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James P. Best, Yan Yan, and Frank Caruso*

The Role of Particle Geometry and Mechanics in theBiological Domain

1. Introduction

In the past few decades a diverse spectrum of particulatedelivery systems have been developed, with sizes ranging froma few nanometers to micrometers. Among these delivery sys-tems, drug-loaded liposomes and albumin nanoparticles havereached clinical application and have shown increased efficacyand minimized toxic side effects in the treatment of cancer.[1]These successes promise momentous advances in healthcare,as these particulate systems offer a number of advantages overtraditional therapy[2] including: i) improved single or multipletherapeutic loading while shielding potentially fragile or toxiccomponents; ii) tailored pharmacokinetics to evade mononu-clear phagocytic system (MPS) clearance,[3,4] allowing for opti-mized biodistribution;[5] iii) subcellular targeting to delivertherapeutics to the intracellular site of action; iv) overcomingsubcellular barriers, such as drug pump-related multidrugresistance (MDR);[6] and v) triggered therapeutic release inresponse to specific physiological stimuli.[7]

The preparation of particulate carriers typically involvesbottom-up approaches, due to the inherent high degree of

molecular-level specificity afforded. Polymersomes and lipo-somes,[812] polymer capsules,[7,13,14] mesoporous particles,[15]along with polymer,[1618]gold,[19,20]carbon,[21,22] and silica[21,23]nanoparticles have been fabricated using this approach. Only

recently have several top-down methods,such as PRINT (particle replication innonwetting template) or microlithography,been explored to fabricate delivery sys-tems for biomedical applications, largelyowing to the ability to precisely controlshape, size, and scalable production.[2426]Efforts have been directed to the control ofchemical properties such as surface func-tionality and cargo release. Surface func-tionalization is achieved using a variety ofconjugation chemistries, including thiol/disulfide, biotin/avidin and alkyne/azidecoupling, and affords increased controlover particle interactions in biological sys-tems. Hydrophilic polymer brushes, suchas poly(ethylene glycol) (PEG), may be

used to improve circulation times due to reduced bio-foulingand opsonization,[27,28]while surface-conjugated targeting moi-eties such as ligands or antibodies can selectively promote theinteraction with specific tissues or cells.[29,30] Coupling chem-istries have also been employed to engineer triggered releasein particulate systems;[13,3133] reducible disulfide linkagesunder cellular concentrations of glutathione[34,35] and cleavage

of hydrazone-doxorubicin conjugates under acidic conditions[36]are notable examples. Using these approaches, a range oftherapeutics, including small cytotoxic compounds, peptidesand siRNA, have been successfully delivered in vitro and invivo.[1,35,3739]

In addition to the effect of bulk and surface chemistry, morerecent studies have shown that the physical properties of par-ticle delivery vectors also have a profound effect on the bloodcirculation dynamics and lifetime, biodistribution, and cellularinteraction and uptake.[40]To ultimately control the in vivo per-formance of particle systems, both theoretical and experimentalbiological studies of material elasticity, deformability,[4148] andgeometry[40,46,4852]have been undertaken. This Review focusesexclusively on the fabrication and characterization of advancedparticle delivery vectors with variable physical properties suchas size, shape, and elasticity and implications of these proper-ties upon biological interactions and material performance.

2. Particle Geometric Ratio

While the influence of particle size on circulation clearance,cell-uptake mechanisms, and flow effects has been studied indetail,[7,19,5355] only recently has it been reported that shape,roughness, and the resulting surface area of particles mayalso have a significant impact upon biological response.[40,56]

J. P. Best, Dr. Y. Yan, Prof. F. Caruso

Department of Chemical and Biomolecular EngineeringThe University of MelbourneParkville, Victoria 3010, AustraliaE-mail: [email protected]

DOI: 10.1002/adhm.201100012

Nanostructured particulate materials are expected to revolutionize diagnos-

tics and the delivery of therapeutics for healthcare. To date, chemistry-derived

solutions have been the major focus in the design of materials to control

interactions with biological systems. Only recently has control over a new set

of physical parameters, including size, shape, and rigidity, been explored to

optimize the biological response and the in vivo performance of nanoengi-

neered delivery vectors. This Review highlights the methods used to manipu-

late the physical properties of particles and the relevance of these physical

properties to cellular and circulatory interactions. Finally, the importance offuture work to synergistically tailor both physical and chemical properties

of particulate materials is discussed, with the aim of improving control over

particle interactions in the biological domain.
http://doi.wiley.com/10.1002/adhm.201100012

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James Bestis a Ph.D. stu-dent in the Department ofChemical and BiomolecularEngineering at The Universityof Melbourne, and works

under the supervision of Prof.Frank Caruso. He receivedhis Bachelors degree inChemical Engineering(Hons.) and Science(Chemistry) also from TheUniversity of Melbourne

in 2008. His current research interests include the mechan-ical analysis of nanoparticles for biomedical applicationsusing atomic force microscopy.

Yan Yanreceived her Ph.D. inBiochemistry and MolecularBiology from Peking University(P. R. China) in 2008. Currently,she is a post-doctoral researchfellow in the NanostructuredInterfaces & Materials groupheaded by Prof. Frank Carusoat The University of Melbourne.Her research focuses on theinterface between materialsscience and biology.

