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Silicon–polymer hybrid materials

for drug delivery

Silicon and its oxides are widely used in biomaterials research, tissue engineering and drug delivery. These materials
are highly biocompatible, easily surface functionalized, degrade into nontoxic silicic acid and can be processed into
various forms such as micro- and nano-particles, monoliths, membranes and micromachined structures. The large
surface area of porous forms of silicon and silica (up to 1200 m2/g) permits high drug loadings. The degradation
kinetics of silicon- and silica-based materials can be tailored by coating or grafting with polymers. Incorporation of
polymers also improves control over drug-release kinetics. The use of stimuli-responsive polymers has enabled
environmental stimuli-triggered drug release. Simultaneously, silicon microfabrication techniques have facilitated
the development of sophisticated implantable drug-delivery microdevices. This paper reviews the synthesis, novel
properties and biomedical applications of silicon–polymer hybrid materials with particular emphasis on drug delivery.
The biocompatible and bioresorptive properties of mesoporous silica and porous silicon make these materials
attractive candidates for use in biomedical applications. The combination of polymers with silicon-based materials
has generated a large range of novel hybrid materials tailored to applications in localized and systemic drug delivery.

Drug-delivery principles Silicon-based materials for Steven JP McInnes &

Enhanced therapeutic effects have been
observed using controlled drug-delivery sys-
tems in comparison with conventional drug
delivery. Consequently, improving the delivery
of an existing drug is often considered as a com-
mercially viable alternative to the development
of a new drug [1,2] . Controlled drug-delivery
systems enable drug delivery to specific sites
and allow the rate of delivery to be finely tuned,
thereby minimizing toxicity, side effects and
increasing therapeutic benefits (Figure 1) [2–9] .
To sustain the maximum therapeutic benefit
of drugs, a constant sustained-release (zero-
order) profile with little or no burst effect is
usually desired [1,10,11] . However, it is impor-
tant that the release profile is carefully con-
trolled and matched to the application. For
example, wound-healing patches need to be
tailored with a release profile that matches
natural wound healing to fully facilitate long-
term healing and minimize scarring [3] . The
design of new drug-delivery systems should
also focus on extending the therapeutic release
by providing a pulsatile or continuous-release
or, alternatively, exploiting a triggered-release
mechanism [10,12–15] .
The silicon–polymer hybrid materials
reviewed here have useful properties for con-
trolled drug release and are, therefore, attrac-
tive candidates for the development of systems
and devices for drug delivery.
drug delivery Nicolas H Voelcker †
Silicon-based materials are commonly used in †
Author for correspondence
drug delivery for the simple fact that they are The Flinders University of South
relatively bio-inert and degrade into nontoxic Australia, School of Chemistry,
silicic acid (Si[OH]4). Silicon-based materials Physics and Earth Sciences,
are also easily surface functionalized with con- GPO Box 2100, Adelaide,
ventional methods of synthesis. This allows a SA 5001, Australia
wide variety of hybrid materials to be produced Tel.: +61 882 015 338
by the addition of organic or polymeric layers. Fax: +61 882 012 905
There are three main forms of silicon used in E-mail: nico.voelcker@
drug-delivery applications: silica, porous silicon flinders.edu.au
(pSi) and micromachined silicon. Within these
three broad categories exist many possible mor-
phologies, including films, membranes, micro- Porous silicon
and nano-particles and monoliths. A form of the chemical
element silicon containing
Silica
„„ an array or network of
nanoscale pores produced by
Silicon dioxide or silica (SiO2) is composed of electrochemical etching
repeating SiO4 tetrahedrons. The Si-O bond
length is 0.162 nm, smaller than the covalent
radii of the constituent Si and O atoms. This
creates a partial ionic character [16] . Synthetic
silica is generally fabricated by sol–gel chem-
istries using the condensation of Si(OH) 4 and
tetraethyl­orthosilicate (TEOS). The freshly
synthesized silica surface contains a mixture
of surface siloxane bridges, silanediol groups
and silanol groups (Figure 2A–C) , which allow
for further functionalization via silanization,
esterification and other reactions (Figure  2D) .
Sol–gel-synthesized silica nanoparticles can have

10.4155/FMC.09.90 © 2009 Future Science Ltd Future Med. Chem. (2009) 1(6), 1051–1074 ISSN 1756-8919 1051
Review | McInnes & Voelcker
Maximum desired (toxic) drug level
Drug level
Minimum effective
drug level
Figure 1. Drug level in body fluid over time from traditional drug-delivery
methods using multiple doses (solid line) and drug levels in a simple
controlled-release system (dashed line).
Adapted with permission from [9] .
Biocompatibility
The ability of a material to
perform with an appropriate
host response in a
specific application
1052
Therapeutic window
Second dose Third dose
Time
a surface area of up to 1200 m2 /g [10] . Sol–gel-
produced silica can also be processed to create
xerogels and bioactive glass monoliths.
Silica xerogel solids are formed from the dehy-
dration of a SiO2 polymer network and they
usually retain high porosity (25%) and large
surface area (150–900 m 2 /g), along with very
small pore size (1–10 nm). They can also be used
as monoliths [17–19] or as particles [20–22] in both
wet [23] and dry [24–26] forms. These materials
are popular for drug delivery [18,21,24–26] because
release kinetics can be tuned by changing the
sol–gel synthesis parameters, such as the silica
precursor:catalyst ratio [18] , the gelation time [26]
or temperature [19] .
Another type of silica, bioactive glass, is com-
monly composed of CaO and SiO2, but can also
contain P2O5. These materials are able to induce
carbonate hydroxyapatite layer formation on the
surface of the material upon contact with physi-
ological fluids, facilitating bonding to both hard
and soft tissue [27] . Research has been directed
towards the incorporation of growth factors
and proteins that promote cell recognition and
adhesion [28–30] . Bioglasses also feature a range
of porosities and hence surface areas, which is of
interest for controlled drug release. In addition,
exposed hydroxyl groups on the glass surface
are available for chemical functionalization [31] .
Silicon
„„
The most common form of elemental silicon
used for drug-delivery applications is pSi. pSi
is fabricated by anodization of monocrystalline
silicon, typically carried out in hydrofluoric acid
Future Med. Chem. (2009) 1(6)
electrolyte [32] . The chemistry and mechanism of
this electrochemical process has been reviewed
elsewhere [14,33] . pSi has four particularly
attractive qualities for in vivo drug delivery:
n High surface area (up to 800 m 2 /g) [34] ;
n Photonic properties (exploitable for bio­sensing
[35–38] and for self-reporting drug delivery
[33,39] );
n Ability to be processed into membranes and
micro- or nano-particles [40–45] (suitable for
applications including implantation
or injection);
n Degradation into silicic acid in aqueous
environments, such as exist in vivo [46] .
The biocompatibility of pSi has been dem-
onstrated by the attachment and proliferation
of mammalian cells on various pSi structures as
well as by in vivo studies [36,47–50] .
Porous silicon can be functionalized by a
range of chemical reactions including oxidation,
silanization, hydrosilylation and electrografting.
Hydrosilylation of hydride-terminated freshly
etched pSi can be achieved using thermal [51,52] ,
white light [53–55] , Lewis acid [56–58] and micro-
wave-assisted [59] methods. Both cathodic and
anodic electrografting methods have also been
performed on freshly etched pSi and are reviewed
elsewhere [60,61] . The ageing of freshly prepared
pSi under ambient conditions or treatment with
ozone or high temperatures leads to the formation
of silanol (Si-OH) and silicon (di)oxide (SiO2)
A B
O O HO OH
Si Si Si Si
O O
C D
CH3
H3C CH3
Si
H H H
O O O O O
Si Si Si Si Si
O O O
Figure 2. (A) Stable surface siloxane bridges,
(B) silanediol groups, (C) silanol groups that
can be free (isolated) or hydrogen bonded
(vicinal) and (D) silica surface functionalized
with a monoalkoxy silane (left) to create
Si-O-Si bonds and esterified (right) to create
Si-O-C bonds.
Adapted with permission from [16] .
future science group
 Silicon–polymer hybrid materials for drug delivery | Review

Calcination
and template
Surfactant Deposition removal

Template
nanoparticle

Figure 3. Synthesis of porous hollow silica nanoparticles using calcium carbonate

nanoparticles as templates.
Adapted with permission from [87] .

