Ebook microfluidic devices in nanotechnology applications part 2

5 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY CLEMENT KLEINSTREUER Department of Mechanical and Aerospace Engineering and Department of Biomedical Engineering, North Carolina State University, Raleigh,[.]

MICROFLUIDIC DEVICES FOR

NANODRUG DELIVERY

Department of Mechanical and Aerospace Engineering and Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA

JIELI

Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, NC, USA

5.1 INTRODUCTION

Nanodrug delivery, employing microscale devices, is a broad and complex research topic with several major application areas For example, cost-effective drug discovery, development, and testing are of great concern to the pharmaceutical industry, while clinical diagnostics and drug delivery, ideally in combined form, are of interest to healthcare providers The associated microfluidic devices include lab-on-a-chip (LOC) systems for drug discovery/development and bio-MEMS (biological/biomed-ical microelectromechan(biological/biomed-ical system) for controlled biolog(biological/biomed-ical processing and optimal (nano-) drug delivery Powered by microfluidics, the use of LOC devices can be a robust and fast method to discover, refine, and test a drug This is important in light

of the fact that presently only one-tenth of the drug compounds that enter the clinical trial phase succeed in becoming commercially available (see 03/31/07 Report at BioMarket Research.com)

Bio-MEMSs are being used for controlled biological processes, such as cell sorting and multinodal bioimaging/identification, as well as for targeted drug delivery The

Microfluidic Devices in Nanotechnology: Applications, Edited by Challa S Kumar

Copyright
2010 John Wiley & Sons, Inc.

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latter entails biochemical or mechanical methodologies, that is, either a passive mode

or different active delivery modes.1

1 Passive multifunctional nanoparticle systems (MFNPSs) include injected porous (micrometer) particles carrying nanodrugs and releasing them near/at the desired site

2 Active nanodrug carriers (NDCs) of engineered size, shape, and surface characteristics circulate in the bloodstream and may actively attach to diseased cells/tissues

3 Active (mechanical) drug delivery systems (DDSs) concentrate on 100% targeting methodologies, nanofluid flow in microchannels, nanodrug mixing, and microdevice optimization

This chapter focuses on both biochemical and mechanical drug delivery systems with an emphasis on experimental/computational simulation aspects of bio-MEMSs, where some function as implanted microfluidic devices for controlled nanodrug release In any case, the overriding optimization objectives include biocompatibility, controlled nanodrug release, performance accuracy and reliability, minimization of side effects, size reduction, and cost-effectiveness

Previous reviews concentrated on particular topics For example, Suh et al.2 discus-sed biological MFNPSs in nanotechnology, stressing nanotoxicity concerns and nanodrug applications to neuroscience, while Emerich and Thanos3 outlined the potential of nanomedicine enabling targeted delivery of diagnostic and therapeutic agents, and Kim et al.4provided a past-to-future overview on nanotechnology in drug delivery Riehemann et al.5outlined recent developments and applications in nanome-dicine Parallel reviews on nanodrug (and gene) delivery systems are treatment specific toward particular diseases or organs For example, Kasuya and Kuroda6summarized nanomedicine for the human liver and Subramani7considered nanodrug treatment applications for cancer and diabetes, while Kleinstreuer et al.8 reviewed targeted delivery of inhaled drug aerosols to predetermined sites to combat lung tumors or even systemic diseases, outlining the underlying methodology of a smart inhaler system

5.2 MICROFLUIDIC DEVICES

To appreciate the mechanics of microfluidic devices as well as ongoing modeling and simulation aspects, this section starts out reviewing a few basic elements of micro-fluidics and microsystems as well as their modeling assumptions This brief discourse

is especially useful for readers interested in a state-of-the-art sample application given

in Section 5.4

The main focus of microscale research and development is on device fabrication and expansion of microsystem application areas, which implies innovative advances

in the material sciences, manufacturing technology, as well as supportive design software creation Electromechanical components of consumer goods, vehicles, and machinery, as well as entire devices, especially medical implants and laboratory test

equipment, are being built on a microscale Examples include MEMS, microheat sinks, iPods, and appliance control parts, as well as sensors and drug-release patches in medicine, or lab-on-a-chip units and reactors in biomedical and chemical engineering Clearly, it is the low production cost, compactness with a very high surface-to-volume ratio, rapid throughput with very small sample volumes, and integrated multifunc-tionality, for example, nanodrug mixing or particle separation or stream positioning, that make microscale fluid devices attractive alternatives to conventional flow systems.9

