REVIEW

Clinical Applications of Biomedical Microdevices for Controlled Drug Delivery Pablo Gurman, MD; Oscar R. Miranda, PhD; Kevin Clayton, BS; Yitzhak Rosen, MD; and Noel M. Elman, PhD Abstract Miniaturization of devices to micrometer and nanometer scales, combined with the use of biocompatible and functional materials, has created new opportunities for the implementation of drug delivery systems. Advances in biomedical microdevices for controlled drug delivery platforms promise a new generation of capabilities for the treatment of acute conditions and chronic illnesses, which require high adherence to treatment, in which temporal control over the pharmacokinetic profiles is critical. In addition, clinical conditions that require a combination of drugs with specific pharmacodynamic profiles and local delivery will benefit from drug delivery microdevices. This review provides a summary of various clinical applications for state-of-the-art controlled drug delivery microdevices, including cancer, endocrine and ocular disorders, and acute conditions such as hemorrhagic shock. Regulatory considerations for clinical translation of drug delivery microdevices are also discussed. Drug delivery microdevices promise a remarkable gain in clinical outcomes and a substantial social impact. A review of articles covering the field of microdevices for drug delivery was performed between January 1, 1990, and January 1, 2014, using PubMed as a search engine. ª 2015 Mayo Foundation for Medical Education and Research

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iomedical microdevices are fabricated devices with critical features on the order of 1 to 100 mm. These microdevices range in complexity from simple microstructures such as microchannels to more sophisticated microfunctional parts such as microtransducers and microelectromechanical systems (MEMS).1 These devices integrate mechanisms that activate a variety of physical signals to achieve a specific function. For example, MEMS-based inertial sensors transduce a mechanical signal input to an electrical signal response. Current transducers are able to combine multiple physical inputs with multiple output signals. Biomedical microdevices present a variety of key advantages for applications in health care owing to their (1) extremely small sizes providing minimally invasive procedures, (2) low power consumption, (3) batch fabrication processes with high reproducibility, and (4) low cost per device, in conjunction with their multiple functionalities and compatibility with very large-scale integration electronics. These novel technologies have accelerated the development of a variety of micromedical devices, such as catheter pressure sensors, microelectronic components for pacemakers,

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hand-held point-of-care diagnostic devices, and drug delivery systems, all of which have provided significant improvement over treatment possibilities for numerous chronic and nonchronic illnesses.1-4 Figure 1 shows a variety of biomedical microdevices for several therapeutic applications. Controlled drug delivery systems that are based on microdevices contain structural microparts, such as microchannels and microreservoirs, to store drugs. In addition, drug delivery systems based on MEMS incorporate microtransducers such as microactuators and microsensors, which improve the device capabilities. Drug delivery devices based on MEMS provide an opportunity for improved diagnosis, monitoring, and treatment of numerous illnesses. The MEMS can deliver a variety of drugs, including drugs in combination, using a single device. The MEMS drug delivery devices have the ability to control the rate of drug release to a target area. They can be programmed for pulsatile or continuous delivery and can release the drug locally, which increases treatment efficacy using a smaller amount of drug, reducing systemic concentration levels1-6 and associated toxicity.

Mayo Clin Proc. n January 2015;90(1):93-108 n http://dx.doi.org/10.1016/j.mayocp.2014.10.003 www.mayoclinicproceedings.org n ª 2015 Mayo Foundation for Medical Education and Research

From the Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge (P.G., O.R.M., K.C., Y.R., N.M.E.); and Department of Materials Science, University of Texas at Dallas, Richardson (P.G.).

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ARTICLE HIGHLIGHTS n

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Drug delivery systems can be classified as passive and active. Passive devices do not incorporate sensors and actuators for drug delivery. Active microdevices include microelectromechanical systems (MEMS), which comprise microparts such as microchannels and microvalves and transducers, including microsensors and microactuators, integrated into a singular microdevice. Advantages of MEMS drug delivery systems include miniaturization, integration with microelectronics, actively controlled, low cost, multiple pharmacologic therapies in a single device, controlled over release rate, and in vivo long-term storage of drugs. The MEMS are being used for a variety of clinical conditions, including diabetes, neurologic disorders, inner ear diseases, and cancer. Fluzone is an example of a Food and Drug Administratione approved drug delivery microdevice for vaccine delivery. The MEMS drug delivery devices can be considered combination products. Many combination products are considered drugs, requiring a New Drug Application for Food and Drug Administration approval. Finally, the scope of novel materials for biomedical devices has expanded the potential use of biocompatible platforms with high biological performance, eg, less toxic and nonreactive devices, enabling new therapeutic applications. This review provides a summary of current state-of-the-art biomedical microdevices for controlled drug delivery and their corresponding clinical applications. The following sections describe passive and active delivery devices based on MEMS technology. Each section provides a technical description of a microdevice followed by its suggested clinical application. The review continues with a summary of the regulatory strategies for obtaining Food and Drug Administration (FDA) approval for such microdevices. Finally, a perspective on the future of these novel devices is presented. DATA SOURCES AND SEARCHES A PubMed search between January 1, 1990, and January 1, 2014, was performed. The search terms were drug delivery AND MEMS, implantable devices AND MEMS, control release AND microchip, controlled release AND BioMEMS,

