminescent colors (e.g., blue,
orange and red) [53]. This design adopts an electrochemical cell with graphite as anode and silicon wafer as cathode
(Fig. 1a). H3 PMo12 O40 (POM) is introduced into our electrochemical etching system as catalyst due to its unique
properties. Signiﬁcantly, highly monodispersed SiQDs with
a narrow size distribution are directly synthesized without
further separation via this electrochemical method. Moreover, SiQDs with controllable sizes are readily achieved by
adjusting the current density (Fig. 1b). Higher current density yields small-size particles, while lower density yields
larger particles. Also of note, the resultant SiQDs display
serial PL maximum emission wavelengths from 450—700 nm.
Fig. 1b and c inset displays SiQDs with sizes of ∼1, ∼2, ∼3
and ∼4 nm emitting a blue peak at 450 nm, a green peak
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Y. He et al.
Figure 1 (a) Schematics for the POMs-assisted electrochemical etching process. (b) TEM picture of serial sizes of SiQDs and
their corresponding luminescence colors under UV irradiation (inset). (c) Typical PL spectra of SiQDs with sizes from ∼1 to ∼4 nm.
(Reprinted with permission from [53], 2007 American Chemical Society).
at 520 nm, a red band at 640 nm and an infrared band at
740 nm, respectively.
Synthesis of SiNWs
SiNWs are well-known one-dimensional nanomaterials with
many attractive electronic properties [14,15]. Several techniques have been developed to fabricate SiNWs, such as
metal-catalyzed vapor—liquid—solid (VLS) [54,55], oxideassisted growth (OAG) [14,56], laser ablation [57,58] and
thermal evaporation with catalyst [59,60]. Particularly, the
OAG and VLS approaches are widely recognized as two classic methods for synthesizing SiNWs.
In 1998, the groups of Lieber [61] and Lee [62] independently reported the method of laser ablation-assisted
VLS growth for the synthesis of single-crystal SiNWs with
diameters of 6—20 nm and lengths ranging from 1 to 30 ␮m
[61,62], realizing the ﬁrst large-quantity fabrication of
SiNWs [62]. Thereafter, the VLS method has been extensively
optimized to be a well-established approach for preparing
SiNWs [54—56,61,62]. In a typical VLS growth, nanometerdiameter metals or metal compounds (e.g., Fe, Au) act
as catalysts that effectively deﬁne the diameter of wires.
Once metal catalysts induce SiNW growth, SiNWs would
continue to grow as long as the Si vapor source continues. In the VLS process, different reaction temperatures are
required to produce SiNWs when varying the catalytic metals
because of their distinct melting temperatures. For example, 1150 or 370 ◦ C is favorable for preparation of SiNWs
when using Fe or Au as the catalyst, respectively [63]. On
the other hand, the OAG method is considered as another
established strategy for preparation of the SiNWs, which is
well complementary to and coexistent with the metal catalyst VLS approach. Instead of metal catalysts used in the
VLS method, oxides play an important role in inducing the
nucleation and growth of nanowires in the OAG process.
Consequently, SiNWs free of metal impurities are readily
achieved via the OAG technique. Besides, with comparison to the metal-catalytic VLS growth, the OAG method has
three additional advantages [56]. First, large-scale synthesis
of SiNWs can be realized by simple vaporization and condensation of readily available silicon monoxide or a mixture of
Si and SiO2 powders. Second, myriad structural morphologies such as rods, chains and ribbons could be produced.
Third, ultrasmall-diameter SiNWs can be readily prepared.
For instance, signiﬁcantly, SiNWs with a diameter of ∼1 nm
have been successfully synthesized via the OAG approach by
our group (Fig. 2) [14]. In contrast, the smallest SiNW diameter with the metal-catalyzed VLS approach is larger than
4 nm [56]. Nevertheless, the VLS method still possess the
unique characteristics that the diameter and growth alignment of the nanowires can be more readily controlled by
using uniformly distributed metal seeds with well-designed
sizes on the substrate [56,59—62].
Peng et al. recently developed a HF-etching-assisted
nanoelectrochemical method to produce SiNWs [64—70].
