a nanocage for nanomedicine: polyhedral oligomeric...

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A Nanocage for Nanomedicine: PolyhedralOligomeric Silsesquioxane (POSS)

Hossein Ghanbari, Brian G. Cousins, Alexander M. Seifalian*

Ground-breaking advances in nanomedicine (defined as the application of nanotechnology inmedicine) have proposed novel therapeutics and diagnostics, which can potentially revolu-tionize current medical practice. Polyhedral oligomeric silsesquioxane (POSS) with a distinc-tive nanocage structure consisting of an inner inorganic framework of silicon and oxygenatoms, and an outer shell of organic functional groups is one of the most promisingnanomaterials for medical applications. Enhanced biocompatibility and physicochemical(material bulk and surface) properties have resulted in the development of a wide rangeof nanocomposite POSS copolymers for biomedical applications, such as the development ofbiomedical devices, tissue engineering scaffolds, drug delivery systems, dental applications,and biological sensors. The application of POSS nanocomposites in combination with othernanostructures has also been investigated including silver nanoparticles and quantum dotnanocrystals. Chemical functionalization confers antimicrobial efficacy to POSS, and the use ofpolymer nanocomposites provides a biocompatible surface coating for quantum dot nano-crystals to enhance the efficacy of the materials for different biomedical and biotechnologicalapplications. Interestingly, a family of POSS-containing nanocomposite materials can beengineered either as completely non-biodegradable materials or as biodegradable materialswith tuneable degradation rates required for tissue engineering applications. These highlyversatile POSS derivatives have created new horizonsfor the field of biomaterials research and beyond.Currently, the application of POSS-containing poly-mers in various fields of nanomedicine is under inten-sive investigation with expectedly encouragingoutcomes.

Dr. H. Ghanbari, Dr. B. G. Cousins, Prof. A. M. SeifalianCentre for Nanotechnology and Regenerative Medicine, UCLDivision of Surgery & Interventional Science, University CollegeLondon, London, NW3 2QG, UKE-mail: [email protected]. A. M. SeifalianUniversity College London, Royal Free Hampstead NHS Hospital,London, NW3 2QG, UK

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Introduction

Recent advances in nanotechnology have resulted in the

emergence of advanced novel nanomaterials with

improved properties capable of being used in several

biomedical applications. The application of nanotechnol-

ogy in medicine has led to an emerging interdisciplinary

field called nanomedicine, which can revolutionise current

medical practice. In particular, the development of

advanced diagnostic and therapeutic tools based on

nanotechnology hold great promise in overcoming

library.com DOI: 10.1002/marc.201100126

Hossein Ghanbari completed hismedical degree in 2002 andwas awarded a Ph.D scholarship inmedical nanotechnology in2007. He did his PhD at University College London, Centre for Nanotechnology and Regenerative Medicine and aftergraduation in 2010 has been working as an Assistant Professor in the Department of Medical Nanotechnology, School ofAdvance Technologies in Medicine of Tehran University of Medical Science. His research interests are development ofbiomedical and cardiovascular devices using nanomaterials, application of nanotechnology in regenerative medicine anddevelopment of nanoparticles and nano-structured composite materials for medical application.

Brian G. Cousins joined the groupworking on haemocompatibility and endothelisation of bypass graft materials funded bythe Welcome Trust. He has degrees in Biochemistry and Biophysics studying physical analysis of biological interactions atsurfaces (University of Liverpool, MRes 2001). He completed his Ph.D in Clinical Engineering investigating surfacemodification of biomaterials with nanoparticulate coatings to evaluate cellular behaviour. He is experienced at workingat the interface of interdisciplinary science studying nanomaterial interactions. He is currently at UCL in the Division ofSurgery and Interventional Science in the Royal Free Hampstead NHS Trust Hospital as lecturer in Nanotechnology andBiomaterials.

Alexander Marcus Seifalian is Professor of Nanotechnology and Regenerative Medicine and Director of Centre forNanotechnology & Regenerative Medicine at University College London. He is based within Division of Surgery &Interventional Science. He has completed his education at University of London and University College London MedicalSchool. He is Fellow of the Institute of Nanotechnology (FIoN) and has published over 325 peer-reviewed research papers, 31book chapters and 4 families of patents. During his career, he has led and managed many large projects with multi-disciplinary teams with very successful outcomes in terms of commercialisation and translation to patients, includingdevelopment and commercialisation of a bypass graft for vascular access for haemodialysis; laser activated vascularsealants that have been commercialised for liver and brain surgery, and regeneration of lacrimal duct using nanomaterialsand stem cells. His current projects develop cardiovascular implants using nanomaterials and stem cells technology, organsusing tissue engineering, nanoparticles for detection and treatment of cancer, and he is also working on nerveregeneration and development of skin. He has been awarded the top prize in the field of development of nanomaterialsand technologies in the development of cardiovascular implants in 2007 by Medical Future Innovation and in 2009received a Business Innovation Award from UK Trade & Investment (UKTI) in the Life Sciences and Healthcare category.His current grant sum is £3.2 million.

A Nanocage for Nanomedicine . . .

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unsolved problems of traditional medicine. Several nano-

structured materials have been explored for potential use

in medicine, ranging from the application of nanoparticles

or nanostructures in cell labelling,[1] to diagnostic and

imaging tools[2] for advanced therapeutic modalities such

as precise drug delivery systems using nanocarriers for

cancer treatment.[3,4] Since synthetic nanomaterials are

inherently small, with at least one dimension in the

1–100nm range, they can widely interact in the physio-

logical environment by crossing the biological membrane

barrier.[5] This is of particular advantage in developing

novel diagnostics and therapeutics based on nanomater-

ials.

The properties of the materials change considerably

when the size is significantly smaller in comparison to the

larger micrometer-scale components of the samematerial.

Nanomaterials generally exhibit improved physical, che-

mical, and mechanical properties compared to their

conventional counterparts. The superior properties of

nanomaterials offer potential applications in a wide range

of scientific disciplines. They can be used directly or

indirectly by being incorporated into polymeric systems

to create nanocomposite materials. Principally, composite

materials are combinations of at least two constituents

with significantly improved physicochemical properties.