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neural probes AND drug delivery, vaccines AND microneedles, diabetes AND microneedles, intraocular AND drug delivery devices, and inner ear AND drug delivery AND microfluidics. Papers were selected following the definition of microdevices and MEMS. Selection also was performed with the aim of having examples of different types of microdevices (passive and active, actuation mechanism, and materials). Examples of different clinical applications for drug delivery microdevices assisted in selecting papers more close to the clinical application than those focused solely on fundamental science. Diagnostic microdevices were specifically excluded from the search. PASSIVE DEVICES Passive biomedical microdevices for drug delivery do not rely on an actuation mechanism or on monitoring for feedback. These devices are reservoir based, relying on mass transfer across a permeable membrane to deliver pharmaceutical drugs, the biodegradation of a hermetic membrane, or a unique reservoir structure to achieve controlled release. The rate of release can be controlled by taking into account the following design parameters: (1) the effective permeability of the membranes by fine-tuning structural dimensions and materials (pore size, thickness), (2) the rate of degradation of the polymer contained on the membrane or in the reservoir, (3) the diffusivity properties of the drug, and (4) the osmotic pressure. Passive delivery of drugs cannot be modified after implementation. Other passive-release devices operate based on actuation resulting from in vivo conditions inside the body, such as pH or temperature, to accelerate degradation of the materials that encapsulate the pharmaceutical drugs. Typically, the controlled release is achieved by considering the pharmacokinetics of the selected drug for delivery. Design and material parameters are thereafter adjusted and selected during the design process to provide a constant and superior pharmacokinetic performance, such as an improvement in treatment efficacy duration over the typical half-life of the pharmaceutical drug. Existing passiverelease devices, such as the fentanyl transdermal system (DURAGESIC; Janssen Pharmaceuticals Inc) and the fluocinolone acetonide intravitreal implant (Retisert; Bausch & Lomb Inc), are used for either short-term (3 days) or

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Microchannel

MEMS Chip Into inner ear for intra cochlear delivery

Pt conducting wire

Pump

Cochlear implanted device with pump and electronic control (Figure 10)

Microneedles

Neural probe with microchannels for drug delivery (Figure 4)

Stratum corneum Epidermis

Drug reservoir

Drug solution

Into cannula

Parylene cannula

Dermis Subcutaneous tissue Dendritic cell Hypodermic needle Langerhans cell

Pump outlet Electrolysis pump Eye wall

Into eye

Ocular device with electrolysis pump (Figure 7)

Microneedle transdermal patch (Figure 8)

MEMS delivery for emergency (Figure 6)

Implantabe MEMS device for drug delivery (Figure 9)

Microchip drug delivery for osteoporosis (Figure 5)

FIGURE 1. Technology map for applications of biomedical microdevices. MEMS ¼ microelectromechanical systems.

long-term (2.5-3 years) continuous treatment of diseases. The lack of integrated electronics reduces the complexity of these devices.7,8

Hydrogels Implantable devices based on environmentally sensitive hydrogels were developed for controlled release (Figure 2).9 The device architecture consists of a reservoir and a 100mm-thick silicon membrane with orifices measuring 140 mm in diameter. Each orifice contains a support post in the center and is tethered to confine the hydrogel to the membrane. The hydrogel is loaded around the Mayo Clin Proc. n January 2015;90(1):93-108 www.mayoclinicproceedings.org

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central support post such that the entire orifice is blocked by the hydrogel in the swollen state. Under activation by chemical or physical stimuli, the hydrogel shrinks and the drug is allowed to diffuse through the resulting orifice. The response of the hydrogel opening or closing is critical in controlling the rate of drug delivery. Additional control of drug delivery can be gained by manipulating the membrane thickness, the size of the orifices, the support posts, and the tethers. The temperature, pH, and glucose sensitivity of different hydrogels are some of the parameters that provide additional control over activation. For example, N-isopropylacrylamide hydrogels

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Flow

Front side tethers

Silicon membrane

Central tethered post

Back side tethers

FIGURE 2. Schematic of silicon membrane with structured orifices. From Sens Actuators B Chem,9 with permission.

were found to rapidly contract at 34 C, resulting in a sharp increase in the flow rate of the drug from 0 to approximately 1 mL/min. This type of hydrogel exhibited a fast response to environmental conditions, contracting in 10 seconds at 25 C and expanding back to close the orifice in 20 seconds at 50 C. N-butan-2-ylbutan-2amine/anodic alumina membrane hydrogel was measured to respond to a change in pH of 3.0 to 10.0 in 4 minutes, whereas for changes in glucose levels from 0 to 20 mmol/L, this hydrogel responded in 40 minutes.9 Clinical Application: Diabetes Diabetes represents a significant burden in health care as the number of people with type 2 diabetes is increasing dramatically owing to a pandemic of obesity worldwide.10 One of the key issues in diabetes is adherence with insulin administration. Adherence is limited owing to the frequent and uncomfortable subcutaneous (SC) injections that the patient needs to treat his or her diabetes. Glucose-responsive hydrogels provide an opportunity for the controlled delivery of insulin. Incorporating more channels with various types of hydrogels and channel sizes could improve control and treatment. Further work is needed to better understand and engineer response kinetics and the reliability of such hydrogel-based devices for clinical applications. 96