bonds. Other types of oxidations may be per-
formed to stabilize pSi, including chemical [62–
65] , anodic [66,67] and photo-induced [68,69] oxida-
tions. Nitridization of pSi has also been described
[70,71] . The presence of Si-OH groups on oxidized
pSi surfaces allows for the functionalization with
alkoxy- or chloro-silanes. Ambient conditions
and only moderately elevated temperatures are
sufficient for common silanization reactions.
Silanizations can be used to introduce a wide
range of functional groups, including amines,
isocyanates, methacrylate and polyethylene gly-
col (PEG) functionalities. The functionalization
of pSi has been previously reviewed [60,72] .
An additional benefit of pSi-based drug deliv-
ery is that the optical properties of the mate-
rial allow the noninvasive measurement of the
drug-release rate. A self-reporting drug-delivery
system based on pSi particles has been recently
reported in living animal eyes [73] .
Flat (single crystal) silicon lacks the high sur-
face area of pSi, but is a popular model system
for developers of drug-delivery platforms. Flat
Si can be surface-functionalized by silanization
and hydrosilylation in much the same way as pSi.
However, when performing silanization reac-
tions, the silicon wafers must first be cleaned and
activated with piranha solution, which is known
to generate Si-OH groups [74] . On the other hand,
complete removal of the native oxide layer with
HF (to create Si–H surfaces) is required before
as CsOH and KOH. The design of these silicon-
based devices can be as simple as an array of wells
or needles [75] or as complicated as the production
of intricate flaps that control the release of drugs
from polymer-coated reservoirs [76] . During the
design stage of any MEMS device for drug deliv-
ery, there are four major components that should
be considered for inclusion: microreservoirs,
micropumps, valves and sensors [15] .
The three major forms of silicon discussed
above are all easily functionalized with vari-
ous polymer chemistries (e.g., surface-initiated
and surface-tethered polymerization), grafting
techniques and noncovalent depositions (e.g.,
spin- and dip-coating). In this manner, sili-
con–polymer hybrid materials with enhanced
properties for drug delivery can be formed. This
review will focus on the use of these three silicon
forms in three major approaches to drug delivery
with silicon–polymer hybrid materials, including
micro- and nano-particles, monoliths (e.g., films
and membranes) and micromachined devices.
When designing materials for drug delivery,
issues such as structural parameters, release and
biodegradation kinetics and mechanisms, load-
ing capacity and material toxicity must be taken
into account. It is important to note that the
hybrid materials discussed in this paper are novel
and require further testing to fully characterize
their properties. We have endeavored to discuss Microelectromechanical
all relevant data where available. systems

functionalization via hydrosilylation reactions. The integration of mechanical

Due to its simple surface chemistry, wide avail-
ability, ease of ana­lysis and flat morphology,
single crystalline silicon is useful as a testing
platform for many functionalization techniques
that can be applied later to pSi.
Micromachined
„„ silicon
Microelectromechanical systems (MEMSs) are
commonly produced by the micromachining of
complex structures into the surface of single crys-
talline silicon wafers with etching solutions such
Micro- & nano-particles for
drug delivery
„„Mesoporous silica nanomaterials
High surface area silica nanoparticles
(~700–1200 m 2 /g) have been investigated for
their ability to store and release drugs in a con-
trolled manner [10] . These silica nanoparticles
can be used as drug carriers and release platforms
without further surface modification or polym-
erization. However, a lack of functionalization
can lead to uncontrollable payload release [77,78] .
structures with
microelectronics.
Microelectromechanical systems
are custom designed, allowing
mechanical actions to be
controlled by external stimuli
Biodegradation
The capability of decomposition
of a material into innocuous
products by natural biological
activity within the body

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Review | McInnes & Voelcker
A drugs has been published by Chen et al. who
TMOS
Microgel
B wall and also loaded in the inner core of the
Shell cross-linking
Diblock
polymer micelle
Figure 4. (A) Microgel-templated porous silica and (B) core–shell nanoparticles
with a silica shell.
TMOS: Tetramethyl orthosilicate.
Adapted with permission from [97,98] .
Mesoporous silica
Common mesoporous
nanoparticles, such as MCM-41
and SBA-15 contain well-defined
hexagonal pores less than 30 nm
diameter. Applications include
catalysis, drug delivery
and imaging
Controlled release
The release of drugs at
predetermined intervals or
gradually over time, in order to
maintain therapeutic levels
during the treatment period
1054
Calcination
Microgel–silica Porous silica
TMOS
Crosslinked Silica-coated
core–shell micelle micelle
Two of the most widely studied mesoporous
silica materials are Mobil composition of matter
(MCM)-41 and Santa Barbara Amorphous type
material (SBA)-15. MCM-41 was first synthe-
sized in 1992 by the Mobil Inc. corporation and
possesses uniform hexagonal arrays of pores with
pore sizes in the range of 1.5–10 nm [79] . SBA-15
was synthesized 6 years later and possesses the
same ordered pore structure but with larger pores
ranging from 5 to 30 nm [80] . These mesoporous
silica structures are synthesized by condensation
of TEOS around micellar rods used as templates.
Calcination removes the template rods and leaves
particles with a regular pore structure. The use
of mesoporous silica structures in place of solid
particles is advantageous in terms of their loading
capacity, since the drug can attach to the internal
pore volume as well as the external surface. The
presence of an internal structure also serves to pro-
tect the drug from the external environment and
to control the release via capping moieties [81,82] .
Approaches to improve control of drug release
from mesoporous silica have involved varying
synthetic parameters  [83,84] , composition  [85,86] ,
morphology [87–90] , pore size [91] , loading param-
eters [92] or surface chemistry [77,78,93–95] of the
silica nanoparticles.
„„Silica particle morphology &
pore-size modulation
One particularly intriguing example exploiting
morphological changes in silica nanoparticles
to control the release profile of small molecular
Future Med. Chem. (2009) 1(6)
studied the controlled-release behavior of
avermectin (a pesticide) from porous hollow
silica nanoparticles (PHSNs) (Figure  3) [87,90] .
The synthesis was performed via a sol–gel route
using inorganic calcium carbonate nanoparti-
cles as templates. Avermectin was adsorbed on
the external surface, the pore channels in the
PHSN carriers, thus giving rise to a multistage
sustained-release pattern. It was found that the
shell thickness was one of the most important
factors in controlling the release rate: by increas-
ing the shell thickness a more sustained release at
an overall decreased rate ensued [90] . The same
approach has been adapted to release other com-
pounds including Brilliant Blue® and Cefradine®
[89,96] . With appropriate washing procedures,
drugs adsorbed to the outer surface could be
removed and the molecules stored in the pores
and the internal core of the nanoparticles could
be controllably released without a burst effect.
These PHSN carriers could allow for the devel-
opment of new drug-delivery technologies with
variable nanoscale morphologies, which, owing
to their small size (compared with conventional
drug carriers), hold promise for transmucosal
and systemic drug-delivery applications [89] .
Silica–polymer
„„ hybrids
To improve the release kinetics and inherent
properties of silica particles, research has focused
on the creation of silica–polymer hybrid mate-
rials. For example, Zhou et  al. used cationic
microgels to template the deposition of silica
from tetramethyl orthosilicate (TMOS) precur-
sors (Figure 4A) [97] . The hybrid nanoparticles
described possessed tunable porosities and iso-
electric points that could be varied depending on
the TMOS concentration. This may allow for
the controlled delivery of biomolecules such as
DNA. On a similar theme, Yuan et al. synthesized
silica nanoparticles with cationic coronas and
hydrophobic polymer cores [98] . They employed
diblock copolymers of poly(2-[dimethylamino]
ethylmethacrylate)-co-(2-[diisopropylamino]
ethylmethacrylate) to template the hydrolysis
of TMOS (Figure 4B) in the hydrophilic coro-
nas. This produced silica nanoparticles with a
diameter of 35 nm and well-defined core–shell
morphology. Silica deposition effectively cross-
linked the polymeric nanoparticles, leading to
an increased stability at pH 2 (where the non-
crosslinked polymeric nanoparticles would com-
pletely dissociate). This technique has currently
future science group