Frank Carusoreceived hisPh.D. degree in 1994 from

The University of Melbourneand then moved to the CSIRODivision of Chemicals andPolymers in Melbourne tostudy the interfacial alignmentof receptor molecules for bio-sensor applications. He wasan Alexander von HumboldtResearch Fellow and thengroup leader at the MaxPlanck Institute of Colloids

and Interfaces (Berlin, Germany) from 1997 to 2002.Since 2003 he has been a professor in the Department ofChemical and Biomolecular Engineering at The University

of Melbourne. His research focuses on polymers at inter-faces, nanostructured colloidal systems, nanocompositethin films, and biomaterials.

Because these geometric features, including size, shape, andsurface area, interdependently affect biodistribution and cel-lular uptake, an integrative parameter, namely the surface-area-to-volume ratio (SAV), may be used in analyzing these systems.It can be noted that the SAV increases when the particle sizedecreases and the geometry becomes more complex, as can beseen for the systems in Figure1.

A trend can be noted in the literature describing a loga-rithmic decrease in phagocyte uptake with increasing SAV dueto flow alignment effects, whilst cellular uptake into target cells

increases logarithmically due to improved surface interaction.Therefore, this chapter will first address progress in fabricatingnonspherical particles, followed by an analysis of recent litera-ture on how the geometric components of particulate systemsaffect blood flow dynamics, cellular uptake and intracellulardynamics.

2.1. Nonspherical Particle Fabrication

Fabrication of particles with controlled sizes can be achievedwith relative ease through adjustment of discrete fabricationparameters on both micro- and nanoscales.[5760] Althoughgood examples exist of nonspherical particle systems(Figure 2), obtaining a high degree of control over particleshape still remains a challenge, limiting investigation into highSAV particulate drug-delivery systems. Recently, review articleshave focused on the fabrication of nonspherical drug deliverycarriers,[61,62] and as such, synthetic methods will not be dis-cussed in great detail here, but will be briefly addressed to pro-vide context for the current review.

The biological interactions of metal nanoparticles of variousshapes have received much attention,[63,64] with gold nano-rods being the most widely investigated due to their extensivesynthesis library.[65,66] Gold nanorods have also shown poten-tial for ablation therapy due to their strong surface plasmon

Figure 1. Impact of particle geometry upon the surface area to volumeratio (SAV). A 5.5 m diameter sphere (top left, SAV 1) displays areduced SAV when compared to biconcave RBCs (top right), whilethe internal volume (V1) is held constant. Additionally, as particle sizedecreases toward a 350 nm diameter nanosphere (bottom left), the SAVincreases dramatically, and even more so for a long filomicelle (bottom

right) with an equal internal volume to the nanosphere (V2).

resonance effects.[67] Gold nanorods are generally synthesizedusing a surfactant-based stabilizer[68]and can be simply modi-fied with polyelectrolytes[69]or PEG for low bio-fouling.[20]Simi-larly, chemically stabilized silica-,[70,71]carbon-,[72]and palladium-based[73] rod structures have been fabricated with biological

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applications in mind. Although good growth control of nanorodsystems has been demonstrated, their use is restricted by rapidrenal clearance, in some cases inherent toxicities, and chal-lenges in producing monodisperse suspensions of nanoparti-cles with a major axis greater than 200 nm.

In contrast to inorganic systems, the volume of recent litera-ture describing the fabrication of nonspherical polymer particlesis limited. Many techniques focus on lithographic, microfluidic,and PRINT methods, often incorporating photopolymeriza-tion,[7480] or through the self-assembly of colloids[81,82] or pol-ymer chains to form filomicelles.[8387]In addition, mechanicallymodified polystyrene (PS) and poly(lactide-co-glycolide) (PLGA)particles with a broad range of possible geometries have beenfabricated through the controlled stretching of a hydrogel pol-ymer matrix containing a dispersion of the particles. [49,62,8892]Although anisotropic hollow polymer capsule systems havebeen reported,[93,94] capsules with nonspherical shapes havenot received much attention. Studies include polyelectrolyteadsorption and then dissolution of either red blood cell, [95100]bacterial,[97]or large glass-fiber[101]micro-templates, along withthe controlled deposition of polypyrrole onto hydrogen bubbleswith variable detachment geometries.[102] On the nanometer

scale, researchers have fabricated hollow polyeletrolyte nano-tubes using pressure filters,[103]nickel nanorods,[104]and poroustemplates,[105]while Muller et al. produced hollow DNA nano-tubes using an electrospun fiber template that is soluble intetrahydrofuran.[106]

2.2. Biological Effects

Particles of variable size and shape have been increasingly

investigated in the literature due to their effect on biologicalsystems both in vitro and in vivo. In terms of flow-dynamics,reports have shown that the SAV may affect the propagation ofparticles in both interstitial and intravascular compartments,margination toward capillary walls, clearance through fenestra-tions, and alignment and turbulence in flow fields. For cellularassociation, the SAV and associated curvature effects influenceantibody interaction area and adhesion strength,[107]opsoniza-tion,[108] and internalization kinetics and mechanisms.[49] TheSAV also affects intracellular aspects through nuclear align-ment and particle degradation. This section will thereforefocus on these effects within the context of recent literature.