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Passive Nanochannel-Based Drug Delivery Device A novel, high-throughput nanochannel drug delivery system for the sustained delivery of chemotherapeutics was developed and tested in vitro.11 The device was developed to be implantable to improve patient adherence and quality of life by avoiding the need for repeated administrations and frequent visits to the clinic. The device passively controls the release of drugs by physical-electrostatic confinement. By manipulating the size of the nanochannels, zero-order release of chemotherapeutics was achieved. The nanochannel membrane comprises a silicon substrate reservoir and a capping layer. An array of 161 channels, measuring 200200 mm and spaced by 50mm-thick walls, makes up the membrane surface (Figure 3). It consists of 30-mm-wide microchannels that connect the reservoir and the capping layer. The nanochannels connect the inlet and outlet channels at the interface of the silicon substrate and the capping layer. Clinical Application: Melanoma Melanoma, a tumor originating from melanocyte cells, represents the most aggressive form of skin cancer, with 5-year survival of 20% for advanced cases. Current pharmacologic therapies include the use of interferon alfa-2b as an adjuvant for stage III melanomas. Interferon alfa-2b is an immunomodulatory drug that activates the immune system against the tumor, increasing patient relapse-free survival. An important issue with interferon alfa-2b is its adverse effects. Interferon alfa2b in high doses has been linked to hepatotoxicity and suicidal ideation.12 The use of implantable, controlled nanochannel delivery systems could potentially overcome some of the limitations associated with current therapies by decreasing the amount of drug that reaches the systemic circulation. This improvement could avoid adverse effects in healthy tissues while keeping high concentrations of interferon alfa-2b at the targeted site where the tumor is located. Clinical Application: Prostate Cancer Prostate cancer represents the sixth leading cause of cancer death in men, with an incidence of 233,000 new cases and 29,480 deaths in

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2014.13 Leuprolide acetate is a synthetic analogue of gonadotropin-releasing hormone. Gonadotropin-releasing hormone stimulates the release of follicle-stimulating hormone and luteinizing hormone, which promote the production of estrogen and testosterone. Testosterone is metabolized in the interior of prostate cells to dihydrotestosterone, which upregulates cell proliferation, gene expression, and protein synthesis. It is thought that leuprolide acts as a gonadotropin-releasing hormone analogue and when given continuously by the SC or intramuscular route (leuprolide acetate could not be administered orally because is a peptide) leads to testosterone deprivation. Deprivation of prostate cells from testosterone would lead to apoptosis and cytoreduction of tumor volume.14 Interferon alfa-2b and leuprolide acetate were chosen to test the nanochannel microchip delivery device. The release of interferon alfa-2b was tested using 20-nm membranes and was measured to be a mean  SD of 29.71.5 mg/d for 6 days, which is in agreement with current maintenance doses of interferon alfa-2b used in patients with melanoma (10 million IU/m2 SC 3 times/wk; 10 million international units ¼ 38 mg). The release of leuprolide was tested using 5- and 15-nm channels and was measured to be zero order for the 5-nm channel at a mean  SD rate of 10010 mg/d for 3 days, which is close in agreement with current leuprolide doses used in prostate cancer (250 mg/d). By increasing reservoir sizes, the nanochannel-based delivery system has the potential to achieve the current dose regimens used for interferon alfa-2b and leuprolide. Multifunctional MEMS for Neural Recording and Drug Delivery Multifunctional MEMS for simultaneous recording of neural activity and drug delivery were developed (Figure 4).15,16 One such device has been reported by Altuna et al16 based on flexible microprobes made of SU-8. The polymer SU-8 was used as the structural material for the probes, with platinum for the electrodes. Tetrode-like probes with a single microfluidic channel and linear probes with 2 microfluidic channels were tested. Electrodes for the tetrode-like probe were spaced 25 mm apart, with diameters of 20 mm to sense individual neuronal firing at the tip of the probe. Mayo Clin Proc. n January 2015;90(1):93-108 www.mayoclinicproceedings.org

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FIGURE 3. Schematics (A, C, and D) and optical microscopy (B) of a passive nanochannel delivery system designed for drug release with zero-order kinetics. The innovative architecture of the device includes macrochannels, microchannels, and nanochannels. M ¼ macrochannel; mO ¼ microchannel outlet; mI ¼ microchannel inlet; n¼ nanochannel; w ¼ supporting walls. From Pharm Res,11 with permission.

The microfluidic channel measured 5020 mm, with 3 outlet ports also near the tip of the probe. In the linear probe, 8 electrodes were spaced 100 mm apart, allowing for sensing at different depths of the brain. The 2 microfluidic channels measured 4020 mm and had independent outlet ports. Both devices were 55 mm thick. The tetrode-like probe was 90 mm wide, and the linear probe was 150 mm wide. The probes were tested in vivo in anesthetized rats. The SU-8 linear probes were used to deliver kainate at the CA1 cell and dendritic layers at a flow rate of 3 to 6 mL/min to induce seizures. Neuronal excitability was recorded against a control delivery of saline to confirm delivery of the drug. The tetrode-like probe delivered potassium at a high flow rate of 0.6 to 1.5 mL/min to the CA1 cell layer. The probe was able to record isolated neurons together with multi-unit firing. Both probes had the ability to measure ripples and spikes common during large irregular brain activity at the CA1 cell layer. Clinical Applications: Parkinson Disease and Epilepsy Effective treatments for neurologic diseases are still lacking. Parkinson disease, the second most