The whole process does not require high temperature,
vacuum, templates, complex equipment, or hazardous
silicon precursors. In this method, noble metal atoms
deposited from HF solution on the silicon wafer surface
could form nuclei that behave as a cathode, and the area
surrounding these nuclei behaves as an anode, and can
subsequently be etched and dissolved into the solution by
the galvanic cell reaction [64,65,70]. As a result, silicon
nanowire arrays could be readily grown on silicon wafers
in noble metal HF solution via selective etching, based on
the principle of micro-electrochemical redox reaction. For
instance, large-area growth of ordered silicon nanowire
arrays on silicon wafers can be prepared in an aqueous
HF solution containing silver nitrate at room temperature.
Moreover, the SiNWs of controllable lengths are ﬁnely
Silicon nanostructures for bioapplications
285
Figure 2 Constant-current scanning tunneling microscopy (STM) image of a SiNW prepared via OAG method. The wire axis is along
the [1 1 2] (left) and [1 1 0] (right) direction. Scale bar: 1 nm. (Reprinted with permission from [14], 2003 Science).
achieved through adjusting the reaction conditions (e.g.,
etching time, precursor concentration) (Fig. 3) [64—70].
biology, particularly ﬂuorescence bioimaging and ultrasensitive biosensing. We will summarize their interesting
bioapplications in this section (Fig. 4).
Bioapplications of SiQDs and SiNWs
SiQDs-based ﬂuorescent biological probes
SiQDs and SiNWs are attractive low-dimensional silicon
nanostructures that have found important applications in
Fluorescent biological probes are powerful tools for biological and biomedical studies [71]. A high-performance
Figure 3 SEM images of silicon nanowires arrays prepared via metal-assisted chemical etching method. SiNWs with controllable
lengths of 2 ␮m (a), 4 ␮m (b), 6 ␮m (c) and 10 ␮m (d), could be readily achieved through adjustment of etching time.
286
Y. He et al.
Figure 4 Future prospects of silicon nanomaterials. Left: four issues (large-scale synthesis, surface modiﬁcation method,
biosafety-relative investigation and manipulation of intrinsic properties) are essential to biological applications of silicon nanomaterials. Right: a new era of silicon-based bioapplications, especially on ﬂuorescence bioimaging and ultrasensitive biosensor, is
expected in the near future.
Figure 5 (a) Schematic mode of synthesis of silicon-based nanospheres. The whole process is performed under N2 -protection
environment. To simplify the model and make it easier to comprehend, only ﬁve SiQDs are shown in one nanosphere. (b) TEM images
of three nanospheres with a size of ∼60 nm (top left), ∼120 nm (top right) and ∼200 nm (bottom left), as well as HRTEM image
(bottom right) of a single SiQD inside the as-prepared nanospheres. (c) Photoluminescent spectra of the free-standing SiQDs and
as-prepared nanospheres, and the corresponding photograph of the luminescence from the samples of the free-standing SiQDs and
nanosphere solution under irradiation by 365 nm light from UV lamp (inset). To ensure the objective comparison, the samples of
SiQDs and nanosphere solution were directly extracted respectively from the original solution in the initial or the ﬁnal state of
the whole process shown in Fig. 1c. Neither samples received any post-treatment. (d) Temporal evolution of the absorption and
corresponding PL spectra of the as-prepared nanospheres over one-half year in ambient air condition without any special protection.
(Reprinted with permission from [30], 2009 Wiley).
Silicon nanostructures for bioapplications
ﬂuorescent cellular probe should be water-dispersible,
highly ﬂuorescent, anti-photobleaching and biocompatible
[4,5]. Organic dyes and ﬂuorescent proteins have been
widely used in biological studies. Notwithstanding, these
287
dyes and proteins usually suffer from severe photobleaching that hampers long-term imaging in vitro or in vivo
[5]. Over the past decade, semiconductor II—VI QDS have
been developed as high-performance ﬂuorescent biological
Figure 6 (a) Schematic illustration of silicon nanospheres conjugating with goat-anti-mouse IgG. The carboxylic acid groups of
nanospheres readily reacted with the amino groups of IgG by using EDC and NHS as zero-length cross-linkers (Figure is not to scale).
