Silicon Quantum Dots: From Synthesis [618699]

Chapter 13
Silicon Quantum Dots: From Synthesis
to Bioapplications
Miruna Silvia Stan, Cornelia Sima and Anca Dinischiotu
Abstract Silicon quantum dots (Si QDs) represent a special class of nanomaterials
with distinctive properties, being used in different applications such as photo-voltaics, optoelectronics devices, and biomedical ones. They have excellent lumi-
nescence at UV irradiation, tunable band gap, and resistance against photobleaching
compared to standard dyes. Being less toxic in comparison with conventionalmetal-containing QDs, they received growing research interest in the last decade asa more biocompatible alternative to which displayed toxicological concerns. Thereare several physical and chemical methods for Si QDs synthesis, each of theminvolving advantages and disadvantages. In physical methods, the experimentalsetup is very simple and parameters can be adjusted from outside in order to obtainthe desired size of nanoparticles. Chemical methods seem to be attractive due to the
huge scale of productions, but the purity control of the material and experimental
setup are more complicated. For biomedical applications, many techniques havebeen established to achieve water-soluble Si QDs and for their conjugation withbiomolecules that render them to speci fic biological targets. Si QDs have become
powerful nanomaterials in various biomedical applications, a promising approachfor in vivo imaging, tumor biology investigation, and cancer treatment. Besides ofall these advantages, their characteristics can also trigger cytotoxicity in healthycells by different mechanisms that have been in vitro and in vivo investigated in the
last years. This chapter summarizes the major methods of synthesis and recent
advances in bioconjugation strategies for preparing high-quality Si QDs, with afocus on their toxicity evaluation and bioapplications.
Keywords Silicon quantum dots
/C1Semiconductors /C1Self-fluorescence /C1
Biocompatibility /C1Biomedical applications
M.S. Stan /C1A. Dinischiotu ( &)
Department of Biochemistry and Molecular Biology, University of Bucharest,91-95 Splaiul Independentei, 050095 Bucharest, Romania
e-mail: [anonimizat]
C. Sima
Laser Department, National Institute of Laser, Plasma and Radiation Physics,409 Atomistilor, 077125 Bucharest, Magurele, Romania
©Springer Nature Singapore Pte Ltd. 2017
B. Yan et al. (eds.), Bioactivity of Engineered Nanoparticles ,
Nanomedicine and Nanotoxicology, DOI 10.1007/978-981-10-5864-6_13339

13.1 Si QDs Synthesis
13.1.1 Quantum Dots Versus Organic Dyes
Silicon is a chemical element widely used in many industrial and biomedical
applications. Compared with other semiconductor materials, silicon is found in alarge quantity in the earth ’s crust. Although it is an indirect band-gap semicon-
ductor material, in the bulk form is less used for optoelectronics and biologicalapplications. However, by decreasing the size of the particles (usually less than5 nm), silicon acquires special properties exhibiting luminescence due to the
existence of quantum con finement effect [ 1–5]. Several parameters in fluence the
quantum con finement, such as particle size and size distribution, particle density,
and surface properties [ 6,7].
Crystalline silicon nanoparticles show emission from infrared to blue when their
size is less than 5 nm meaning an increasing of the band gap: blue (2.64 –3.0 eV),
green (2.25 eV), orange (2.05 eV), red (1.70 –1.80 eV) and infrared (1.2 –1.6 eV)
[8,9]. It is assumed that the quantum con fined effect appears in quantum dots
(QDs) when their size becomes comparable with the exciton Bohr radius (4 nm for
silicon) [ 9–11].
Wei-Wi et al. [ 12] noticed that photoluminescence of silicon quantum dots (Si
QDs) at room temperature, in an atmosphere type dependent manner. So inhydrogen or in a vacuum, the emission was from infrared to ultraviolet with a blueshift observed with the decreasing of nanocrystal size, whereas in oxygen, air ornitrogen a stronger emission in a narrower wavelength range occurred [ 12].
Over the years, several semiconductor QDs were studied: CdS, CdSe, CdTe,
InP, InAs, GaAs, and PbSe, PbS. One of the main disadvantages of these standard
QDs is that they use heavy metal elements and are not suitable for in vivo appli-
cations being very toxic for biological systems [ 1].
In order to surpass these drawbacks, extensive researches were developed to
synthesize reliable QDs with less toxicity, for use in optoelectronic and bioimagingapplications [ 13–15]. In this context, silicon proved to be one of the ideal candi-
dates having signi ficant advantages over standard QDs (PbS(Se) and CdSe(Te)):
less toxic, increased photostability, emission in near infrared range, and not at leasttheir compatibility with biological medium [ 14,16].
In the biological experiments, conventional fluorophores used are organic sub-
stances composed of either chemically synthesized fluorescent dyes or genetically
encoded fluorescent proteins that have some limitations such as short fluorescence
duration, narrow excitation, and broad bandwidth emission [ 17]. In contrast, QDs
have broad absorption and at the same time a narrow wavelength-tunable emissionpeak. The molar absorption coef ficients are larger than 100,000,000 M
−1cm−1at
the excitation peak wavelength compared to organic fluorophores which is less than
250,000 M−1cm−1[1]. Additionally, the emission peak of QDs is also tunable by
varying size of the particles, which is not possible for organic dyes that have often
the emission bands unsymmetrical [ 1–4]. Moreover, the quantum yield of QDs is340 M.S. Stan et al.

