5 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY CLEMENT KLEINSTREUER Department of Mechanical and Aerospace Engineering and Department of Biomedical Engineering, North Carolina State University, Raleigh,[.]
5 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY CLEMENT KLEINSTREUER Department of Mechanical and Aerospace Engineering and Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA JIE LI 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/biomedical microelectromechanical system) for controlled biological 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 187 188 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY latter entails biochemical or mechanical methodologies, that is, either a passive mode or different active delivery modes.1 Passive multifunctional nanoparticle systems (MFNPSs) include injected porous (micrometer) particles carrying nanodrugs and releasing them near/at the desired site Active nanodrug carriers (NDCs) of engineered size, shape, and surface characteristics circulate in the bloodstream and may actively attach to diseased cells/tissues 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 discussed 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.4 provided a past-to-future overview on nanotechnology in drug delivery Riehemann et al.5 outlined recent developments and applications in nanomedicine Parallel reviews on nanodrug (and gene) delivery systems are treatment specific toward particular diseases or organs For example, Kasuya and Kuroda6 summarized nanomedicine for the human liver and Subramani7 considered 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 microfluidics 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 MICROFLUIDIC DEVICES 189 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 multifunctionality, 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 reservoirs, 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, including microscale device manufacturing methods, may be found in the books by Tabeling,10 Nguyen and Wereley,11 Saliterman,12 and Tesar.13 Reviews of engineering 190 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY flows in small devices have been provided by Stone et al.,14 Hilt and Peppas,15 Whitesides,16 Hu and Zengerle,17 and Geipel et al.,18 to 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 500 mm This is rather small in light of the fact that the diameter of the human hair is about 80 mm When considering fluid flow in such tiny conduits, we should recall that the underlying macroscale modeling assumptions are valid only when 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; 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 103 kg m3 with an intermolecular distance lIM ¼ 0:3 nm Now, if the key macroscopic length scale, for example, microchannel effective diameter (or height or width), is of the order of 10 mm 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, Re ¼ 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 systems 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 MICROFLUIDIC DEVICES 191 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.19 Nevertheless, when solving problems 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 Newtons 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 “noslip” conditions may not hold for hydrophobic liquids, electrokinetic forces may come into play, and surface roughness effects may be substantial Early onset of laminarto-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 192 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY FIGURE 5.1 Bio-MEMS components and flow chart 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 bioMEMS, 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 MICROFLUIDIC DEVICES 193 through transdermal patches; drug-eluting stents maintaining patency of, say, coronary 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 Bhatia26 discusses 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 macromolecular 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 complications, 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 and mTAS 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 that Dp L=D4h , where Dp is the pressure drop across the conduit of length L and hydraulic diameter Dh ¼ 4A/P, with A being the cross-sectional area and P the wetted perimeter For example, Zahn37 reviewed 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 194 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY 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 bioMEMS 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 NANODRUG DELIVERY 195 Such nanomedicine carriers can be microparticles made of soluble, insoluble, or naturally biodegradable polymers, microcapsules, porous particles, cells, liposomes, and so on Emerich and Thanos3 provided an overview of typical nanoparticles used in drug and gene delivery, while Kasuya and Kuroda6 summarized 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.38 The 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 nanoparticles caused little DNA damage and were nontoxic, zinc oxide nanoparticles 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 specificity 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; 196 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY 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 applications 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 hydrophobicity, 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 patients 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 NANODRUG DELIVERY 197 cholesterol and nontoxic phospholipids Liposomes can be filled with drugs and used to deliver drugs for cancer and other diseases Membranes are usually made of phospholipids, which are molecules having a head group and a tail group The head is attracted to water and the tail, which is made of a