Figure 2. Images of nonspherical particles. a) Transmission electron microscopy (TEM) image of cylindrical 1 m diameter polymer particles in HeLacells fabricated using PRINT. Reproduced with permission.[24]Copyright 2008, Springer. b) Scanning electon microscopy (SEM) images of RBC shapedPLGA particles generated using electrohydrodynamic jetting. Reproduced with psermission.[153]Copyright 2009, National Academy of Sciences. c) SEMof high-aspect-ratio triangular prisms fabricated using flow lithography. Reproduced with permission.[26]Copyright 2006, Nature Publishing Group.d) SEM image of long PLGA particles fabricated using mechanical stretching. [52]e) SEM image of discoidal particles fabricated using a combinationof microlithography and reactive ion etching. Reproduced with permission.[25]Copyright 2010, Elsevier. f) SEM image of PS vase fabricated usingdirect replica transcription from silica. Reproduced with permission.[177]Copyright 2006, Nature. gj) TEM images of surfactant-stabilized gold nano-

rods with increasing aspect ratio. Reproduced with permission.[129]Copyright 2010, Elsevier. Scale bars are 100 nm (gj), 1 m (f), 5 m (b,d), 6 m(e), 10 m (c).

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2.2.1. Flow Dynamics and Biodistribution

According to fundamental fluid dynamic science, the movementof a particle within a flow regime is governed by both shape andsize. The size of particles administered in blood vessels may dic-tate their velocity and diffusion,[109]while particle movement in

tissue is limited by size due to steric hindrance within the extra-cellular matrix.[49] For nonspherical particles, angular move-ment under flow is often described using the rotational Pecletnumber, Pe =

. Dr/ , which takes into account Brownian and

non-Brownian motions of particles. The rotary diffusivity, Dr, isclosely related to the aspect ratio of the particle, and quantifiesthe extent of Brownian motion. For high Pevalues, anisometricparticles are not prone to Brownian effects and solely tumbleend over end periodically, as described by Jeffery.[110]The rate oftumbling,

., can be quantified according to Equation 1:

.=

.

1

r2e + 1

r2

ecos

2+ sin2

(1)

Where . is the strain rate, re is the effective particle aspectratio, and is the angle between the long particle axis and theplane orthogonal to the flow direction.[111,112]Larson states thatfor a Jeffery orbit, the period of rotation increases for increasingaspect ratio. Large-aspect-ratio particles decelerate in rotationalvelocity when the long axis is nearly parallel to the flow direc-tion, and accelerate otherwise.[112]Mueller and co-workers veri-fied that re, which is determined experimentally and relatedto the actual aspect ratio, impacts dramatically upon angularvelocity, and in turn determines the particle position probabilitydensity.[111] This is shown in Figure 3 for prolate and oblateellipsoidal particles. It is important to note that a nonsphericalparticle will therefore spend a greater amount of time aligned

with a flow field, reducing the available cross-sectional areafor interaction with other particles or cells. This was recentlyobserved experimentally in vitro by Discher and colleagues forlong filomicelles, which avoid interaction with phagocytic cells,using flow rates similar to those found in the spleen.[48]As thefilomicelle length increased from 1 to 3 m, uptake into macro-phages decreased dramatically and logarithmically due to align-ment of the filomicelle within the flow field.

When investigating the effect of the SAV on the shear rateand the turbulent nature of a particle suspension within a flowregime, a modified Reynolds number, Rep = 4Gc

2/, can beadopted where G is the shear rate, and the kinematic vis-cosity.[113]Qi and Luo investigated the effect of aspect ratio onRepand particle rotational state in Couette flow, and observed

that particle shape had a clear impact upon Rep. The authorsobserved several distinct regions of Repwhere independent rota-tional states such as tumbling, wagging, flow aligning, log-rolling, and kayaking occurred.[113] In terms of particle size,Decuzzi and co-workers showed that for silica microspheres ini-tially adhered to a flow-chamber substrate, the critical shear rateincreased dramatically as the particle diameter increased from1.3 to 5 m,[25]which is consistent with the conclusions of bothGoetz et al. and Lamprecht et al.[54,55]This illustrates that par-ticle geometry has a large influence on the shear experienced inboth the capillary and vasculature, affecting cellular interactionand adhesion with immune-system cells under flow conditions.

These observations can be placed further in a biological con-text by examining literature describing the margination proper-

ties of particles. Margination is defined as the movement andinteraction of particles toward the endothelial wall in blood cap-illary channels. This is a critical aspect of therapeutic delivery toendothelial cells and also in being able to exploit the enhancedretention and permeability (EPR) effect for passive deliveryto tumor sites, where EPR is a size dependent process with amaximum limit of approximately 500 nm.[114]Decuzzi and co-workers discussed the margination propensity of particles withdifferent geometries, where due to the core movement of redblood cells in capillaries, there exists a cell-free layer within closeproximity of the endothelial wall in which particles with littlepropensity for longitudinal and lateral drift would remain. [115]This result was also found by Goldman et al. for spherical par-

ticles, which were found to reside within this laminar phaselayer unless an external lateral force was applied. [116]Nonspher-ical particles, however, exhibit an intrinsic hydrodynamic lat-eral force and torque, meaning that these particles marginatehighly, interacting with the endothelial wall to a greater extentthan spherical particles. This has been validated by experimentsperformed by Gentile and co-workers using a parallel plateflow chamber to measure the margination propensity of silica

Figure 3. The effect of particle geometry on capillary flow behavior. a) The aspect ratio (re) governs the magnitude of angular velocity under simpleshearing flow. Reproduced with permission.[111]Copyright 2010, Royal Society Publications. b) Platelets interact heavily with the endothelial walldue to their irregular shape. 1) Tethering, 2) rolling angular velocity and activation, and 3) firm adhesion with the wall are all affected by the plateletgeometry.