Matrix (host) and reinforcement (guest) phase components

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are themain reactive constituents behind the vastmajority

of composite materials. The interactions between mono-

mers that form the macromolecular components and their

final structures vary according to the type of starting

materials and fabrication techniques used. When at least

one of the components is of nanometer-scale dimensions,

the resulting composite is considered a nanocomposite

material.[6] In nanocomposite polymers, the synthesis

method and the nature of the nanofiller or monomer

(method of nanoreinforcement) determines the type of

micro- andmacromolecular scale interactions between the

polymeric matrix to regulate the behaviour of the

nanocomposite’s physical and structural properties.[7–9]

Among the most commonly studied nanofillers or

monomers for developing composite materials is the

silsesquioxane family. The chemical structure of the

silsesquioxane family is defined as RnSinO1.5n, which forms

structures consisting of an inorganic framework of silicon

and oxygen atoms, surrounded by organic side chains (R

group).[8,9] The R group can represent a range of functional

species such as hydrogen, alkyl, alkene, aryl, and arylene

moieties. Based on their molecular architecture, silses-

quioxanes can be classified into two main categories. The

first category includes non-caged silsesquioxanes that form

ladder, random, and partial-caged molecular struc-

tures.[10,11] Suchsilsesquioxaneswith ladder-like structures

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H. Ghanbari, B. G. Cousins, A. M. Seifalian

inpolymeric systemsshowenhanced insulatingproperties,

gas permeability, and play host to a range of applications

from surface coatings and gas separation membranes to

binding agents for carcinostatic drugs.[8,10–12] The second

category includes the caged silsesquioxanes.[8,9]

Conventionally, caged molecular structures such as

polyhedral oligomeric silsesquioxanes (POSS)[13] are one

group of the silsesquioxane family that posses a regular

three-dimensional (3D) shape formed by a few units each

containing silsesquioxane.[9] This structure consists of an

inner inorganic framework of silicon atoms (n¼ 8) linked

with oxygen atoms (n¼ 12), and an outer shell of organic

groups (n¼ 8) that merge together to form a 3D cubic

nanocaged structure (Figure 1). Hence, each silicon atom is

bonded to threeoxygenatomsbysiloxanebonds (Si�O�Si),

and one carbon silicon bond (Si�C) that may be inert or

reactive, thus rendering the nanostructures compatible

with polymeric and biological systems. These are highly

Figure 1. Schematic structure of A) trans-cyclohexane chlorohydrin isobatoms, surrounded by organic side chain groups (R¼�CH2CH3CH3), anapplications.



symmetrical molecules with a nanoscopic feature size of

approximately 1.5 nm in diameter (including the R side

chain groups), and can be considered as the smallest of

achievable silsesquioxane particles.[8,14] POSS differs in

structure and chemistry to silica (SiO2). Inorganic SiO2, both

colloidal and amorphous, have a defined 3D spherical

morphology composed of cross-linked Si�O�Si with sur-

face silanol (Si�OH) groups (instead of Si�C), and range in

size from 5 to 100nm in diameter (leading to micrometer

scaledimensions for amorphous SiO2).When thenumber of

silicon atoms increase within the POSS structure (were

n¼ 10 or 12) the nanocages are somewhat larger than

1.5 nm, but usually< 5nm in diameter. Despite their small

size it is conceivable that aggregation of POSS occurs

naturally in polymeric systems (when acting as a

nanofiller) forming dispersions of nanoparticulate materi-

als ranging from 10–100nm in diameter.[8] For example,

studies have shown that gas phase cross-sectional analysis

utyl-POSS consisting of an inner inorganic core of silicon and oxygend B) POSS-PCUnanocomposite polymers developed for cardiovascular

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of POSS (RnSinO1.5n) with increasing cage size (n¼ 6, 8, 10,

12, and 14) revealed structures ranging from 14 to 26nm in

diameter with similar dimensions to amorphous and

colloidal SiO2.[15,16]

Theorganic side chaingroup (R) on theouter shell of POSS

has a potentially unlimited supply of organofunctional

inert or reactive groups derived from alkyl, olefin, alcohol,

ester, anhydride, acid, amine, imide, epoxide, thiol,

sulfonate, fluoroalkyl, silanol, and siloxide functional-

ities.[9] Indeed, researchers have shown that reactive POSS

monomers can be incorporated as nanomolecular scale

building blocks[17] forming hybrid inorganic–organic copo-

lymers.[18,19] In this way, copolymerization of POSS

monomers results in covalent modification driven by

self-assembly processes, e.g., hydrogen bonding, electro-

static, andp–p stacking interactions (in the caseof aromatic

functional groups), which leads to aggregation, crystal-

lization, and cross-linking of POSS nanocages within the

hard segments of the polymeric matrix and results in

enhanced thermal, mechanical, and physical proper-

ties.[9,18,19] Thesize rangeofPOSSaggregatesandcrystalline

segments embedded within the polymeric matrix range

from 10 to 20nm in diameter.[16] Physical and thermal

properties are improved by the incorporation of POSS with

low dielectric constants (K),[20] increased glass-transition

temperatures (Tgs),[20–22] a low coefficient of thermal

expansion, thermal stability, and heat evolution.[14,23]

Improvements in the mechanical properties show

increased tensile strength,[21,22,24] viscosity,[14,24,25] and

enhanced viscoelastic properties.[19,26,27] Further improve-

mentshavealsobeen reported suchas oxidation resistance,

reduced flammability, oxygen permeability, and reduced

inflammatory reactions, which highlight the key advan-

tages of using such materials for biological applica-

tions.[21,22,24,28] The incorporation of POSS influences the

surface properties such as surface chemistry (wettability),

energy, and topography. Efficient surface coverage and

stability under a variety of environmental and physiolo-

gical conditions are part of the POSS derivatives’ unique

features thatmake them attractive as surfacemodification

agents.[29] Incorporating POSS structures by non-covalent

modification of nanoparticles yields a variety of 3D

materials composed of palladium, magnetic (iron, nickel

and cobalt), and gold nanostructures.[30–35] The unique

characteristics of POSS nanomaterials offers a diverse

application potential in a wide range of areas from

biomedical to biotechnological fields, and are currently

under intensive investigation.