long hydrocarbon chain, is repelled by water Because they are natural materials, liposomes are considered attractive, harmless drug delivery carriers that can circulate in the bloodstream for a long time Another interesting property of liposomes is their natural ability to target cancer The endothelial wall of all healthy human blood vessels is encapsulated by endothelial cells that are bound together by tight junctions These tight junctions stop any large particle in the blood from leaking out of the vessel Tumor vessels not contain the same level of seal between cells and are diagnostically leaky This ability is known as the enhanced permeability and retention effect Liposomes of certain sizes, typically less than 400 nm, can rapidly enter tumor sites from the blood but are kept in the bloodstream by the endothelial wall in healthy tissue vasculature Anticancer drugs such as doxorubicin (Doxil), camptothecin, and daunorubicin (DaunoXome) are currently being marketed in liposome delivery systems Despite a relatively long history of investigation, liposomes exhibit limited stability and have not made significant medical impact Micelles provide considerable advantages among drug carrier systems for their solubilization to contribute the increasing bioavailability of poorly soluble drugs and the characteristics to stay in the blood long enough to afford a gradual accumulation in a particular area A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid A typical micelle in aqueous solution forms an aggregate with the hydrophilic “head” regions in contact with surrounding solvent, sequestering the hydrophobic tail regions in the micelle center This type of micelle is known as a normal phase micelle (oil in water micelle) Inverse micelles have the head groups at the center with the tails extending out (water in oil micelle) Micelles are approximately spherical in shape Other phases including shapes such as ellipsoids, cylinders, and bilayers are also possible Micelle formation is essential for the absorption of fat-soluble vitamins and complicated lipids within the human body When membrane phospholipids are disrupted, they can reassemble themselves into tiny spheres, smaller than a normal cell, either as bilayers or as monolayers The bilayer structures are liposomes and the monolayer structures are called micelles Microemulsions have great thermodynamic stability, which allows for self-emulsification at a wide range of temperatures and affords easy preparation The structural variability of microemulsions together with its composition and the pH of the environment can obviously influence the drug release rate Other positive characteristics include the low viscosity of the majority of the system Organogels are systems resembling the structure of microemulsions but are semisolid Most organogels utilized in pharmaceuticals are lecithin, gelatin, or sorbitan ester-based systems in biocompatible solvents Complex aqueous phases such as vesicle suspensions entrapping drugs can be eventually incorporated into the organogel systems They can entrap hydrophilic or hydrophobic drugs and antigens; it is possible to achieve controlled release systems 198 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY 5.3.1.3 Desirable Characteristics of Nanodrug Carriers With this large family of nanodrugs available (see Sections 5.3.1.1 and 5.3.1.2), it is important to consider suitable (or even optimal) attributes of nanodrugs and their carriers Specifically, the following properties should be optimized for the in vivo use of conventional nanoparticle carriers for drug or gene delivery Acceptability to Versatile Payloads: The nanoparticle carrier (NPC) should allow payloads of various therapeutic materials This facilitates the development of a general purpose carrier and concurrent administration of different drugs Low or No Toxicity: The NPC should not be made of or contain potentially dangerous materials Active Targeting: The NPC should recognize and attach target cells and tissues by a sensor molecule displayed on its surface NPC of about 100 nm are likely to accumulate spontaneously in tumors after systemic injection, but this passive targeting mechanism based on the enhanced permeability and retention effect39 is excluded from these criteria Appropriate Size: The size of NPC should be about 40–150 nm in diameter Too small nanoparticles (150 nm) are nonspecifically removed from blood circulation by the function of kidney and reticuloendothelial system in the liver, respectively.40 NPC of about 40–150 nm could be used to target both tumors utilizing the enhanced permeability and retention effect and hepatocytes by passing through the fenestrae in liver endothelial cell.41 Appropriate Surface Charge: The surface charge of NPC is known to affect severely the stability and biodistribution of systemically administrated nanoparticle carriers For ideal delivery, the surface of nanoparticle carriers should be optimized so as not to be entrapped by unexpected tissues For example, one positively charged nanoparticle (i.e., polyplex of polyethyleneimine and DNA) was efficiently accumulated in the lung after systemic administration.42 Efficient Cell-Penetrating Activity: The nanoparticle carriers should possess cell-penetrating activity for active and rapid intrusion across the plasma membrane or the endosomal membrane of target cells and tissues because many therapeutic materials (particularly, genes and siRNAs) function intracellularly Mechanism of Intracellular Targeting: The nanoparticle carriers in target cells should bring and release payloads to the intracellular destination precisely (e.g., genes and siRNAs should be released in the nucleus and cytoplasm, respectively, not in endosomes) 5.3.2 Nanodrug Targeting As mentioned, targeting is the ability to direct in controlled fashion the drug particles, or a drug-loaded