(b) Optical micrographs of the prepared silicon bioconjugates under UV (365 nm) irradiation. The prepared bioconjugates preserve
stable and bright ﬂuorescent intensity for over 1 month (right). (Reprinted with permission from [31], 2009 American Chemical
Society).
Figure 7 (a) Dual-color cellular imaging photos. The HEK293 cells are distinctively labeled by the bioconjugates (left: green)
and Hoechst (middle: blue); right: bright ﬁeld image. (b) The bioconjugates ﬂuorescently label the cells incubated with monoclonal mouse anti-actin antibody. Left: 488 nm excitation; middle: superposition of ﬂuorescence and transillumination images; and
right: bright ﬁeld image. (c) Comparison of ﬂuorescent signals of HEK293T cells imaging with the nanospheres (top) and FITC (bottom) excited by different wavelengths. (d) Temporal evolution of ﬂuorescence of the HEK293T cells labeled with the as-prepared
nanospheres (top) and FITC (bottom). The nanospheres and FITC were both excited at 488 nm by argon laser with 8 ␮s dwell time and
∼15 mW power. (Parts (a) and (b) reprinted with permission from [31], 2009 American Chemical Society; parts (c) and (d) reprinted
with permission from [30], 2009 Wiley).
288
probes because of advantages such as size-tunable emission
color, strong ﬂuorescence and high resistance to photobleaching [72]. However, the potential toxicity problem of
the II—VI QDs associated with release of heavy metal ions
(e.g. Cd ions) has not yet been fully addressed, which limits
their widespread biological and medical applications [73].
Consequently, novel ﬂuorescent probes with robust photostability, strong ﬂuorescence and favorable biocompatibility
are still urgently required to satisfy various requirements of
biological studies.
Recent exciting progress on SiQDs synthesis provides
promising new solutions for a range of applications such as
SiQDs-based light-emitting diodes [74] and SiQDs lasers [75].
Due to their biocompatibility and low toxicity, ﬂuorescent
SiQDs are potentially ideal ﬂuorescent probes for biological and biomedical studies. Nevertheless, most as-prepared
SiQDs are not well water-dispersible since their surfaces are
covered by hydrophobic moieties (e.g., styrene, alkyl and
octene) [40—43]. Extensive efforts have been undertaken
to realize aqueous dispersibility of SiQDs. In 2004, Ruckenstein and Li developed a UV-induced graft polymerization
for surface modiﬁcation of SiQDs [27]. These SiQDs became
well water-dispersible with the grafting of a water-soluble
poly(acrylic acid) (PAAc) layer. In addition, the grafted
PAAc also improved the photoluminescence stability of the
SiQDs. Moreover, high density of carboxylic acid moieties of
PAAc could be used to immobilize biomolecules (e.g., protein). Photo-stability comparison of SiQDs and four types
Y. He et al.
of organic dyes (e.g., Alexa 488, Cy5, ﬂuorescein isothiocyanate (FITC) and laser dye styryl (LDS751)) demonstrated
superior resistance to photobleaching than the conventional
organic dyes. Such modiﬁed SiQDs with quantum yield of 24%
were employed as biological probes for cell imaging, suggesting potential bioimaging applications of modiﬁed SiQDs.
Tilley and co-workers later reported a room temperature
synthesis for preparing water-dispersed SiQDs that exhibited
strong blue photoluminescence [28]. In their method, a platinum chemical was utilized as catalyst for initiating reaction
between Si—H surface bonds of the SiQDs and C C bonds
of allylamine. The resultant blue-emitting SiQDs became
hydrophilic because their surfaces were modiﬁed with allylamine. In addition to the good aqueous dispersibility as
well as relatively high quantum yield (∼10%), the allylaminecapped SiQDs possessed robust storage- and photo-stability.