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co-workers found that clathrin-mediated endocytosis dominatedfor PS-based microspheres with a diameter less than 200 nmincubated with eukaryotic cells, with a shift towards caveolae-mediated internalization as the microsphere size increased.[125]

While the cellular uptake of particles is influenced by thesize, more recent studies have also demonstrated the significant

impact of the shape on cell dynamics. DeSimone and co-workersinvestigated cationic PRINT particles with various sizes andshapes, examining both uptake kinetics and mechanisms.[126]Cylinders (150 nm 450 nm) were internalized quicker andto a greater extent than 200 nm diameter spherical particles inHeLa cells, even though the internal volume of the cylinderswas greater. By using endocytic inhibitors, it was found thatthe cylinders utilized multiple mechanisms to a greater extentthan the spheres to enter the cells, correlating with other exten-sive studies by DeSimone and co-workers for 1 m cylindricalPRINT particles with both positive and negative charges, whichshowed both dual clathrin-mediated endocytosis and macropi-nocytosis uptake routes were predominantly utilized in a rangeof cell lines.[24]This is consistent with the observation that the

increased SAV of cylinders would further promote interactionbetween the cationic surface and the cell membrane proteins.Mitragotri and co-workers compared the cellular internaliza-tion of 1 m PS spherical and elliptical particles with the sameinternal volume in endothelial cells.[52] It was found that thespheres internalized much more rapidly, however this differ-ence was seen to decrease over time. This work was extended byexamining the effect of the alignment of the particle major axisto the cellular membrane, quantified by the initial contact angle(), on cell membrane penetration velocity and internalizationusing rat alveolar macrophages.[127] Particles with their majoraxis oriented tangentially to the cell membrane, that is as approaches 90, exhibited dramatically reduced internalization.

This was mainly attributed to the necessary expansion requiredto form an actin cup for phagocytosis, while similar internaliza-tion trends were seen for the static incubation of long worm-like polymer particles with phagocytes, as seen in Figure4.[15,48]Similar time-dependant high-aspect-ratio particle alignmentwas also seen by Mitragotri and co-workers for elliptical disk-shaped PLGA particles tangentially aligning in the cytoplasmwith the nucleus of pooled human umbilical vein endothelialcells.[52]Over long time scales spherical particles were found tohave a shorter average distance to the cell nucleus, which hasimportant implications for the delivery of therapeutics that havelimited diffusion coefficients in the cell cytoplasm.

Yang and Ma also simulated the effect of for different SAVnanoparticles on the penetration of a model lipid bilayer. [128]

They showed that the minimum driving force of the ellipsoidalparticle for breaching the lipid bilayer was dependent uponinternal volume, aspect ratio, and approach angle. It was alsoshown that the process was time dependent; with time, theellipsoid aligned itself tangentially with the bilayer, alteringthe angle . Placing this in context with experimental goldnanoparticle interactions with cell-lines, Chan and co-workersshowed that 14 nm 40 nm and 14 nm 74 nm gold nanorodsinternalized into HeLa cells at a much slower rate than spher-ical nanoparticles with a diameter of 74 nm. [19]This correlateswell with the modeling of Yang and Ma[128] and experimentalwork on surfactant-stabilized gold nanorod internalization

into human breast adenocarcinoma cells, where increasing theaspect ratio slowed uptake.[129]Chan and co-workers also dem-

onstrated that gold nanoparticles with a diameter of 50 nm wereoptimal for HeLa internalization, an effect most likely due toharnessing multi-mechanism internalization, and differencesin adsorption of serum proteins due to curvature effects.[19] Inaddition to the work on gold nanorods, several groups have alsostudied DNA or protein delivery using carbon nanorods, andhave found them to deliver effectively into the cellular cyto-plasm via an endocytotic mechanism.[130,131]

In therapeutic delivery applications, cargo must be oftenreleased in a controlled manner, and delivered into the cyto-plasm in order to interact with the cell nucleus. In some cases,degradation and cargo release may depend upon the particleSAV. Dunne and co-workers investigated PLGA microspheremass loss due to hydrolysis, and found that larger spheresdegraded at almost twice the rate of smaller ones, primarily dueto longer diffusion path lengths allowing autocatalytic degra-dation.[132]However for a similar system, Labhasetwar and co-workers found that a 100-fold decrease in particle diameter hadlimited effect on bovine serum albumin release.[133]

3. Stiffness and Deformability

The assembly or arrangement of a material within a structureis of design importance, and the Youngs Modulus (EY) is oftenused to characterize the intrinsic mechanical properties of the

Figure 4. Phagocytosis of nonspherical particles. Images of PS disksorientated end-on (a), disks side-on (b), spheres (c), and IgG adsorbedworms (d) fabricated via mechanical stretching of spherical beads. ac)Reproduced with permission.[127]Copyright 2006, Natioanl Academy ofSciences. d) Reproduced with permission.[15]Copyright 2009, Springer.