high, in the range of 60 –80%, in visible and near infrared domains, whereas in the
case of organic dye it is less than 20% in the near infrared region [ 1].
Thefluorescence lifetime of the Si QDs is longer (tens of ns or µs), while in the
case of organic dye it is shorter (5 ns in the visible region and 1 ns in the near
infrared) [ 1,4]. On the other hand, it was shown that “short fluorescence lifetime in
Si QDs is often associated with core-related recombination and longer lifetime isdue to the existence of ultrafast trapping of excited carriers in surface states, pre-venting core recombination ”[1].
The emission properties of QDs are dependent on the particle size, morphology,
composition, surface architecture, as well as shell ligands.
In consequence, QDs are more convenient than conventional dye for bioimaging
applications due to strong stability to photobleaching, high quantum yield, broad
absorption pro file, and size-tunable emission [ 18–20].
13.1.2 Physical, Morpho-Structural, Optical
and Surface Properties
QDs are semiconductor nanocrystals with size smaller than the exciton Bohr radius
that present quantum size effect [ 1,11,13,21]. They present special and unique
properties due to quantum con finement phenomenon [ 20]. More exactly, the
quantum con finement in the case of QDs consists of limitation of few electrons
inside of a semiconductor that when are excited, emit a light with a speci fic
wavelength which depends on the dot size [ 22].
It is well known that silicon has a very weak absorption in the visible range due
to its indirect band gap. As a result of the quantum con finement phenomenon,
optical band gap of the QDs can be adjusted as a function of size [ 14]. They have
wavelength-tunable visible light emission, which depends on the core size of the
nanoparticles [ 23].
There are many studies concerning the photoluminescence properties, on the
nanoparticles size and size distribution, surface functionalization (surface passiva-tion), crystallinity, shape of the nanoparticles, temperature, aging, etc. [ 21].
Studies regarding the variation of photoluminescence depending on the
nanoparticle size revealed that larger nanoparticles (8 nm) exhibited luminescencetoward longer wavelengths while those with size about 2 nm presented lumines-cence at higher energy (blue region) [ 24,25].
The advantage of the Si QDs compared to other materials is mainly due to the
low toxicity of silicon and possibility of modifying the nanoparticle size in a widerange [ 26,27]. Other characteristics such as rates of radiative recombination,
lifetimes, and quantum ef ficiency strongly depend also on the size of QDs.
In the synthesis process, nature of the ambient gas had a strong in fluence on the
crystallization state. Due to this fact, Si QDs grown in NH
3with plasma enhanced
chemical vapor deposition (PECVD) had a crystalline structure, whereas those13 Silicon Quantum Dots: From Synthesis to Bioapplications 341

synthesized in N 2gas were amorphous, suggesting that hydrogen present in gaseous
NH 3favored the crystallinity [ 28]. Analyzing the photoluminescence intensity of Si
QDs prepared in SiH 4/N2,it was observed that the highest intensity was noticed for
those prepared in SiH 4/NH 3, and the lowest was observed in the case of the ones
prepared in SiH 4/N2,probably due to the effect of hydrogen passivation on reducing
dangling bonds and nonradiative species [ 28,29]. The decrease of size by
increasing of N 2flow rate resulted in an enhancement of quantum con finement and
appearance of a blue shift [ 30,31].
A clear dependence between band gap, size, and shape of QDs was reported
[32]. Also, it was demonstrated that “cubic Si QDs exhibit larger wavelengths while
octahedral nanoparticles exhibit smaller wavelengths and truncated Si QDs exhibitwavelengths between cubic and octahedral ”[32]. It was also proved that
plasma-based methods produced cubic shapes which are advantageous for “maxi-
mization of amount surface hydrogen absorption ”while the other synthesis meth-
ods generated pseudospherical shapes which, after annealing, leaded to facetedshapes [ 32].
In the chemical etching synthesis method, the etching time also in fluences the
photoluminescence; therefore, increasing the etching time, reduces the size ofnanoparticles leading to a blue shifting in the photoluminescence peak [ 33].
Previous studies revealed that Si QDs with average size of about 3.6 nm did not
present any photoluminescence immediately after synthesis. But, after about 20 min
in air, they exhibited a weak photoluminescence at about 1.72 eV; by increasing theaging time in air to 25 days, the photoluminescence peak was at about 1.87 eV. Itwas concluded that the photoluminescence peak shifted toward shorter wave-lengths, in an oxidation time dependent manner, probably due to the decrease of thecore size and the increase of the oxide layer [ 24]. Also, the full width at half
maximum (FWHM) after 20 min of aging was about 0.23 eV, and increased to0.31 eV after 25 days. After 1 month, the peak intensity increased by about 16
times [ 24]. After 6 months of aging in air after SiO
2removal, the luminescence
peak position did not change, but FWHM returned to approximately the same valuebefore oxidation. Additionally, the intensity strongly increased by about 70-fold[24]. Similar observations have been done by Ledoux et al. [ 25].
One of the most important parameters which in fluences the photoluminescence
are the surface properties of Si QDs as well. Absence of a semiconductor shell
reduces the degree of exciton con finement in the core and broadnesses the emission
peak. It was demonstrated that Si QDs prepared via colloidal solution method have
emission in blue –green while the red emission could be observed when Si QDs are
prepared at high temperature. Also the crystallinity and size of the core of Si QDsare in fluenced by the oxidation of dots; therefore, by adding an organic monolayer
on the Si QDs surface, oxidation of the surface could be avoided leading to stablephotoluminescence properties [ 1].
Taking into account that surface of Si QDs is very active, several ways to modify
the surface properties for improvement of the photoluminescence were studied [ 34].
So the surface of Si QDs (4.9 –6 nm) was covered with an oxide layer by gradual342 M.S. Stan et al.

