Drug delivery devices have revolutionized the course of therapeutic treatment in the recent past. These devices provide a firm foundation for diverse strategies to overcome the limitations of systemic administration that cannot provide a high drug potency at the specific disease infected body tissues. The ongoing developments in the pharmaceutical industry have focused on exploring the reliable actuating mechanisms that can provide therapy and dispense drugs precisely to control therapeutic effects with minimum toxicity. The wireless actuation of drug delivery devices has been considered as an intervening noninvasive approach to release encapsulated drug compounds. This review paper highlights implantable and transdermal drug delivery devices that are based on wirelessly controlled microchips, micropumps, microvalves, and magnetic robots. Their key features, such as working principle, dimensions, materials, operating frequency, and wireless actuation through radio frequency for drug delivery are explained. The interaction of radio waves with electrically conductive and magnetic nanoparticles is also discussed for drug delivery. Furthermore, the radio frequency assisted data telemetry and wireless power transfer techniques are elucidated for drug delivery devices. The opportunities to enhance the patients' control on therapeutic indexes and release mechanisms are still possible by incorporating advanced wireless sensors for concocting future innovations in the wirelessly controlled drug delivery devices.

Chronic diseases concomitant with the aging population are augmenting challenges to improve healthcare and quality of life. The traditional drug delivery methods are not suitable when predefined drug pharmacokinetics, low toxicity levels, and time specific release are required for therapeutic treatment.1 Moreover, systemic administrations, such as oral, topical, inhalation, and injection are unable to reduce the harmful side effects on the healthy tissues.2 The recent advances in the field of biomedical engineering have enabled therapeutic treatment with drug delivery devices that can provide more drug efficacy than systemic administration. These devices can regulate therapeutic treatment by targeting drugs toward the tumors' locations with a high potency that is particularly desirable for cancer patients. In addition, the release mechanism of a drug delivery device can be modified according to the clinical requirements by the patient or physician.

Drug delivery devices are divided into two categories, active and passive. In an active device, the geometry becomes large as it mostly contains a battery to power the control circuitry and on-board electronics of the device. The microfabrication techniques thus become essential to particularly miniaturize an implantable active device for a minimally invasive drug delivery procedure to the tiny biological tissues.3 On the other side, passive devices exclude the need for active circuit elements and depend on the pathophysiological characteristics of the disease site.4 Several passive mechanisms5–7 have been proposed in the literature for drug release through stimulus responses, such as body temperature,8,9 pH,10,11 hydrogels,12,13 and photoresponsive materials.14,15 The release mechanisms also rely on the chemical and physical properties of different organs in the body. In addition, these properties are important for the development of efficient pharmacokinetics for improved therapeutic benefits.16–18 Although passive devices offer the advantage of miniaturized devices, they are still unable to provide the patient or physician control of the release kinetics.19 

The drug delivery devices can be implantable20 or transdermal.21 The implantable devices are mostly in the form of a microrobot22–25 or capsule.26,27 In general, they consist of actuators, microreservoirs, electronic components, battery, and antennas for bidirectional communication with an external transmitter.28 The device once swallowed or injected traverses through the body until it reaches the vicinity of the desired location (Fig. 1). Afterwards, an external transmitter delivers information wirelessly to the device. The received information triggers the actuating mechanism for releasing the drug. Moreover, the drug diffuses around the targeted site more than other parts of the body, resulting in reduced side effects on healthy tissues. This targeted drug delivery technique can also effectively release pharmaceutical agents at deep intricate pathological sites that are not directly accessible with systemic administration.

FIG. 1.

Targeted drug delivery concept using a swallowable capsule device. The drug is expelled from the device through tiny microneedles under the influence of external actuation.

FIG. 1.

Targeted drug delivery concept using a swallowable capsule device. The drug is expelled from the device through tiny microneedles under the influence of external actuation.

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The aforementioned drug delivery process can also be used to target a pathological site that requires a specific amount of drug concentration. This requires an external control unit that can trigger the device for drug delivery, according to the predefined dose concentration prescribed by the physician. Hence, the physiochemical and pharmacokinetics behavior of drug compounds can be controlled externally for curing pathological sites. For instance, cancer tumors require a high drug concentration and specific pharmacokinetic parameters for early recovery.

For patient's adaptability and compliance, the device should be miniaturized, bioadhesive,29,30 and convenient to implant at the targeted disease location. In addition, the protection of drug composition before the release from the device also necessitates the utilization of novel biocompatible materials.31,32 For instance, nanomaterials have shown a tremendous potential for their applications in drug delivery.33–37 Similarly, silicon,38–40 polymers,41,42 and liposomes43–45 are used for drug delivery devices owing to their biomaterial and biodegradable properties. The promising technology that has been significantly emerged to miniaturize a drug delivery device is based on microelectromechanical systems (MEMS).46–54 The current MEMS based drug delivery devices consist of micropumps,55–57 microprobes,58,59 cantilevers,60,61 microneedles,62–65 shape memory alloys,52,66,67 and microchips.3,7,62,68–71

Radio frequency (RF) waves have been envisioned as the most prevalent approach for noninvasive control of the aforementioned MEMS devices. Few decades ago, the applications of RF were not very common for medical treatment due to the challenges emanating from the inherent lossy dielectric properties of biological tissues. However, comprehensive progress in understanding the interaction of electromagnetic waves with the heterogeneous nature of the human body has enabled therapeutic treatment with RF controlled devices.72 For instance, RF ablation has been considered as a widespread procedure for cancer treatment using probes.73 In addition, RF wireless technologies have become significantly important for data telemetry and power transfer to implantable devices.