not been used for drug-delivery tests; however,
one could envisage the biphasic release of both
hydrophobic and hydrophilic drugs from these
nanoparticle preparations.
A system that has been tested for its drug-
delivery properties was synthesized by Huo et al.
The authors used F127 micelles of ethylene
oxide and propylene oxide (EO106 -PO70-EO106)
to template TEOS hydrolysis to form core–shell
nanoparticles [81] . These particles showed signifi-
cantly slower release rates and increased loading
capacities compared with noncrosslinked F127
surfactant micelles with papaverine (basic),
nabumetone (neutral) and naproxen (acidic)
loadings. This system showed almost zero-order
release kinetics. In general, silica crosslinked
nanoparticles retain the biocompatibility of the
original micelles [99] , but are much more stable
and do not break down upon dilution, mak-
ing them excellent candidates for drug-delivery
applications. The particles also show reduced
diffusion of drugs due to the presence of the
silica shell; they have physiochemical proper-
ties that can be tuned by changing the synthe-
sis parameters and a surface chemistry that is
tailorable by one-pot and postfunctionalization
techniques. Due to the hydrophobic core, hydro-
philic and hydrophobic drugs can both be loaded
and delivered.
„„Silica coatings on polymeric nanoparticles
Silica nanoparticles are able to self-assemble to
form a coating on polymeric microparticles.
Prestidge et al. coated micron-sized polydimeth-
ylsiloxane (PDMS) emulsion droplets,
A 100
Cumulative drug release (wt%)
80
60
40
20
50 µm
0 0
0 10
Figure 5. (A) Gentamicin release from SiO2–poly(dl-lactide-co-glycolide)-encapsulated single- and (B) double-layered silica xerogel
microspheres. Insets show representative scanning electron microscopy images of encapsulated microspheres.
Adapted with permission from [20] .
future science group
Silicon–polymer hybrid materials for drug delivery | Review
encapsulating dibutylphtalate with both hydro-
phobic and hydrophilic silica nanoparticles
[100,101] . The resulting microparticles featured
silica multilayers, the architecture of which was
controlled by nanoparticle properties and elec-
trolyte concentration. The layered microstruc-
ture, its thickness and hydrophobicity deter-
mined the drug-release rate from the PDMS
droplets. Colloidal and spray-drying approaches
may also be used to coat polymeric micropar-
ticles [102] . Such preparations have been shown
to have good gastric resistance (minimal release
at pH 2) and subsequent release at neutral pH,
making them suitable for the oral delivery of
drugs requiring release in the lower digestive sys-
tem. Engineering of the silica nanoparticle layer
offers a wide range of possible release profiles and
has the potential to help enhance the delivery of
relatively insoluble drugs.
Polymer
„„ coatings on silica nanoparticles
The inverse architecture, polymeric multilay-
ers coated on silica microparticles, has also
been reported with a view to exploiting con-
trolled drug delivery. These structures can be
created via layer-by-layer (LBL) techniques or
encapsulation.
The encapsulation of SiO2 xerogel particles
has also been performed by Xue et  al. SiO2-
poly(dl-lactide-co-glycolide) (PLGA) single
and double layered microspheres (Figure 5) were
formed via solvent evaporation [20] . The thus-
formed microspheres allowed the controlled
release of the antibiotic gentamicin. The release
pattern from these composites included a 1-day
B 80
Cumulative drug release (wt%)
60
40
20
10wt% xerogel loading
20wt% xerogel loading 50 µm
20 30 40 50 0 10 20 30 40 50 60
Time (days) Time (days)
www.future-science.com 1055
Review | McInnes & Voelcker
The LBL deposition of poly(diallylmethyl­
+ +
+ +
ammonium chloride) and poly(sodium 4-sty-
- renesulfonate) on the surface of negatively
+ + -
- - charged silica microparticles allows stable poly-
+ + electrolyte films to be formed (Figure  7) [104] .
PAA Release
+ + coating at pH 7 Such a coating could obviate the need for the
+ + SiO2 to encapsulate the drug.
Stimuli-responsive LBL coatings have also
been described as a capping layer on drug-loaded
BSA-loaded SBA-15 PPA-coated PAA and BSA
BSA-loaded SBA-15 release from SBA-15 hollow mesoporous silica spheres, incorporating
ibuprofen. These structures allowed loading up
Figure 6. Electrostatic coating of SBA-15 microparticles containing BSA to threefold higher than uncoated controls. The
with PAA. The system is stable at low pH and unstable at high pH, preventing release of the stored ibuprofen could be stimu-
drug release in the stomach, but facilitating release in the intestine. lated by changing the environmental pH or the
BSA: Bovine serum albumin; PAA: Poly(acrylic acid); SBA: Santa Barbara amorphous. salt concentration [105] .
Adapted with permission from [103] .
Other stimuli-responsive drug-delivery sys-
tems typically rely on poly(N-isopropylacryl-
initial burst of less than 10%, followed by three amide) (PNIPAAm), which is thermosensitive
Stimuli responsiveness
sustained-release phases. The first sustained- and switches from a hydrophilic to a hydropho-
A physicochemical change in a release stage was attributed to the erosion of bic state above the lower critical solution temper-
material (e.g., color or
wettability) upon introduction the outer PLGA layer, the second stage was ature (LCST) of approximately 30–35°C [106] .
of environmental stimuli such as attributed to the erosion of the inner PLGA Silica can be functionalized with PNIPAAm via
pH and temperature layer and the last release phase was attributed surface-initiated polymerization from surface-
to the release of the gentamicin from the xero- bound atom transfer radical polymerization
Surface-initiated gel. Release was sustained for approximately (ATRP) initiators, such as 3-trimethoxysilylpro-
polymerization 9 weeks. By contrast, single-layered PLGA com- pyl methacrylate [107] and surface-bound 2-bro-
A polymerization technique that posites showed a 50% burst release in the first mopropionyl bromide [108,109] . Nanoparticles
allows for the direct growth of day followed by 6 weeks of slow release. possessing photoluminescence (from CdTe),
polymer chains from surface-
bound initiators In order to model protein drug delivery, Song thermosensitivity (from PNIPAAm) and mag-
et al. loaded bovine serum albumin (BSA) into netism (from Fe3O4) have been demonstrated
amino-modified SBA-15 and then encapsulated to deliver water-soluble, photosensitizing drugs
the microparticle, via electrostatic assembly, for photodynamic therapy [106] . Nanoparticles
with poly(acrylic acid) (PAA) (Figure  6) [103] . were taken up by cells below the LCST and the
This imparted stability to the system at low pH drug was successfully released into the cyto-
(uncharged carboxylic acid side-chains allow plasm upon switching to 37°C. Bikram et al.
PAA to contract on the SBA) and instability created silica–gold nanoparticles embedded with
at neutral pH (carboxylic acid side-chains are poly(N-isopropylacrylamide-co-acrylamide)
charged, causing the PAA to swell and dissociate hydrogels that could slowly release the drug in a
from the SBA). The authors propose that this manner dependent on its molecular weight or be
technique could be used to enhance the deliv- switched when heated by means of laser irradia-
ery of peptide and protein drugs into the lower tion to induce complete release [110] . The devel-
digestive tract, where the pH is close to neutral. opment of these stimulated-release systems will

Cationic Anionic
polymer polymer Multiple
- - deposition - - deposition - - depositions - -
- - - - - - - -
- - - - - - - -
- - - - - - - -
- - - - - - - -
- - - - - - - -

Silica nanoparticle Polyelectrolyte-coated

silica nanoparticle

Figure 7. Layer-by-layer deposition of polyelectrolytes on silica particles.

Adapted with permission from [104] .