They kept stable optical properties for several-month and
long-time (more than 1 h) UV irradiation. As a comparison, the photoluminescence from rhodamine 6G dropped
by 60% under the same illumination conditions. Sato and
Swihart utilized photoinitiated hydrosilylation to successfully attach propionic acid (PA) to the surface of SiQDs,
thereby producing water-dispersible, PA-terminated SiQDs
with average diameter of less than 2.4 nm [76]. Compared
to the former two reports showing water-dispersed SiQDs
of a single emission color (red or blue), this work is signiﬁcant because the size and corresponding PL emission
color of SiQDs could be controlled by varying conditions. PA-
Figure 8 (a) SEM images of as-prepared SiNWs with lengths larger than 2 mm. (b) TEM and high-resolution TEM (inset) images
of a single silicon nanowire with a diameter of 35 nm (c) TEM image of a silicon nanowire coated with Au nanoparticles. (d)
Cyclic voltammograms of BSA with a concentration of 0 ␮M (a) and 0.38 ␮M (b). pH = 7, scan rate: 100 mV s−1 . (e) Peak current vs.
concentration of BSA showing a linear range beyond 1 ␮M. (Reprinted with permission from [85], 2005 American Institute of Physics).
Silicon nanostructures for bioapplications
terminated SiQDs with continuous luminescent color from
yellow to green were readily synthesized in their work.
Recently, Erogbogbo et al., Swihart et al. revealed that most
of the modiﬁed SiQDs often showed obvious PL degradation especially in biological media with different pH, despite
their high storage- and photo-stability in water [29]. Low pH
stability would severely hinder their broad applications in
biology. For example, conjugation of SiQDs with antibodies
would be technically difﬁcult if they were instable at neutral
and alkaline pH environment. They further developed a new
kind of SiQDs encapsulated by phospholipid micelles. Significantly, such micelle-encapsulated SiQDs kept stable optical
properties under various biologically relevant conditions of
pH values (4—10) and temperatures (20—70 ◦ C). However,
the quantum yield of such micelle-encapsulated SiQDs dramatically decreased from 17 to 2% after the encapsulation
process [29]. Very recently, Tilley and co-workers systematically investigated the chemical reactions on molecules
attached to the surface of SiQDs, and further developed a
multi-stepped chemical method for surface modiﬁcation of
SiQDs [77]. This stepwise approach offers new opportunities
to prepare the SiQDs with diverse and desirable functionalities. This study sheds new insight into biological applications
of silicon quantum dots.
289
Lee and co-workers recently presented an EtOH/H2 O2 assisted oxidation method to synthesize water-dispersed
Si/SiOx Hy core/shell quantum dots with a Si core of different controlled diameters [78]. Signiﬁcantly, this method
allows for ﬁne tuning emission wavelengths of QDs, producing seven luminescent colors from blue to red. On the
basis of such studies [53,78] and theoretical prediction
[20—22], we developed a new class of ﬂuorescent silicon
nanospheres (SiNSs) that each containing several hundreds
of SiQDs (Fig. 5). The as-prepared nanospheres possesses
excellent aqueous dispersibility, strong ﬂuorescence (quantum yield: ∼15%), robust photo-stability and favorable
biocompatibility [30]. Further, we developed a novel kind
of water-dispersed oxidized SiNSs (O-SiNSs) prepared via
thermal oxidation of the precursor SiNSs [31]. The quantum
yield of the O-SiNSs was dramatically increased to as high
as 25%. More signiﬁcantly, O-SiNSs are stable under highpower UV irradiation and in acidic-to-basic environments
covering pH = 2—12. This extremely high pH stability leads to
facile conjugation of nanospheres with antibodies, resulting
in brightly luminescent silicon bioconjugates for immunoﬂuorescent bioimaging (Fig. 6). Our cellular experiments well
demonstrated the great promise for real-time and long-term
bioimaging with our silicon nanospheres (Fig. 7) [30,31].
Figure 9 (a) Schematic mode of the SiNW optical sensor. (b) Relative ﬂuorescence intensity of the QlOEt-modiﬁed SiNWs (68 ␮g/ml:
9 × 10−6 M) in the presence of various metal ions alone (20 ␮M, red) and interfering ions with Cu (II) (20 ␮M, green). EtOH—water
solution (30%) of 0.05 M HEPES buffer (pH 7.0). ex = 324 nm, em = 490 nm. Fluorescence spectra (c) and titration curve (d) of QlOEtmodiﬁed SiNWs (68 ␮g/ml: 9 × 10−6 M QlOEt) with Cu (II). EtOH—water solution (30%) of 0.05 M HEPES buffer (pH 7.0). ex = 324 nm,
em = 490 nm. (Reprinted with permission from [90], 2008 American Chemical Society).