This review paper recapitulates recent research in the development of wirelessly controlled drug delivery devices. The main objective is to provide a comprehensive comparison of different systems and components of a device that can be triggered wirelessly for drug delivery. The applications of radio frequency are discussed for wireless actuation of drug release mechanisms. In addition, components that constitute radio frequency assisted wireless power transfer (WPT) and data telemetry with an external transmitter are also highlighted. The remaining part of this paper is divided into five sections. Section II presents the microchip based drug delivery devices that are controlled by an external RF signal. In Sec. III, we describe RF actuated micropumps and microvalves for drug delivery. Section IV provides the discussion about drug delivery devices that incorporate RF triggered magnetic microrobots. In Sec. V, the direct exposure of RF onto nanoparticles (NPs) with regard to local therapy and drug delivery is discussed. Our conclusions are presented in Sec. VI.

The quest for desirable therapeutic efficacy is one of the major motives of pharmaceutical research and biomedical engineering. The expediting growth in micro and nanotechnologies has permeated extensively into biomedical devices over the past few years.74 For this reason, microchip based drug delivery devices have become a potent technology owing to their capability of containing drugs for extended periods of time.2,62,68,70,75–81 Their applications have been explored for sustained drug release to maximize the therapeutic efficacy.62 In addition, microchips miniaturize the overall size of a device by incorporating multiple electronic components within the compact space. The smaller devices require less invasive surgical operation to implant at the tumor location and thus enhance patient convenience.

For treating chronic diseases, microchip based devices can provide complex release patterns76 and can be programmed wirelessly for on-demand delivery of stored drug formulations.2,20,79,81 The wireless link between the device and external interrogator is also useful for noninvasive therapy and data telemetry.81 The microchip devices are categorized into two classes, solid state silicon chip and resorbable polymeric chip.78 They generally contain several integrated components to perform drug delivery operation, such as reservoir arrays, battery, microcontroller, post IC processing unit, and an antenna for wireless communication with an external transmitter [Figs. 2(a) and 2(b)]. These components are fabricated on the printed circuit board (PCB) substrate using sophisticated microelectronic integrated circuits technology, such as photolithography, etching, and bonding3,77 [Fig. 2(c)]. Tiny reservoirs of microchips carry drug formulations in the form of liquid or gel78 and are capped with thin metallic membranes of titanium (Ti) and platinum (Pt).81 The purpose of membranes is to protect the drug composition from the external environment before releasing from the device79 and thus a controlled environment is provided in the reservoirs. The Ti coating is also used as a biocompatible layer for implantable microchip based devices82 [Fig. 2(d)]. For dispensing drugs out of the reservoirs, the membranes can be dissolved by electrothermal68,81,82 or electrochemical51,83,84 processes. These processes are activated by the control circuitry of the device according to the programmed schedule. Apart from reservoirs, microchips integrated with microchannels have also been demonstrated for drug delivery applications.62 

FIG. 2.

(a) and (b) Schematic illustration of a drug delivery system in package with the integrated components. Reprinted with permission from Yang et al., in International Solid-State Circuits Conference-Digest of Technical Papers, ISSCC (IEEE, 2009), pp. 288–289. Copyright 2009, Institute of Electrical and Electronics Engineers. (c) Fabricated integrated components on the PCB. (d) Assembled drug delivery device based on a microchip. The Ti casing is used for the biocompatibility of the device. Reprinted with permission from Prescott et al., Nat. Biotechnol. 24, 437 (2006). Copyright 2006, Springer Nature.

FIG. 2.

(a) and (b) Schematic illustration of a drug delivery system in package with the integrated components. Reprinted with permission from Yang et al., in International Solid-State Circuits Conference-Digest of Technical Papers, ISSCC (IEEE, 2009), pp. 288–289. Copyright 2009, Institute of Electrical and Electronics Engineers. (c) Fabricated integrated components on the PCB. (d) Assembled drug delivery device based on a microchip. The Ti casing is used for the biocompatibility of the device. Reprinted with permission from Prescott et al., Nat. Biotechnol. 24, 437 (2006). Copyright 2006, Springer Nature.

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The complementary metal oxide semiconductor (CMOS) based system on chip (SoC) technology has also shown a great potential for precise drug delivery with a low power consumption.79 The chip contains an on-off keying (OOK) receiver, a microcontroller unit (MCU), a switch array, a clock generator, and 8 individually addressable reservoirs. These components are integrated in a 0.35 μm CMOS that is processed with a chip size of 1.77 × 1.4 mm2 [Fig. 3(a), left]. The volume of each reservoir is approximately 5 nl as shown in the backside view of the chip [Fig. 3(a), right]. The reservoirs are capped with metallic membranes, fabricated by multiple layers of Ti and Pt. The capacity of the chip reservoirs is increased by bonding the polydimethylsilicane (PDMS) reservoir layer on the backside of the chip using the soft-lithography process. The final prototype after bonding the PDMS reservoir layer with the chip is shown in Fig. 3(b). The chip has an integrated wireless controller/actuation circuitry for controlling the drug delivery process at 403 MHz. This frequency is in agreement with the Medical Implant Communication Service (MICS-402–405 MHz) band that is dedicated for data transmission and reception throughout the body. The external OOK radio signal in the RS232 format is used to trigger the electrothermal process inside the chip. The electrothermal activation melts the metallic cap of the reservoirs that enables drug release from the chip. The chip demonstrates successful release of the drug under the influence of the received wireless commands.