1056 Future Med. Chem. (2009) 1(6) future science group


prove important for future drug-delivery appli-
cations. The main advantage of these stimuli-
responsive systems is the ability to switch from
a passive release of drugs to an accelerated one
upon application of stimuli. Release rates can be
tuned by variations in the polymer composition,
loading technique and the stimulation condi-
tions. The use of external stimuli such as heat,
magnetism or light to induce drug release could
lead to the creation of drug-delivery devices that
can be surgically implanted subcutaneously and
activated by the patient when required, eliminat-
ing the need for multiple injections or frequent
medical consultations.
Particle encapsulation is a simple yet powerful
technique to prepare silicon–polymer hybrids
for drug delivery. The encapsulation can be per-
formed by electrostatic or physiosorption tech-
niques and the drug-release rates can be tuned by
the addition of multiple polymeric layers.
Monoliths, films & membranes
„„ Bioglasses & xerogels
Unmodified bioglasses (or bioactive glasses) have
been investigated for their ability to store and
release drugs in a controlled manner [111,112] . One
of the most interesting recent examples of drug
delivery from bioglasses is the incorporation of
mesoporous silica (SBA-15) by precipitation into
a bioactive glass–ceramic (SiO2-CaO-K 2O) scaf-
fold. This material combines the biocompatibil-
ity of the bioglass and the drug-release properties
of the SBA-15 [113] , and could find applications
as an implantable sustained-release device for the
therapy of bone diseases or for bone regeneration
after trauma.
To further improve the properties of these
bioglasses, they can be combined with poly-
mers. Bioglasses, of the general form SiO2-
CaO-P2O5, have been combined with polymers
to improve their properties. Ladron de Guevara-
Fernandez et al. prepared bioactive glass by the
hydrolysis and polycondensation of TEOS,
triethylphosphate and calcium nitrate tetrahy-
drate, followed by the free radical polymeriza-
tion of a mixture of poly(l-lactic acid) (PLA),
poly(methylmethacrylate) (PMMA) and meth-
ylmethacrylate [114] . They found that ibuprofen
release (incorporated during the polymerization
stage) lasted for approximately 3 weeks and that
the composites were still bioactive and able to
induce the formation of an apatite layer in SBF.
Bioactive glasses coated with poly(vinyl alcohol)
have also been shown to induce the formation
of apatite layers. Degradation of the composite
future science group
Silicon–polymer hybrid materials for drug delivery | Review
could be controlled by addition of more P2O5 or
poly(vinyl alcohol), which decreases the surface
area and porosity, in principle allowing tunabil-
ity of drug release [115] . These silicon–polymer
hybrid systems could be used as nonload-bear-
ing bone defect fillers and control the release of
small-molecule drugs, such as ibuprofen, to the
surrounding bone tissue, in order to suppress
tissue inflammation. There is potential to incor-
porate a wider range of drugs into polymer-mod-
ified bioglass monoliths to stimulate bone regen-
eration, including drugs such as bisphosphonates
and platinum anti-tumor compounds [24,116] .
The incorporation and release of drugs and
biomolecules such as the antibiotic vancomy-
cin  [21] , the anticancer drug doxorubicin [25] ,
novel platinum compounds [24] and larger
molecules such as heparin [18] have already
been studied from unmodified silica xerogels.
However, the drug-release rate from silica xero-
gel monoliths can be tuned by the addition
of biocompatible polymers such PEG [17,19,22] ,
PDMS [17] or PLGA [20] . Addition of PEG to the
sol–gel mix during preparation of silica xerogels
was shown to increase the drug-release rate in
general, owing to the increased hydrophylic-
ity of the network  [19] . Pegylation of silicon-
based materials also helps avoid rapid degrada-
tion or clearance as well as evade the immune
response  [22,117–122] . Pegylation and associated
advantages gained for biomedical applications
have been reviewed extensively and will not be
discussed further [122,123] .
Similar work has indicated that the release
rate is controlled by diffusion from the porous
structure [22] . Czarnobaj et al. have also used
more hydrophobic SiO2-PDMS xerogels to slow
the release of cisplatin [17] . It was found that, for
PDMS-containing xerogels, drug release is by
diffusion only, while the PEG-containing xero-
gel releases drugs via a combination of diffusion,
erosion and swelling of the composite materi-
als. Silica xerogels require only mild synthesis
conditions, which allows for the presynthesis
incorporation of drugs, creating homogeneous
drug distributions within the composite mate-
rial, not only in the pores as per postsynthesis
loading. This direct incorporation of the drug
into the matrix also acts to protect the drug from
premature in vivo degradation, often encoun-
tered with the systemic administration of drugs.
Other advantages include the nontoxicity, hard-
ness and tunable porosity of the composites.
There is certainly also the potential to convert
the monolithic structures into microparticles.
www.future-science.com 1057
Review | McInnes & Voelcker
Polymeric monoliths can also be produced
by casting techniques. Casting involves the use
of a preshaped mould into which a polymeric
solution can be poured and then dried to form
the required monolithic structure; subsequently,
smaller monoliths can also be cut from larger
structures if required. One such example was
demonstrated by Lin et  al. who synthesized
PMMA–silica composites via a sol–gel approach
followed by casting with acetylsalicylic acid
(aspirin) into a Teflon dish [124] . This approach
resulted in a monolith composed primarily of
polymer with interdispersed silica micropar-
ticles. This method still allows for the release
rate to be tuned, in this case by the addition of
a higher percentage of 3-(trimethoxysilyl) pro-
pylmethacrylate into the PMMA component,
causing more polymer to be attached to the silica
and slowing the release rate of the incorporated
aspirin. The amount of drug released could be
controlled by the percentage of silica in the com-
posite. This allowed for the generation of tunable
drug-release materials that have demonstrated
aspirin release for up to 90 days. Biopolymer-
coated bioactive glass has also been incorporated
into a collagen monolith and used as a growth
factor-delivery device. Bergeron et al. cast bio-
active glass microspheres (incorporating bone
morphogenic proteins) into a collagen gel. The
authors demonstrated the release of bone mor-
phogenic proteins to MC3T3-E1 cells and pro-
posed that this system could be used for bone
regeneration [125] .
The monolith structures described can be
used to create implantable devices that will
release their payload as they degrade in  vivo.
The ability to tune these monoliths via the addi-
tion of various polymeric components or surface
polymerization has led to the development of
structures that can potentially be used as bone
defect fillers or implantable devices for the con-
trolled release of incorporated drugs. The abil-
ity of the xerogels to incorporate drugs during
one-pot synthesis is of great importance to the
development of homogeneous matrices that will
release drugs at a constant predetermined rate.
„„LBL deposition on flat silicon
Commonly, silicon is used as a base material
to deposit multilayered structures for funda-
mental studies of drug release. Silicon is one
of the most favored substrates as it is flat, eas-
ily functionalized and primed for LBL coating
and, most importantly, it is amenable for sur-
face ana­lysis. An example is the work of Peng
1058 Future Med. Chem. (2009) 1(6)
et al. who coated silicon wafers with alginate/
chitosan via spin coating [126] . Here, the release
of fluorescent biomolecules was monitored in
both phosphate-buffered saline and simulated
body fluid. A substantial burst release of over
50% of the loaded molecules occurred within
the first 20 min. Release was then sustained over
the next 26 days. The release rate could be tuned
by increasing the thickness of the multilayer
stack or by variation of the molecular weight
of the release molecule. Peng et al. argue that
these thin coatings could prove useful in appli-
cations such as wound healing, which requires a
large burst of the drug in the first few hours fol-
lowed by a slow, but sustained, release. Likewise,
multilayered imine crosslinked poly(allylamine
hydrochloride)-dextran and poly(styrene sul-
fonate) polyelectrolyte microgels fabricated via
alternating dip coating on silicon wafers have
been shown to be capable of storing and releas-
ing model drug entities [127] . Furthermore, due
to the crosslinked nature of the structures, they
were found to be robust enough to be reloaded
and reused for multiple drug-delivery cycles.
Another example of a crosslinked LBL multi-
layered film for the controlled release of DNA
utilized the formaldehyde-induced crosslink-
ing of single-stranded DNA and BSA on sili-
con wafers [128] . The resulting film was stable
and the amount of single-stranded DNA and
BSA could be tailored by the simple addition
or removal of more layers. The formation of
this multilayered stack was not controlled by
electrostatic interactions and, subsequently, the
layer dissolution could be performed by the
addition of proteinase K, allowing the amount
of DNA released to be tuned by limiting the
proteinase incubation time. The development
of systems such as this could lead to films that
are more stable and provide greater control over
the release of biomolecules when compared with
electrostatically constructed LBL systems.
Vazquez et al. were the first to report a LBL
layer system deposited on silicon that was con-
structed from specially synthesized poly(b-
amino esters) (cationic) and calf thymus DNA
(anionic) layers on silicon surfaces [129] . This sys-
tem was able to release DNA via the slow erosion
of the LBL assembly under physiological condi-
tions. Since then, much work with this multi-
layer approach has been performed [130–132] . It
has been found that the released DNA is able
to transfect mammalian cells and promote
the expression of proteins [130] . This leads to
many possible applications in gene transfer. For
future science group
 Silicon–polymer hybrid materials for drug delivery | Review