Application of POSS in Nanomedicine

The unique structures and superior surface properties of

POSS allow them to be used in the structure of different




polymers and copolymers developed for biomedical appli-

cations. In particular, owing to their biocompatibility and

ability to incorporate additional polymers, POSS nano-

structures have been shown to offer high potential in

several biomedical applications such as drug delivery

systems,[36,37] dental composites,[38] biosensors,[39] biome-

dical devices,[40–42] and tissue engineering products.[43,44]

Because of their relatively inert nature and reduced

inflammatory response, the molecular structures of POSS

consisting of Si�O�Si and Si�C groups has similar

chemistry to silicone elastomers (poly(dimethylsiloxane),

PDMS), which has been a preferable biomaterial since the

1960s when it was introduced in breast implantation.[45]

Biocompatibility is one of the key features of POSS

nanomaterials resulting from the increased surface energy

in the foci of silicon-rich areas. Non-toxicity and cytocom-

patibility are other fundamental features of POSS making

them suitable for biomedical applications.[46–48] For exam-

ple, a recent study evaluated the in vivo degradation of

polyester polyurethanes over a 24week period using cross-

linkedPOSSas thehard crystalline segment.[49] Itwas found

that no acute chronic inflammatory response was evident

over a three week time period. Such studies concluded that

polymeric thin films and biodegradable formswere indeed

biocompatible, and did not initiate a chronic inflammatory

response often characteristic of cytotoxic non-compatible

biomaterials.[49] Hence, polymeric POSS-based nanocom-

posites have been largely studied by biomaterial scientists

with the aim of utilizing and understanding their unique

physical and chemical properties, and how these phenom-

enaare translated to influence thebiological responseat the

tissue–implant interface for biomedical and tissue engi-

neering applications.

POSS Nanocomposites in Cardiovascular Implants

Haemocompatibility is an essential requirement in cardi-

ovascular applications of biomaterials. Since cardiovascu-

lar implants are directly in contactwith blood, thematerial

used in their structure and the device itself should not

induce any thrombosis and damage to red blood cells

(haemolysis). To meet the essential requirements for these

applications, we have developed nanocomposite materials

by copolymerization of POSS monomers with poly(carbo-

nateurea)urethane (POSS-PCU) to formcovalentlymodified

and cross-linked nanostructureswithin the hard segments,

and form pendant chain groups.[10,50–53] Studies on its

cytocompatibility, anti-thrombogenicity, and biostability

have shown that this nanocomposite polymer has unique

characteristics for applications at the blood–biomaterial

interface.[52] This nanocomposite polymer can be biofunc-

tionalized by anchoring peptides and growth factors

through surfacemodification in order to attract endothelial

progenitor cells (EPCs) from the circulatory blood, and

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Figure 2. Schematic images showing biofunctionalization of the surface of POSS-PCU to create smart scaffolds for in vivo tissue engineering.A) The surface can be modified by grafting specific bio-active peptide motifs or other ligands or receptors into POSS-PCU. B) Thebiofuctionalized surface can target several biological processes to promote in situ endothelialization by promoting themobilization of EPCsfrom the bonemarrow, encouraging cell-specific (circulating EC, EPC, and stem cells) homing towards the vascular graft, providing adhesionmotifs (of a predetermined spatial concentration), and directing the behaviour of the cells to rapidly form a mature fully functioningendothelium with self-repair capability (C).

Figure 3. Development of cardiovascular devices using a POSS-PCU nanocompositepolymer. Digital images are presented in (A) illustrating an example of a small diameterbypass graft modified with 2% POSS-PCU. The longest portion of the graft (centre) is5 cm in length with an internal diameter of 5mm, and a porous wall structure approx.0.85–0.9mm in thickness. B) A preclinical assessment of the positioning and implan-tation of a small diameter bypass graft composed of 2% POSS-PCU sutured in to thecarotid artery of an ovine model.

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become endothelialized to enhance the bio- and haemo-

compatibility of cardiovascular devices made with this

material (Figure 2). Recently, we have developed small

diameter coronary artery bypass grafts composed of POSS-

PCU, which are undergoing preclinical assessments in vivo

in a large animal model (Figure 3). Heart valves,[41]

percutaneous heart valve prostheses, stent grafts, and

nanocomposite-coated coronary stents using POSS-PCU are

currently under investigation. Novel synthetic leaflet heart

valves based on the POSS-PCU nanocomposite have

recently been developed and are currently undergoing

further evaluation. These valves can potentially combine

the advantage of improved mechanical strength of

bioprosthetic valves, and eliminate their apparent dis-

advantages. In addition, using a electro-hydrodynamic

spraying approach, we have established the application of

POSS-PCU for the coating of metallic stents, and demon-

strated that polymeric nanocomposites have the potential

to be used in the development of anewgeneration of stents


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with improved properties, especially

with small diameter stents for use in

the coronary artery.[54] More recently,

biodegradable drug-eluting stent coat-

ings have been developed using a ther-

moplastic polyurethane (TPU) with POSS

hard segments (POSS-TPU) and soft seg-

ments composed of poly(L-lactide)/capro-

lactone copolymers (P(DLLA-co-CL) with

covalent attachment of poly(ethylene

glycol) (PEG).[55] The soft segments were

designed to modulate the drug release of

paclitaxel, a knownmitotic inhibitor and

anti-proliferative agent used to treat

patients with cancers, and to prevent in

situ restenosis. The results demonstrate

that biodegradable POSS-TPU loaded

with paclitaxel allows drug release that

can be controlled by variation in polymer Tg with

degradation rates tunable by coating thickness under

physiological conditions.[55] Furthermore, recent studies in

thedesignofdegradablepolymers suggest overall improve-

ments in the miscibility of paclitaxel over a range of

concentrations, which can be fine tuned by specific

interactions of degradable POSS-TPUs.[56]

POSS-PCU has been characterized and assessed for

biomedical applications in general, and for cardiovascular

applications in particular, and the results of such studies

reveal that POSS-PCU nanocomposites contain enhanced

physical and chemical characteristics which create a

technology platform for biomedical applications. This

polymer is currently being used in the design, fabrication,

and manufacture of medical devices, including microvas-

cular beds for organ tissue (including liver), muscle,

cartilage, and breast implants,[50] materials for coating

quantum dot nanocrystals for cancer detection, improved

contrast agents for magnetic resonance imaging (MRI),

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small-diameter artificial naso-lacrimal duct conduits, and

several further applications related to tissue engineering

using modern surgical techniques.