FIG. 3.

(a) Chip micrographs after post IC processing. Reprinted with permission from Yang et al., in International Solid-State Circuits Conference-Digest of Technical Papers, ISSCC (IEEE, 2009), pp. 288–289. Copyright 2009, Institute of Electrical and Electronics Engineers. (b) Fabricated drug delivery device. Reprinted with permission from Huang et al., J. Emerging Technol. Comput. Syst. 8, 12:1–12:22 (2012). Copyright 2012, Association for Computing Machinery.

FIG. 3.

(a) Chip micrographs after post IC processing. Reprinted with permission from Yang et al., in International Solid-State Circuits Conference-Digest of Technical Papers, ISSCC (IEEE, 2009), pp. 288–289. Copyright 2009, Institute of Electrical and Electronics Engineers. (b) Fabricated drug delivery device. Reprinted with permission from Huang et al., J. Emerging Technol. Comput. Syst. 8, 12:1–12:22 (2012). Copyright 2012, Association for Computing Machinery.

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The microchip based drug delivery devices mostly require a battery for powering the electronic components and control circuitry. In recent past, wireless power transfer (WPT) has emerged as an effective solution to fulfill the power requirements of drug delivery devices without intricate wires and batteries. For this reason, the RF system for WPT has become an integral part of current microchip based drug delivery devices. The RF system receives power wirelessly from an external antenna and converts it to DC voltages by the rectification process. These voltages can be used to actuate the controlling unit and on-board sensors for drug delivery and pharmacokinetics monitoring.69 

The silicon chip based drug delivery system has been designed for ocular implants.85 The size of the chip is 3 × 3 mm2 and it is fabricated using the anisotropic silicon wet etch process. For WPT, energy is transferred from the external coil to the receiving coil by employing magnetic fields at 7.1 MHz. The receiving coil of the chip acts as a ferrite rod antenna and it is designed using an open core. The chip contains a decoder, a demultiplexer, and 12 microreservoirs that can be addressed individually using a dual-tone multifrequency (DTMF) signaling system. The receiver circuit also contains a voltage regulator to provide constant 3 V for the chip operations. Under the influence of external actuation, the control circuit generates the activation signal to dissolve the gold membrane seal that is covering each of the reservoirs. The experimental results have demonstrated that by using 1.0 W of external RF power, enough power can be generated in the receiver to actuate control circuitry for disintegrating membranes through the electrochemical process.

A similar kind of work has been demonstrated for a wirelessly powered miniaturized drug delivery chip that can communicate with an external transmitter.69 The 3 × 3 mm2 chip comprises of cavities to store drugs. The cavities can be addressed individually through a wireless link. The chip is designed to operate in in vitro and in vivo scenarios. The dual in line package technique is used to integrate the drug delivery chip for in vitro testing [Fig. 4(a)]. The chip is bonded to the package with gold wires. In addition, an ultraviolet (UV) cured epoxy is applied for the protection of wires. For in vivo packaging, a 5 × 5 mm2 double sided printed circuit board (PCB) is used to attach the chip [Fig. 4(b), left]. The gold coated tracks that are etched on the PCB provide wire bonding with the chip. The prototype of the complete packaged chip is shown in Fig. 4(b) (right). The electrical connections are covered with the UV-cured epoxy.

FIG. 4.

(a) The proposed prototype of a drug delivery chip for in vitro testing. (b) Packaging of the chip for in vivo testing. Reprinted with permission from Smith et al., IET Nanobiotechnol. 1(5), 80–86 (2007). Copyright 2007, Institution of Engineering and Technology.

FIG. 4.

(a) The proposed prototype of a drug delivery chip for in vitro testing. (b) Packaging of the chip for in vivo testing. Reprinted with permission from Smith et al., IET Nanobiotechnol. 1(5), 80–86 (2007). Copyright 2007, Institution of Engineering and Technology.

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Clinical trials of a drug delivery device are important to assess the pharmacokinetics and accuracy of the dosing schedules. For this purpose, a wirelessly controlled drug delivery device was tested in the human body at the MICS band [Fig. 5(a)]. The device consists of two silicon microchips that contain an array of tiny reservoirs [Figs. 5(b) and 5(c)]. The antenna in the device establishes a wireless link with an external transmitter for bidirectional communication, providing information about the dose delivery and battery voltage status. The study has found that the release profile of the microchip is more consistent as compared to injections.

FIG. 5.

(a) The prototype of a drug delivery device with two microchips. (b) and (c) Illustration of microchip reservoirs for carrying drugs. The aperture of each reservoir is capped with a metallic membrane. Reprinted with permission from Farra et al., Sci. Transl. Med. 4, 122ra21 (2012). Copyright 2012, American Association for the Advancement of Science.

FIG. 5.