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owing to the progressive loss of dopaminergic neurons. In the long-term, patients start to experience L-DOPA adverse effects that deteriorate their quality of life. Epilepsy, a disorder characterized by uncontrolled propagation of electrical stimuli in the brain, has been managed with drugs that reduce neuron excitability. Some types of epilepsy, however, remain refractory to drugs. Therefore, it is clear that current pharmacologic therapies alone have not reached an acceptable benefit for neurologic disorders requiring additional intervention. Implantable devices such as neural stimulators have emerged as an attractive option for patients with advanced Parkinson disease, refractory epilepsy, and other neurologic conditions.18 Despite the aforementioned benefits, these novel delivery modalities need to overcome issues of poor biocompatibility, such as inflammatory response and fibrosis around the implant, which limit overall device performance. For example, neural probes have been found to elicit glial scar formation and neuronal loss during implantation, impairing device performance. Having an anti-inflammatory drug in the same device could decrease the inflammatory response and, thus, the generation of fibrotic tissue (eg, glial scar formation) surrounding the implant, thus preserving functionality.19,20 Therefore, it is being realized that by combining devices with drug therapies, it is possible to maximize the benefits of both while avoiding their adverse effects. This clinical need has been met by using MEMS technologies, in which neural electrodes are being combined with microfluidic channels or microreservoirs. This combines the capability to record neural data and drug delivery.

Bonding pads Microelectrode film Outlet

Microelectrode sites

Molded PDMS film Microchannel

A Vacuum

B Microchannel

Pt conducting wire

C FIGURE 4. Schematics (A and B) and optical picture (C) of a neural probe with drug delivery capabilities. A, Assembly of device components. B, Method used to incorporate the drug into the microchannels. C, Optical picture of the finished device and microchannels containing a dye solution. PDMS ¼ polydimethylsiloxane; Pt ¼ platinum. From Sens Actuators A Phys,15 with permission.

common neurodegenerative disorder after Alzheimer disease, has been managed for the past few decades with L-3,4-dihydroxyphenylalanine (L-DOPA).17 The L-DOPA is a precursor to dopamine, which is a neurotransmitter that is absent in the brain of patients with Parkinson disease 98

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ACTIVE DEVICES Active drug delivery devices use a variety of mechanisms to release pharmaceutical drugs and provide an increased level of control. The MEMS devices have been developed using different actuation modalities, including micropumps based on gas pressure from electrolysis, integration of magnetic actuators, and electrochemical and electrothermal actuation systems. Active devices can be customized to treat a range of diseases requiring specific pharmacokinetic drug delivery profiles. Moreover, as opposed to passive delivery systems,

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MEMS can be activated and stopped at any time after implantation. Active devices commonly require miniaturized power electronics for actuation, typically increasing the overall form factor, which is a key limiting factor in implantable applications. Alternatively, telemetry systems to transfer energy for activation can be adopted to overcome this limiting issue. Electrothermally Actuated MEMS Drug Delivery Microchip Santini et al21 developed a device for the controlled, pulsatile release of chemicals from single or multiple reservoirs. The controlled drug release was triggered by the application of an electric potential to burst sealing gold membranes electrothermally. Drugs inside the reservoir were then free to diffuse to the targeted site. This original device had the functionality for complex release of kinetics by varying the amount or substance type placed in each reservoir and varying the timing of release. This type of device would be able to deliver drugs in a pulsatile manner. Since then, several works on active drug delivery devices based on MEMS have made substantial progress toward effectively treating various ailments. Clinical Application: Osteoporosis Osteoporosis is the progressive degradation of bone architecture and loss of mass bone density that leads to bone fragility that ultimately increases the risk of fractures. Osteoporosis is more common in postmenopausal women, who are at risk for lower levels of estrogens, which are known to be involved in bone formation. According to the National Institute for Health and Clinical Excellence, 9 million osteoporotic fractures occur annually in the world.22 A microchip device containing parathyroid hormone (PTH) was developed for the treatment of osteoporosis23; PTH is known to stimulate bone formation by increasing osteoblast number and function.24 An implantable microchip device capable of releasing PTH would prevent the need for frequent injections of PTH. The first in-human testing performed in postmenopausal women evaluated the in vivo pharmacokinetic profile of a PTH-release Mayo Clin Proc. n January 2015;90(1):93-108 www.mayoclinicproceedings.org

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microchip (Figure 5) against standard SC injections.25 The microchip was implanted subcutaneously in the abdomen, and the pharmacokinetic profile was measured after a fibrous capsule was formed around the implant. The rationale of the study was to determine the pharmacokinetic performance of the microchip when it was surrounded by a fibrous capsule as a result of the host response to the implant. In addition, bone biomarkers were measured to determine the effect on bone formation of PTH injections vs PTH released by the microchip. A safety laboratory panel was performed to determine the safety of the microchip vs that of the SC injections. Overall, the microchip was found to be bioequivalent to the SC injections even in the presence of the fibrous capsule. The microchip was also found to be as safe as the SC injections based on a laboratory panel.25

FIGURE 5. A microchip drug delivery system for parathyroid hormone (PTH) release for osteoporosis treatment. The picture depicts the titanium packaging used for carryng the microchip. The device has undergone first human trials. From Sci Transl Med,25 with permission.

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A Rapid-Delivery Microchip for Acute Clinical Conditions A microchip drug delivery system for rapid delivery of vasopressin was developed by Elman et al.26 The device consists of a membrane layer, an actuation layer, and a reservoir layer. The membrane layer consists of a biocompatible silicon nitride film that serves as a hermetic seal for the reservoirs. The actuation layer consists of 3 microresistors. Heat is generated when a current is passed through these microresistors. The heat serves to nucleate bubbles and dramatically increase internal pressure inside of the reservoir. This step leads to rupturing of the silicon nitride membrane, followed by rapid release of the pharmaceutical drug, used as a bolus. A picture of the device in action is shown in Figure 6. Clinical Application: Hemorrhagic Shock Hemorrhagic shock is an acute condition that can result from severe traumatic injuries associated with massive bleeding loss, which if not treated within seconds or minutes could result in permanent damage or death. In most cases, critical patients do not have immediate access to a health care facility where basic measures to restore hemodynamic stability are available. These measures include oxygenation; restoration of intravascular volume with colloids, crystalloids, or blood products; and use of inotropic and vasopressor drugs. In settings with limited or no access to health care facilities, interventions to prevent massive hemorrhages include selfapplied hemostatic dressings.