5.2.1 Microfluidics and Microsystems

Microfluidics is the study of transport processes in microchannels Of interest are methods and devices for controlling and manipulating fluid flow, finite liquid volume delivery, and particle transport on a nano- and microscale Although microfluidics deals with fluid behavior in systems with “small” length scales, conventional (i.e., macroscale) flow theory is typically applied, at least for liquid flows in microchannels with Dhydraulic
10 mm and standard gas flows when Dh
100 mm However, for microchannel gas flows in the slip regime, that is, 0:001  Kn ¼ l=L  0:1 (where the Knudsen number is the ratio of the molecular mean free path over a system length scale), modification to the velocity and temperature boundary conditions has to be made Clearly, when the Knudsen number is above 0.1, alternative system equations and numerical solution techniques have to be considered

Microfluidic devices (or microsystems, or bio-MEMS) typically consist of re-servoirs, channels, actuators, pumps, valves, mixers, sensors, controllers, filters, and/or heat exchangers Associated with microfluidic devices are the following R&D areas:

. Microfabrication of components or entire devices, using silicon, glass, polymer,

or steel

. Microfluidic transport phenomena, including mechanical micropumps as well as nonmechanical surface effects

. Task-specific devices, such as micrototal analysis systems (mTAS), LOC, or DDSs

. Reliable detection and measuring systems

. Power systems and microdevice packaging

. Data communication, including telemetry for monitoring system performance

. Biocompatibility and adherence to regulations

Bio-MEMSs for drug delivery are of interest in this chapter, where we focus on nanodrug transport phenomena in microchannels Such devices offer a number of advantages, such as controlled drug release, reliable accurate dosing, targeted treatment, and automated feedback control, all resulting in small size and operational convenience, efficacy, and cost-effectiveness Basic background information, includ-ing microscale device manufacturinclud-ing methods, may be found in the books by Tabeling,10Nguyen and Wereley,11Saliterman,12and Tesar.13Reviews of engineering

flows in small devices have been provided by Stone et al.,14 Hilt and Peppas,15 Whitesides,16Hu and Zengerle,17and Geipel et al.,18to name a few

5.2.2 Microsystem Modeling Assumptions

One of the key elements of all microsystems is the microchannel (soon becoming a nanochannel) with hydraulic diameters, that is, circular-tube-equivalent diameters, typically ranging from 10 to 500mm This is rather small in light of the fact that the diameter of the human hair is about 80mm When considering fluid flow in such tiny conduits, we should recall that the underlying macroscale modeling assumptions are valid only when

1 the fluid is “infinitely divisible,” that is, the fluid forms a continuum, and hence

we can use the conservation laws in terms of the continuity, momentum, and heat/mass transfer equations, often summarized for all practical purposes as the Navier–Stokes equations;

2 all flow quantities are in local thermodynamic equilibrium, that is, no velocity or temperature jumps at fluid–wall interfaces

Concerning the continuum assumption (1), the two main classes of fluids, that is, gases (in case of nanospray delivery) and liquids (primarily nanodrugs in aqueous solutions) differ primarily by their densities and by the degrees of interaction between the constituent molecules Focusing on aqueous solutions, water density is typically

rliquid 103kg m3with an intermolecular distancelIM¼ 0:3 nm Now, if the key macroscopic length scale, for example, microchannel effective diameter (or height or width), is of the order of 10mm or more, fluids with those characteristics appear continuous and hence the Navier–Stokes equations hold The local thermodynamic equilibrium condition (2) implies that all macroscopic quantities within the fluid have sufficient time to adjust to their surroundings That process depends on the time between molecular collisions and hence the magnitude of the mean free path traveled Clearly, a rarefied gas in a small microchannel does not form a continuum and hence would exhibit velocity and temperature jumps at the channel walls, requiring more exotic solution methods, for example, the lattice Boltzmann method (LBM), direct simulation Monte Carlo (DSMC), or molecular dynamics simulation (MDS) The conventional driving force for flow in microchannels is still the net pressure force, using micropumps, when substantial flow rates, that is, Re¼ vh=u > 1:0, are desired, as for rapid nanodrug mixing and delivery However, certain microfluidic devices for biomedical, chemical, and pharmaceutical applications employ more esoteric driving forces, such as surface tension (i.e., capillary or Marangoni effects) and electrokinetic phenomena (i.e., electrophoresis or electroosmosis) In general, the surface-to-volume ratio varies as the inverse of the system’s length scale, that is, 1/L, and hence microsystems with relatively large surface areas may cause significant viscous resistance In turn, it would require relatively powerful actuators, including pumps, valves, and so on, to operate a microfluidic device In order to have such pumps/actuators/valves as integral parts of the microfluidic device, new principles