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constituent materials. The stiffness or rigidity of particle sys-tems can be affected by material variations, such as the porosityof solid particles, as well as the diameter and shell thickness

of hollow systems. There are a number of approaches to tunethe mechanical properties: for instance, co-assemblies affectthe mechanics of colloidal structures; cholesterol incorporatingliposomes[51] and polymer systems doped with metal nano-particles[134,135] exhibit increased rigidity. More frequently, theextent of chemical bonding or crosslinking in polymer systemshas been used to control rigidity and EY. In separate work, theGiasson and DeSimone groups showed for hydrogel nanopar-ticles and microparticles, respectively, that through adjustmentof the crosslinker concentration, control over EY and systemstiffness could be afforded.[41,46]Fery and co-workers also dem-onstrated that by controlling hydrogen bonding interactionsin microcapsules, the stiffness could be controlled using pH,where the stiffness was seen to reversibly increase and decrease

by two orders of magnitude by cycling the pH between 2 and6.[136]This precise control over the mechanical properties of par-ticulate systems has lead to an improvement in the characteri-zation methods available, along with an early understanding asto how particle stiffness and deformability affect cellular inter-action. These will be discussed further in sections 3.1 and 3.3.

3.1. Mechanical Characterization of Particulate Materials

Characterization of elastic properties can be achieved using twodifferent approaches, either through bulk analysis of particulate

suspensions, or through single particle investigation. For singleparticle techniques, while detailed information can be obtainedfor individual system components, collecting enough data for

a meaningful statistical analysis renders it a time consumingprocess. However, bulk analysis data can be difficult to effec-tively process into information on singular elastic componentsdue to intrinsic system effects.

3.1.1. Bulk Techniques

The use of rheological methods and systems for measuringthe bulk properties of polymeric materials is quite commonfor macroscopic hydrogel materials,[46]however, several groupshave also shown that elastic information can be obtained forpolymer nanoparticle systems.[137] Mder and co-workersdemonstrated for lipid based colloidal drug carriers that theelastic storage and loss modulus, along with the complex vis-

cosity of the suspension, could be elucidated using both con-tinuous shear rheometry and oscillatory testing.[138]For hollowpolymer capsules, bulk elastic measurements are generally per-formed using either an osmotic swelling or buckling approach(Figure 5).[42,44] In this method, the osmotic pressure is con-trolled through the addition of polyelectrolyte either inside oroutside the capsule volume, forming a polyelectrolyte-associatedcounterion cloud.[139] This pressure exerts a force, with direc-tion and magnitude dependent on the concentration gradient.Using microscopy techniques and noting the critical osmoticpressure at which a capsule collapses for a given shell thick-ness and radius, or alternatively the degree of radial swelling,

Figure 5. Mechanical characterization methods for nanoparticles and hollow capsules. a) Schematic diagram of a nanoparticle acoustic response toenergy absorption, and associated vibrational spectra. Reproduced with permission.[176] Copyright 2010, American Chemical Society. From thermalequilibrium (1), thermalization occurs upon excitation with an ultrafast electron (2), giving off acoustic vibration (3) and subsequent cooling (4). b)Confocal fluorescence microscopy images of osmotically buckled (left, scale 10 m) and ruptured (right, scale bar 5 m) polyelectrolyte capsules andc) RICM used in tandem with a colloidal-probe AFM set-up to characterize buckling events for polyelectrolyte microcapsules, where region (A) relatesto a small deformation regime, (B) relates to an adhesion area increase, and (C) is capsule buckling. Reproduced with permission.[42]Copyright 2004,IOP Publishing.

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both the elastic and Youngs moduli can be evaluated. Mhwaldand co-workers observed that this technique is limited in theaccessible force range obtained, and that in situ force changesare not possible,[139]while Vinogradova noted that for osmoticdeformation equations to apply, the capsules must not stretch,be infinitely permeable to water, and be impermeable to small

ions, further limiting the technique.[

44

]

Due to these restric-tions and oversimplifications, single particle measurements forhollow polymer systems are often utilized.

Due to their small size and high rigidity, metal nanoparti-cles are inherently difficult to analyze using single-particle tech-niques. Although metal nanorods and wires can be elasticallyevaluated using nanobeam mechanics,[140] recent research hassuggested that using a time-resolved spectroscopic method mayallow for measurement of the mechanical properties for a widerange of metal nanoparticle suspensions.[141]Using this method,the EY and linear elastic response can be determined throughsample irradiation with femtosecond laser pulses and conse-quent measurement of the acoustic response (Figure 5).[141,142]While differences are sometimes found to exist between nano-

particle and bulk elastic properties due to size and defects inthe crystal lattice, it is generally found that the elastic propertiesmeasured are similar to bulk metal properties.[141]