FIGURE 6. Pulsatile controlled delivery profile of a microelectromechanical systems device with a thermally induced actuator releasing drug out of a reservoir for emergency applications. From Biomed Microdevices,26 with permission.

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This approach, however, does not account for internal bleeding sites, which occasionally are the main cause of death. During hemorrhagic shock, the massive loss of blood compromises vital organ activity in the brain, heart, and kidneys, among others. The natural response of the body to avert vital organ damage is to produce vasoconstriction to restore arterial blood pressure and cardiac output to the level required to maintain adequate oxygenation of vital organs while avoiding further blood loss.27 Vasopressin and inotropic agents represent an important tool in the management of hemorrhagic shock.28-30 This biomedical microdevice was designed to be implanted in high-risk patients to deliver vasopressin for the management of hemorrhagic shock in emergency and ambulatory settings. Finally, other potential uses of the rapid-delivery microchip include acute medical conditions that require immediate intervention, such as cardiovascular and neurologic emergencies. Magnetically Controlled MEMS Drug Delivery A magnetic actuator MEMS drug delivery device was developed for the controlled release of a chemotherapeutic agent. The device was designed to avoid the use of batteries, improving form factor. The device consists of a microreservoir sealed by a thin magnetic membrane composite consisting of elastic polydimethylsiloxane material integrated with iron oxide nanoparticles. An external magnetic field applied by a neodymium iron boron permanent magnet creates a force that allows the magnetic membrane to deflect. This process builds up pressure inside the reservoir, enabling the drug to diffuse out through a laser-drilled micron-sized aperture. On-demand release profiles can be created for optimal treatment using this device. With no actuation, the mean  SD release of the drug was measured to be 0.0530.014 ng/ min. With actuation of the membrane by application of a 255-mT magnetic field, the mean  SD release rate increased to 16010.2 ng per actuation. The release rate exhibited sustained delivery for more than 35 days.31 Clinical Application: Cancer Docetaxel was selected as a test drug to study the device release profile. Docetaxel is an antineoplastic agent that disrupts the mitotic spindle, causing cell death; it is used for the

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treatment of a variety of tumors, such as breast cancer.32 An important issue in antineoplastic drugs is to achieve maximum selectivity between cancer cells and healthy cells by increasing the local concentration of the drug while decreasing systemic drug biodistribution, avoiding exposure of healthy tissues.33 This could be accomplished using a magnetically actuated MEMS device that could release the drug locally on demand. In vitro drug-release experiments using cell culture demonstrated that freshly prepared docetaxel solutions and docetaxel from the device described previously herein were found to have comparable effects on target cells. Further development is still required before clinical translation. Micropump MEMS-Based Drug Delivery Devices A refillable intraocular MEMS drug delivery device was developed that uses a micropump for actuation. The device was designed to deliver drugs from a 54-mL reservoir by sending the drug through a cannula and past a 1-way check valve incorporated at the end of the cannula (Figure 7).34 A dose of medication is dispensed from the device via an electrolysis micropump. The device is intended to be implanted under the conjunctiva, with the cannula pointing into the anterior chamber of the eye. Electrolysis of water is triggered by an applied voltage, producing oxygen and hydrogen gases. These gases result in an internal pressure that forces the drug out of the reservoir. For driving currents ranging from 5 mA to 1.25 mA, the flow rate of drug increased linearly from 5 to 439 mL/min. Under normal and abnormal back pressures, the device was able to release 1500 and 1300 nL/min, respectively, with a driving current of 200 mA. Silicone rubber was selected as the reservoir material and was found to be capable of resealing without leakage after repeated refills via a non-coring needle. Replenish Inc further developed a similar system called the Ophthalmic MicroPump System. Two types of micropump systems were developed: an anterior micropump and a posterior micropump. Both devices use a wireless programmer and charger for control of drug delivery. A flow sensor controls the flow rate through a feedback loop, allowing the dispensing of nanoliter volume of drugs. Mayo Clin Proc. n January 2015;90(1):93-108 www.mayoclinicproceedings.org

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Drug reservoir

Drug solution

Parylene cannula Into cannula

Pump outlet Electrolysis pump

Into eye

Eye wall

FIGURE 7. Cross section of the ocular device illustrating the pump and cannula. From Sens Actuators A Phys,34 with permission.