POSS Nanocomposites as Coating Materials forQuantum Dot Nanocrystals

Quantum dots (QD)s are luminescent nanocrystals that are

undergoing intensivedevelopments to create anewclass of

contrast agents for MRI.[57] As the next generation of

fluorescent probes, QDs owe their novelty to their large

absorption, narrowanddiscretemulticolour light emission,

bright photoluminescence, high photo-stability, and nano-

meter-scale dimensions ranging from less than 1.5 nm

to 50nm in diameter. Indicating a range of QDs of around

1-50 nm in diameter. In the next few years, developments

of such nanoparticles will bring improved and unique

insights into a variety of biomedical imaging applica-

tions.[58] QDs are already revolutionizing the processes of

tagging macromolecules, proteins, antibodies, and cells,

and the detection of specific cancers such that they may

guide surgical procedures in vivo.[59,60]

As new approaches in medical engineering of QDs

for biological applications are being developed, there is

concern regardingtheirdegradationrates invivo, especially

their oxidation.[61] To avoid premature degradation,

enhance biocompatibility, and to reduce their potential

toxicity, coating QDs with a biocompatible and biostable

polymer has been proposed. POSS-PCU is a potential

material for coating QDs where nanosized POSS is

covalently attached to PCU, and the nanocomposite used

as a surface coating to enhance the mechanical properties

and impart greater resistance to biodegradation, as

discussed previously. Such POSS-PCU coatings have been

studied in detail, and have been shown to be non-toxic,[48]

biocompatible,[52] and biologically stable.[62] POSS-PCU has

also been shown to possess hydrophilic groups in experi-

ments exploring its putative applications in various

biomedical devices. A recent study characterized the

biocompatibility of QDs encapsulated with POSS-PCU

nanocomposites. In this study, the in vitro cytocompat-

ibility and potential cytotoxic effects were investigated

usinghumanumbilicalveinendothelial cells (HUVECs). The

maximum tissue depth at which these nanocomposite-

coatedQDs (NCCQDs) could bedetectedwas also addressed.

NCCQDs were of a narrow size distribution with a mean

hydrodynamic diameter of 10.5 nm, high photo-stability,

excellent monodispersity, and a large absorption spectrum

with a narrow and discrete emission band at 790nm.

NCCQDs were non-cytotoxic to HUVECs in culture: viable

cells were shown to be present after 14 d when the media

was exposed to NCCQDs. Exposing cells to NCCQD-treated

cell culturemediumresulted innoapparentdamage to cells

at concentrations of 2.25� 10�2 nM. NCCQDswere detected




atamaximumtissuedepthof10mminsolid tissuesamples

using a near infrared camera (Figure 4). POSS-PCU surface

coatings provide an opportunity to modify the QD surface

and alleviate any potential toxic effects of cadmium

telluride (CdTe) nanocrystals to endothelial cells (ECs).

Recent advances in microscopy have shown that two-

photon excited fluorescence (TPEF) can detect POSS

conjugated with oligoelectrolytes (COE) for imaging the

cell nucleus. The 3D hybrid nanodots (COE-POSS) have been

visualized and detected in breast cancer cells (MCF-7), and

were more effective at highlighting and distinguishing

between the nucleoli from other compartments of the

nucleus than one-photon excited fluorescence (OPEF). COE-

POSS was also found to be superior to commercially

available SYBR green (SG) dyes, and may have great

potential in areas such as clinical diagnostics.[63]

Antibacterial Agents Using POSS

Anarrayofquaternaryammoniumcompounds canbeused

to functionalize POSS (Q-POSS) for antimicrobial applica-

tions. In a recent study, Majumdar and co-workers

investigated the antimicrobial activity of Q-POSS coatings

towards Escherichia coli, Staphylococcus aureus, and the

opportunistic fungal pathogen, Candida albicans using a

standard Agar plating method (Figure 5). The results

showed that the composition of Q-POSS and the polysilox-

ane matrix affected the antimicrobial properties. Several

compositionswere identified that inhibited growth in all of

the microorganisms studied on the coated surfaces.

Although their potential benefits warrant further investi-

gation as immobilized quaternary compounds, such

materials are known to cause inflammatory and anaphy-

lactic reactions in general surgery.[64] Recent studies have

also revealed that hydrogels synthesized from PEG and

POSS-containing polyurethanes, electrospun into nanofi-

bers (150nmindiameter)withorwithout silvernitrate, can

beused to inhibit biofilm formationof E.Coli strains.[9] Such

materials hold great promise in the development of novel

wound dressings for localized wound healing applications.

Silver nanoparticles that range from 1 to 100nm in

diameter are attracting interest as antimicrobial agents for

applications in modern medicine. Recent studies suggest

that Ag nanoparticles have potent anti-inflammatory

properties[65,66] and improved wound healing capabil-

ities.[67] The antibacterial properties of Ag are widely

known, andwell established by their current use aswound

dressings, and in topical ointments for treating burn

patients.[68] The use of Ag in the structure of synthetic

polymeric materials can potentially confer antibacterial

bulkandsurfacepropertiesofbiomaterials. It iswell known

that implantable devices are at greater risk in the

development of hospital-acquired infections during surgi-

cal intervention. Modification of the materials with Ag

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Figure 4. Transmission electron microscopy (TEM) image ofmeasurements of CdTe nanocrystals coated with NCCQD (A).In (B) QDs of various sizes were injected at various depths intoa chicken leg, as a simple model tissue to locate their presenceunder excitation with IR. Fluorescent imaging of MCF-7 cells withOPEF microscopy in (C) and (D) show OPEF/transmission over-lapped images stained with 1mM of COE-POSS. TPEF images ofMCF-7 cells incubated with 1mM COE-POSS (E) or SG (F) for 2 hincubation period. (Images C�F were adapted from ref.[63]).

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nanoparticles can possibly eliminate nosocomial infection

rates in devices that incorporate degradable polymeric

materials (described previously in the development of drug

eluting stent coatings). Because of the understandable

controversy surrounding the toxicity of Ag exposed in

previous studies, research into Ag coatings for heart valves

and other fully implanted cardiovascular applications is

understandably tentative. Currently we are investigating

the antibacterial, mechanical, and haemodynamic proper-

ties of Agnanoparticles impregnatedwith POSS-PCU to test

the efficacy of thesematerials.[69] Preliminary results show

effective kill rates with a 99.9% reduction in total viable

counts using E. coli and S. aureus (unpublished data).

Therefore, Ag modified with POSS within the polymeric

matrix may be a promising development, and can be used

for implantable devices, surface coatings, polymeric tubing

such as catheters, and in particular implants with a higher

risk of infection such as the naso-lacrimal duct during

soft tissue repair and reconstructive surgery. The

cytocompatibility and anti-inflammatory properties of

Ag modified with POSS copolymers are currently under

investigation.