had to be employed Thus, complementary to mechanical actuators with moving parts, microscale phenomena were used when the inlet Reynolds number was low (Re O(1)), such as electrokinetic pumping (e.g., electroosmosis) and capillary surface tension effects, electromagnetic force fields, and acoustic streaming Another contrasting macroscale versus submicrometer scale consideration is that conventional fluid flow is described by velocity and pressure fields and by its properties Hence, they are characterized as interacting groups, such as kinematic (i.e., velocity and strain rate), thermodynamic (i.e., pressure and temperature), transport (i.e., viscosity, conductivity, and diffusivity), and miscellaneous parameters (i.e., surface tension, vapor pressure, etc.) However, on the submicrometer scale, matter, that is, solid, liquid, or gaseous, is more realistically described in terms of interacting molecules For example, molecules in a solid are densely packed and arranged in a lattice, where each molecule is held in place by large repulsive forces according to the Lennard-Jones (L-J) potential.19Nevertheless, when solving pro-blems of fluid flow in microchannels, the continuum mechanics assumption is preferred over any molecular approach For the latter approach, the state of each molecule in terms of position and velocity has to be known, and then one has to evolve/simulate that state forward in time for each molecule That implies the solution of Newton’s second law of motion with the L-J force (i.e., the spatial derivative of the L-J potential) for billions of molecules In contrast, when continuous fluid flow behavior can be assumed, that is, system length scales Lgas> 100 mm (or

Kn 0.1) and Lliquid> 10 mm, we just numerically solve the conservation laws subject

to key assumptions and appropriate boundary conditions, as exemplified in Section 5.4.1

In summary, it is not surprising that fluid flow in microchannels may differ from macrochannel flow behavior in terms of entrance, wall, and thermal flow effects.20 Specifically, because of the typically short microchannel length, entrance effects (i.e., developing 2D or 3D flows) may be dominant At the microchannel wall, the “no-slip” conditions may not hold for hydrophobic liquids, electrokinetic forces may come into play, and surface roughness effects may be substantial Early onset of laminar-to-turbulent flow transition may occur and viscous dissipation of heavy liquids in high shear rate fields may increase the fluid temperature measurably

5.2.3 Categories of Microfluidic Devices

The development and use of microfluidic devices, including bio-MEMS (see Figure 5.1), are naturally being driven by application areas, that is, drug delivery routes and targets for specific clinical treatment needs, and ultimately by business interests For successful treatment, rapid administration of the right dosage of medication is important: too low a dosage may be ineffective and too high may be harmful Furthermore, dose frequency and duration, drug toxicity and interaction, as well as allergies must all be considered on a patient- and disease-specific basis

A smart drug delivery system (SDDS) connects a patient, that is, the specific disease site, with an appropriate drug An SDDS is a formulation (or device) with which nanomedicine is introduced into the body, released at a controlled rate, and

subsensitively transported across cell membranes for therapeutic action with minimal side effects

The two most common delivery routes are oral, that is, drugs taken by mouth and swallowed and hence a device is not needed, and via injection (i.e., parenteral administration) directly into the bloodstream or affected area More modern routes include targeted drug aerosol inhalation for lung, sinus, and systemic diseases employing smart inhaler systems, transdermal delivery via microneedles, and body implanted microfluidic devices with controlled nanomedicine release The oral route

is the typical way to deliver drugs into the body because it is cheap and most convenient However, it may not be very efficient because of drug absorption and/

or degradation before it reaches the bloodstream and ultimately the affected area or organ While injection is effective for relatively high quantities of large-molecule drugs, it is also inconvenient, somewhat expensive, and not easy to control Hence, with the advent of nanodrugs and gene therapy, new delivery devices, including bio-MEMS, had to be developed Key components of such systems include microchannels, micropumps (i.e., mechanical and electrokinetic), microvalves, microreservoirs, and micromixers.21–25 Application-driven drug delivery devices can be categorized into several groups—for example, microneedles providing active medicine infusion

FIGURE 5.1 Bio-MEMS components and flow chart

through transdermal patches; drug-eluting stents maintaining patency of, say, coro-nary arteries; smart inhalers, with which drug aerosol streams (nasal sprays) are controlled, to improve targeted particle deposition; and self-contained external or implantable bio-MEMS