The final piece of the system is a separate console unit to refill the implant with drug.35 Clinical Application: Ocular Disorders Traditional ocular drug treatments, such as oral drugs and eyedrops, require significant overdose because less than 5% of the drug is able to pass the physiologic barriers and reach the site of action.36 The overdose needed to achieve therapeutic concentrations results in potential systemic adverse effects. A variety of passive implants were developed to overcome this issue. Current passive intraocular implants depend on polymer degradation to release the drug and have no control over the drug-release profile, which could lead to subtherapeutic or supratherapeutic (toxic) drug concentrations. Using the electrolysis micropump, it is possible to circumvent these limitations by providing the drug locally and controlling the pharmacokinetic profiles. Release profiles can be programmed by adjusting the current applied to the electrolysis pump. The ability of this device to be refilled makes it attractive for long-term treatment of ocular diseases of the posterior segment, such as age-related macular degeneration. The anterior micropump developed by Replenish Inc was adapted to address disorders of the anterior chamber (glaucoma), whereas the posterior micropump was adapted to address disorders of the posterior chamber (retina disorders). Transdermal MEMS Microneedle Patch Array Delivery System Researchers developed a wearable patch based on a microneedle array for the transdermal

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delivery of macromolecular drugs. Microneedles provide painless administration because they are designed to penetrate through the stratum corneum (the outer layer of the skin) without reaching the nerve terminals located deeper in the skin. Studies have reported a strong correlation between microneedle length and pain perception, although other features, such as drug volume and number of microneedles, have also been associated with pain development during microneedle insertion.37,38 Figure 8 compares injection depth and physiologic impact between an array of microneedles and a hypodermic needle.39 A device was developed consisting of 400mm-long microneedles that are inserted through the outermost layer of the skin, resulting in pain-free drug delivery. The whole device consists of an array of 25 microneedles, each with 300-mm through-holes on a 44mm cross section. A thermally expandable silicone composite is layered below the reservoir. A printed circuit board with heaters to expand the silicone composite layer into the reservoir layer was designed to perform controlled release of the drug through the microneedles. The amount of power applied to the electrical copper heaters controls the amount of

Microneedles Stratum corneum Epidermis

Dermis

Subcutaneous tissue Dendritic cell Hypodermic needle

Langerhans cell

FIGURE 8. Schematic comparing a traditional hypodermic needle with a microneedle array. Note how the microneedle array reaches the dermis, where Langerhans cells are found, and does not reach the subcutaneus tissue, rich in nervous terminals. Both properties make microneedles a very attractive option for vaccine delivery systems. From Clin Exp Vaccine Res,39 with permission.

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expansion and, therefore, the flow rate of the drug. The microneedles use side openings to allow an incredibly sharp apex to avoid coring of tissue during its therapeutic application.40 Clinical Application: Diabetes The reduction of frequent SC injections of insulin can improve adherence to insulin therapy in diabetic patients. Moreover, emulating the physiologic release of insulin by the pancreas is a highly desirable feature. In this regard, the transdermal microneedle MEMS array provides painless administration (improving patient adherence) and control over the flow rate that mimics the kinetics release of insulin by the pancreas (improving efficiency while avoiding adverse effects). Furthermore, a transdermal patch is an easy-to-use device compared with current insulin SC injections. The device was tested in vivo on diabetic rats. With applied power of 150 to 450 mW, the device was measured to dispense 0.1 to 300 mL/h of insulin (a vial of insulin contains 100 IU/mL; therefore, 0.1 mL¼0.01 IU and 300 mL¼30 IU). Based on the pancreatic secretion of insulin (1 IU/h), it is likely that the operational space of the micropump is well suited to replicate the physiologic insulin production by the pancreas. Further work is needed to determine the optimal response of the thermally expandable material to allow for a precisely defined low flow rate with no leakage. In this study, an external power source was used, but a micro-sized battery for practical use could be tested in future work. Clinical Application: Vaccines Vaccines have greatly reduced the incidence of several infectious diseases and represent one of the most cost-effective interventions in health care.41 Therefore, adherence with vaccine administration has an important role in public health. Microneedle technologies for vaccines can provide painless vaccines, improving patient acceptability and adherence. This is particularly relevant because most vaccines are administered to pediatric populations.42,43 Moreover, it is expected that painless vaccines could also improve adherence in the adult population, eg, tetanus vaccine. Another important advantage of transdermal microneedles over intramuscular vaccines is the

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possibility of stimulating antigen-presenting cells, located in the skin, to improve antigen transport to lymph nodes, which enhances the immune response. Microneedles also could overcome the technical problems related to intradermal vaccines (eg, poor reproducibility over the injection site and the need to train health care personnel). Electrothermal MEMS Drug Delivery Device A MEMS-based intracranial drug delivery device has been developed and tested for the treatment of malignant brain tumors (Figure 9).44 Passive-release implants have demonstrated some effectiveness, but incorporating active MEMS to gain more control over the release kinetics could improve efficacy and decrease toxicity. The MEMS drug delivery device consisted of an injection-molded liquid crystal polymer reservoir measuring 3.73.22.2 mm and containing a total drug payload of 10 mg of temozolomide. A 300-mm-thick silicon microchip sits on top of a 200-mm lip on the interior reservoir walls. The silicon microchip contains three 300300-mm suspended silicon nitride membranes, which provides an effective, biocompatible barrier to diffusion. The actuation mechanism relies on using resistive heating to melt a metallic fuse that sits on top of the silicon nitride membranes. Titanium and gold layers are deposited on top of the silicon nitride membrane and are shaped into thin metallic fuses by using photolithography followed by wet etching. The fuse is melted using resistive heating by applying an electrical pulse. This burst results in a membrane fracture and release of the reservoir content. Each membrane can be designed to be independently opened by varying the thickness of the gold and titanium layers or the width of the fuse to require more or less resistive heating. This allows for a variable drugrelease profile. Clinical Application: Glioblastoma Glioblastoma is a devastating type of human cancer with mean survival of 12 months and survival of less than 5% after 5 years.45,46 A variety of pharmacologic therapies have been explored, with very poor clinical outcomes.47 A major challenge in drug delivery to the brain is circumventing or passing the blood-brain Mayo Clin Proc. n January 2015;90(1):93-108 www.mayoclinicproceedings.org