3.1.2. Single-Particle Techniques

In contrast to bulk measurements, single-particle measure-ments allow for a high level of control over the application offorces to each system component. One such way of achievingthis is through the use of an atomic force microscope (AFM)on a single, substrate immobilized particle. Several groupshave thoroughly investigated the mechanical properties of filmsusing AFM,[143145] and recently advances in optics and force

control systems have allowed for single analysis of particles. Ina similar fashion to parallel-plate compression experiments, aspherical probe with a high radius of curvature is attached tothe end of an AFM cantilever to effectively apply a controlledcompression to a micro- or nanoparticle.[146,147]This techniquehas been applied to both hollow capsules[43]and polyelectrolytemicrotubes,[101]where it has been proven that system stiffnessand the EYcan be derived, along with important information onbuckling forces, characterized using a combination of AFM andreflection interference contrast microscopy (RICM) (Figure 5).[148]Polymer particles and pressurized microgel template capsuleshave also been investigated using this technique,[149,150] whileErath et al. were able to measure the mechanical properties ofpolydimethylsiloxane microspheres adhered to a tipless canti-

lever.[45] Similar to cell-poking experiments using a stylus,[151]it has been demonstrated that the EY for hydrogel nanoparti-cles can be obtained using AFM with a sharp, noncolloidal,probe.[41]However for a small probe, the geometry is often dif-ficult to accurately quantify, and it may also impart an excessiveaxial strain leading to measurement errors in EY.

With regards to single-particle investigation using a flow-field,Doyle and co-workers observed the deformability of lithographi-cally fabricated PEG hydrogel particles with similar sizes to redblood cells, using a 4 m microfluidic channel.[152]Similarly, theMitragotri and co-workers, and DeSimone and colleagues inde-pendently performed capillary flow experiments to investigate

the deformation extent of red blood cell (RBC) shaped particlesof variable EYwithin a flow regime (Figure6).

[46,153]While Doyleand co-workers measured the pressure differential for particlesof different shapes passing through the capillary, Mitragotri andco-workers observed the stretching of individual protein shellsdue to flow field effects using an optical method. Suction pres-sure due to micropipette aspiration was used by Hochmuth tomeasure the elastic properties of cells,[154]while Barths-Bieseland co-workers were recently able to quantify the elastic proper-ties of large crosslinked ovalbumin microcapsules as a function

of pH, using a cylindrical microchannel coupled with a high-speed optical set-up to model the deformation.[155]

3.2. Comparison to Biological Systems

Recent approaches for the design of particulate materials forheathcare applications involve tuning the elastic properties tomatch that of biological particles, such as RBCs. [46,153] RBCshave a circulatory lifetime of up to 120 days, are able to evadephagocytosis, and demonstrate high elastic deformation inorder to pass through splenic fenestrations. However, old RBCsare removed from circulation in the spleen when the mechan-ical properties of the cells change, becoming more rigid.[156,157]

This has inspired work aimed at designing novel particulatesystems to mimic healthy RBCs, in order to increase the cir-culation lifetime in the body. The elastic modulus of RBCs hasbeen measured by various groups, with Lekka and co-workers,and Mitragotri and colleagues obtaining values of 26 7 kPaand 15.2 3.5 kPa, respectively, using AFM techniques.[153,158]The elastic shear modulus for the RBC membrane has beendetermined to be approximately 10 N m1, determined experi-mentally using both shear flow[159] and micropipette aspira-tion[160]techniques. The shear modulus, important to the natureof RBCs, is quite low in comparison to most particle types, asthey need to be able to squeeze through thin fenestrations, and

Figure 6. Studying particle deformation using microfluidics. a) A syringepump drives the flow through the device. b) Particles with low EY arehighly deformed as they pass through the fenestration, c) while parti-cles with a high EY are not able to deform and therefore cannot pass

through (scale bar 30 m). Reproduced with permission.[

46

]

Copyright2011, National Academy of Sciences.

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demonstrate high reversible deformation under flow. For othercell types, cancer cell lines have been found to be elasticallysofter than healthy cells based upon scanning force microscopymeasurements by Lekka et al.,[161] and later through experi-ments by Gimzewski and co-workers for metastatic cancercells from lung, chest, and abdominal cavities, compared to

the benign cells which usually line these cavities.[

162

]

Lekka etal. found that the EY for normal Hu609 ureter cells was 12.94. kPa compared to 1.0 0.5 kPa for T24 bladder carcinomacells, while it was later postulated that this decrease in elasticityallows cancer cells to metastasize or spread. [163] Mooney andco-workers noted that more elastic cells were able to take uppolyplexes to a greater extent, also enhancing cell proliferationand survival.[164] Levental et al. also presented a summary onthe elastic moduli of different biological tissues, and the testingmethod used.[165]

In comparison, synthetic systems demonstrate a widevariation in elastic modulus based upon AFM force spectros-copy characterization methods. Soft hydrogel particles varybetween roughly 1 kPa to 1 MPa depending on the polymer

type and extent of crosslinking within the system, [41,46] solidpolymer particles such as PLGA generally have an EY inexcess of 1 GPa,[153]while synthetic surface-bound liposomesare much softer with an EY of approximately 3 kPa.