Development of POSS-Containing Breast Implants

Silicone implants are used extensively for a range of

augmentation procedures worldwide, especially in breast

implants. The procedure was first introduced during the

1960s, and used what was originally thought to be a

relatively inert biomaterial with minimal complications

and inflammation rates. However, long-term studies

suggest that silicone delays wound healing,[70] and

is responsible for capsular contracture and repetitive

movement causes pseudo-inflammation because of the

release of microparticles (forming silicone wear debris).[71]

POSS derivatives can potentially be an alternative option

for silicone in breast implant products. In a recent in vivo

study[50] it was shown that POSS-containing polymeric

materials revealed no sign of significant inflammation and

material degradation compared with siloxane controls.

Hence, it was concluded that these nanocomposites

improved the interfacial surface properties and biological

stability compared with conventional silicone materials,

which significantly reduced the risks associated with

augmentation procedures.

POSS Nanocomposites in Tissue Engineering

Tissue engineering is a rapidly emerging field, combining

various aspects of medicine, cell and molecular biology,

materials science, and engineering to regenerate diseased

andmalformed tissues and improve organ function.[26] The

3D scaffold materials in tissue engineering are categorized

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Figure 5. Three different antimicrobial responses to Q-POSS. For some coatings, no microorganism growth was observed in a zonesurrounding the coated specimen (zone of inhibition (þ,þ ). In addition, coatings were identified that showed nomicroorganism growth onthe coated surface, but no zone of inhibition (þ,–). Coatings that showed no microorganism growth inhibition or a zone of inhibition weredesignated (–,–) (Image adapted from ref.[9]).


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as natural or synthetic materials. The advantage of

synthetic scaffolds over natural biological materials is that

their production techniques are known, their structure is

controllable on both macro- and microscopic scales, and

they are biodegradable over time with controlled degrada-

tion rates. In principle, polymer scaffolds are desired to be

biocompatible with various mechanical properties, which

sustain hydrodynamic shear stress at a specific site of

application.[27,72,73] They should possess good cell adher-

ence, and subsequent proliferation and differentiation.

Moreover, cytotoxicity of the polymer scaffolds is another

crucial factor affecting cell viability either by direct contact,

or by releasedproducts throughdegradation, and should be

taken into consideration during their design.[74]

The physical characteristics of porosity such as pore

structure, volume, and size are responsible for the regula-

tion of cell function. Highly porous scaffolds offer a

significant surface area for cell attachment and inclusion.

The key factor responsible for successful cell adhesion,

proliferation, and differentiation is pore interconnectivity.

Good pore interconnectivity provides a sustainable envir-

onment for uniform cell distribution within the scaffold,

and plays an essential role in regulating the diffusion of

nutrients and recycling of waste products.[27,72,73]

The most common POSS-containing polymer to date for

biomedical and tissue engineering applications is a non-

biodegradable nanocomposite based on POSS-PCU. Despite

the traditional view, which describes an ideal polymeric




scaffold for tissue engineering applications to be biode-

gradable and able to reduce the potential of immunogenic

reactions, recent research implies that anon-biodegradable

polymer may be equally as effective in terms of providing

mechanical strength and stability. The presence of POSS on

the surface of the polymer induces specific micro- and

nanometer-scale topography through cross-linking, which

favours cell attachment and proliferation in certain cell

types (Figure 6).

The incorporation of POSS into polycaprolactone (PCL)

andPCUhas resulted in thedevelopmentofabiodegradable

polymer that preserves its mechanical properties as it

undergoes oxidation, hydrolysis, and degradation in the

biological environment. This has been trademarked at

University College London (UCL) (UCL-NanoBio) and con-

sists of 80% (w/w) polyhexanolactone and 20% (w/w) PCU.

The nanomaterial provides a ‘shielding effect’ on the soft

segments of the nanocomposite polymer.[75]

Gupta et al.[26] studied non-biodegradable POSS-PCU and

biodegradable POSS-PCL-PCU which had been subjected to

an electro-hydrodynamic printing technique in the pre-

paration of tissue engineering scaffolds for use in the small

intestine and liver, and for cartilage repair. The results

demonstrate that the technique can offer significant

benefits in the development of artificial organs.

In a further study, the cell compatibility of the UCL-

NanoBio polymeric system was investigated in vitro. The

direct effect of the polymers with peripheral blood mono-

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Figure 6. A) Atomic force microscopy (AFM) image of POSS-PCU showing micro- andnanotopography induced by agglomeration of POSS nanocages on the surface (scanarea: 100� 100mm2). In (B) a SEM image highlights EPCs cultured on POSS-PCU showingthe presence of colonies (arrows) attached to the surface after 7 d of culture. Thissupports the view of in situ endothelialization potential of POSS-PCU nanocompositesfor cardiovascular applications.

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nuclear cells (PBMCs) and human stem cells was studied by

seeding cells on to circular polymeric disks prepared by

electro-hydrodynamic jetting. To assess effects of the

polymer, different polymer concentrations ranging from

1 to 100 mg �mL�1 were added to culture media and left to

incubateonacell orbital shaker for10d.Theprecipitatewas

removedandthemediaextractswereused for testing incell

culture. Cell viability and growth at 48 and 96h were

analysed using Alamar Blue and lactate dehydrogenase

(LDH) assays. Cell morphology was studied using scanning

electronmicroscopy (SEM). Cellswere shown to adhere and

spread on the polymer surface with metabolic activity

comparable to that found on tissue culture polystyrene

(TCPS). Cell viability on the polymer scaffolds formed using

both electro-spraying and electro-spinning was compar-

able with cells seeded on TCPS, but infiltration into the

scaffold was much more evident on the electro-spun

scaffolds. Itwas foundthat thenanocompositematerial can

support cell adhesion, growth, and viability of human stem

cells, and that the scaffolds fabricated by electro-hydro-

dynamic jetting methods have potential for tissue engi-

neering applications in the near future.[44] The application

of this biodegradable nanocomposite was explored for the

development of scaffolds for the small intestine. Scaffolds

of the POSS-PCL-PCU nanocomposite produced a range of

porous structures with surface porosity ranging from 40 to

80% and a mean pore size of 150 to 250mm. The polymeric

scaffolds were seeded with rat intestinal epithelial cells

over 21 d. The results demonstrate that such scaffold

materials support intestinal epithelial cell proliferationand

growth with improved physical and chemical properties

that resulted in sustained viability and proliferation.[43]

As mentioned earlier, chemical compositions can have a

significant influence on themechanical properties of tissue

engineering scaffoldsandontheadhesionandproliferation

of cells within the scaffold structure.[76,77] Therefore,

various studies have been implemented to manipulate


� 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinhe

the chemical composition of synthetic

biomaterials for improved cellular and

tissue responses in tissue engineering

applications.