oxidation for 2 years in the air. After dispersion in ethanol, they exhibited a
luminescence at about 763 nm, while the freshly prepared QDs had no photolu-minescence [ 34].
It was assumed that the presence of dangling bonds on the silicon surface is a
disadvantage for the photoluminescence occurrence and a passivation of Si QDs
surface by hydro fluoric acid (HF) has been done in order to remove the oxide layer
leading to a narrow band from 0.4 eV (before HF treatment) to 0.26 eV (after HFtreatment) [ 35].
It was demonstrated that the dangling bonds (nonradiative defect) could be
passivated using NH
3instead of N 2. Furthermore, photoluminescence was very
strong and the peak position was strongly in fluenced by the flow rate of NH 3being
shifted to lower wavelengths (blue shift) when the flow gas rate increased from 10 to
900 sccm at a fixed SiH 4flow rate of 400 sccm. On the other hand, when the NH 3
flow rate was maintained at 30 sccm and SiH 4flow rate was varied in the range 100 –
900 sccm, the photoluminescence peak shifted toward longer wavelengths [ 28].
When the Si QDs were capped with SH, NH 2, OH, photoluminescence spectra
presented signi ficant modi fications, whereas when alky groups ( –Si–C–) were
added low alterations appeared in the photoluminescence spectrum [ 36].
The halogenation of the Si QDs strongly in fluenced the optical properties of
QDs. So under direct UV irradiation of the halide attached on the Si QDs, no any
photoluminescence was detected; but after oxidation it was noticed. Therefore, a
blue photoluminescence was observed in the case of chlorine terminated siliconquantum dots surface, while for bromide and iodide, yellow –orange photolumi-
nescence was observed. It was assumed that blue photoluminescence is due tooxychloride defects while the yellow orange is generated by oxide defects [ 37].
The photoluminescence of Si QDs is also in fluenced by temperature. A shifting
toward red after an increase of temperature between 110 and 350 K, when thesilicon sample was excited with 266 nm wavelength occurred [ 38]. Also after
heating from 700 to 1000 °C the photoluminescence peak was shifted toward
longer wavelengths due to the fact of the increase of the grain size at high tem-peratures [ 39].
The optical properties of the Si QDs are dependent on their electronic structure
[40]. Theoretically, a strong correlation between the split of the energy level in the
dot and the dot size, crystallographic directions, and shape exist [ 40]. Therefore,
Zianni et al. [ 40] assumed that “for [001] level, the lifetime is not in fluenced by the
crystallographic direction ”and in the case of small dots (2 nm), it is of µs order
while “for [100] level the lifetime is strongly in fluenced by the crystallographic
direction ”being about ms order [ 40].
It is considered that the photoluminescence lifetime is a result of radiative and
nonradiative recombination processes. The study of Wu and Lin [ 41] on Si QDs
revealed that “non-radiative recombination rate is much lower than radiative
recombination rate, ”that means that the photoluminescence lifetime of these is the
result of radiative recombination only [ 41].13 Silicon Quantum Dots: From Synthesis to Bioapplications 343

13.1.3 Synthesis Methods
The synthesis methods of Si QDs are various being both physical and chemical
ones. Each of them has advantages and disadvantages.
Physical methods produce high purity particles, the experimental setup being
very simple and parameters can be adjusted from outside in order to obtain thedesired size of nanoparticles; on the other hand, the particles have a lower yield [ 4].
Chemical methods seem to be attractive due to the huge scale of production, but
the purity control of the material and experimental setup are more complicated.Unlike the physical methods, in order to enhance the QDs luminescence, additionaltreatment, such as annealing is necessary; moreover, multistep procedures arerequired [ 4].
There are several synthesis methods such as: laser ablation [ 6,12,26,27,42–
52], magnetron sputtering [ 13,53–55], solution phase oxidation/reduction [ 1,4,19,
56], thermolysis/laser pyrolysis [ 1,4,24,25,34,35], electrochemical etching
(anodic oxidation) [ 4,5,33,38,57,58], microwave-assisted method [ 8,11,59–61],
atmospheric pressure plasma [ 7,62].
13.1.3.1 Laser Ablation
First experiments for preparing silicon nanoparticles by laser ablation have been
done by Okada and Iijima [ 4,42]. The method is advantageous due to the fact that
no chemical precursors which could contaminate the nanoparticles is used (there-fore, it is considered a very clean method); the experimental setup is very simplewithout the requirement of high temperatures or pressures; it is versatile, giving thepossibility to vary from outside any experimental parameters [ 10].
There are two types of environments to prepare nanoparticles by laser ablation:
in liquid or gas. Laser ablation in liquid demonstrated a good capability to produce
pure nanoparticle colloidal solution. The photoluminescence of the siliconnanoparticles obtained in liquid is dependent of laser wavelength and pulse duration[43]. Intartaglia et al. [ 43] synthesized silicon nanoparticles in aqueous solution
(deionized water) using a Ti: sapphire femtosecond laser, (110 fs pulse duration,800 nm wavelength, 1 kHz repetition rate) at two different energies/pulse (0.15 and0.4 mJ). In the case of high energy (0.4 mJ), the nanoparticles were in the range of10–120 nm with an average size of about 65 nm. On the other hand, at low energy
of 0.15 mJ, the size of the silicon nanoparticles was in the range of 1 –8 nm with
average size of about 5.5 nm. In both cases, the nanoparticles were crystalline.
After synthesis, they were excited with 400 nm wavelength; the small nanoparticles(obtained at low energy) exhibited a blue green emission; the large ones (synthe-sized at high energy) exhibited a luminescence peak at 575 nm and decreasedintensity [ 43].
Vaccaro et al. [ 44] evidenced also the versatility of the laser ablation in water,
offering the possibility to control each parameter during the experiments344 M.S. Stan et al.