290
SiNWs-based biosensor
SiNWs biosensor
One-dimensional nanomaterials (e.g., carbon nanotubes
(CNTs) and SiNWs) have been employed as an effective
substrate for various sensing applications because of their
favorable biocompatibility, convenient surface modiﬁca-
Y. He et al.
tion, huge surface-to-volume ratios, fast response and good
reproducibility [7,14,15,79]. These unique properties make
CNTs and SiNWs attractive in the development of ﬁeld-effect
transistor (FET), chemical and biological sensors [80—90].
For example, Dai and co-workers developed CNT-based FET
for sensing of proteins or detecting protein-protein interactions in the range of 100 pM to 100 nM [81]. Ryon and Choi
modiﬁed CNT biosensor to enable detection sensitivity to
Figure 10 (a) TEM image of AgNPs-modiﬁed SiNWs, (b) HRTEM image of AgNPs-modiﬁed SiNW, the Moiré fringes marked with
arrow indicates that Ag nanoparticles are embedded in the surface. Raman spectra obtained from Ag-modiﬁed SiNWs coated with
25 ␮l of (c) 1 × 10−16 M R6G solution, (d) 1 × 10−16 M crystal violet solution, (e) 1 × 10−14 M nicotine solution and (f) 1 × 10−8 mg/ml
CT DNA solution in water. Curves in (1) and (2) are, respectively, the Raman spectrum collected from R6G powder and solid CT DNA.
(Reprinted with permission from [97], 2008 American Institute of Physics).
Silicon nanostructures for bioapplications
1 pM protein [82]. Lieber and co-workers reported SiNWsbased FET for spatially resolved, high-sensitivity detection
[83]. Li et al. fabricated SiNWs sensor for high-sensitivity
and sequence-speciﬁc DNA detection with a detection limit
of 25 pM [84].
Lee and co-workers have investigated SiNWs for detection of various biological molecules and metal ions [85—90].
Notably, an individual strand of OAG-growth SiNWs was
fabricated into a sensor with proper surface modiﬁcation
(e.g., decorated with gold nanoparticles) taking advantage of the large dimensionality of SiNWs of >2 mm in
lengths and diameters of 35 nm. The SiNW sensor could
291
sensitively detect a typical kind of protein (bovine serum
albumin (BSA)) via cyclic voltammetric (CV) detection
(Fig. 8) [85]. The SiNWs sensor could also be used for highly
sensitive and reproducible detection of glucose, hydrogen peroxide, and pesticide via electrochemical methods,
due to the high electrical conductivity of the modiﬁed
SiNWs [86—88]. More recently, SiNWs FET were developed for detection of toxic heavy metal cations at low
concentrations (e.g., 10−7 M Hg2+ and 10−4 M Cd2+ ) via
current change of the FET [89]. In addition, Lee and coworkers designed a new SiNWs optical sensor for high
sensitive and speciﬁc detection of Cu2+ , an important ele-
Figure 11 Characterization of SERS-active substrate for immunoassay: (a) and (b) are respectively top and cross-section SEM
images of as-prepared SiNWs array, (c) and (d) are respectively TEM and HRTEM images of AgNPs coated SiNWs and (e) Raman spectra
of mIgG, gamIgG and their corresponding controls. (Reprinted with permission from [98], 2008 American Institute of Physics).
292
ment for hemopoiesis, metabolism, growth and immune
system. This optical sensor was fabricated via covalent
modiﬁcation of SiNWs with ﬂuorescein, i.e. N-(quinoline8-yl)-2-(3-triethoxysilyl- propylamino)-acetamide (QlOEt).