More recently, the effect of POSS on

polyester urethane (PEU) was analysed

for the purpose of tissue engineering

applications using different analytical

measurements (e.g., microscopic analy-

sis, NMR spectroscopy, X-ray diffraction

(XRD), differential scanning calorimetry

(DSC), thermogravimetry, and dynamic

mechanicalanalysis).[78,79] Itwasdemon-

strated that the incorporation of POSS

(6%w/w) into themacromolecular struc-

ture of PEU by in situ homogeneous

solution polymerisation resulted in a

new hybrid POSS-PEU nanocomposite with remarkable

improvement in thermal and hydrolytic stability, stiffness,

strength, and degradation resistance compared to PEU

controls.[79,80] Further investigations of the surface and

structuralproperties, andcell compatibilityof thePOSS-PEU

nanocompositeusingmurineembryonic stemcells (mESCs)

revealed that although the incorporation of POSS did not

have a direct influence on cell adhesion, viability,

proliferation, and differentiation, it significantly changed

the surface architecture of PEU into a 3D matrix with

regular pore features and could potentially enhance the

biocompatibility of the nanocomposite polymer. The SEM

image analysis illustrated that there were approximately

950 randomlydistributedporespermm2within thematrix,

which equates to approximately 7.6% of the total matrix

surface areawith ameanpore diameter size ranging from1

to 15mm in diameter.[78] Although these structures were

randomly distributed, and the poreswere not large enough

for cell infiltration, the overall matrix appeared to be

uniform with interconnected grooves, and they supported

the access of cells to nutrients and growth factors, and

provided effective nutrient/waste exchange. Under cell

culture conditions the growth rate of mESCs was similar to

that seen in gelatin, exhibiting undifferentiated morphol-

ogywith the expression of pluripotencymarkers. However,

after cell stimulation for differentiation, themorphology of

the mESCs changed dramatically, and the differentiated

cells formed a continuous cell monolayer, which was

embedded within the polymer matrix.[78,79] In summary,

these studies suggest that incorporation of POSS into the

polymer provides a non-toxic nanocomposite with the

potential of fabricating 3D scaffolds aswell as a thinmatrix

with the desired porosity, mechanical strength, and

biodegradability by precise and tuneable reaction proce-

dures.[79,80] In addition, it provides a conducive environ-

ment for cell–cell or cell–matrix interactions, which are

essential for newly formed tissue formation, andhold great

im www.MaterialsViews.com


www.mrc-journal.de

potential in mESC-based soft tissue engineering applica-

tions.[78]

Drug Delivery Systems

In general, the systemic administration of drugs is

associatedwith some clinical side effects. The aimof newly

proposed drug delivery systems is to carry the intended

drug(s) directly to the site requiring therapeutic interven-

tion. The basic scientific concepts surrounding the use of

nanotechnology-based drug delivery systems closely cor-

relate with the modulation of the pharmacokinetics of

incorporated molecules. With this intimate co-association,

the fundamental properties that govern drug absorption,

distribution, and elimination out of the human body are

determinedby thephysicochemical properties, particularly

by surface exposed functional groups that influence their

surface charge and size.[81] For instance, currently devel-

oped silicone hydrogels can be utilized as a matrix for

transdermal drug delivery,[82] while silicone microspheres

have been developed for pH-controlled drug delivery in the

gastrointestinal tract.[83] Nanocomposites are also being

considered for use in drug delivery systems. Biodegrada-

tion, thermodynamic stability, and biocompatibility, along

with improved surface features are all desired character-

istics that allow the nanocomposites to be considered as

ideal nanocarrierswithahighdistributionpotentialwithin

biological systems. The application of POSS nanomaterials

in drug delivery systems has potential advantages, such as

their being easily transferred by transmembrane and

vascular pores, owing to their small size and high charge

density, which increases the likelihood of cell and tissue

uptake (Figure 7).[36]

In order to assess the efficacy of silsesquioxane

nanocomposites to be used as drug delivery vehicles,

McCursker et al.[36] labelled octaammonium-POSS with a

fluorescent marker (boron-dipyrromethene, BODIPY) by

neutralization of ammonium on the POSS subunits with

triethylamine and substitution with a succinimidyl ester

derivative. BODIPY is a commonly used fluorescent marker

of the cell membrane, which can be readily conjugated to

various other systems to track cellular migration patterns

in vitro. In this study, it was found that the unique

chemistry of POSSwas the key element in the dispersion of

BODIPY conjugates (POSS-BODIPY) in the cytoplasm when

compared with BODIPY alone. Moreover, the conjugate did

not influence the cellular morphology in COS-1 cells. Cell

viabilityassaysproved that thecellswithconjugatehadthe

same activity level as the controls, indicating that POSS

represented low levels of toxicity. Furthermore, dispersion

in the cytoplasm demonstrated that the POSS-BODIPY

conjugate entered into the cells by passive diffusion, not by

endocytosis. The results demonstrated that specific locali-

sation of the conjugate could be achieved within the cell,




and observations showed that POSS could be used as a

potential drug system by direct conjugation with func-

tional drug moieties that are insoluble in aqueous systems

or that exhibit lower cellular uptake (Figure 7).[36]

More recently Tanaka et al. demonstrated an enhanced

entrapment ability of dendrimers by incorporation of a

POSS central core. Their results showed that the POSS-core

dendrimer can entrap a larger amount of guest molecules

without loss of affinity, and consequently, the water

solubility of the entrapped guest molecules can be

increased. In addition, they demonstrated that a fluor-

ophore entrapped in the POSS-core dendrimer was pre-

vented from undergoing fluorescence photo-bleaching.[37]

Not only do the chemical and physical properties of the

nanosystems, as determinant factors in drug distribution

and kinetics in the biological environment, need to be

optimized, but optimization of manufacturing techniques

for mass production for commercialisation and clinical

translation should be investigated further.[84] Simplifica-

tion of the manufacturing techniques, and optimisation of

targeted drug delivery systems by self-assembly of pre-

functionalised materials, can facilitate high volume man-

ufacturing processes.[85,86] The self assembly process leads

to the construction of a vesicle shell, which contains the

active drug molecules in the centre. These shells are

expected to have strong characteristics in order to prevent

any drug leakage and to avoid immune system recognition

by impeding protein adhesion.[84] Because of their strong

framework and degradation resistance, which results from

intermolecular forces between constituent molecules and

their nearest neighbours, POSS molecules can be used as

templates for the production of drug delivery core–

shells.[36] More recently, a self-assembled spherical amphi-

philic nanoparticle composed of a POSS hydrophobic core

and a poly(vinyl alcohol) (PVA) hydrophilic outer shell has

been studied.[87] In vitro tests have shown that these

nanoparticles areable to releasemodel drugs ina controlled

manner. POSS incorporation also improved the thermal

stability and hydrophilicity of PVA making it a

potential carrier for peptides, drugs, and DNA.[88,89] In

addition, owing to its size and unique nanostructure this

drug delivery system is capable of travelling within the

body and carrying the drug to target regions within the

tissues.[87,90]

In a further recent study, a new nano-drug delivery

system has been proposed based on poly(L-glutamic acid)

dendrimerswith POSS composed of a central core (Figure 7).