(wavelength, energy, fluency, pulse duration, liquid) leading to the desired prop-
erties of the silicon nanoparticles (crystallinity, composition, size). A nanosecondNd:YAG laser (1064 nm, 10 Hz, 5 ns, 0.6 J/cm
2energy density) was used. The
nanoparticles were in the range of 2 –10 nm with the mean size of about 4 nm.
Concerning the photoluminescence, it was observed an emission peak at about
1.95 eV, being in accordance with quantum con finement. Therefore, decreasing the
size of nanoparticle, the emission peak is shifted toward shorter wavelength andincreasing the band gap. The measured photoluminescence lifetime was in the rangeofµs. It was demonstrated that the photoluminescence peak depends on the size of
nanoparticle according to expression:
E
PL¼E0ț3:73=d1:39/C0/C1
; ð13:1Ț
where E0= 1.17 eV (the band gap energy of bulk silicon) and d= size of
nanoparticle in nm [ 44].
Starting from a p-type silicon wafer, with a nanosecond Nd:YAG laser (532 nm,
13 ns, 10 Hz), Chewchinda et al. [ 45] synthesized silicon nanoparticles in ethanol,
energy density from 0.15 to 0.45 J/cm2. The nanoparticles were spherical, and their
size was in the range of 2 –30 nm, the average size decreasing with increasing of
energy density. So at highest energy density of 0.45 J/cm2, the average size was
about 6 nm. In this case, the photoluminescence peak increases with increasing theenergy density when small nanoparticles are generated and at the same time areblue shifted [ 45].
Eroshova et al. [ 26] studied the in fluence of the pulse duration on the
nanoparticle characteristics. So, a picosecond laser (Nd:YAG, 1064 nm, 34 ps,
10 Hz, 1 mJ) was used for the ablation of a silicon wafer in distilled deionizedwater and femtosecond laser (1250 nm, 120 fs, 10 Hz, 300 µJ) in liquid nitrogen.
The average size of nanoparticles obtained using picosecond laser was about 18 nmand these were crystalline. On the other hand, using fs laser for ablation in liquidnitrogen, the average size of the silicon nanoparticles was about 5 nm. In this case,the photoluminescence spectrum exhibited an emission peak at about 750 nm(1.65 eV).
Concerning the synthesis of Si QDs in a gas atmosphere, it was studied the
temperature dependence of these nanoparticles produced by laser ablation in heliumatmosphere [ 46]. Using a Nd:YAG laser (532 nm, 210 mJ, 10 Hz) a silicon wafer
target was irradiated in an atmosphere of 7 Torr. Spherical nanoparticles with avery narrow lognormal distribution (6 –8 nm) and average size about 7 nm were
obtained. Additionally, it was observed that the silicon nanoparticles were coveredwith an amorphous silicon oxide shell due to the oxidation after exposure to theambient atmosphere. From the photoluminescence spectra measured at different
temperatures from 300 to 4 K, Orii et al. observed a “gradually increasing of the
luminescence intensity, peaked at about 60 K and then decreasing rapidly. Thephotoluminescence intensity at 60 K was increased relative to the value of 300 Kby a factor of 5 and that at 4 K decreased roughly to the value at 300 K ”[46].13 Silicon Quantum Dots: From Synthesis to Bioapplications 345

Another study used a KrF excimer laser (248 nm, 20 ns, 2 J/cm2fluency,
10 Hz), starting from a silicon target. The experiments were made in heliumatmosphere at 10
−1mbar. All the silicon samples were almost spherical. The mean
size of the nanoparticles was in the range of 1 –5 nm. At room temperature, a UV –
VIS photoluminescence attributed to direct band recombination from quantum
confinement of silicon was observed. The photoluminescence lifetime was about
1.5 ns [ 6].
Laser ablation experiments in two different inert gases (helium and argon with
pressure in the range of 250 –550 mbar) were also made by Grigoriu et al. [ 47,48].
A Nd:YAG laser (532/355 nm, 5 ns, 10 Hz and 4 –8 J/cm2) was used.
The synthesis of Si QDs by laser ablation in reactive gases was also done in
oxygen atmosphere, using a KrF excimer laser (248 nm, 17 ns, 20 Hz, 5 J/cm2)
[49]. It was observed a strong dependence of the photoluminescence intensity on
oxygen pressure and size of crystals. It was observed that increasing the oxygenpressure leads to a decreasing of the intensity photoluminescence. Additionally, theposition and shape of the photoluminescence spectrum depend on the crystal sizeand size distribution; the crystal size decreases with increasing of oxygen pressure[49].
Wei-Qi et al. prepared Si QDs using infrared radiation, 1064 nm, 60 –80 ns pulse
duration, and 1000 –3000 s
−1repetition rate [ 12]. They prepared Si QDs in different
atmospheres: oxygen, nitrogen, air. A p-type silicon wafer was used as target. After
synthesis, the samples were annealed at 1000 °C for 5 –30 min in oxygen, nitrogen
or air, in order to eliminate dangling bonds from the surface of Si QDs; theannealing produced a narrowing of the size range. Another method to reduce thedangling bonds was “the passivation of hydrogen in HF liquid ”[12].
Concerning the correlation between pulse duration and nanoparticle character-
istics, it is considered that laser ablation with picosecond pulses is more advanta-geous in comparison with nanosecond laser pulses. Therefore, when a laser with
nanosecond pulse duration impinges the target, due to the high energies/pulse and
low repetition rates, the ejected macroparticles interact with the gas leading to theformation of large particles. Conversely, using picosecond pulses, lowenergies/pulse and high repetition rates, a fine material is ejected from the target
creating particles with small size [ 50].
13.1.3.2 Magnetron Sputtering
The method consists of bombardment of a target with energetic ions that come from
gaseous plasma. Following the interaction between the ions and the atoms fromtarget surface, the individual atoms condensed onto a substrate [ 53]. The method is
very fast, simple, with high productivity, being similar with laser technique. Theshape and size of the particles depend on the “distance between magnetron and exit
aperture ”[54]. Also, the aggregation of the particles is dependent on the distance
between magnetron and exit aperture, gas pressure, and time [ 54].346 M.S. Stan et al.