Table 1. Polymers with potential application to silicon- and silica-based drug-delivery composites.
Polymer Useful properties Ref.
Poly(7-allyloxycoumarin) Photodimerization (with drugs or interchain) [138]
Poly(vinylbenzylthymine) Photodimerization (with drugs or interchain) [139]
Poly(ethyleneimine)-co-poloxamer diacrylate High transfection efficiency, good DNA binding, low cytotoxicity [140,141]
or
poly(ethyleneimine)-co-glycerol
dimethacrylate
Poly(N-isopropylacrylamide)-co-(4- Temperature and pH sensitive, fluorescent [142]
vinylpyridine)-co-(N-
pyrenemethylacrylamide)
High-molecular-weight polyethylene glycols Easily modified, reductively cleavable S-S bonds, hydrolytically degradable, [143]
modified with cysteine bonding to drugs, proteins and DNA
Poly(glycerol-adipate) Nontoxic, biological monomer, low cytotoxicity, high drug loading [144]
Poly(pyridyldisulfide ethylmethacrylate) Multifunctional (able to bind DNA, proteins and sulfur-containing compounds), [145]
variable physicochemical properties
Crosslinked acid liable poly(acrylamide) pH-stimulated release, protection from nuclease degradation [146]

example, in coatings for biomedical devices such
as intravascular stents, the coating could locally
release gene-based therapeutics for cardiovascu-
lar disease [131] . In these works, the time for com-
plete drug release was between 30 and 100 h,
however these release times could be tuned by
introducing variations in the layer thickness and
number of bilayers used. Zhang et al. have also
released antisense DNA oligonucleotide strands
from phosphorylcholine-containing polymer
films on flat silicon wafers [133] . Oligonucleotide
loading increased with increasing film thick-
ness and also when the charge density of the
cationic side chains increased. The film sus-
tained the release of oligonucleotides for 8 days.
Released oligonucleotides were able to enter
vascular smooth muscle cells. LBL assemblies
have been tuned to do more than just release
functional DNA. These multilayered structures
are able to infer protein resistance to surfaces, or,
if coated with a top layer such as PLL-g–PEG/
PEG–biotin, they are able to selectively bind
streptavidin-bound proteins [134] . Polyelectrolyte
LBL-deposited films on silicon have also been
used to deliver therapeutic polysaccharides [7]
and gentamicin [135] .
stack size to allow higher loading can lead to
the retardation of drug diffusion from the film.
Other issues include the inability to release drugs
under physiological conditions and the need to
modify some substrates before deposition [127] .
However, the LBL deposition of polymers onto
surfaces such as silicon has many advantages,
including the high number of polymers available
as well as the composition and stack-size of the
polyelectrolyte films. The ability to coat compli-
cated structures and to store and release a wide
range of compounds, including nanoparticles,
still makes these systems exciting candidates for
use in drug-delivery applications.
Polymer
„„ grafting on flat silicon
The grafting of polymers to surfaces can be
performed via ‘grafting-to’ or ‘grafting-from’
polymerization techniques. The ‘grafting-to’
method uses prepolymerized macromolecules
(commonly biomolecules) with functional
end-groups to react with complementary func-
tional groups residing on the surface; whereas
the ‘grafting-from’ approach uses surface-
bound monomer (surface-tethered polym- Surface-tethered
erization) or initiator groups (surface-initi- polymerization

Although LBL films on silicon are themselves
unlikely to find applications in in vivo drug deliv-
ery, they are widely studied as model coatings,
with the aim to transfer the optimized coatings
to more relevant substrates such as intravascular
Ti stents [131] . There are some issues involved
with the use of LBL systems for drug release,
the most notable being the inability of the films
to load large quantities of drugs. Poor loading
is usually caused by the ionic nature of the mul-
tilayered stack; however, simply increasing the
ated polymerization) as anchor points for the A polymerization technique that
allows the tethering of growing
polymerization process.
polymer chains to surface-
This type of surface ‘grafting-from’ approach bound monomer groups
has been used by Cole et al. to covalently link
PNIPAAm to flat silicon [107] . These surfaces
were anchored via the use of a methacrylate-
terminated silane, followed by the free radi-
cal polymerization of N-isopropylacrylamide
(NIPAAm), tethering the resulting polymer
chains to the surface. The resulting coatings
were protein-binding above the LCST and

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Review | McInnes & Voelcker

Table 2. Polymers that have been covalently attached to silicon, silica and pSi (since 2007).
Polymerization Polymer Surface Switchable? Ref.
technique (stimulus)
ATRP Poly(2-hydroxyethyl methacrylate) Silica and silicon No [147,148]

Poly(styrene) Silica and silicon No [149,150]

Poly(4-[10-methacryloydecyloxy]-4´-pentylazobenzene) Silicon Yes [151,152]
(light)
Poly(methyl methacrylate) Silica No [150]
Poly(methyl methacrylate) pSi No [153]
Poly(N-isopropylacrylamide) (PNIPAAm) SiO2 nanoparticles Yes [109]
(temperature)
Polyacrylamide (PAAm) Silicon No [154]
Poly(ethyleneglycol methacrylate) Silicon No [155–157]
Poly(1-[4-vinylbenzyl]-3-butylimidazolium hexafluorophosphate) Silicon Yes (counter- [158]
anions)
Poly(2-[dimethylamino] ethylmethacrylate) Silicon No [159]
Co-polymer preparations Silicon No [160–162]
Poly(butylmethacrylate)-co-(boc-aminoethyl methacrylate)
Poly(butyl methacrylate)-co-2,2-dimethylaminoethyl methacrylate)
Poly(styrene)-b-(acrylic acid)
‘Grafting-to’ Poly(glycidyl methacrylate) and aromatic aliphatic Silicon No [163,164]
hyperbranched polyester
Poly(glycidyl methacrylate) Silicon No [163,164]
Poly(methyl methacrylate) Silicon No [165,166]
Poly(ethylene glycol) Silicon No [165–168]
Poly(N-isopropylacrylamide) pSi Yes [169]
(temperature)
Poly(acrylamide) and poly(2-vinylpyridine) Silicon Yes [170]
(pH)
Poly(tert-butyl acrylate) Silicon No [171]
RAFT Poly(methyl methacrylate) Silicon No [172,173]
Poly(styrene) and poly(butyl acrylate) Silicon No [174]
Poly(styrene), poly(styrene)-b-acrylic acid), poly(styrene)-b- Silicon Yes [175]
(N-isopropylacrylamide) and poly(methyl methacrylate)-b-poly (solvent)
(N,N-(dimethylamino)ethylacrylate)
Free radical Poly(N-isopropylacrylamide) Silicon Yes [107,176]
(temperature)
Poly(N-isopropylacrylamide)-co-poly(acrylic acid) Silicon Yes [130]
(temperature)
Nitroxide-mediated Poly(styrene) Silicon No [177]
Poly(styrene) and poly(acrylate) SiO2 No [178]
ROMP Poly(spiropyan) Silicon No [179]
ROP Poly(l-lactide) pSi No [32]
Electrografting Poly(acrylic acid) Silicon No [180]
Poly(nitrophenylene) Silicon No [181]
ATRP: Atom-transfer radical polymerization; pSi: Porous silicon; RAFT: Reversible addition–fragmentation chain transfer; ROMP: Ring-opening metathesis
polymerization; ROP: Ring-opening polymerization.

resisted protein adsorption below the LCST.
PNIPAAm surfaces have also been used by
Tsukagoshi et al. to load and release aspirin [8] .
At temperatures above the LCST, the release
of aspirin was much slower due to the polymer
chains in the collapsed state entrapping the aspi-
rin molecules. Kurkuri et al. prepared copolymer
coatings of PNIPAAm and PAAc to reversibly
bind fluorescein isothiocyanate (FITC)-labeled
BSA [136] . In this case, the polymer network was
crosslinked with N,N´-methylenebisacrylamide
and the maximum switching of the hydrogel,
in terms of wettability, occurred at a monomer
ratio of 36:1 PNIPAAm:PAAc. LeMieux et al.