By incorporating pH-sensitive functional groups by hydra-

zine bonds and a targeting moiety, the cellular internaliza-

tion and anti-tumour potential of the OAS-G3-Glu den-

drimer conjugated with doxorubicin was assessed in

vitro.[91] In this study the release of doxorubicin at different

rates and pH was investigated and the cellular uptake of

conjugated antibodies using biotin was also analysed. The

2011, 32, 1032–1046


Figure 7. Fluorescence confocalmicroscopy imageswith POSS-BODIPY show efficient uptake in the cytosol (A). B) Controlmicroscopy imageswith amine-terminated BODIPY show no cellular uptake of the dye in the absence of POSS (image adapted from ref.[36]). In (C) a novel nano-drug delivery and bioresponsive system is presented based on poly(L-glutamic acid) dendrimers with POSS composed of a nanocubic core(image adapted from ref.[91]). In (D) a schematic illustration of therapeutic targeted drug delivery systems based on POSS nanoparticles arehighlighted as follows: I) POSS incorporated into the drug delivery system, II) migration of the drug delivery system through capillary wallstowards the targeted primary tumour cell site, III) attachment of the nano-drug to the malignant cells by specific receptors, and IV)therapeutic effects of the drug and significant reduction and elimination of the malignant cell population.

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results demonstrated that the spherical morphology,

compact structure, and functional groups around the

periphery of the core–shell enabled this nanosystem to

be a suitable candidate for drug delivery applications.[91]

In line with established pharmacological studies, it

appears that attention is growing towards the application



of nanoparticles for chemotherapy, drug delivery, and

imaging. For example, in tumour diagnostics, the physi-

cochemical features of the nanoparticles such as particle

size, surface coating, charge, and stability allow the

qualitative or quantitative in vitro detection of tumour

cells at the site of interest. In this case, nanoparticles can

2011, 32, 1032–1046



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act either by direct or indirect mechanisms. Taking

advantage of tumour vasculature hypermeability can

give the nanomaterials the flexibility of direct targeting of

primary tumours in the tissues. However, in an indirect

way these particles can target the tissue or cells near the

tumour and act as a drug reservoir to prevent proliferation

and migration of adjacent neoplastic cells. A controlled

drug delivery system at the site of interest, cell inter-

nalisation, efficient drug protection, and prevention from

premature inactivation during transportation seems to be

achievable if designed appropriately by utilising the

physicochemical properties of the nanoparticles by way

of design, e.g., incorporating chemical functionality and

specificity into the 3D structure.[92]

Dental Nanocomposites

Dental composites and methacrylate-based polymeric

systems have been used extensively for hard and soft

lining materials (usually alongside metallic and ceramic

materials). Resin-based acrylic polymers, inorganic glass,

or ceramic fillers are commonly used materials as filling

and restorative composites in dentistry.[93] The acrylate

resinmatrix is usually cured (hardened) byphoto-initiated

free radical polymerisation.[38] Despite increased efforts to

improve the overall mechanical properties of dental

materials, there is still considerable research efforts in

addressing their physicochemical characteristics. For

example, polymerisation shrinkage, wear resistance,

biocompatibility, lack of strength, toxicity of monomers,

and modulus of elasticity are all key research themes. In

addition, inflammation as well as hypersensitivity reac-

tions to dental materials, although rare, have been

reported.[47,94]Much effort is nowbeingmade to overcome

potential drawbacks in specific applications. More

recently POSS-containing nanocomposite materials are

being considered as potential candidates to improve

material and surface properties. The potential for POSS

inclusion in the modification of dental materials was first

proposed by Sellinger and Laine in 1996.[95] The small size

of POSS structures when compared with other nanofillers

(10–100 nm) is a unique characteristic, as well as having a

wide range of chemical functionality to incorporate

reactive chemical groups. Moreover, an increased Tg and

oxygen permeability have been demonstrated when

POSS derivatives are incorporated into polymer

matrices.[94,96,97] In a study by Culbertson et al. three

differentmethods of incorporating amono-methacrylated

POSS into dental compositeswere studied as follows: 1) by

manufacturingPOSS-containingmacromonomers, and co-

polymerization with dental monomers, 2) by using a one

steppolymerisationof POSSwithdentalmonomers, and3)

by developing a POSS co-polymer followed by in situ

polymerisation with dental monomers. The results




demonstrated that reacting methacrylate POSS into

known dental polymeric formulations significantly

decreased polymer shrinkage, although a slight reduction

in mechanical properties was observed, especially at

loadings greater than 10wt.-%. Their work indicated that

synthesising POSS-containing macromonomers enabled

the improved overall dispersibility of POSS when reacted

with dental monomers.[96,97]

Methacrylated and octaphenyl-POSSmoieties have been

reacted with HEMA (2-hydroxyethylmethacrylate),

BisGMA (bis-phenol A-glycidyldimethacrylate), and

TEGDMA (tetraethylglycidylmethacrylate)-based restora-

tive fillers, and Dodiuk-Kenig et al. compared the effect of

the two different terminal functional groups on POSS by

investigating the thermal, mechanical, and physical

properties. They found that acrylated POSS resulted in a

5 8C increase inTg, a7% increase in compressive strength, an

increase in bond shear strength (36%), and a decrease in

polymer shrinkage by 28%, while incorporation of octa-

phenyl-POSS decreased the compressive strength by 20%,

the bond shear strength by 49%, and polymer shrinkage by

67%. Itwas concluded that themechanical properties of the

dental composites were significantly improved by acry-

lated POSS, but diminished with octaphenyl-grafted POSS,

indicating that the chemical functionality of the side-chain

groups had a strong influence on the dental materials and

their adhesive behaviour.[98]

The main obscurity in developing dental materials with

low polymer shrinkage rates is the shortfall in mechanical

properties to achieve the requirements that are necessary

for clinical use. It hasbeen frequentlymentioned that POSS-

modified polymers can be achieved at relatively low cost

and have good processability, toughness, and thermody-

namic and anti-oxidative surface properties.[99,100]

Recently, Wu et al. evaluated the effect of methacrylated

POSS incorporated into Bis-GMA and TEGDMA dental

composite resins. In this study, POSS was incorporated

into the resins at different weight percentages ranging

between 0 and 15wt.-%. The microstructure was char-

acterised using FT-IR spectroscopy and XRD studies. It was

found that adding 2wt.-% of POSS resulted in improved

mechanical properties with a 15% increase in flexural

strength, a 12% increase in compressive strength, a 15%

increase in hardness, as well as enhanced toughness of the

resins. They concluded that incorporation of as little as

2wt.-% POSS improved themechanical properties of dental

materials.