[150] It isimportant to note that it has already been experimentallydemonstrated that the EY controls the rigidity and deform-ability of solid particles.[46] Metal nanoparticles examinedusing time-resolved vibrational spectroscopy generally havean EY in the range of 10 GPa to 1 TPa, where a value of64 8 GPa has been measured for gold nanorods. This valuecan be compared to the bulk gold value of 78 GPa. [141] Forpolyelectrolyte capsules, single particle AFM experimentsreveal that the EYgenerally falls within the range of 101000

MPa, which represents a transition between rigid cross-linkedrubber and soft glass.[44]

3.3. Biological Effects

Similar to the effects of the SAV on biological activity both invitro and in vivo, particle rigidity and deformability have alsobeen found to be important factors. Control over flow dynamics,biodistribution, and cellular interactions are also dependentupon the elasticity of particle systems, although the volumeof literature is more limited than in the SAV case. However,results indicate that softer particles in general will circulatelonger in vivo, and will be internalized into cells at a reducedkinetic rate, or for very soft particles even completely evadephagocytosis.[166]

3.3.1. Flow Dynamics and Biodistribution

Rigidity has been found to affect clearance from the blood-stream, most notably through splenic clearance. It has beenpostulated that the increased splenic clearance of cholesterol-modified liposomes is due to increased stiffness compared tounmodified liposomes,[51] while nanoparticles not function-alized with a polymer brush layer are generally cleared veryquickly via renal excretion.[20,72]Discher and co-workers found

that long filomicelles display extended circulation lifetimesin vivo.[48]To test the effect of filomicelle rigidity on the life-time, the micelles were crosslinked to form solid cylinders,which were found to clear within hours compared to days forflexible systems. This led to the conclusion that the circula-tion time is dependent on the ability of a particle to relax andfragment in a flow stream, also affecting flow-alignment andsystem extension within phagocyte streamlines (Figure7).[48]Also in regards to flexibility and deformability, in order topass through spleen fenestrations of the order of 200500 nmwide,[108] DeSimone and Petros observed that particles musteither be smaller than approximately 200 nm, or be sufficiently

elastically deformable to pass through and remain in circula-tion.[33] In other work, it was shown that tuning the deform-ability via variation in EY allowed for large particles to passthrough narrow microchannels.[46]Mitragotri and co-workersobserved optically the deformability of particles with a similarEYand geometry to RBCs, and found that the particles werestretched by approximately 70%, and retained their discoidalshape upon exiting the microchannel, demonstrating elasticdeformation.[153]

The only comparable study at this time, to our knowledge,which involves investigating the effect of elastic moduluson both circulation and biodistribution was performed byDeSimone and co-workers.[46] The EY was tuned using vari-able crosslinking concentrations for 6 m diameter discoidal

hydrogel particles. Similar to the results reported above,with increasing EY the circulation lifetime decreased drasti-cally, correlating well with the theory that stiffer particles arecleared from circulation more rapidly. Interestingly, in regardsto a 2 h biodistribution study in mice, particles with a mod-ulus of 39.6 10.4 and 63.9 15.7 kPa were predominatelyfound in capillary beds in the lungs, while particles with alower modulus of 7.8 1.0 and 16.9 1.7 kPa were able toavoid clearance in the lung and were found to accumulate inthe spleen. This work highlights the importance of particlerigidity in maximizing circulatory lifetimes, and also in bio-distribution control.

Figure 7. Flow and deformation of filomicelles in vivo and in vitro. Invivo filomicelle circulation time increases with particle length (a), whilelong filomicelles have been shown to deform and align in flow fields andavoid phagocytic interaction (b). Scale bar 5 m. Reproduced with per-mission.[48]Copyright 2007, Nature Publishing Group.

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3.3.2. Cellular Interaction and Uptake

Compared to literature on the effect of geometry and sizeon cellular interaction, studies on the effect of elasticity andrigidity in this area are rather limited. While not a cell study,Fery and colleagues investigated the adhesion of hollow poly-electrolyte shells onto both flat and polyelectrolyte-coveredglass substrates.[167] It was found that as the shell thicknessdecreased, the radius adhesion area increased dramaticallydue to the shell becoming more flexible and deformable. Thishas broader implications in regards to the ligand/receptor-mediated adhesion interactions between particles and cells,

where an increased adhesion area correlates toward increasedparticle/cell interaction. Based on recent fundamental studies,Gao et al. found that the elastic energy changes in a cell mem-brane mean that stiffer particles would be internalized favo-rably via cell wrapping when compared to softer particles,which tend to spread along the membrane.[168] This factorprobably influenced results observed by Wang and Beningofor interactions between opsonized microparticles with vari-able EY, and mouse bone-marrow macrophages.

[169]The poly-acrylaminde particles were 1 to 6 m in diameter and coatedwith bovine serum albumin, and it was found that, as the bis-acrylamide crosslinker concentration, and hence EY, increased,so did the preference for phagocytosis (Figure 8). As bothsurface chemical and geometric properties were kept con-

stant between the two systems, the effect was solely ascribedto phagocytosis being a mechanosensitive process. Similarly,for 150 nm hydrogel particles, Giasson and co-workers inves-tigated the effect of rigidity on macrophage internalizationrates and mechanisms.[41] Stiffer nanoparticles were seen tobe taken up faster than softer particles, and by different mech-anisms; particles with an EYof 18.0 5.0 kPa were exclusivelytaken up by the RAW 264.7 macrophage cells using macropi-nocytosis, while particles with an EYof 211.4 43.3 kPa wereexclusively taken up via a clathrin-mediated endocytosis route.Interestingly, hydrogel nanoparticles with a modulus betweenthese two values were able to be taken up via dual effective

pathways, and thus internalized at a quicker rate. In terms ofintracellular trafficking, Giasson and co-workers also foundthat accumulation into lysosomal compartments is dependenton the nanoparticle elastic modulus. [41]An increasing elasticmodulus generally led to increasing colocalization with FITC-labeled dextran, a common lysosomal marker, and nanopar-

ticles were found not to be released into the cytosol. It wasalso found that the kinetics of early endosomal entry waselasticity dependent, where only the stiffest nanoparticle wasfound to be colocalized to the early endosome marker after15 minutes.