(a) The prototype of a drug delivery device with two microchips. (b) and (c) Illustration of microchip reservoirs for carrying drugs. The aperture of each reservoir is capped with a metallic membrane. Reprinted with permission from Farra et al., Sci. Transl. Med. 4, 122ra21 (2012). Copyright 2012, American Association for the Advancement of Science.

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The role of therapeutic management is to enhance drug pharmacokinetics and efficacy. The pharmacokinetics is influenced by the device mechanism through which it shepherds the drug to the disease infected areas of the human body. In addition, the mechanism should release drugs within a specified concentration level to reduce unwanted side effects.

Micromachined technology is playing a vital role in developing low cost and robust drug delivery devices by integrating miniaturized micropumps48 and microvalves.86 The micropumps employ pressure to extract drugs from tiny reservoirs of the device. They have the ability to overcome physiological barriers for targeting tumor locations that cannot be accessed directly.87,88 Moreover, the micropumps can reduce premature drug degradation due to precise control on the release mechanism. The efficiency of a micropump can be improved by optimizing its dimensional constraints.89 There are several types of pumps that have been studied in the literature for drug delivery, such as infusion pumps, peristaltic pumps, osmotic pumps, and positive displacement pumps.48 By incorporating RF technology, these micropumps can be controlled through a noninvasive process.2,87,89 The RF technology also provides wireless control on a micropump for regulating its drug flow rate.87 

Although micropumps have become an essential foundation for many drug delivery devices, the control routing of drug formulations can be further enhanced by incorporating microvalves.90 In addition, microvalves can provide precise release kinetics and they are useful to protect the drug composition from other components of the device.91 The RF technology has the advantage of actuating multiple microvalves wirelessly on a selective basis.86 This technique is helpful to release drugs at different dose quantities.

The wirelessly actuated microvalves are mostly fabricated using thermoresponsive materials, such as hydrogels.92,93 In addition, parylene,94,95 ionic polymer metal composite (IPMC),60 and piezoelectric86 materials have been widely used for the fabrication of microvalves.

The WPT is one of the major strategies that eliminates the need for a battery to power and actuate the microvalve.87,89,95,96 The inductance capacitance (LC) circuit resonating at the RF is the most widely used technique for the WPT. When the LC resonant circuit of a drug delivery device is exposed to external RF waves, electric current is produced in the circuit and power is consumed as heat. The maximum heat is generated when the frequency of external RF waves becomes similar to the frequency of a LC resonant circuit.92 The produced heat can be used to activate the thermoresponsive92 and piezoelectric86 microvalves for drug delivery. For instance, a piezoelectric microvalve is activated by employing an LC resonant circuit in a drug delivery device86 [Fig. 6(a)]. The device (42 × 22 × 4 mm3) contains a PDMS balloon reservoir in a housing mold for storing 88.9 μl fluid [Fig. 6(b)]. The LC resonant circuit is formed by a multilayer coil which is connected to the piezoelectric actuator (PEA) [Fig. 6(b)]. For demonstrating the drug delivery mechanism, the LC resonant circuit is excited by a 10 KHz magnetic field which produces a pressure difference in the reservoir for releasing the stored fluid. The piezoelectric microvalve can also be controlled wirelessly to vary the drug release kinetics and flow rates [Fig. 6(c)]. A similar kind of work has been explained using an integrated ionic polymer metal composite (IPMC) cantilever valve that is attached to an embedded LC resonant circuit60 [Fig. 6(d)]. Repeated cycles of 25 MHz field frequency at 0.6 W input power are used to control the switching operation of the microvalve [Fig. 6(e)]. The device performance is tested to estimate the percentage of the released fluorescein [Fig. 6(f)]. The spiral coil fabricated from a biocompatible nitinol material has demonstrated its capabilities as a wireless LC resonant heater for actuating the drug delivery process2 [Fig. 7(a)]. The coil generates a cantilever sort of actuation when it is excited by external RF magnetic fields at 185 MHz. The cantilever movement helps in actuating the pump chamber and parylene C check the valves to pump the stored agents out of the 10 × 10 × 2 mm3 chip that is packaged with a 305 μm polyimide casing [Fig. 7(b)]. The release of stored agents from the 76 μl reservoir of the device is experimentally demonstrated by placing the complete device in a water environment and then exposing using 1.1 W radio waves. The scanning electron microscope (SEM) image of the complete device illustrates the integration of the nitinol actuator and pump chamber [Fig. 7(c)]. In addition, the outlet nozzle that is used to eject the stored agents is also visible in the SEM image.

FIG. 6.

(a) Schematic illustration of the working principle of the proposed device. (b) Fabricated prototype of the piezoelectrically actuated microvalve (PEA). (c) Demonstration of active and in-active control on the release mechanism of the device under the influence of external RF magnetic fields. Reprinted with permission from Nafea et al., Sens. Actuators, A 279, 191–203 (2018). Copyright 2018, Elsevier. (d) Prototype of the proposed device based on the integrated IPMC cantilever valve for drug delivery. (e) The fabricated device releasing liquid at different RF power levels during the in vitro performance evaluation of the device. (f) Percentage of fluorescein released from the device. Reprinted with permission from Cheong et al., Lab on a Chip 18, 3207–3215 (2018). Copyright 2018, Royal Society of Chemistry.