The influence of POSS on the biocompatibility of

methacrylate-based dental composites was also studied

by Kim et al.[47] In this study, an acrylic-based hybrid

composite with POSS showed improved biocompatibility.

Therefore, taking advantage of the aforementioned proper-

ties and its rigidity, POSS can be used as a potential

candidate in reducing the shrinkage of dental composite

2011, 32, 1032–1046


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materials based on multi-methacrylate functional groups,

as well as improving their biocompatibility confirmed by

metabolic and mutagenic studies.[47,96] In a further study

investigating novel dental restorative composites, metha-

cryl-functionalizedPOSS (POSS-MA)wasused to replaceBis-

GMA. The mechanical properties, shrinkage rate, and

degree of double bond conversion of the methacrylates

by photo-polymerization were investigated. The results

demonstrated that a percentage substitution of 10% (or

less) of Bis-GMA with POSS-MA improved the flexural

strength and Young’s modulus, but quantities greater than

25% led to poor mechanical performance, and diminished

properties with a reduced conversion of methacrylate

double bonds, and significantly reduced the rate of photo-

polymerization.[38]

The use of POSS for dental composites in both hard and

soft lining materials highlights a challenging and promis-

ing area that warrants future investigation. Although, it

should be stressed that the uniform dispersion of POSS

throughout the polymeric matrix and their correct synth-

esis routes to achieve dispersibility needs to be addressed,

as both are crucial in understanding their mechanical

performance and physicochemical properties for their use

indentistry, and their influenceon the cells andhost tissues

in the biological environment.

Biological Sensors

POSS has the unique capability of being combined with a

variety of organic compounds in order to specify its

functionality. The eight vertices of a cubic POSS structure

can bond with different side-chain functional groups such

as amine (�NH2), sulfydryl (�SH), hydroxy (�OH), carboxy

(�COOH), and in particular ammonia (�NH3), which leads

to cationic groups on POSS that have been widely used in

applications such as gene and targeted drug delivery, and

detection of DNA and peptides. In particular, POSS

structures have beenused as probes for detecting biological

macromolecules using resonance light scattering (RLS)

techniques as considered by Zou et al.[39] It was demon-

strated that by adding DNA to an aqueous solution of

cationic POSS that the intensity of RLS at l360 nm was

significantly improved. Thus, the RLS intensity strongly

correlatedwith the increasedamountsofDNAandthis type

of interaction was dependent on the pH value and ionic

strength suggestive that it was primarily electrostatic in

nature. This system has many advantages over conven-

tional techniques as a result of sensitivity and the speed of

data acquisition, and can be potentially used as a probe to

determine the concentration ofDNA. Several types of POSS-

containing networks such as octa-aminophenyl POSS

(cationic POSS) have been employed as new reagents for

RLS studieswithDNAsince theyhavegoodwater solubility,



stability in a wide range of pH, and high sensitivity and

selectivity.[39]

Conclusion and Future Perspectives

The emerging field of nanomedicine will continue to

revolutionize current medical practice. The unique proper-

ties of POSS and its ability to be incorporated into a wide

range of biocompatible polymers make POSS an attractive

nanomaterial for a versatile array of applications in

medicine. The application of POSS-containing nanocompo-

sites for cardiovascular biomaterials has been widely

explored with very promising results. As these materials

are safe, biocompatible, compliant, resistant to degrada-

tion, anti-thrombogenic, and haemocompatible, the prob-

ability of microvascular occlusion and thromboembolic

events is sufficiently lowered. In addition, such materials

can be tailored to show resistance to calcification and

enhanced mechanical and surface properties, and may be

capable of grafting biologically active macromolecules to

enhance the adhesion, proliferation, and differentiation of

circulatory stem cells into endothelial cells, which are

amongtheotheradvantagesofusingPOSSnanocomposites

in the development of cardiovascular devices. Enhanced

biocompatibility of POSS nanomaterials can be merged

withunique featuresofothernanoparticulate systemssuch

as quantum dot nanocrystals, and silver nanoparticles to

develop novel diagnostics and therapeutics for clinical

applications. POSS-basednanocomposites havebeen inten-

sively studied for novel approaches to tissue engineering.

Thesehighly biocompatiblematerials canbedesignedwith

tunable biodegradation rates and intricate chemistries that

providesuperior scaffolds for tissueengineeringwithmany

different cell types, tissues, and organ systems. Recent

efforts are now being concentrated on using microfabrica-

tion technology and microelectromechanical system

(MEMS) tools to create smart scaffolds that have an

inherent ability and regenerative capacity within the body

for in vivo tissue engineering approaches. If successful, and

in the long run, the clinical implications would offer

significant benefits as the ability to ‘grow’ new tissue in the

laboratory would diminish the need for tissue transfers

during surgery, the transplantation of vital organs, such as

the liver, and would obviate the need for in vivo testing

using animal models. Work continues on the use of POSS

nanomaterials indevelopingbreast implants, drugdelivery

systems, dental materials, biological sensors, and other

areas related to nanomedicine. The immense potential of

POSS nanomaterials for a wide range of biomedical

applications has now opened up new horizons into the

emerging field of nanomedicine with bright future

prospects.

2011, 32, 1032–1046



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Acknowledgements: The authors thank Yasamin Rafiei Naeeni,Dr. Gaetano Burriesci, Dr. Bala Ramesh, and Arnold Darbyshire ofUCL for very useful comments and suggestions.

Received: March 2, 2011; Published online: May 19, 2011; DOI:10.1002/marc.201100126

Keywords: biomaterials; nanocomposites; nanomedicine;polyhedral oligomeric silsesquioxane; tissue engineering

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