It can also be noted that a macropinocytosis pathwayfor the internalization of polyelectrolyte capsules has beenobserved.[35,170,171]This is an interesting finding, as polyelectro-lyte capsules generally have a material EY at least an order ofmagnitude greater than the hydrogel nanoparticles studied byGiasson and colleagues, indicating that the particle structureand size will strongly mediate cellular uptake.

Regarding intracellular therapeutic release, Fernandes andco-workers investigated the forces and deformations requiredfor polyelectrolyte capsules to release their cargo,[172] whilstDelcea et al. extended the work to examine polyelectrolytecapsules with different shell thicknesses and, consequently,rigidity.[173] It was found that the capsule stiffness had a pro-nounced effect upon the applied force at which the cargo wasreleased, and that the forces applied (02 N) were within lit-erature estimates for an applied intracellular force range. This

Figure 8. Phagocytic internalization of both antibody-functionalized stiffand soft polyacrylamide beads. a) Stiff antibody-functionalized beads (lefttwo bars) were six times more likely to be internalized than soft beads(right two bars). This was confirmed optically for both stiff (b) and softbeads (c), where stiff beads were more readily internalized. Reproducedwith permission.[169]Copyright 2002, The Company of Biologists Ltd.

Figure 9. Surface-patterning on gold nanoparticles affects cell internali-zation and intracellular fate. Schematic diagrams and STM images ofboth disordered (a) and ordered (b) patterning of hydrophilic and hydro-phobic regions on gold nanoparticles. Dendritic cells show much lowerlevels of cytosolic accumulation for disordered (c) than ordered (d) par-ticles incubated at 4 C. The scale bar in (a,b) is 5 nm. Reproduced withpermission.[176]Copyright 2008, Nature Publishing Group.

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was coupled with ex situ electroporation experiments, where itwas estimated that the African green monkey kidney cells usedexert at least 0.2 N upon intracellular incorporation of the cap-sules,[173]confirming that particles will be affected by mechan-ical intracellular action to different extents depending on theirresistance to deformation.

4. Perspectives

Recent developments in both top down and bottom upfabrication strategies for advanced particulate systems allowfor improved control over several particle physical properties,such as size, shape, and rigidity. Increasingly, evidence hasshown that the geometric and physical characteristics of parti-cles have a pronounced effect on biological interactions, whereincreasing either the deformability or SAV allows particles to:align in flow fields more effectively and reduce interaction withmacrophages; improve cellular surface interaction under lowshear conditions; and generally reduce the rate of cell uptake.

Although these studies have opened new ideas and routes tocontrol biological responses, comprehensive knowledge gapsremain. In many instances, a precise knowledge of how particlechemistry affects these physical properties remains deficient,so that tuning of particle shape and mechanics remains diffi-cult. Further exploration of particle biomechanics will requirethe development of robust synthetic methodologies to allowthe tuning of physical properties in a wide variety of particledelivery systems. Moreover, a detailed understanding of thecomplex mechanisms governing interactions between particlesand biological systems, such as internalization and sub-cellulartrafficking, still remain unclear.

While this Review focuses solely upon the affect of physical

parameters on biological interactions, it is clear that approachesbased upon controlling both physical and chemical propertiesare required, extending work by Gratton et al. on cylindricalpolymeric particles with variable surface charge.[24] Whilephysical properties strongly influence circulatory and cellularinteractions, equally important to the success of particulatehealthcare materials are chemical-based properties, such asstealth, targeting, and triggered degradation.[174] This is high-lighted by work on the surface patterning of colloidal materials,allowing for dual chemical and active surface area modifica-tion.[175]Of particular relevance is the work of Stellacci, Irvine,and co-workers, demonstrating that the patterning of alternatingsubnanometre striations of anionic and hydrophobic groups ongold nanoparticles, as seen in Figure9, modulated the intrac-

ellular fate. Patterned particles accumulated in the cell cytosolas opposed to being trapped in an endosome, likely due to thepatterning and related surface roughness providing a resistanceto nonspecific protein adsorption.[176]Although significant chal-lenges to the field remain, we expect that future multidisiplinarywork will afford an improved understanding of the mechanismsand parameters governing the interactions between biologicalsystems and particle delivery vehicles at the circulatory, cellular,and sub-cellular level. This work will provide the foundationstoward the rational design of advanced particle therapeutics withspecific and optimized in vivo behavior, resulting in the moreeffective treatment of diseases and enhanced patient outcomes.

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Acknowledgements

This work was supported by the Australian Research Council under theFederation Fellowship scheme (FF0776078) (F.C.) and by the NationalHealth and Medical Research Council (NHMRC) Program Grant 487922(F.C.).

Received: October 25, 2011Published online: December 14, 2011

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