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FIGURE 9. Microelectromechanical systems (MEMS) drug delivery device for the treatment of glioblastoma. Assembled MEMS device (A) and computer-aided design model of the reservoir (B). From Biomaterials,44 with permission.

barrier (BBB). The BBB is the separation of the vasculature system from the brain.48 The BBB maintains brain homeostasis by restricting the transport of molecules present in the circulatory system to and from the brain. This is achieved by the unique characteristics of the brain microvasculature that possess endothelial cells connected by very tight junctions. These tight junctions impede the passage of large macromolecules from the blood to the brain. To circumvent the BBB, local implants that release drugs directly in the brain were developed and commercialized.49 Although commercial polymeric implants already exist, survival rates are poor and new approaches are needed. By using active implantable microchips, a multitarget approach using a combination of drugs with controllable pharmacokinetics could lead to better clinical outcomes. It is important to note that active devices that require frequent drug refilling or power source exchange are not suitable alternatives for MEMS implanted in the central nervous system owing to the implicit requirement for repeated neurosurgical procedures. Repeated neurosurgical procedures may lead to a variety of serious complications in the central nervous system. Therefore, several design considerations for implantable MEMS drug delivery systems must be considered owing to the unique anatomical and physiologic features of the central nervous system. The electrothermal MEMS described previously herein was tested in vitro and in vivo via intracranial implantation in rats. In vitro tests

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confirmed that more membranes being opened leads to more rapid drug release. With 3 membranes activated, the release rate was measured at 0.3 mg/h, and the mean  SD total release was 90%3.2% in 30 hours. The release rate and mean  SD total release decreased to 0.136 mg/h and 82%1.9%, respectively, in 60 hours for 2 membranes activated; further decreases to 0.007 mg/h and 60%12%, respectively, in 800 hours was observed for 1 membrane activated. Implantation and activation of the device was found to be effective in increasing survival time of 9-L glioblastoma rats. Activation of all 3 membranes in the device on the day of implantation was the most effective. This device showed improved efficacy via control of drug pharmacokinetics, but further studies are needed to determine optimal release rates and timing.

Microfluidic Hydraulic MEMS-Based Drug Delivery Devices The MEMS devices for drug delivery to the inner ear were developed using microfluidics (Figure 10).50-52 A microcannula connected to a closed microfluidic circuit allows fluid to flow in and out of the cochlea. Differences in the micron-sized tubing used for the outlet and inlet loops results in discharge and recharge of fluid on the order of seconds and minutes, respectively. As the solution is continuously pumped in and out of the cochlea and mixed with perilymph, dilution of a dissolved compound results in net delivery. The first and second generations of devices use micropumps, and the third generation uses a reciprocating delivery system to control fluid flow. Reciprocating delivery involves infusing and drawing the same volume of liquid, resulting in zero net volume transfer.

MEMS chip Fluidic channel Fill port Drug loading port

~13 mm

Infuse withdraw port

Displacement diaphragm and chamber

MEMS chip

Pump Into inner ear for intracochlear delivery

FIGURE 10. Schematic diagram describing a cochlear microfluidic delivery device to prevent sensorineural hearing loss. The miniaturized device comprises several components, including a microfluidic chip, tubing and cannula for delivery, and electronic circuitry and a battery to power the device. Device dimensions are 5.54.03.8 cm. The device operates under the principle of reciprocating delivery, used for drug delivery into small and sensitive regions of the body, such as the cochlea, where a volume of drug is infused while the same amount of liquid is withdrawn, keeping constant the volume in the cochlear space and allowing higher instantaneous flow rates. MEMS ¼ microelectromechanical systems.

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This technique is suitable for small spaces where overall volume is limited, such as delivery of drugs in the cochlea. Biological back pressures in the cochlea were confirmed to have no noticeable effect on discharge. The distribution of agents in the cochlea was tested using 6,7-dinitroquinoxaline2,3-dione to alter the generation of compound action potential. In vitro and in vivo studies in guinea pigs found increases in the compound action potential threshold, indicating effective drug penetration. Clinical Application: Inner Ear Disorders Inner ear disorders comprise a variety of clinical conditions affecting the inner ear structure or the auditory nerve. The inner ear anatomy involves the cochlea and the vestibular system. The cochlea is responsible for transducing sound waves into electrical impulses that are transported through the auditory nerve to the region in the brain responsible for audition perception. Disorders that affect either the sensing (cochlear) or transducing (auditory nerve) component of the auditory system are known as sensorineural hearing loss (SNHL). It is estimated that SNHL affects nearly 250 million people worldwide.52 Disorders affecting the inner ear include infectious diseases (eg, congenital rubella and congenital cytomegalovirus), genetic disorders (such as mutations on the gene for myosin VIIa, a protein found in the stereocilia), and sensing elements of the hair cells located in the cochlea. Other causes include trauma due to longterm exposure to loud sounds and drugs such as aminoglycosides.53 The physiopathology of SNHL involves damage to and death of the hair cells located in the corti organ (a region of the cochlea that contains hair cells and auditory neurons). Hair cells are a specialized type of cell that contain stereocilia, a type of organelle that in response to acoustic waves opens ionic channels, resulting in depolarization of hair cell membranes. This leads to the release of neurotransmitters, which transport action potentials along the auditory nerve to the regions of the brain responsible for auditory function. The development of the cochlear implant has been a great achievement to restore hearing to people with deafness.54 Cochlear implants aim to stimulate ganglion cells. With the continuous degeneration of these cells as a result of Mayo Clin Proc. n January 2015;90(1):93-108 www.mayoclinicproceedings.org