FIG. 6.

(a) Schematic illustration of the working principle of the proposed device. (b) Fabricated prototype of the piezoelectrically actuated microvalve (PEA). (c) Demonstration of active and in-active control on the release mechanism of the device under the influence of external RF magnetic fields. Reprinted with permission from Nafea et al., Sens. Actuators, A 279, 191–203 (2018). Copyright 2018, Elsevier. (d) Prototype of the proposed device based on the integrated IPMC cantilever valve for drug delivery. (e) The fabricated device releasing liquid at different RF power levels during the in vitro performance evaluation of the device. (f) Percentage of fluorescein released from the device. Reprinted with permission from Cheong et al., Lab on a Chip 18, 3207–3215 (2018). Copyright 2018, Royal Society of Chemistry.

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FIG. 7.

(a) Conceptual illustration of the nitinol LC wireless resonant heater integrated in the chip to perform cantilever actuation for drug delivery. (b) Fabricated drug delivery chip without (left) and with (right) polyimide casing. (c) Scanning electron microscope (SEM) image of the nitinol actuator coupled with the pump chamber. The SEM image also shows the outlet nozzle for ejecting stored agents from the device. Reprinted with permission from Fong et al., Lab on a Chip 15, 1050–1058 (2015). Copyright 2015, Royal Society of Chemistry.

FIG. 7.

(a) Conceptual illustration of the nitinol LC wireless resonant heater integrated in the chip to perform cantilever actuation for drug delivery. (b) Fabricated drug delivery chip without (left) and with (right) polyimide casing. (c) Scanning electron microscope (SEM) image of the nitinol actuator coupled with the pump chamber. The SEM image also shows the outlet nozzle for ejecting stored agents from the device. Reprinted with permission from Fong et al., Lab on a Chip 15, 1050–1058 (2015). Copyright 2015, Royal Society of Chemistry.

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Another approach for reliable and durable drug delivery operation is demonstrated by a wirelessly controlled thermopneumatic micropump97 [Fig. 8(a)]. The size of the micropump is 22 × 7 × 4 mm3 and it consists of three flexible layers [Fig. 8(b)]. This work is based on a frequency controlled LC heater that is placed underneath the pump chamber. The LC heater is designed to operate at its resonant frequency of 81.5 MHz. When it is excited at its resonance with a 0.22 W RF signal, the heat is generated and quickly transferred to the pump chamber [Fig. 8(c)]. The maximum flow rate of 2.86 μl/min is achieved using this process which can be further increased by additional heating of the chamber using RF. The transportation of the fluid and its flow direction are physically demonstrated [Fig. 8(d)].

FIG. 8.

(a) Schematic illustration of a thermopneumatic micropump. (b) The fabricated micropump with multiple layers of cover lid, fluid directing channel, and LC wireless heater. (c) The heat transfer behavior from the LC wireless heater to the chamber. (d) The transportation of fluid from the reservoir to the outlet port. Reprinted with permission from Chee et al., Sens. Actuators, A 233, 1–8 (2015). Copyright 2015, Elsevier. (e) Schematic representation of integrated components in the micropump. (f) The fabricated micropump with integrated sensors and components. Reprinted with permission from Sheybani et al., Biomed. Microdevices 17, 74 (2015). Copyright 2015, Springer. (g) Schematic illustration of attractive and repulsive forces between magnets for drug release. (h) The fabricated prototype of a helical robot. Reprinted with permission from Nam et al., IEEE/ASME Trans. Mechatronics 22, 2461–2468 (2017). Copyright 2017, Institute of Electrical and Electronics Engineers.

FIG. 8.

(a) Schematic illustration of a thermopneumatic micropump. (b) The fabricated micropump with multiple layers of cover lid, fluid directing channel, and LC wireless heater. (c) The heat transfer behavior from the LC wireless heater to the chamber. (d) The transportation of fluid from the reservoir to the outlet port. Reprinted with permission from Chee et al., Sens. Actuators, A 233, 1–8 (2015). Copyright 2015, Elsevier. (e) Schematic representation of integrated components in the micropump. (f) The fabricated micropump with integrated sensors and components. Reprinted with permission from Sheybani et al., Biomed. Microdevices 17, 74 (2015). Copyright 2015, Springer. (g) Schematic illustration of attractive and repulsive forces between magnets for drug release. (h) The fabricated prototype of a helical robot. Reprinted with permission from Nam et al., IEEE/ASME Trans. Mechatronics 22, 2461–2468 (2017). Copyright 2017, Institute of Electrical and Electronics Engineers.

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The near field inductive coupling is considered to be the most prevalent technology for WPT and data telemetry in a drug delivery device.95 The inductive coupling is subject to the propagation of magnetic fields that undergo minimum attenuation while propagating through the biological tissues.96 However, the WPT relying on inductive coupling has some limitations due to misalignment between coils (transmitting and receiving) and short distance requirement for suitable functionality.87 The near field inductive coupling can be encoded for securely activating the microvalve of a drug delivery device. A surface acoustic wave (SAW) system has shown its application for activating the microvalve at a specific encoded sequence.96 The transmitter generates a coded RF signal that interacts with the microvalve front end. The microvalve is only actuated when the code of the received RF signal is matched with the embedded code in the microvalve. The study was performed within the frequency range of 10–100 MHz. The inclusion of tiny sensors in a drug delivery device can help in monitoring the dispensed drug volume and flow rate wirelessly, which is particularly important for an implantable scenario. These sensors can be controlled by frequency and amplitude modulation schemes. For instance, an RF signal modulated with amplitude shift keying (ASK) is used to control the flow rate of an implantable micropump by employing dosing sensors87 [Fig. 8(e)]. The sensor is constructed by using a pair of electrodes and it is placed in the drug reservoir of the fabricated prototype [Fig. 8(f)].