By this method, Fujioka et al. obtained Si QDs with mean diameter about 6.5 nm
and a core structure of silicon with average size of about 2.5 nm. At excitationwavelength of 300 nm, the photoluminescent emission was at 414 nm [ 13].
Ohta et al. synthesized Si QDs with diameter about 3 nm exhibiting lumines-
cence at 450 nm after irradiation with 360 nm wavelength [ 55]. Generally, use of
QDs in biological environments requires their dipping in aqueous medium thusleads to aggregation of the nanoparticles. In order to avoid the interaction betweenparticles, it was necessary to modify their surface. For biomedical applications, theirsurfaces were modi fied by allylamine and amphiphilic block copolymers that did
not modify the photoluminescence emission peak [ 55].
13.1.3.3 Solution Phase Oxidation/Reduction
Thefirst experiment using this method has been performed by Heath in 1992 [ 56].
This is a simple method due to the flexibility of choosing different reducing agents
[4,56]. Ghosh et al. described in 2014 the synthesis method as consisting of a
“reduction of SiCl
4and RSiCl 3(where R could be hydrogen or octyl group) by
sodium metal in a non-polar organic solvent at high temperature of 385 °C andpressure higher than 100 atmosphere ”[4]. The obtained silicon nanoparticles were
in the range between 5 nm and 3 lm with hexagonal shapes in trichlorosilane or
about 5.5 nm in the presence of trichlorooctylsilane [ 4]. On the other hand, this
method is considered disadvantageous due to the dif ficulty of controlling or
adjusting the nanoparticle size.
13.1.3.4 Thermolysis/Laser Pyrolysis
This method generates freestanding nanoparticles and was first demonstrated by
Cannon et al. in silane gas, using a CO
2laser [ 1,4]. It consists in dissociation of
SiH 4and nucleation of the silicon nanoparticles [ 4]. Several authors investigated
the Si QDs produced by laser pyrolysis [ 24,25,34,35]. Ledoux et al. explained the
principle method as follows: “a conical nozzle is placed near the pyrolysis “flame ”
and the clusters and nanoparticles are extracted from the flow reactor ”[25].“They
are skimmed into a low-pressure vacuum chamber and form a “molecular beam ”of
noninteracting clusters. ”“In this molecular beam, the cluster velocity is mass
dependent; the smaller the particles, the faster they are; therefore, a rotating chopper
synchronized with the pulsed pyrolysis laser, the size distribution of the clusters canbe signi ficantly narrowed ”[25]. This method can produce high quantities com-
paring with other methods; by laser pyrolysis about 200 mg/h particles with sizeless than 3 nm could be obtained [ 34]. The disadvantage is that is more complicated
to obtain pure QDs and not at least silane is very explosive and should be takenadditionally adequate protections which generate other supplementary costs.13 Silicon Quantum Dots: From Synthesis to Bioapplications 347

13.1.3.5 Electrochemical Etching/Anodic Oxidation
Generally, the method consists in dissolving of the material which is subjected for
obtaining of nanoparticles using some acids, basis, or several chemical agents. It
could use different semiconducting materials (in this case silicon), metals or glass.
Thus, after the interaction between the material and the respective chemical agents,the target is corroded and finally the material is removed. In order to adjust the size
of the nanoparticles, the etching time could be varied as well as the etching solu-tions. One can be concluded that the characteristics of the nanoparticles depend onthese parameters. Examples of etching solution could be considered nitric acid(HNO
3) and hydro fluoric acid (HF) [ 58]. More exactly, silicon wafer is etched and
the resulted materials are dispersed in different solvents leading to a suspension
with Si QDs of irregular shapes, with size from few nm to microns [ 4]. Wang and
his coworkers [ 5], synthesized photoluminescent (red –orange) silicon nanoparticles
(about 2.7 nm size) by electrochemical etching, starting from a silicon n-type or p-
type wafer. Both wafers were etched in a mixture of HF/H 2O/ethanol [ 5]. This
method is a promising one but it should be mentioned that the size of nanoparticlescannot be easy controlled “at the single nanoscale ”[4].
13.1.3.6 Microwave-Assisted Synthesis Method
One experimental setup for obtaining silicon nanoparticles is reported by
Chinnathambi et al. [ 11]. The method is based on a heating mechanism being
known as “microwave dielectric heating ”[60]. Baretto et al. [ 59] and Atkins et al.
[60] give some explanation of the synthesis method with their advantages as fol-
lows. The heating takes place through two processes: dipolar polarization and ionicconduction. Thus, after the electromagnetic field is applied to the sample, the
electrical component produces “dipols and ions which try to align with the electric
field.”Procedure of the alignment of the dipols with electric field involves “energy
which is lost as generation of heat ”[60].
The microwave-assisted synthesis method proved to be advantageous being a
very fast and simple method. So, 0.1 g Si QDs of 4 nm size are obtained in about15 min [ 61]. These have shown excellent aqueous dispersibility and a strong
fluorescence. The spherical shape, high crystallinity and average size of about
3.1 nm were obtained. The emission peak of Si QDs was at 660 nm. Under UV
irradiation, it could be seen a very strong red luminescence [ 61].
13.1.3.7 Atmospheric Pressure Plasma
Synthesis of Si QDs by atmospheric pressure plasma is considered one recent
method with high capabilities for different applications.
An experimental setup of synthesis of Si QDs by plasma was described by Yu
et al. [ 62]. Between two parallel aluminum electrodes covered with quartz as348 M.S. Stan et al.