Possibly, the largest group directly benefitting from bio-MEMS is diabetic patients ensuring exact glucose control via embedded monitors and insulin dispensers Patients with pacemakers or defibrillators may receive needed medication from an implanted bio-MEMS during an arrhythmia event Severe asthma patients typically requiring several drugs, such as bronchodilators and anti-inflammatory medicine, may rely on real-time disease analysis and subsequently controlled, targeted drug release Pain management can be handled by a programmable pump for, say, small-dose intraspinal morphine administration to block neurotransmitters from reaching the brain Clearly, a lot of R&D work and clinical testing have to be accomplished before most conceived bio-MEMS gains public acceptance The book edited by Desai and Bhatia26discusses bio-MEMS for drug delivery in several chapters, while the review by Elman et al.27 briefly summarizes next-generation bio-MEMS, which the authors classified as passive or active delivery devices

Microneedles, made out of silicon, polymer, steel, or metal oxides, are only a few hundred micrometers long; that is, they generate microconduits past the outer skin permeation barrier without encountering a nerve In array formation, connected to a liquid drug reservoir, they allow for dispersion and systemic uptake of macromolecu-lar drugs, possibly replacing hypodermic injections, say, for vaccinations and insulin delivery.28–30

Drug-eluting stents are slow-release nanodrug implants that mainly function as scaffolds to keep arteries open after coronary angioplasty, reduce the likelihood of restenosis, and reject foreign object After initially very positive response worldwide, they have recently encountered mixed reviews because of postoperative complica-tions, such as late stent thrombosis in some patients.31–35

Micropumps are vital for direct drug delivery when connected to a microreservoir,

or for nanodrug mixing in microchannels (see Section 5.4.1) Other micropump applications include movement of nano- to microliter solutions in LOC andmTAS devices, molecular particle sorting with microfilters or via hydrodynamic focusing, and flow measurements with microsensors However, one should note that a majority

of hydrodynamic microscale and certainly most nanoscale processes are driven by electrokinetic flow or surface-mediated transport.36 Thus, due to the very high frictional resistance, pressure-driven flow in a nanofluidic device is inappropriate The reason is thatDp  L=D4, whereDp is the pressure drop across the conduit of length L and hydraulic diameter Dh¼ 4A/P, with A being the cross-sectional area and

P the wetted perimeter For example, Zahn37reviewed the physics and fabrication

of mechanical and nonmechanical micropumps

Hundreds of microreservoirs can be embedded into a single silicon microchip that

is covered by a thin metal or polymer membrane The microreservoirs may contain any combination of drugs, chemicals, and/or biosensors, where the membrane seal can be activated for controlled drug release, using preprogrammed microprocessors, wireless telemetry, or biosensor feedback Clearly, these microchips can store and release

nanodrugs in a controlled fashion, and they are advantageous because of their small size, low power consumption, and absence of moving parts

5.3 NANODRUG DELIVERY

It is apparent from the previous sections that drug delivery systems based on bio-MEMS are just beginning to reach the market Self-regulated insulin delivery systems, drug-eluting stents, and microneedle arrays with reservoirs on a chip are some of the more mature examples In this section (Figure 5.2), nanodrug carriers for biochemical drug/gene delivery systems as well as associated clinical application areas and mechanical nanodrug delivery methodologies are discussed

5.3.1 Nanodrugs

Nanodrugs (or genetic material) embedded in nano/microspheres are promising candidates for treatment of various diseases, such as cancer, infections, metabolic and autoimmune diseases, and diseases related to the brain (http://nano.cancer.gov)

FIGURE 5.2 Strategies of targeted nanodrug delivery systems

Such nanomedicine carriers can be microparticles made of soluble, insoluble, or naturally biodegradable polymers, microcapsules, porous particles, cells, liposomes, and so on Emerich and Thanos3provided an overview of typical nanoparticles used

in drug and gene delivery, while Kasuya and Kuroda6summarized the desirable properties and characteristics of nanomedicine carriers Their modified and updated lists are given below

5.3.1.1 Solid Nanoparticles

Ceramic nanoparticles are made from inorganic nonmetallic compounds with porous characteristics such as oxides, that is, silica (SiO2), alumina (Al2O3), hydroxyapatite (HA), and zirconia (ZrO2) They are stable in the typical range of temperatures and

pH encountered in the body and can be used to deliver proteins and genes However, their lack of biodegradation and slow dissolution raises safety questions For example,

it was found that those made of silica can efficiently transport therapeutic genes to the spleen and trigger a potent immune response capable of attacking tumors.38The results released in 2008 in Chemical & Engineering News (http://pubs.acs.org/ isubscribe/journals/cen/86/i35/html/8635scic.html#6) showed that iron oxide nano-particles caused little DNA damage and were nontoxic, zinc oxide nanonano-particles were slightly worse, and titanium dioxide caused only DNA damage