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infectious, traumatic, or genetic disorders, cochlear implants lose their efficacy. Therefore, drug delivery devices such as the reciprocating micropumps described previously herein represent a novel and promising modality for restoring auditory perception. These devices may allow delivery of neurotropic factors with zero net volume transfer, thus maintaining intracochlear pressure constant and preserving the sensing elements of the cochlea.55 REGULATORY PROCESS FOR CLINICAL TRANSLATION To date, there are a few examples of MEMS for medical applications approved by the FDA, including the CardioMEMS wireless pressure sensor (St Jude Medical, Inc), the i-STAT point-of-care blood analyzer device (Abbott Laboratories), and Fluzone (Sanofi Pasteur Inc), an influenza vaccine based on microneedles.56-60 Several of the MEMS drug delivery devices described previously herein have not been approved by the FDA for clinical use. It is possible, however, based on previous technologies, such as prefilled syringes (a device prefilled with a drug) and the case of Fluzone (which was approved under a Biologics License Application), to describe a potential regulatory pathway for future drug delivery microdevices. First, MEMS drug delivery systems involve at least 2 components: a device and a drug. If the MEMS device incorporates the drug into the final packaged product (it is expected, owing to their small size, that the device and the drug will be copackaged in a single product), they will be considered combination products.61,62 Second, according to the FDA Office of Combination Products, because the drug incorporated into the device provides the main mechanism of action (the therapeutic effect is due to the drug; the device only releases the drug), the system is considered a drug. Drug products are subjected to premarket approval through a New Drug Application (NDA) submission or an Abbreviated NDA (ANDA) submission.61,63 As mentioned previously, Fluzone was approved under a Biologics License Application, which is similar to an NDA.60 An NDA requires a complete description of the manufacturing process and preclinical and clinical studies with the device to establish safety and effectiveness. When the drug being used in the device has already been approved,

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an ANDA might be required. An ANDA is less stringent than an NDA, demanding only bioequivalence studies to establish a similar pharmacokinetic profile with existing devices or formulations using the same drug.4 The future of drug delivery microdevices is promising. Their novelty, their complexity, and the fact that they are implantable, however, will make regulatory approval a challenging endeavor. PERSPECTIVE Biomedical microdevices for controlled drug delivery represent the next generation of delivery modalities that combine miniaturization, low cost, batch manufacturability and reproducibility, and integration with very large-scale integration electronics, allowing programmability and active control over drug release. The current development of drug delivery microdevices is at an early stage, and most of the technologies are still in the proof-of-concept stage. There are a few examples of successful clinical translation of biomedical microdevices, such as the clinical use of vaccine microneedles. There are several reasons that some of the microdevices are still in the drug delivery pipeline. From a clinical standpoint, there must be a clear and identified unmet clinical need where current solutions are still lacking. Even if the clinical need exists and is identified, many applications (eg, infectious diseases) demand large drug payloads that cannot be accommodated with microdevices or that would require periodic refilling. Moreover, bringing these devices to the market entails a very high-risk endeavor. Finally, regulatory issues could also pose a significant barrier for bringing microedrug delivery devices to the market. Some recent initiatives at the FDA, such as the Center for Devices and Radiological Health Medical Innovation Initiative, potentially will help ensure a faster transition of novel biomedical microdevices into the market. CONCLUSION Recent advances in drug delivery devices that use biomedical microdevices for controlled delivery promise improved treatment for a variety of acute and chronic illnesses. Passive devices operate by releasing the pharmaceutical drugs from reservoirs through permeable structures, which can also be degraded by 106

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environmental triggers, such as pH and osmotic forces, to regulate the release rate. Active devices require power to actuate a part that releases the drug after the device is deployed. The release profile of the drug can be actively controlled after the device has been implanted. Passive and active devices can be used as part of minimally invasive procedures and have the ability to deliver drugs with a precise pharmacokinetic profile, enhancing the efficacy and decreasing the toxicity of the drug being used. These devices offer a range of clinical applications in which tailored pharmacokinetics, local release, and high adherence are prerequisites. These clinical conditions include cancer, endocrine disorders, and ocular diseases, among many others. Drug delivery devices represent a novel technology but face a variety of regulatory challenges. Further understanding of biocompatible materials, alternative techniques for drug release actuation, and closed-loop microdevices will enhance the capability of microdevices for clinical drug delivery. Microdevices for drug delivery represent the next generation of platforms for more accurate and efficient drug delivery systems that will enable new therapeutic modalities. These novel platforms promise to increase patient adherence and overall significantly improve treatment outcomes. Abbreviations and Acronyms: ANDA = Abbreviated New Drug Application; BBB = blood-brain barrier; FDA = Food and Drug Administration; L-DOPA = L-3,4dihydroxyphenylalanine; MEMS = microelectromechanical systems; NDA = New Drug Application; PTH = parathyroid hormone; SC = subcutaneous; SNHL = sensorineural hearing loss Grant Support: This work was supported by the US Army Research Office via the Institute for Soldier Nanotechnologies at Massachusetts Institute of Technology (contract W911NF-07-D-0004). Correspondence: Address to Noel M. Elman, PhD, Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, 500 Technology Square, Cambridge, MA 02139 ([email protected]).

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