dielectric barrier vertically in the reaction chamber, plasma was generated. As
working gases, argon, silane, and hydrogen flow through the electrodes conducted
at a discharge. Thus, the electrons from plasma dissociate the silane resulting intosilicon clusters and after about several milliseconds generated few nanometers
particles which were collected onto a substrate when an RF power is attached. The
photoluminescence of the nanoparticles remain unchanged more than 1 month [ 62].
One of the main drawbacks of this method is that it takes long time for obtaining
important quantities. The aim is to have a continuous flow-through process;
therefore it was demonstrated that RF frequencies were more suitable from pro-duction rate point of view, comparing with DC excitation [ 7].
13.2 Si QDs Bio-Interaction
13.2.1 Si QDs Biocompatibility and Cytotoxicity
As stated before, Si QDs have proved an increased in vitro biocompatibility and
low cytotoxicity, or even the absence of it [ 61,63–66]. Compared with the heavy
metal-based QDs, the toxicity of Si QDs was not observed at 112 µg/ml, and these
proved to be more than ten times safer than CdSe QDs [ 13]. Despite the bio-
compatibility observed for low doses of nanoparticles, a reduced viability wasnoticed when the concentration was increased in respect with the type of synthesiswhich certainly in fluences the toxicity [ 13,61,63,67–70]. Erogbogbo et al. con-
sidered that residual chloroform used in synthesis could be responsible for the toxiceffects. The mechanism of toxicity suggested by the group of Fujioka pointed out
that Si QDs can generate reactive oxygen species (ROS) which could be associated
with membrane damage [ 63]. Similar, Stan et al. revealed the absence of toxicity in
human lung cells for doses up to 200 µg/ml after 24 h of exposure, but toxic effects
appeared for high concentrations after 48 and 72 h [ 70]. Similarly, HepG2 hepatic
cells tolerated high doses of Si QDs without suffering signi ficant damage [ 71]. The
negative in fluence of Si QDs on redox homeostasis of pulmonary fibroblasts was
reflected by increased levels of ROS, lipid peroxidation and oxidized proteins,
together with decreased glutathione content, the intracellular distribution of GSH
being altered during longer incubation intervals [ 70]. Taking into account all these
in vitro data, it could be suggested that cell death induced by high doses of Si QDsis mediated by oxidative stress, a common key factor involved in the cytotoxicity ofvarious types of nanoparticles, which disturbs protein functions and cell signaling[72]. In addition, an in flammatory response in lung cells characterized by the
release of pro-in flammatory cytokines was triggered by Si QDs which modulated
also the expression and activity of matrix metalloproteinases [ 69]. A schematic
representation of the most important effects induced by Si QDs is depicted in
Fig.13.1.13 Silicon Quantum Dots: From Synthesis to Bioapplications 349

The surface chemistry of Si QDs can modulate their cytotoxicity, nanoparticles
capped with polar molecules being less toxic than QDs with more relative func-
tionalities [ 73]. In addition, our group considered that toxic effects of Si QDs could
be related to the siloxane rings formed through the condensation of silanol groups
which were expected to appear due to the hydroxylation of SiO 2surface consec-
utively to laser ablation synthesis [ 69].
Studies over the past decade have shown that autophagy is part of the biological
effects triggered by different nanoparticles, including QDs [ 69,74], highlighting an
increased expression of LC3-II and ATG7 proteins, and the possibility that
autophagy could be triggered by the oxidized environment created after the
exposure, and not directly by the nanoparticles [ 75]. Induction of autophagy could
be seen as a cellular survival mechanism which allows self-clearance of nanopar-
ticles which were frequently detected in lysosomes upon internalization, although
their biopersistence could cause lysosomal disfunction [ 76]. Moreover, the degree
of cellular uptake QDs might determine the cytotoxic potential.
The in vivo biocompatibility of Si QDs has been previously assessed especially
to provide the con firmation for a future safety use in humans of these nanoparticles
in biomedical applications [ 2,77,78]. The results obtained suggested that systemic
reactions were speci fic to each type of model organism used and cytotoxicity
appeared mostly at higher doses [ 77–83].
In addition, complex investigations were performed on gibel and crucian carp to
establish the effects induced in fish on short and long terms because fish represent
attractive alternative models to mammalian species for the analysis of toxicity
mechanism induced by nanoparticles. Oxidative stress induced in fish liver by Si
QDs was revealed 1-week post-administration [ 80]. Further, the pro file of oxidative
Fig. 13.1 A schematic
representation of the most
important effects induced by
Si QDs350 M.S. Stan et al.