Carbon nanotubes (CNTs) are extremely small tubes that can be categorized as single-walled nanotubes (SWNTs) and multiwalled nanotubes (MWNTs) These compounds have become increasingly popular in various fields simply because of their small size and amazing optical, electric, and magnetic properties when used alone

or with other materials, such as drugs Carbon nanotubes have potential therapeutic applications in the field of drug delivery, diagnostics, and biosensing For example, SWNTs have been shown to shuttle various cargos across cellular membrane without cytotoxicity SWNTs can be used as a platform for investigating surface–protein and protein–protein binding These nanotubes can act as highly specific electronic sensors for detecting clinically important biomolecules such as antibodies associated with human autoimmune diseases Functionalized carbon nanotubes can also act as vaccine delivery systems The basic concept is to link the antigen to carbon nanotubes while retaining its conformation, thereby inducing antibody response with the right speci-ficity Overall, the future use of carbon nanotubes in drug delivery systems may enhance detection sensitivity in medical imaging, improve therapeutic effectiveness, and decrease side effects

Nanocrystals are aggregates of molecules that can be combined in a crystalline form of the drug surrounded by a thin surfactant coating High dosages can be achieved and poorly soluble drugs can be formulated for improved bioavailability Both oral and parenteral delivery systems are possible and the limited carrier in the formulation reduces potential toxicity Limitations include poor drug stability

Polymers such as albumin, chitosan, and heparin occur naturally and have been

a material of choice for the delivery of oligonucleotides, DNA, protein, and drugs The drug is physically entrapped in the polymer capsule The characteristics can be summarized as follows: (i) water soluble, nontoxic, and biodegradable; (ii) surface modification (pegylation); (iii) selective accumulation and retention in tumor tissue;

and (iv) specific targeting of cancer cells while sparing receptor-mediated targeting

of normal cells with a ligand Polymer nanostructured fibers, core–shell fibers, hollow fibers, and nanorods and nanotubes provide a platform for a broad range of applica-tions For example, biological objects, including drugs, of different complexities carrying specific functions can be incorporated into such nanostructured polymer systems Biosensors, tissue engineering, drug delivery, and enzymatic catalysis are just a few applications Another example is superparamagnetic particles, known to display strong interactions with external magnetic fields leading to large saturation magnetization By using periodically varying magnetic fields, the nanoparticles can

be heated to provide a trigger for drug release

Solid lipid nanoparticles are lipid-based submicron colloidal carriers They have a solid hydrophobic core surrounded by a monolayer of phospholipid The system is stabilized by the inclusion of fairly high levels of surfactants They are less toxic than polymer nanoparticles and can be used to deliver drugs orally, topically, or via the pulmonary route While stability is a concern, it is better than that observed with liposomes

5.3.1.2 Colloidal Soft Matter

Dendrimers are artificial, polymer-based molecules formed from monomers such that each layer of branching units doubles or triples the number of peripheral groups (i.e., they look like a foam ball) The void area within a dendrimer, its ease of modification/ preparation, and size control offer great potential for targeted gene and drug delivery Improvements in cytotoxicity profiles, biocompatibility, and biodistribution are needed Dendrimers are repeatedly branched molecules They are emerging as a rather new class of polymeric nanosystems with applications in drug delivery The properties of dendrimers are dominated by the functional groups on the molecular surface Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics the structure of active sites in biomaterials because dendritic scaffolds separate internal and external functions For example, a dendrimer can be water soluble when its end group is a hydrophilic group, like a carboxyl group

It is theoretically possible to design a water-soluble dendrimer with internal hydro-phobicity, which would allow it to carry a hydrophobic drug in its interior Another property is that the volume of a dendrimer increases when it has a positive charge

If this property can be applied, dendrimers can be used for drug delivery systems that can give medication to the affected part inside a patient’s body directly

Hydrogels (also called aquagels) are a network of polymer chains that are water insoluble, and sometimes found as a colloidal gel in which water is the dispersion medium Hydrogels are superabsorbent (they can contain over 99% water) natural

or synthetic polymers Hydrogels also possess a degree of flexibility very similar to natural tissue due to their significant water content Hydrogels are responsive to specific molecules, such as glucose or antigens, that can be used as biosensors as well

as in drug delivery system

Liposomes were tiny bubbles (vesicles) made out of the same material as a cell membrane Liposomes are small spherical systems that are synthesized from