Fluorescence intensity of the QlOEt-modiﬁed SiNWs gradually decreased with increasing Cu (II) concentration, since
the 8-aminoquinoline derivative could effectively coordinate with Cu2+ , leading to ﬂuorescence quenching of QlOEt.
As a result, Cu2+ at low concentration of 10−8 M was selectively detected despite in the presence of interference
metal ions (e.g., Zn2+ , K+ , Ca2+ , Fe2+ and Na+ ) (Fig. 9) [90].
These systematical studies suggest that SiNWs are promising, effective electrical and optical signal transducer which
could be exploited in widespread sensing applications.
SiNWs-based SERS biosensor
Surface-enhanced Raman scattering (SERS) is an attractive
phenomenon raising scattering cross-sections of molecules
residing at or near the surface of roughened or nanostructured materials to ∼1014 compared to normal Raman signals
[91—94]. This huge enhancement factor is widely ascribed to
the strong light-induced electric ﬁeld at locations in metallic
nanostructured spaces, dubbed as ‘‘hot spots’’. SERS features narrow Raman bands that minimize background signals
and favor multiplexing assays. Moreover, Raman scatter-
Y. He et al.
ing is highly resistant to interferences of exoteric factors
(e.g., humidity, oxygen and foreign species), indicating SERS
technique is particularly suitable for various applications
in diverse environments. As a consequence, SERS offers
promising opportunities for ultrasensitive chemical or biochemical analysis on single-molecule level [93,94]. A series
of ultrasensitive SERS-based biosensors has been developed
over the past few years [93—96]. Particularly, metal (e.g.
gold and silver) nanoparticles (AgNPs or AuNPs) are wellestablished as SERS substrate for biomolecular detection.
Notwithstanding, the enhancement factor (EF) of these
metal nanoparticles often only reaches 104 —105 , which is
far lower than the maximum EF value [95,96].
Recently, Lee and co-workers reported that SiNWs decorated with meal (e.g., silver and gold) nanoparticles can
serve as highly effective SERS-active substrate with a high
EF of up to 109 for detection of various biological molecules,
including DNA, proteins. They showed that AgNPs coated
OAG-grown SiNWs (SiNWs@AgNPs) as substrates could enable
sensitive SERS detection of various chemical and biological moieties at extremely low concentrations (e.g.,
25 ␮l 1 × 10−16 M Rhodamine 6G, 1 × 10−16 M crystal violet,
1 × 10−14 M nicotine and 1 × 10−8 mg/ml DNA) (Fig. 10) [97].
Interestingly, AgNPs-coated SiNWs array (etched on a Si
wafer) for SERS-active substrate could provide ultrasensitive protein detection and immunoassay. Under optimized
condition, trace amounts (4 ng) of mouse immunoglobulin
Figure 12 Raman spectra of different amounts of Sudan dyes on the SiNWs@AgNPs SERS substrate. The red curves show the
Raman spectra from 10−13 mol Sudan dye molecules, and the green curves show the Raman spectra from 10−16 or 10−17 mol Sudan
dye molecules. (Reprinted with permission from [99], 2010 American Chemical Society).
Silicon nanostructures for bioapplications
G (mIgG) and goat-anti-mouse immunoglobulin G (gamIgG)
were readily detected (Fig. 11) [98]. Sudan dyes down to
several tens of molecules (e.g., Sudan I—IV and G) were
detected by using the resultant SiNWs array-based SERS substrate (Fig. 12) [99]. Recently, Lee and co-workers designed
a SiNWs-based sandwich structural DNA sensor based on
the SiNWs@AgNPs nanostructure immobilized with capture
probe DNA. A remarkably low DNA concentration down to
0.1 fM could be detected via this new SiNWs-based biosensor
[100].
The exceptional ability of metal nanoparticles coated
SiNWs as SERS-active substrate has also been reported for
detecting other biological molecules. Zhang et al. reported
silver-coated silicon nanowire arrays, prepared by a chemical etching method, as a stable and efﬁcient SERS-active
substrate for sensitive molecular detection [34]. Calcium
dipicolinate, a biomarker for anthrax, was readily detected
at low concentration of ∼10−6 mol. Galopin et al. explored
the VLS-grown SiNWs substrates capped with Ag NPs as ultrasensitive SERS interfaces with a high EF value of ∼108 ,
allowing a low detection limit of 10−9 M for R6G [35]. Fang et
al. developed a simple method to metalize SiNWs via deposition of metal ions on the top of the SiNWs [36]. Particularly,
an extremely strong Raman signal was observed and a detection limit of ∼600 molecules was reached when the resultant
metalized SiNWs was employed as a SERS substrate.