stress markers and of heat shock proteins after 3 weeks post-injection indicated
liver recovery after Si QDs-induced redox imbalance, suggesting that a longerperiod of time was necessary to overcome the harmful effects of QDs [ 81]. Besides
degenerative processes, nephrogenesis was initiated after a week post-injection
which indicated the ability of kidney to regenerate after the Si QDs-induced injury
hallmarked by the increased lipid peroxidation and decreased level of reducedglutathione and of glutathione reductase and glutathione peroxidase activities [ 82].
Interestingly, an effective adaptative response was activated in the white muscle ofgibel fish, and thus the oxidative stress induced by QDs did not cause any per-
manent damage in this tissue [ 83].
13.2.2 Si QDs Internalization and Accumulation
The typical pathway described for in vitro Si QDs uptake was endocytosis as
reviewed by Cheng et al. [ 1]. Differences on the uptake rate were reported between
normal and cancer cells, many more Si nanocrystals being found in the neoplasticcells after the internalization via cholesterol-dependent endocytosis [ 84]. Time
course observations of Si QDs uptake revealed their transport to late endosomes/
lysosomes, the number of internalized nanoparticles increasing with time and
reaching a plateau value [ 69,85]. Consequently, the removal of Si QDs from
endothelial cells was reported via exocytosis, a kinetic model based on the massbalance of QDs and cell receptors being proposed [ 85]. Tu et al. showed a
receptor-mediated accumulation of manganese-doped Si QDs in macrophages dueto the dextran sulfate coating [ 68].
Although blue- and green-emitting Si QDs synthesized by atmospheric plasma
method were visualized manly in the cytoplasm, along with a signi ficant fraction
inside the nucleus of the monocytes [ 2], our group observed the red-emitting Si
QDs obtained by laser ablation only in the cytoplasm of lung fibroblasts [ 69]. These
differences are most probably based on the QDs synthesis method, concentrationand cellular type used in the experiments. Anyway, a concentration-dependentincrease in LDH level and in the number of apoptotic and necrotic cells was noticedin both studies, underling the cytotoxicity of high doses of Si QDs.
Regarding the Si QDs accumulation in animals, studies showed the presence of
high levels in liver and spleen of mice after three months of treatment investigated
by Liu et al. [ 78]. However, these effects were not noticed in monkeys, suggesting
that some systemic reactions could be dependent on the animal model [ 78].
A recent study on zebra fish model revealed a distribution of blue and green
fluorescence of Si QDs mainly in the yolk-sac region, probably due to their
interaction with lipid-rich yolk cells during embryonic development [ 2]. Although
the authors stated that Si QDs induced a low toxicity in zebra fish, abnormalities,
such as yolk-sac edema, head edema, and tail truncation, were observed, possiblydue to a miss-regulation of certain genes, as it was noticed also for silver
nanoparticles [ 2].13 Silicon Quantum Dots: From Synthesis to Bioapplications 351

Furthermore, Tu et al. evaluated the biodistribution in mice of64Cu-DO3A
derivative four labeled dextran-coated Si MnQDs (1% manganese-doped Si QDs) by
in vivo positron emission tomography (PET) imaging [ 77]. The main sites of
accumulation were urinary bladder and liver during the first hour after injection, and
via gamma counting of ex vivo tissues after 48 h PET scan the liver was found to
be the major organ where QDs accumulated. Regarding the nanoparticle excretion,it was demonstrated that the particles smaller than 7 nm are rapidly eliminatedthrough renal filtration, and the larger ones are taken up by the reticuloendothelial
system being excreted into the biliary system [ 77].
Tissue fluorescence microscopy revealed a gradual accumulation of Si QDs in
gibel carp liver during the next 7 days post-injection which induced importanthistological changes in the hepatic tissue [ 80]. Also the presence of Si QDs in the
liver of crucian carp was evidenced after 2 weeks post-administration and signi fi-
cantly disappeared after 3 weeks [ 81]. Regarding the biodistribution of Si QDs in
thefish kidney, a progressive loading of renal tubular epithelial cells with
nanoparticles was noticed along with their accumulation in the macrophages [ 82].
Visualization of Si QDs in the white skeletal muscle of gibel fish showed a
localization pattern in the subsarcolemmal space and inside muscle fibers which
generated degenerative changes [ 83].
13.3 Bioapplications of Si QDs
Their special optical properties make Si QDs a promising material for a large
variety of applications ranging from optoelectronic devices, solar cells, energystorage materials to in vivo imaging labels, therapy, and contrast agents inbioimaging (Fig. 13.2). Due to their large emission in the infrared region are very
useful for deep-tissue penetration [ 11,20,43]. Also, they can be used as photo-
luminescence probes in photodynamic diagnostics and therapy [ 26].
Fig. 13.2 The most important biomedical applications of Si QDs352 M.S. Stan et al.