1060 Future Med. Chem. (2009) 1(6) future science group


have incorporated an additional hydrophobic
layer of poly(butyl acrylate) over the PNIPAAm
layer [137] . This poly(butyl acrylate) layer could
be used to control premature drug release from
the composite until the PNIPAAm layer is
switched. The authors found that the distance
of poly(butyl acrylate) from the surface could
be changed from 17 to 34 nm upon switching
of the underlying PNIPAAm layer (Figure 8) . It
is conceivable that the aforementioned proof-of-
principle studies will soon lead to commercial
temperature-switchable drug-delivery devices.
Novel monomers are also being constantly
designed and incorporated into drug-delivery
systems. Table 1 contains examples of polymers
that have interesting properties and have not
yet been applied to porous scaffolds and should
be considered when designing new materials
for biomedical devices [138–146] . Table 2 shows a
list of polymers and polymerization techniques,
which have been applied to silicon, silica and pSi
since 2007 [32,107,109,136,147–181] .
Biopolymer
„„ grafting on flat silicon
Just as synthetic polymers can be grafted onto
silicon, biopolymers (e.g., peptides and oligo-
nucleotides) can also be used as the polymer
for surface modification, however they are
commonly attached via ‘grafting-to’ methods,
for example, the immobilization of DNA onto
undecylenic acid-patterned silicon surfaces was
performed by Voicu et al. as early as 2004 [182] .
This coupling required activation of the surface
COOH groups with N-hydroxysuccinimide and
then a subsequent reaction with an amine-termi-
nated DNA strand. Böcking et al. have also used
epoxide groups to immobilize thiol-terminated
DNA [183] . Similarly, Hone et al. have conju-
gated proteins to silicon surfaces functionalized
by hydrosilylation with undecenylaldehyde [184] .
Click chemistry has also been used to covalently
bind trypsin into mesoporous silica [185] . To
improve the density of the biopolymer chains, a
few groups have examined the grafting of DNA
[43,186] and peptides [187,188] from the surface with
conventional solid-phase synthesis protocols.
However, the design of linker chemistry that is
cleavable under physiological conditions in order
to release bioactive biopolymers has not come
to fruition.
The modification of surfaces with biomol-
ecules such as peptides and DNA can also
be performed by means of polymeric spacers
between the silicon and the biomolecule, spe-
cifically designed for the purpose of attaining
future science group
Silicon–polymer hybrid materials for drug delivery | Review
Temperature 34 nm
change
PBA
17 nm
PNIPAAm
Silicon
50°C PNIPAAm 10°C PNIPAAm
compressed state expanded state
Figure 8. PNIPAAm (light region) and hydrophobic PBA (dark region) on a
flat silicon substrate. The poly(N-isopropylacrylamide) layer can exist in the
contracted or expanded state depending on the temperature.
PBA: Poly(butyl acrylate); PNIPAAm: Poly(N-isopropylacrylamide).
Adapted with permission from [137] .
high biopolymer binding. Popular in this con-
text are NHS-modified monomers, which can
be conjugated to any amine-presenting biomol-
ecule. NHS-containing polymers have been
applied to silicon surfaces via spin coating [189] ,
surface-initiated ATRP [190] and polymeric self-
assembled monolayers [191] , and to silica via oxi-
dative polymerization [192] . The surface-initiated
ATRP of PAA on silicon surfaces has also been
used to generate a high loading surface for any
NH2-containing biomolecules (Figure 9) , again
via NHS-mediated amide bond formation [193] .
Recent research in this area has also exploited
click chemistry [194,195] to immobilize biomol-
ecules on silicon functionalized with a polymeric
self-assembled monolayer-containing terminal
alkyne groups. However, this method requires
the biomolecule to be azido-functionalized prior
to forming the self-assembled monolayer [196] .
Burnham et al. have grafted hydrogels on silicon
surfaces containing a disulfide crosslinker, which
can be reduced to generate reactive sulfhydryl
groups suitable for biomolecule conjugation [197] .
This approach also allowed the authors to pat-
tern multiple biomolecules onto the hydrogel
surface via microcontact printing techniques.
Potentially, biomolecules attached to the
hydrogel via disulfide bonds could be released
when exposed to a reducing environment inside
the body.
Flat crystalline silicon is not considered a bio-
degradable or bioresorbable material due to its
stability in bodily fluids. The surface is passivated
and therefore hydrolyzes very slowly, at time-
scales not relevant to drug delivery and other
biomedical applications. However, the behavior
of crystalline silicon can be tuned from rela-
tively bioinert to bioactive and even bioresorb-
able by the introduction of porosity [34,198] . The
introduction of porosity or micro­structuring of
www.future-science.com 1061
Review | McInnes & Voelcker
crystalline silicon increases the low surface area
and assists in improving drug loadings [10,41,199] .
Devices made from polymer and flat silicon
hybrid materials would need to be surgically
retrieved after drug release. Postsurgical removal
of the device is not desirable. The development
of drug-delivery devices composed of only biore-
sorbable materials would enable the device to
automatically be eliminated by the body upon
degradation in  vivo. For these reasons, there
needs to be scope to transfer the polymer coat-
ings developed on flat silicon to more biodegrad-
able scaffolds, such as mesoporous silica and pSi
films and microparticles [32,200] .
„„Porous silicon
There are many examples of the release of drugs
from polymer-free pSi scaffolds [42,201,202] .
However, in order to improve control over the
release behavior of drugs from pSi scaffolds,
polymeric functionalization is currently being
investigated. Some of the most interesting and
novel developments in recent years include the
work of Batra et  al., who have covered dye-
loaded pSi substrates via repetitive coating with
a poly(e-caprolactone) (PCL) layer of varying
thickness [203] . The PCL layer slowed down the
release rate of the dyes as well as lowering the
equilibrium amount of the dye released. The
release rate could be controlled by tailoring the
thickness of the PCL layer. Similarly, Coffer
et al. have formed composites of high-porosity
pSi particles and PCL to create scaffolds that
are highly biocompatible and could potentially
Br ONa Br O N
Br O O
O O O O
O O O O
ONa EDC, NHS
CuBr, CuBr2, H2O,
2,2´-bipyridine, rt
Si Si Si
Surface silanization Surface-initiated ATRP NHS activation
of sodium acrylate
Figure 9. Grafting of biomolecules to the activated carboxyl groups of surface-initiated poly(acrylic acid) chains.
ATRP: Atom transfer radical polymerization.
Adapted with permission from [193] .
1062 Future Med. Chem. (2009) 1(6)
be used for the sustained release of drugs [204] .
Demonstrating increased control over drug
release, Wu and Sailor prepared a pSi scaffold
containing a crosslinked chitosan–hydrogel cap-
ping layer. The insulin release was stimulated by
immersion in buffer at pH 6, avoiding the burst
release observed for uncapped pSi [205] .
Koh et  al. investigated composites of pho-
tonic pSi films and polymers as a smart patch
that allows for the delivery of drugs to be moni-
tored in real-time [39] . The reflectance peak of the
photonic material (Distributed Bragg Reflector
[DBR]) can be tuned to a wavelength spanning
the visible spectrum by varying the layer thick-
ness and the refractive index contrast. In particu-
lar, reflection peaks in the region of low optical
absorption for human tissue (500–600 nm in
this case) will allow the smart-patch DBR to be
monitored in vivo. The free-standing pSi DBR
was cast in a PMMA solution containing the
drug to be released. The resulting composite
was approximately 140 µm thick, flexible and
chemically robust. Release of caffeine from the
smart patch was monitored in vitro by UV–Vis
and changes in the reflection peak. The caffeine
release could be controlled by varying the num-
ber of etching repeats used to create the initial
DBR. The porous structure of pSi can also be
transferred to polymers via the use of templating
techniques. Polymer infusion and subsequent pSi
dissolution allows for the creation of porous poly-
meric materials that retain photonic properties of
the pSi and allow for monitoring of drug release
or scaffold dissolution [206,207] . These polymer
H
Br N
( )n
O O
O
NH2
Si
Binding of NH2-containing
biomolecule
future science group
 Silicon–polymer hybrid materials for drug delivery | Review
replicas of pSi can also be formed into micropar- earliest examples was demonstrated by Yoon
ticles via the use of microdroplet patterning [208] et al., who impregnated a fresh pSi membrane
and bead patterning [209] . Structures such as with a ring-opening metathesis precursor and
these can be made from biocompatible and bio- subsequently crosslinked the pSi scaffold with
degradable polymers and could allow for high poly(norbornene), generating a composite
drug loading and, at the same time, self-reporting material that was chemically and mechanically
drug release. very stable [212] . Recently, ATRP has also been
The Sailor group produced a thermo­ used for the surface grafting of polymers such
responsive pSi–PNIPAAm composite by polym- as PMMA [153] . The resulting composites have
erizing a NIPAAm hydrogel into the pores of been studied to determine the effect the porosity
pSi [210] . The temperature-dependent swelling exerts on the molecular weight and polydisper-
of the polymer led to refractive index changes sity during the surface-initiated polymerization.
that were monitored by interferometric reflec- These composites have not yet been studied for
tance spectroscopy. It is conceivable that this their ability to store and release drugs; however,
composite material is infused with drugs and we feel that the expansion of these surface-
used for controlled release triggered by a tem- initiated polymerization techniques with new
perature change that is sustained for a certain polymers, such as those listed in Table 1, could
time period. This could potentially give greater lead to the creation of composites with new and
control over the release of drugs, particularly if interesting properties for applications such as
multiple delivery cycles are required. Mukherjee drug delivery and tissue engineering.
et al. prepared drug-loaded blocks of various
shapes and sizes, approximately 3 mm3, from Micromachined silicon
PCL. pSi microparticles were subsequently Silicon microfabrication techniques allow the
embedded in selected faces of the blocks by production of complex structures with a wide
localized melting of the PCL. The blocks could range of advantages, including very well-defined
be self-assembled into networks by exploiting size, shape and patterns. MEMS are commonly
the hydrophilic attraction of the oxide-ter- produced by the micromachining of complex
minated pSi regions and the use of starch to structures into the surface of single crystalline
help drive the coupling of the enrichment sites.
The composites released the widely studied
model compound Ru(bpy)3Cl 2 at varying rates
depending on the physical structure, spatial
organization, pSi enrichment site and compo-
sition of the polymer blocks (Figure  10) [211] .
It was found that the blocks of Si-containing
cubes are nontoxic to HEK 293 cells.
In the above examples, there is no covalent
bond between the polymer phase and the pSi
scaffold. However, our group recently reported
on a new type of hybrid biodegradable material
composed of a pSi substrate covalently grafted
with PLLA chains [32] . The grafting of PLLA
from the pSi-tethered hydroxyl initiator groups
was studied by various surface analyses, includ-
ing atomic force microscopy, that revealed PLLA
nanobrushes. While no drug-release studies have
been carried out with this material, we anticipate
that these hybrid materials will widen the scope
of applications for biodegradable materials in
medicine and, in particular, will be useful in sit-
uations where drug delivery devices, implants
and scaffolds for tissue engineering with complex
biodegradation behavior are desired. There are a Figure 10. Hexagonal poly(e-caprolactone) blocks enriched with porous
few other examples of ‘grafting-from’ approaches silicon (dark interfacial regions) for the controlled release of Ru(bpy) 3Cl2.
Reproduced with permission from [211] .
that use pSi as the scaffold material. One of the