While the exceptional SERS activity of SiNWs@AgNPs
appears to be widely observed, however the enhancement
mechanisms of SiNWs for SERS are not well understood. We
proposed that the quasi two-dimensional array arrangement
as well as the unique pseudo three-dimensional arrangement
of AgNPs on the SiNWs surface as two contributing factors for
the high SERS enhancement efﬁciency [97—100]. In addition,
a large amount of SERS hot spots are prone to be generated
on such nanowire-based substrates, which may contribute
to the observed ultrahigh enhancement factor of the SiNWs
decorated with metal NPs [101]. We envision the waveguide
and microcavity effects of SiNWs substrate may additionally
play a role in the SERS effect. Large SERS effect has also been
observed from AgNPs-coated AgVO3 nanoribbons [102]. This
raises the question if the substrate material and shape is also
important. These open questions demand investigations and
understanding, which are essential for further development
of the SiNWs-based SERS technique.
Conclusion and perspectives
In the past few years, there have been considerable advances in the synthesis and bioapplications of
silicon quantum dots and silicon nanowires. Several
efﬁcient synthetic strategies including solution-phase reduction, plasma-assisted aerosol precipitation, microemulsion,
mechanochemical and chemical etching synthesis have
been developed to synthesize highly ﬂuorescent SiQDs so
far. Importantly, SiQDs become well water-dispersed after
appropriate surface modiﬁcation with either hydrophilic
molecules or polymers. The favorable biocompatibility as
well as the robust photo-stability renders SiQDs promising
candidates for ﬂuorescent biological probes. While there
have been several exciting reports on the utility of SiQDs
for biological imaging, further efforts are necessary to mod-
293
ify and tailor SiQDs architectures to ﬁt the demands of
biological and biomedical applications. One big challenge
remaining is the development of economic and facile strategies for the large-scale synthesis of highly luminescent SiQDs
with controllable colors, which is the fundamental basis
for their widespread bioapplications. Furthermore, effective methods of surface modiﬁcation are required to further
improve aqueous dispersibility and optical properties of
SiQDs. Moreover, a number of biological parameters have
to be satisfactorily addressed before eventual in vivo and
in vitro applications. While silicon is expected to be biocompatible, it is critically important to carry out systematic
studies to assess their biosafety, including biodistribution
and interactions between SiQDs and biomolecules, cells and
animals for in vivo bioimaging.
Three strategies have been well-established for
synthesizing
well-deﬁned
SiNWs,
metal-catalyzed
vapor—liquid—solid (VLS), oxide-assisted growth (OAG)
and metal-assisted chemical etching. Each approach has its
own advantages. In VLS method, the diameter and growth
alignment of the nanowires can be readily controlled by
using uniformly distributed metal seeds with well-designed
sizes on the substrate. The OAG method is favorable for
large-scale synthesis of SiNWs without metal contamination, and capable of producing ultrasmall-diameter
(∼1 nm) SiNWs exhibiting quantum conﬁnement effects.
The third method provides a facile wafer-scale production
of robust SiNWs without the need of high temperature,
vacuum, templates, complex equipment and hazardous Si
precursors. Recent investigations demonstrated that SiNWs
could act as efﬁcient SERS-active substrate with a large EF
factor of 107 —109 . Such SiNWs-based SERS biosensor can
provide highly sensitive and speciﬁc detection of various
biomolecules (e.g., DNA and protein). Despite the progress,
there remain a number of open questions on how to design
sophisticated SiNWs-based SERS-active architectures, as
well as how to achieve reproducible and sensitive signals in
SERS detection. Additionally, satisfactory SERS mechanisms
are absent and urgently require systematic investigations,
which are highly essential for developing ultrasensitive and
robust SiNWs-based SERS biosensors. Also of note, we have
preliminarily and systematically investigated the cytotoxicity of SiNWs on different cellular lines, revealing that SiNWs
prepared through metal-assisted chemical etching method
[103] are indeed compatible with cells. We expect that
it will be a rewarding direction to develop a SiNWs-based
platform for cellular studies, which is potentially a new way
to study cellular morphology, behavior and physiological
functions at the nanoscale [104—106].