It was proved that they could be used as drug and gene carriers for different
treatments and imaging agents in magnetic resonance imaging (MRI), ultrasound(US), computed tomography (CT), photoacoustic (PA), and fluorescence imaging.
For these applications, the particles should be nontoxic with increased photosta-
bility and highly resistant to the enzymatic degradation in physiological medium.
Consequently, semiconductor QDs have been successfully demonstrated as in vitroand in vivo imaging probes in the field of medicine because they do not damage
upon continuous light exposure [ 2,45].
Since 2004 when Li and Ruckenstein [ 86] opened the research of Si QDs
fluorescence imaging, several recent reports have illustrated the applicability of
highly luminescent Si QDs as nontoxic in vitro and in vivo bioimaging probes.First, Erogbogbo et al. published in 2008 the preparation of biocompatible
micelle-encapsulated Si QDs used for imaging pancreatic cancer cells [ 63]. Later
on, water dispersible Si QDs of low toxicity coated with Pluronic F127 blockcopolymer were developed by Shen et al. for a long-term real-time observation ofendoplasmic reticulum in live cells [ 64]. Other biocompatible and photostable Si
QDs suitable for long-term imaging of cell nuclei for up to 60 min were describedby Zhong et al. [ 65]. The use of Si QDs synthesized by one-step hydrothermal
method as probes for fluorescent imaging was also illustrated by Wu et al. [ 66].
The excellent photophysical features of Si QDs have permitted the combination
of their surface chemistry with optical microscopy in the context of bioimaging.
Nanocrystalline Si QDs were used in fluorescence lifetime imaging microscopy
(FLIM), which was successfully combined with F örster resonance energy transfer
(FRET) studies where QDs revealed an enhanced performance as biosensors overconventional molecular fluorophores [ 18]. In this case, organic dye acceptors were
conjugated onto the nanoparticle surface and contributed to the color tuning ofnanoparticles [ 18]. Also, an energy transfer micelle platform was created in order to
improve the QD emission yield for biological applications [ 67]. By combining Si
QDs with an anthracene-based dye in the hydrophobic core of 1,2-distearoyl-sn-
glycero-3-phosphoethanolamine- N-[methoxy(polyethylene glycol)-2000] (DSPE-
PEG) micelles the luminescence was enhanced by more than 80% [ 67].
Nanostructured multimodal imaging probes can be achieved by combining the
MRI technique and the optical imaging methods. Although Si QDs do not exhibitparamagnetic properties, the dual character can be obtain through theirco-encapsulation with paramagnetic Fe
3O4nanoparticles in phospholipids [ 87],
being doped with manganese [ 68] or by direct attachment of DOTA-chelated Gd3−to
the PEGylated micelles with hydrophobic Si QDs in their core [ 88], resulting a
prolonged T1 relaxation time for an improved contrast while the fluorescence
intensity was maintained. Also, Tu et al. demonstrated the ef ficiency of64Cu-DO3A
derivative four labeled dextran-coated Si MnQDs (1% manganese-doped Si QDs) as a
new biomedical candidate for in vivo positron emission tomography (PET) imaging[77]. Moreover, luminescent Si QDs functionalized with 2-vinylpyridine were
developed by Klein et al. in 2009 as self-tracking vehicle for siRNA delivery in tumorcells. The biocompatible and water-soluble luminescent Si QDs were internalized by
endocytosis, and the Si QDs-siRNA complexes formed via electrostatic interactions,13 Silicon Quantum Dots: From Synthesis to Bioapplications 353

were internalized by endocytosis [ 89]. Prasad and his team succeeded to encapsulate
Si QDs in Pluronic®block copolymers (PSiQDs). These were water dispersible,
protected against oxidation and aggregation and with preserved optical properties[90]. Their surface modi fication with anti-claudin-4 and anti-mesothelin in order to
target pancreatic cancer cells led to an improved uptake of these nanoconstructs
compared to folate-conjugated PSiQDs, being competitive for tumor targeting incancer applications without exhibiting toxicity. Moreover, the same group of Prasaddeveloped a nanoplatform with both plasmonic and luminescent properties formultimodal imaging by incorporating multiple Si QDs into the core of a micelle anddepositing plasmonic gold on its surface [ 91].
The potential of Si QDs as carriers in drug-delivery systems was evaluated after
their conjugation with alminoprofen, a non-steroid anti-in flammatory drug for
rheumatism [ 92]. The results revealed a lower toxicity of the “silicon drug ”com-
pared to the parental alminoprofen due to a condensed surface integration ofligand/receptor-type drugs which might reduce the adverse interaction between thecells and ligants, and also an enhanced functionality of the anti-in flammatory drug
[92]. In addition, doxorubicin-loaded Si QD aggregates were designed for the
intracellular release of drug in response to endosomal pH decrease [ 85]. Recently, a
drug-delivery system based on amine functionalized Si QDs and covalently conju-gated phototrigger o-nitrobenzyl with caged anticancer drug chlorambucil onto it,
was designed as a photoresponsive theranostic which combines multiple functions
[93]. Besides the nanocarrier role for drug delivery and the controlled drug release
under one- and two-photon excitation, these photoswitchable fluorescent nanopar-
ticles allowed the real-time monitoring of drug release based on the photoinducedelectron transfer process [ 93].
The in vivo imaging using QDs was reported especially for lymph node map-
ping, blood vessel visualization, and tumor targeting. Si QDs with a hydrodynamicsize of 20 nm, injected subcutaneously to mice were observed in the axillary lymph
nodes and a long tumor accumulation time in vivo, without any important adverse
effects which suggest their biocompatibility compared with cadmium containingQDs [ 79]. This opportunity to track the lymphatic flow in real time and to guide the
nodal resection given by the noninvasive fluorescence detection of sentinel lymph
nodes using QDs is very useful.
Recently, Erogbogbo and his coworkers managed to translate the metabolomic
and proteomic data obtained in a human model of cardiac ischemia into a potentialtherapeutic diagnostic (theranostic) containing Si QDs. The fabrication of such
theranostic nanoconstruct represents an important step which should be adopted in
the pathway to a personalized medicine [ 94].
Besides fluorescence imaging and drug-delivery applications, the large variety of
biomedical purposes of Si QDs includes also the regenerative medicine. In this way,the group of Olson has investigated the capability of intravitreal Si QDs to deliverelectrical stimulation to the retinal cells and the effects on retinal electrophysiologyand anatomy [ 95]. The use of Si QDs in the rat model of retinal photoreceptor
degeneration was safe, providing a prolonged cell survival rate and increased354 M.S. Stan et al.

amplitude of the b-wave, mainly in the rod ’s response. This great opportunity of
nanotechnology to deliver electrical stimulation at molecular level should representa priority for future biomedical research on Si QDs to raise the cure rate of variousdiseases.
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Invest Ophthalmol Vis Sci 53:5713 –572113 Silicon Quantum Dots: From Synthesis to Bioapplications 359