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Review | McInnes & Voelcker
silicon wafers to create microscale mechanical
structures. There have been many recent exam-
ples of polymer-free micromachined devices
used for the delivery of drugs [213–217] . These
devices feature unit operations at the nano- and
micro-scale:
n Nanochannel arrays can be tailored with chan-
nel sizes ranging from 7 to 100 nm to control
the release rates of molecules flown across them
in a zero-order manner [213,215,216] . The size of
the channel can be tuned depending on the
drug to be delivered; small channel widths
(7 nm) are useful for controling the release of
small organic drugs (~3–5 nm), while larger
channels (13  nm) are suitable for larger
molecules such as BSA [213] ;
n Microscale reservoirs can be used to store drugs
prior to delivery and can be opened via the
dissolution of a biocompatible capping material
such as gold [217,218] , gelatin or starch [15] . Drug
release can be stimulated via the electrochem-
ically triggered dissolution of the gold capping
layer [217] ;
n Micromachined pumps are able to move and
deliver nanolitre amounts of fluids in a con-
trolled fashion. These devices have been
reviewed recently [219] and some examples of
pioneering works on implantable micro-pumps
Microneedle were demonstrated by Ikemoto and Sharpe [220]
Micromachined needle that
and Havlik et al. [221] ;
operates by mechanically
n Valves in conventional MEMS systems can be
perforating the epidermis and
allowing for transdermal drug controlled pneumatically or piezoelectrically [15];
absorption or fluid sampling however, the development of more reliable,
20 kV ×230 100 µm
Figure 11. Fabrication procedure and
scanning electron microscropy
micrograph of a silicon microneedle array
with porous tips.
Reproduced with permission from [232] .
1064 Future Med. Chem. (2009) 1(6)
Drug-loaded hyrogel
Stratum corneum
Viable epidermis
Diffusion of drug
into epidermis
Figure 12. An array of microscale
channels generated by the application of
a microneedle array to the skin. A drug-
loaded hydrogel is then applied to fill the
channels.
Adapted with permission from [240] .
efficient valve systems adapted for drug-delivery
applications is currently being explored. Many
researchers have turned to hydrogels  [222] or
PDMS [223,224] to generate such valves;
n Chemo- or bio-sensors may be incorporated into
an implanted micromachined delivery device to
detect certain environmental conditions, such
as pH, blood pressure and the presence of cer-
tain analytes including glucose [15,225,226] . Bio-
sensors and bio-MEMS systems and device
fabrication have been extensively reviewed
elsewhere [226–230] .
When loaded and surgically implanted into
patients, such devices maximize the local effec-
tiveness of drug delivery and minimize the toxic
effects of fully systemic therapies [3,5,6] .
Micromachined devices, which have featured
prominently in the recent literature, are silicon
microneedles [75,231,232] for transdermal drug
delivery. Microneedle arrays (Figure  11) are a
viable alternative for the delivery of drugs that
are unable to be effectively delivered via oral
ingestion or hypodermic injection. The array of
microneedles disrupts the outer layer of the skin
at multiple sites and increases drug permeabil-
ity through the epidermis into the bloodstream,
thereby increasing the drug-delivery efficiency.
Micro­needle injection is painless as the needles are
not long enough to reach the nerves and induce a
pain response. The therapeutic agent to be deliv-
ered can be coated onto the microneedles before
insertion, applied to the skin as a gel after the
application of the microneedle array (Figure 12)
or delivered from an external reservoir in the case
of hollow microneedles [231,233,234] . Microneedles
have been reviewed elsewhere [235,236] .
future science group