Acknowledgements
This work was supported by the Research Grants Council
of HKSAR (CityU5/CRF/08 and N CityU108/08), Ministry of
Health (2009ZX10004-301), National Basic Research Program
of China (2007CB936000) and NSFC (30900338, 20725516,
90913014) 973 (2010CB934502). The authors would like to
acknowledge signiﬁcant contributions from Dr. K.Q. Peng,
Dr. M.W. Shao, Dr. Z.H. Kang, Dr. J. Antonio Zapien, Dr. Y.Y.
Su, Dr. M.L. Zhang, Dr. X. Fan, Dr. S. Su, Dr. T.T. Xu and Mr.
C.W.C. Michael.
294
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295
Yao HE received his bachelor degree (2003)
in chemistry from Fudan University (China),
and continued the graduate study (Master
and Doctor) in Fudan University (China) in
2003—2007. He was a visiting scholar for
the joint program in Shanghai Institute of
Applied Physics, Chinese Academy of Sciences (2005—2007). Afterwards, he worked in
the Center of Super-Diamond and Advanced
Films (COSDAF) in the City University of Hong
Kong, HKSAR, China, as a research fellow. He
became an associate professor in Institute of Functional Nano &
Soft Materials (FUNSOM) at Soochow University (China, 2009). His
research interest focuses on development of functional nanomaterials and exploration of nanomaterials-based bioapplications (e.g.,
bioimaging and biosensors).
Chunhai Fan received his BS (1996) and PhD
(2000) degrees in biochemistry and molecular biology from Nanjing University (China).
After postdoctoral research at the University
of California, Santa Barbara (USA), he became
a professor in Shanghai Institute of Applied
Physics (SINAP), Chinese Academy of Sciences
in 2004. He is now the director of the Division
of Physical Biology of SINAP. He was the recipient of the Chinese Chemical Society Prize for
Young Scientists (2006) and NSFC Outstanding
Young Investigators (2007). His research interests focus on electrochemical and optical biosensors and the design of nanoprobes for
biological systems.
Shuit-Tong Lee received his BS (1969) from
The Chinese University of Hong Kong, HKSAR,
China, MS (1971) from University of Rochester
(USA), PhD (1974) from the University of
British Columbia (Canada), and postdoctoral
training (1974—1976) in University of California, Berkeley, all in Chemistry. He worked in
the Research Laboratories of Eastman Kodak
Co. (USA) in 1976—1994 as Senior Scientist and
Project Manager. He joined City University of
Hong Kong in 1994 as a Senior Lecturer, and
became Chair Professor of Materials Science in 1996 and Founding Director of the Center of Super-Diamond and Advanced Films
(COSDAF) in 1998. He is Founding Director of Institute of Functional
Nano & Soft Materials (FUNSOM) at Soochow University, Suzhou
(China). He was elected a Member of Chinese Academy of Sciences
in 2005 and a Fellow of the Academy of Sciences for the Developing World in 2006. His research interests are in nanomaterials and
nanotechnology, organic electronics, diamond and superhard coatings, and surface science. He has published over 650 peer-reviewed
SCI articles, six book chapters and 20 US patents. He was bestowed
the Humboldt Senior Research Award (Germany, 2001), Croucher
Senior Research Fellowship (Hong Kong, 2002), two National Natural Science Awards of China (second rank, 2003 and 2005), Scientiﬁc
and Technological Progress Award of Ho Leung Ho Lee Foundation
(Hong Kong, 2008) and Hans Fischer Senior Fellowship of Institute of
Advanced Study of Technical University of Munich (Germany, 2009).
He is the Associate Editor of Applied Physics Letters and Diamond
and Related Materials.