The radio signal suffers from attenuation while penetrating through the biological tissues. The attenuation increases with the increase in the signal frequency and thus it becomes important to design an external RF transmitter that can provide adequate power levels to an implantable drug delivery device. A technique based on transmitting antenna arrays is indicated to increase the power levels at the capsule that is implanted in the middle of a human torso phantom.98 The capsule contains a drug reservoir and a split ring resonator (SRR) that is attached to a lid. When the frequency of external radio waves matches with the resonance frequency of the SRR, highly intense electric fields are generated around the lid and heat is produced due to power loss. The generated heat is useful to dismantle the lid for releasing the drug out of the capsule.

Magnetically controlled devices, such as microrobots have shown a tremendous potential for drug delivery applications due to recent developments in MEMS technology.99,100 The microrobots encompass swimming capability and their propulsion through the blood vessels can be controlled by external magnetic fields.101 In addition, microrobots can access tiny biological parts of the body that is not possible with systemic administration. The microrobots are fabricated with magnetic bodies and comprise of tiny magnets, coils, batteries, antenna, and a controlling system.26,102,103 The tiny reservoirs in the microrobots are fabricated using microfabrication technologies. To achieve biocompatibility, a thin layer of titanium25 or gold104 is used for implantable microrobots.

The applications of microrobots have been demonstrated for minimally invasive ocular therapies.25,104 Obstructions in retinal veins can create clots which may result in the loss of vision. The magnetically triggered microrobots can be used to generate a force that can puncture the retinal veins through microneedles for delivering drugs.25 Fluorescence analysis is performed and the experimental results are investigated for such a system.

A wirelessly controlled helical shaped microrobot has also addressed the drug delivery problems associated with twisted and narrow tubular environments102 [Figs. 8(g) and 8(h)]. The microrobot contains fixed and rotating magnets that can be actuated by external magnetic fields for drug delivery, navigation, and drilling motion. For instance, the drug is expelled from the nozzle of the proposed helical robot by controlling the attractive and repulsive forces between the rotating and fixed magnets. In addition, the magnetic torque produced in the helical robot due to the interaction of magnetic fields with the magnets is responsible for navigating the microrobot with a drilling motion. The drilling motion is used to sluice the clogged parts in the blood vessels. The device was tested for drug release in the frequency range of 0–15 Hz. Another microrobot actuated by electromagnetic (EM) waves to deliver the drugs toward the targeted location in the blood vessels has been discussed.103 The electromagnetic actuation mechanism consists of Helmholtz and Maxwell electric coils. The Helmholtz coil is used to magnetize the microrobot for alignment toward the targeted location, whereas the Maxwell coil is used to generate magnetic flux for providing the propulsion force to the microrobot.

The advancements in biomedical engineering have assisted medical care with actively controlled systems for improving the therapeutic efficacy and pharmacokinetics. However, bulky scaffolds and batteries pose limitations when a miniaturized device design is required for repeated and rapid drug delivery.

In recent years, the direct exposure of radio waves to nanoparticles has emerged as an alternative approach of minimally invasive drug delivery.5,98 A direct therapeutic effect of the RF can be achieved by means of absorbing nanoparticles which serve a sensitizer. Nanoparticles have to be accumulated in the site where the therapy is to be provided. Gold nanoparticles (AuNPs) have the ability to generate heat after absorbing the RF105,106 and can be used for local treatment. This technique, known as nano-radio-frequency ablation, is a noninvasive method which allows localized therapy, such as treating tumors, without needle insertion with selective destruction of cancer cell in some cases.