A B
Photoresist
PMMA
Silicon
First mask and
reactive ion etch
Second photoresist
Second mask and
reactive ion etch
Photoresist and
device removal
PMMA drug-
delivery devices
Figure 13. (A) Fabrication process for poly(methylmethacrylate) drug-delivery devices. (B) 150 ×
150 × 3 µm poly(methylmethacrylate) devices with four reservoirs. (C) 150 × 150 × 5 µm PMMA
devices with single reservoirs.
PMMA: Poly(methylmethacrylate).
Adapted from [241] .
Microneedles have also been fabricated with
porous tips (Figure 11) that could potentially be
used to store increased amounts of drugs and
to safeguard against any biocompatibility issues
caused by broken tips [231–233] . New fabrication
processes have been used to generate arrays fea-
turing both short (400-µm) and long-shanked
(900-µm) microneedles that can simultaneously
deliver drugs (short needles) and withdraw blood
samples (long needles) [237,238] .
Microneedles have proven difficult to coat
uniformly [239] . As an alternative, drug-loaded
polymer gels have been used after application of
the microneedle array. To this end, the hydrogel
formulation containing therapeutic DNA was
placed into the microscale channels created in
the skin after the insertion and removal of the
microneedles to the epidermis (Figure 12) . The
DNA can now diffuse from this reservoir into
the surrounding epidermis [240] .
„„Polymer-enhanced MEMS
The use of polymers in MEMS is not limited
to biocompatible coatings. On the contrary,
the polymers in some of the most interesting
future science group
Silicon–polymer hybrid materials for drug delivery | Review
150 µm
C
150 µm
examples act as actuators to control the release
of drugs from the device. Tsai et al. have used
a polypyrrole film to induce a conformational
change on a gold membrane upon the applica-
tion of a voltage. This gold membrane is laid
across a micromachined silicon aperture inside
a PDMS drug reservoir. This system is actuated
based on the volume change in the polypyrrole
layer as cations move in and out of the polymer
layer. When the bias is applied, the gold flap
opens and releases the drug to the surrounding
area [76] .
Micromachined
„„ polymeric
drug‑delivery devices
As early as 2000, microfabrication processes
were being applied to biodegradable polymers in
order to create implantable biomedical micro-
devices. Armani et  al. used micromachined
silicon moulds to create 3D microstructures in
PCL, as well as demonstrating that both dry-
and liquid-filled microcavities could be covered
with thin gold films, which could potentially
be removed via anodic dissolution in biological
tissue [218] .
www.future-science.com 1065
Review | McInnes & Voelcker
A more recent example of a micromachined
drug-delivery device comes from Tao et al., who
used micromachined PMMA layers on silicon
substrates to create microdevices that can poten-
tially be used for oral drug delivery to the GI
tract. The devices were manufactured to be 150 ×
150 µm2 and 3-µm thick with multiple reservoirs
(Figure 13) [241] . The devices were also functional-
ized with lectin to facilitate binding to the cells in
the GI tract and ensure that the drug is released
in close proximity to the intended delivery site.
Very recently, biopolymer delivery has been
attempted with micromachined systems. One
of the most versatile is the particle replication in
the nonwetting templates method pioneered by
DeSimone [242,243] . This technique allows for the
creation of ‘smart particles’ as small as 160 nm
with controlled and monodisperse sizes, shapes,
compositions, cargo encapsulation and surface
functionality [242] . Such nanomolded particles
can be varied in size and shape via the creation
of a suitable silicon master template. The pro-
cess allows the encapsulation of biological drugs
including DNA, proteins and RNA into polymers
such as PEG, poly(d-lactic acid) and poly(pyrrole).
Most importantly, they can be easily released and
dissolved under physiological conditions and used
for therapeutic drug-delivery systems [242] .
Glangchai et  al. have also fabricated drug-
loaded nanoparticles with controlled size, shape
and composition using an imprint lithography
technique [244] . They have demonstrated a high-
throughput nanofabrication technique using
synthetic and biological macromonomers (PEG
diacrylates, PEG dimethylacrylates and a synthe-
sized enzymatically degradable peptide [Gly-Phe-
Leu-Gly-Lys-diacrylate]) to produce highly mono-
disperse, enzymatically triggered nanoparticles.
Biodegradable and nonbiodegradable particles as
small as 50 nm were created via imprinting with
a quartz template and were harvested directly into
aqueous buffers using a biocompatible, one-step-
release technique. The authors also demonstrate
successful encapsulation (via mixing with the
monomer precursor) and enzyme-triggered con-
trolled release of antibodies and nucleic acids from
these nanoparticles.
Micromachining techniques are being improved
constantly, mostly driven by a drive within the
electronics industry to increase feature density
and functionality in order to develop higher-
performing devices. Some of these advancements
will no doubt be translated to micromachined
drug-delivery devices. Although the microfabri-
cated devices presented here are fully polymeric in
1066 Future Med. Chem. (2009) 1(6)
their final form, they have been created via the use
of common silicon micromachining techniques,
such as photolithography and etching, or from
micromachined moulds. These polymeric drug
devices could prove to be advantageous as they
will degrade naturally in vivo and avoid any need
for surgical retrieval [218] .
Conclusion
The preparation of silicon-based monolithic mate-
rials for implant applications such as bone regen-
eration can be tailored with various polymers to
ensure that they release therapeutic agents such as
anti-inflammatories. The incorporation of poly-
mers into these silicon-based materials can help to
tune the drug release by modifying the structural
properties, such as hydrophobicity and porosity,
which in turn can influence the degradation and
drug-release rate. Polymeric layers can also be used
as coatings for silicon-based particles to control
the drug release from the particle; these coatings
can be deposited via LBL techniques, electrostatic
assembly, encapsulation or covalent polymeriza-
tion. In some cases, inverse architectures have been
described where silica has been used to coat PDMS
microparticles and slow down the release of drugs.
Single crystalline silicon has been modified by
LBL techniques and grafting approaches in a range
of fundamental studies with drug-delivery appli-
cations in mind. The in vivo use of these devices
is unlikely, as silicon is not biodegradable and its
low surface area limits drug-loading capabilities.
pSi, however, shares common functionalization
techniques with single crystalline silicon and ben-
efits from a much larger drug-loading capacity.
The use of pSi in composite production is also
advantageous as it is biodegradable, so no fur-
ther surgical intervention is required to remove
implantable devices. pSi can be processed into
micro- and nano-particles, which increases the
range of delivery options.
Stimuli-responsive polymers integrated into
silicon-based materials allow environmental
stimulus-triggered drug release. Alternatively,
micromachining techniques offer drug release
from reservoirs upon electronic actuations.
In summary, this review has shown a range of
silicon–polymer hybrid architectures resulting in
materials with properties well suited for controlled
drug delivery.
Future perspective
The composite structures and devices described
above have demonstrated many potential uses
of silicon–polymer hybrid materials for the
future science group

controlled delivery of small-molecule and macro­
molecular drugs. In the near future, improvements
in surface modification with polymers, proteins,
antibodies and other site-directing agents could
allow for site-specific targeting and stimuli-
responsive drug release from nanoparticle com-
positions. Further research into new monomers
and polymers could lead to improved composite
materials that are capable of better protecting
therapeutic agents in vivo, while also improving
the release properties. We envision the future use
of fully biodegradable silicon–polymer composite
implants that have tailored release characteristics.
The progression of silicon- and polymer-based
MEMS devices could lead to the development of
environmentally responsive, pulsatile drug-release
systems that are able to sense the need for a drug
and release the required amount of a therapeutic
molecule accordingly.
Some very recent newly emerging nanostruc-
tured silicon–polymer morphologies have the
potential to be used for drug-delivery applica-
tions. For example, polymer brush-coated silica
nanowires have been recently synthesized and
vesicular and tubular topography may also be
Silicon–polymer hybrid materials for drug delivery | Review
accessible [245] . Another recent example relates to
the demonstration of nanotapes of silica nano-
composites combining self-assembly and pep-
tide-directed silicification of Si(OH) 4 [246,247] .
Although not yet demonstrated as drug-delivery
devices, the future incorporation of drugs into
these new materials could lead to the creation of
new structures or devices that display promising
drug-release properties.
Acknowledgements
Our thanks go to Emily Anglin and Frances Harding for
critical reading of the manuscript.
Financial & competing interests disclosure
Financial support from Flinders University and the Australian
Research Council is duly acknowledged. The authors have no
other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript. This includes employment, consultancies, hono-
raria, stock ownership or options, expert t­estimony, grants or
patents received or pending, or royalties.
No writing assistance was utilized in the production of this
manuscript.

Executive summary
„„ Single crystalline silicon is a popular platform for the initial design and testing of new silicon–polymer hybrid materials. However, the
inability of the silicon to degrade in vivo renders these devices unsuitable for in vivo applications.
„„ Mesoporous and porous silica are attractive candidates for biomedical applications as they are highly tunable for pore size and

morphology, and they are also easily modifiable with a wide variety of chemical moieties.
„„ The optical properties of porous silicon (pSi) or its polymer replicas are sensitive to the release of molecules from the porous matrices.

This allows for self-reporting of drug release.

„„ Encapsulation of silica and pSi with polymers can help improve biocompatibility and tune the biodegradation and drug-release kinetics,

as well as facilitate the site-targeted release of drugs.

„„ The use of composite materials could help improve drug resistance to first-pass metabolism and degradation in vivo and increase the

bioavailability at the site of delivery.

„„ Microneedles can penetrate the epidermis and allow the painless delivery of therapeutic agents from porous or hollow reservoir or

polymeric coatings.
„„ Microelectromechanical system devices can control the release of drugs via electrically stimulated flaps or the dissolution of

capping layers.
„„ The application of microelectromechanical system technology to drug-delivery devices including features such as reservoirs,

sensors, pumps and valves is producing smart devices with improved control over drug delivery and the possibility of sensor-release
feedback loops.
„„ The development of polymeric devices based on micromachining principles could lead to implantable biodegradable devices that will not

require further surgical removal after their payload is exhausted.

2 Castro G, Panilaitis B, Kaplan D. Emulsan, a 4 Elvira C, Gallardo A, San Roman J,

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