system, to the predetermined site of interest There are mechanical and biochemical methodologies of drug targeting (Figures 5.2 and 5.3a and b) As Kaparissides et al.43 mentioned, in biochemical targeting two approaches can be NANODRUG DELIVERY 199 FIGURE 5.3 (a) Passive drug targeting by nanodrug carriers in blood vessels and (b) active nanodrug targeting with conjugated antibodies distinguished, that is, passive and active targeting They give as an example for passive targeting the observed preferential accumulation of chemotherapeutic agents in “solid” tumors as a result of the enhanced vascular permeability of tumor tissues compared to healthy tissue (Figure 5.3a) As a variation to nanodrugs cruising in the bloodstream and hopefully reaching the right site, drug carriers with surface functionalities, for example, ligands interacting with tumor cell receptors, can seek out, bind to, and penetrate target cells (Figure 5.3b) In contrast, mechanical drug targeting is the delivery of a controlled fluid–particle stream from an optimal release (or arterial injection) point to a predetermined deposition site.44,45 Specifically, Kleinstreuer45 200 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY discussed several mechanical drug delivery applications within the framework of fluid–structure interaction simulations For example, targeted drug aerosol delivery can be potentially accomplished with a smart inhaler system.46 Another application is the targeting of liver tumors with radioactive microspheres,47 where the particles are released, via a microcatheter, from an optimal inlet position of the hepatic artery Most of the drug targeting literature deals with biochemical targeting, especially “colloidal soft matter” (see Section 5.3.1.2) as reviewed by Bonacucina et al.48 Such “soft matter,” for example, microemulsions and organogels (as passive drug carriers) as well as liposomes, micelles, and dendrimers (as active drug carriers), can increase drug solubility and bioavailability and can attach/penetrate tumor cells, especially where micelles are used Clearly, all present biochemical targeting efforts are disease/ treatment specific.1,49–54 Drug targeting via mechanical delivery devices include reservoirs, pumps, inhalers, catheters, needles, drug-eluting stents, and implants releasing drugs (Section 5.2.3) The next two sections provide some physical insight into the microfluidics of bioMEMSs, focusing on nanodrug mixing, microchannel flow, and device optimization 5.4 Bio-MEMS APPLICATIONS To illustrate some aspects of bio-MEMS research and development, nanodrug mixing and microchannel designs are discussed in the next two sections 5.4.1 Nanofluid Flow Simulations Microfluidics deals with methods and devices for manipulating and controlling fluid–particle flow in microchannels.55 A recent application area is nanomedicine with the goal of controlled nanodrug delivery to specified target areas.12,56 A key aspect of this goal is the development of integrated drug delivery systems to monitor and control target cell responses to pharmaceutical stimuli, to understand biological cell activities, or to facilitate drug development processes An important part of such drug delivery systems, belonging to the family of bio-MEMS, is active or passive micromixers25,57 to assure near-uniform nanodrug concentrations Static micromixers, not requiring any external energy source, rely on chaotic advection and/or enhanced diffusion, typically to mix two fluids.58,66 For example, Hardt et al.61 reviewed recent developments in micromixing technology, focusing on liquid mixing with passive micromixers Four kinds of mixers that employed different hydrodynamic principles are discussed: hydrodynamic focusing, flow separation, chaotic advection, and split and recombine flows Diffusive mixing can be improved by increasing the interfacial contact area between the different fluids and reducing the diffusion length scale Thus, selecting the right type of micromixer for a specific application is very important Li and Kleinstreuer67 analyzed rapid nanoparticle mixing in a carrier fluid, employing low-cost micromixers and heat transfer to achieve two system design goals, that is, uniform exit particle concentration and minimum required channel length Specifically, a microfluidics device for controlled nanofluid flow in Bio-MEMS APPLICATIONS 201 microchannels (Figure 5.4) is investigated for basic nanomedicine applications Presently planned for laboratory-scale testing, uniform, predetermined concentrations of a stimulus (e.g., cocaine particles) should be delivered via multiple microchannels to an array of wells containing brain cells to measure cell responses (e.g., dopamine production levels) Their study focuses on device miniaturization in light of the ultimate goal of bio-MEMS implantation into the diseased brain region of, say, Parkinsons patients Most important, the impact of two types of static micromixers (Figure 5.4c) is analyzed to achieve uniform nanoparticle concentrations at the exit of a representative microchannel of minimum length Figure 5.5 shows Lmin(Pe) for the different scenarios Clearly, any micromixer module reduces Lmin significantly for all Peclet numbers While an increase in slotted baffle plates reduces Lmin, the simple three-sided injection unit performs best FIGURE 5.4 Microfluidics system: (a) laboratory-scale nanodrug supply device, (b) representative microchannels, and (c) static mixer inserts 202 FIGURE 5.5 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY Micromixer influence on minimal uniformity length/system dimension.67 Alternative to the Peclet number, which is based on the average velocity of nanofluid plus carrier fluid, the Reynolds number ratio of nanofluid to carrier fluid is a suitable operational parameter The associated Reynolds numbers are Rei ẳ uDh ịi ni 5:1ị with i ẳ indicating