A variety of absorbing agents mostly include electrically conductive and magnetic nanoparticles. Nanoparticles convert the electromagnetic energy of the RF field into heat and release it to the surrounding tissues leading to thermal damage. First, gold nanoparticles and carbon nanotubes were shown to exhibit significant heating under exposure to RF radiation.107–109 Relatively low concentrations of the absorbing components on the order of 1 mg/ml undergo heating at a rate of 20 K/s under an intense source of RF radiation with a frequency of 13.6 MHz and a power of 600 W. That noninvasive radiation in the radio wave range causes thermal ablation of cancer cells in vitro. Although gold nanoparticles are quite inert materials, their surface can be chemically modified with antibodies, peptides/proteins, and sugar residues to facilitate their targeting to cancer cells that makes them a promising RF sensitizer agent once they reside in these cells.110 Gold nanoparticles can range from 2 nm to several hundreds of nanometers and their size, shape, and composition can be precisely tuned in order to provide the desired properties such as characteristic extinction spectra [Fig. 9(a)]. For example, the ratio between the inner silica core and the outer layer of gold in composite gold-silica nanoshells determines the absorption characteristics of the particle. The modification of gold nanoparticles with cancer specific antibodies significantly improves the internalization of nanoparticles in comparison with those modified with nonspecific antibodies or nanoparticles without any antibodies [Fig. 9(b)]. Figures 9(b)(2) and 9(b)(3) demonstrate a significant increase in the number of nanoparticles within the cell when specific antibody modification is applied [Fig. 9(b)(3)] in comparison with those with nonspecific antibody modification [Fig. 9(b)(2)]. These pictures do not reveal any limit in the internalization of nanoparticles, however, they show that a significant number of nanoparticles can be reached within the cell so that the thermal effect of nanoparticles under the influence of RF fields could affect the cell. Carbon nanotubes have also been shown to be targeted to specific cells by means of covalent functionalization or through noncovalent wrapping.107 Apart from conductive nanoparticles such as gold and carbon nanotubes, the RF ablation has also been investigated to produce magnetically inducible effects. In this scenario, the iron based nanoparticles (Fe3O4, for example) are employed to generate heat by means of their interaction with the magnetic component of the electromagnetic field in a broad range of frequencies from 0.2 to 30 MHz.111–113 The reported heating effects are mainly related to losses during the relaxation (Neel-Brownian) of the particles, although at high frequencies (30 MHz), nonspecific and irrelevant iron nanoparticle heating contributes to this process114 (Fig. 10).

FIG. 9.

(a) Illustration of size dependent gold nanoparticle spectra. (b) Transmission electron microscopy image of gold nanoparticles targeted against PANC-1 cancer cells. (1) Gold nanoparticles without the antibody label. (2) Gold nanoparticles with IgG antibodies. (3) Gold nanoparticles with C225 antibodies. (4) The magnified image of PANC-1 cells with gold nanoparticles. Reprinted with permission from Cherukuri et al., Adv. Drug Delivery Rev. 62, 339–345 (2010). Copyright 2009, Elsevier.

FIG. 9.

(a) Illustration of size dependent gold nanoparticle spectra. (b) Transmission electron microscopy image of gold nanoparticles targeted against PANC-1 cancer cells. (1) Gold nanoparticles without the antibody label. (2) Gold nanoparticles with IgG antibodies. (3) Gold nanoparticles with C225 antibodies. (4) The magnified image of PANC-1 cells with gold nanoparticles. Reprinted with permission from Cherukuri et al., Adv. Drug Delivery Rev. 62, 339–345 (2010). Copyright 2009, Elsevier.

Close modal
FIG. 10.

The comparison between tissue hyperthermia and thermal ablation is illustrated as a function of nanoparticle concentration CMNP and specific absorption rate SARMNP.

FIG. 10.

The comparison between tissue hyperthermia and thermal ablation is illustrated as a function of nanoparticle concentration CMNP and specific absorption rate SARMNP.

Close modal

Thereafter, various other conductive particles were applied as radio frequency field sensitizer agents. As such, crystalline silicon nanoparticles heat efficiently under RF radiation115 and platinum nanoparticles were shown to exhibit an even higher heat generation efficacy in comparison with gold nanoparticles.116 Quantum dots (QDs) seem to be a promising agent in RF ablation due to their capability to convert electromagnetic energy into heat almost as efficiently as gold nanoparticles.117 Thus, QDs could contribute to cell imaging and at the same time promote RF induced heating and therapeutic effect serving as theranostic systems.

Tailoring different functions to nanoparticles via a number of synthetic routes have enabled researchers to develop new agents for RF ablation. As such, gold nanoparticles can be hybridized with iron oxide to become contrasting in MRI and to provide fluorescent cancer cell imaging,118–120 while the as synthesized magnetite component exhibits both high MRI contrast and RF heating. More recently, iron-based nanoparticles with a high quantum yield were reported to be multifunctional RF hyperthermia agents.121 Furthermore, RF radiation sensitive porous silicon nanoparticles were employed as drug carrying nanovehicles.122 A thermoresponsive polymer grafted onto the surface of the particles works as a shutter releasing the encapsulated substance in response to RF radiation. Gold nanoparticles were utilized as RF energy transducers inside the titania nanotubes as well for the rapid release of therapeutics from the implantable device.1 

Although the aforementioned strategies have shown a tremendous potential for on demand drug delivery, they still require a rapid repeatable mechanism. As an alternative, the effect of magnetic fields on a sponge like microspouter is demonstrated for precise and repeated on demand drug delivery5 [Fig. 11(a)]. The external magnetic fields can be used to trigger the spouting of the magnetic sponge by employing its reversible deformation. The magnetic sponge is prepared from polydimethylsiloxane elastomers and ferromagnetic carbonyl iron (CI) microparticles. The microspouter is activated at different strengths of the magnetic field to demonstrate rapid release of methylene blue [Figs. 11(b) and 11(c)]. The idea of incorporating nanoparticles susceptible to RF into drug depot devices has been applied in the development of nanocomposite hydrogels. It envisages a great promise in tissue engineering since the properties can be remotely controlled to deploy the drug and to sense the environment. These composite drug depot systems are based on RF sensitizers (such as magnetite NPs, gold NPs, carbon nanotubes, and others) and thermoresponsive hydrogels, whose mechanical properties are influenced by an increase in temperature in different ways, including deformation, shrinking, pore size change, etc.123–125 

FIG. 11.