the carrier fluid in the solution channel and i ¼ denoting the nanofluid channel (Figure 5.4b) For the given system, Figure 5.6 indicates that the main microchannel length can be below mm when employing an injection micromixer, that is, a 70% reduction in channel length The addition of nanoparticles and certainly the installment of micromixers increases the pressure drop in both channels and hence the pumping power requirements Pumping power is defined as the product of the pressure drop across the channel (Dp) and the volumetric flow rate (Q), that is, P ¼ Dp Q ð5:2Þ The pressure differences occur between the nanofluid inlet or carrier fluid inlet and the system outlet, that is, required minimal length The volumetric flow rate is the sum of the volumetric flow rates of both nanofluid and carrier fluid Figure 5.7a and b depicts the relationship of pressure drop and pumping power for the two cases Clearly, the added micromixer increases the local pressure drop, but the decreased system length may reduce any negative effect caused by the micromixer As shown in Figure 5.8a and b, the power requirement even decreases in some cases, 203 Bio-MEMS APPLICATIONS FIGURE 5.6 Minimal uniformity length versus Reynolds number ratio.67 that is, when employing the injection micromixer The employment of baffle-slit micromixers slightly increases the pressure drop; however, when the pumping power/ volumetric flow rate gets larger and larger, the negative effect appears to be less and less For example, for the two- or four-baffle micromixer, the pressure drop is even smaller than that without any micromixer when the nanofluid supply rate is increased to mm s1 In summary, employing an appropriate micromixer decreases the system dimension and the associated power requirement A heat flux was used to ensure that mixture delivery to the living cells occurs at a required temperature of 37 C The change of fluid properties and nanoparticle diffusivity, caused by the added heat flux, also benefits system miniaturization As shown in Figure 5.6, the added heat flux greatly decreases the system dimension; that is, an average 35% reduction is observed 5.4.2 Device Optimization It is obvious that the better an engineering device performs, the lower the (irreversible) losses, that is, the closer it operates at an isentropic efficiency This directly implies that S_ gen should be minimized as part of any device/process design or improvement For example, considering simple heat transfer from an ambient reservoir at T0 ẳ Â, the entropy balance equation can be written as @S S_ gen ¼ @t X Q_ T0 X _ in ỵ mSj X _ out > mSj ð5:3Þ 204 FIGURE 5.7 inlet.67 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY Pressure drop versus pumping power: (a) carrier fluid inlet and (b) nanofluid 205 Bio-MEMS APPLICATIONS FIGURE 5.8 Heat flux influence on minimal uniformity length.67 _ loss ; that is, in general, power loss is due to system, heat Effectively, S_ gen W transfer, and fluid flow irreversibilities: Ploss X @S Q_ X _ _ _ in _ out W loss ¼ T0 Sgen ¼ T0 mSj mSj @t T0 ð5:4Þ Focusing on friction (or viscous effects) as the main cause of irreversibilities and hence entropy generation, the rate of irreversible conversion from flow energy to heat can be expressed as tij S_ gen @vi Ploss ¼ T0 mF ẳ @xj 8 5:5ị Clearly, to minimize entropy production in pressure-driven microchannels, we have to reduce the viscous dissipation function F, that is, achieve minimization of " 2 2 2 # S_ gen m m @u @v @u @v ỵ2 ỵ2 ẳ Fẳ ỵ T T @y @x @x @y ð5:6Þ In general, and exclusively for fully developed flow, the term ðm=TÞð@u=@yÞ2 is most important If wall slip is significant, then u(y) velocity profile is greatly affected and hence the channel pressure drop 206 MICROFLUIDIC DEVICES FOR NANODRUG DELIVERY 5.4.2.1 Liquid Flow in a Microchannel Minimization of entropy generation as a design tool to determine best device geometry and operation, especially for heat exchangers, has been established for macroscale configurations.68–75 However, fluid flow in microchannels exhibits dominant features often nonexisting or less influential in macrochannels, for example, wall slip velocities for some gases, entrance effects because of the short conduit length, significant surface roughness in relation to microchannel height (or hydraulic diameter), and so on.11 Thus, application of entropy generation minimization principles may assist in the optimal design of microchannel heat sinks and bio-MEMS in light of geometric and operational conditions.67,76–79 Classical methods for enhanced heat transfer, for example, an increase of heat transfer area and/or inlet Reynolds number, are limited options for microchannel flow Thus, the use of nanofluids as coolants, for example, CuO or Al2O3 nanospheres with diameters in the range of nm < dp < 150 nm in water, oil, or ethylene glycol, is a third option In case of nanomedicine delivery with bio-MEMS, nanofluid flow analysis is important and measurable reduction of entropy generation is desirable In this section, entropy generation is minimized for steady laminar pure water and nanofluid flows in a representative trapezoidal microchannel in terms of most suitable channel aspect ratio and Reynolds number range One effective operational parameter is the inlet Reynolds number; Figure 5.9 indicates a desirable range of 425 Re 1100 for all fluids and aspect ratios considered, ignoring “slit flow” for AR ¼ 0.9337 Due to slightly enhanced frictional FIGURE 5.9 System entropy generation versus Reynolds number.80 ... background information, including microscale device manufacturing methods, may be found in the books by Tabeling,10 Nguyen and Wereley,11 Saliterman, 12 and Tesar.13 Reviews of engineering 190 MICROFLUIDIC. .. 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... 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 microfluidics