(a) Fabricated prototype of the proposed microspouter. (b) Images of methylene blue released from the microspouter with and without magnetic stimuli. (c) The camera images of flows spouted from the microspouter under the influence of different magnetic field strengths. Reprinted with permission from Shademani et al., Adv. Funct. Mater. 27, 1604558 (2016). Copyright 2016, John Wiley and Sons.

FIG. 11.

(a) Fabricated prototype of the proposed microspouter. (b) Images of methylene blue released from the microspouter with and without magnetic stimuli. (c) The camera images of flows spouted from the microspouter under the influence of different magnetic field strengths. Reprinted with permission from Shademani et al., Adv. Funct. Mater. 27, 1604558 (2016). Copyright 2016, John Wiley and Sons.

Close modal

Although the particular mechanism of electromagnetic energy conversion into heat is still not completely understood and there are some controversies discussed in Ref. 126, the predominant theory accepted by different researchers presupposes Joule heating produced by electrical currents on the surface of conductive nanoparticles.109 Experimental data on the size dependence of the RF induced heating support the Ohmic nature of this process. Moran et al. have shown inverse dependence of the RF heating on the gold nanoparticle size under 50 nm, whereas at larger sizes, the dependence has not been observed.109,127 AuNPs under 50 nm heated almost twice more efficiently than bigger size AuNPs, which can be explained by the higher electrical resistivity of smaller gold nanostructures. Kruse et al. have also investigated the influence of the particle size and have shown that gold nanoparticles with a size of 5 nm can be considered as more efficient RF sensitizers in comparison with larger particles.127 The heating of AuNPs was shown to increase linearly with concentration up to a specific range of saturation. The noncontact RF-EM systems were used to perform the experiment127 (Fig. 12). San et al. and Tamarov et al. have also demonstrated linear dependency of temperature rise on the nanoparticle concentration in the case of Pt and Si nanoparticles.115,116 However, it is a more complex process in the case of single-walled carbon nanotubes (SWNTs) which exhibit a nonlinear dependency of heating on the concentration.107 Nevertheless, RF induced heating cannot be considered as a pure Ohmic dissipation since this process was found to depend on many other factors such as the chemical nature, heat and electrical conductivity, permittivity, and shape of the nanoparticles.115 

FIG. 12.

Measurement setup for exposing E-fields to the sample containing gold nanoparticles. Reprinted with permission from Kruse et al., IEEE Trans. Biomed. Eng. 58, 2002–2012 (2011). Copyright 2011, Institute of Electrical and Electronics Engineers.

FIG. 12.

Measurement setup for exposing E-fields to the sample containing gold nanoparticles. Reprinted with permission from Kruse et al., IEEE Trans. Biomed. Eng. 58, 2002–2012 (2011). Copyright 2011, Institute of Electrical and Electronics Engineers.

Close modal

There are some reports, both theoretical and experimental, which claim that the presence of nonaggregated metallic nanoparticles cannot play a role in heating at certain rates.128–130 These studies attribute the heating process to the movement of ions in the surrounding medium and refer to the cell death induced by NPs to cationic NP cytotoxicity rather than accelerated heating of the biological medium although it contradicts the absence of cytotoxic effects in control samples. However, the so-called “protein corona” was shown to result in a change of the electromagnetic response of the particle leading to high rates of heating under RF fields by enhancement of RF energy loss at the AuNP-protein interface.130 

Nevertheless, many experimental studies have proven the high therapeutic efficiency of different nanoparticles against cancer cells both in vitro and in vivo without cytotoxicity in the absence of RF fields and with low side effects.107,108,110,115,119 In most of the studies, the NPs are targeted by antibody agents specific to cancer cells in order to reach the highest efficiency of the therapy.

Drug delivery devices have transformed the course of therapeutic treatment in the medical field. They offer an advantage over systemic administration that performs suboptimally when a defined concentration of drugs is required for a prolonged duration. In a very short span of time, novel drug delivery devices have provided therapeutic indexes with minimal side effects. The recent advancements in MEMS technology have played a pivotal role in miniaturizing the size of a drug delivery device by integrating components, such as batteries, electronics, processing unit, and tiny reservoirs within a compact space. In addition, many of the nanoparticles are susceptible to the RF and could convert the absorbed energy into heat, causing local therapy via hyperthermia. These particles can be incorporated to larger, micrometer and submicron scale vehicles which could provide the local deployment of the drug upon RF.

The actuating and control mechanisms that initialize the drug release process have a significant importance for on-demand drug delivery. The release mechanism should be reliable enough to protect the drug composition until the release time. This review paper provides a comprehensive vista about the devices that are actuated and assisted by the RF. This technique would leverage noninvasive control on the therapy with release on-demand capability. Recent studies have also shown considerable success in actuating micropumps, microvalves, and microrobots for drug delivery. Moreover, the sensors integrated in the drug delivery device can transmit the information about the drug release status and its concentration levels back to the external transmitter. The RF technology can also be used for wireless power transfer to an implantable drug delivery device and thus exclude bulky batteries.

For the aforementioned advantages, the RF system has now become an integral part of current drug delivery devices for more commercially viable solutions of medical care. In the future, the combination of MEMS, materials engineering, biomedical engineering, and RF technology can provide a platform for novel drug delivery devices to fulfill the unmet medical requirements related to dosing.

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