Implantable Drug Delivery Devices Research Articles

Chemically-Gated and Sustained Molecular Transport through Nanoporous Gold Thin Films in Biofouling Conditions.

Sustained release and replenishment of the drug depot are essential for the long-term functionality of implantable drug-delivery devices. This study demonstrates the use nanoporous gold (np-Au) thin films for in-plane transport of fluorescein (a small-molecule drug surrogate) over large (mm-scale) distances from a distal reservoir to the site of delivery, thereby establishing a constant flux of molecular release. In the absence of halides, the fluorescein transport is negligible due to a strong non-specific interaction of fluorescein with the pore walls. However, in the presence of physiologically relevant concentration of ions, halides preferentially adsorb onto the gold surface, minimizing the fluorescein–gold interactions and thus enabling in-plane fluorescein transport. In addition, the nanoporous film serves as an intrinsic size-exclusion matrix and allows for sustained release in biofouling conditions (dilute serum). The molecular release is reproducibly controlled by gating it in response to the presence of halides at the reservoir (source) and the release site (sink) without external triggers (e.g., electrical and mechanical).

Soft implantable drug delivery device integrated wirelessly with wearable devices to treat fatal seizures.

Personalized biomedical devices have enormous potential to solve clinical challenges in urgent medical situations. Despite this potential, a device for in situ treatment of fatal seizures using pharmaceutical methods has not been developed yet. Here, we present a novel treatment system for neurological medical emergencies, such as status epilepticus, a fatal epileptic condition that requires immediate treatment, using a soft implantable drug delivery device (SID). The SID is integrated wirelessly with wearable devices for monitoring electroencephalography signals and triggering subcutaneous drug release through wireless voltage induction. Because of the wireless integration, bulky rigid components such as sensors, batteries, and electronic circuits can be moved from the SID to wearables, and thus, the mechanical softness and miniaturization of the SID are achieved. The efficacy of the prompt treatment could be demonstrated with animal experiments in vivo, in which brain damages were reduced and survival rates were increased.

Anticancer efficiency of curcumin-loaded mesoporous silica nanoparticles/nanofiber composites for potential postsurgical breast cancer treatment

Recently, implantable electrospun nanofiber-based drug delivery devices have acquired a great interest in treating a tissue defect after tumor resection. In current work, Curcumin (CUR) as a natural antitumor agent was incorporated into the mesoporous silica nanoparticles (MSNs), and the CUR-loaded MSNs (CUR@MSNs) were consequently embedded into poly (lactic-co-glycolic acid) (PLGA) via a blending electrospinning process, resulting in an electrospun nanofiber-mediated drug release system (CUR@MSNs/PLGA NFs). The morphology and physicochemical properties of the prepared CUR@MSNs and the composite NFs were characterized through FE-SEM, TEM, TGA, FTIR, BET, and XRD. Also, the in vitro discharge pattern of CUR from the NFs as well as their anticancer efficiency against MCF-7 breast cancer cells was assessed through MTT, wound healing assay, DAPI staining, and qPCR. The obtained results revealed that CUR@MSNs were successfully embedded into the randomly oriented bead-free electrospun PLGA NFs and exhibited a sustained and prolonged drug release profile. Besides, higher cytotoxicity and lower migration with increased apoptosis induction were detected in the cells treated with CUR@MSNs/PLGA NFs. Thus, the fabricated CUR@MSNs/PLGA composite electrospun NFs might attain a safe and highly promising application for potential postsurgical breast cancer treatment.

Muscle Atrophy: Counteracting Muscle Atrophy on Earth and in Space via Nanofluidics Delivery of Formoterol (Adv. Therap. 7/2020)

In article number 2000014 Alessandro Grattoni and co-workers present the first-ever in vivo study of an implantable drug delivery device in microgravity aboard the International Space Station. In this unprecedented research endeavor, the muscle hypertrophic effect of nanofluidic-mediated sustained low dose elution of formoterol is demonstrated in rodents in space as well as on Earth.

Counteracting Muscle Atrophy on Earth and in Space via Nanofluidics Delivery of Formoterol

AbstractSkeletal muscle atrophy is a critical health problem that affects quality of life and increases morbidity and mortality. At present, exercise training remains the only intervention and pharmaceutical treatments remain elusive. Formoterol (FMT), a β2‐adrenergic receptor agonist, has emerged as a potential therapeutic by triggering skeletal muscle anabolism with daily dosing. Here, the efficacy of sustained FMT release is investigated via a subcutaneously implanted nanofluidic delivery system (nF) to prevent muscle wasting. Pharmacokinetics of nF‐mediated sustained FMT delivery (nF‐FMT) in healthy mice is assessed for 56 days, which demonstrates an anabolic effect on skeletal muscles. Using a hind limb suspension unloading mouse model, it is shown that nF‐FMT treatment attenuates soleus mass loss in comparison to control mice. Further, the very first study of an implantable drug delivery device in microgravity in vivo is launched. The microgravity environment aboard the International Space Station is leveraged to assess the atrophy prevention capability of nF‐FMT in mice for 29 and 55 days. Muscle hypertrophy is observed in both ground control and spaceflight mice treated with nF‐FMT compared to their respective vehicle controls. Overall, the nF system is presented as a viable platform for sustained delivery of FMT for therapeutic intervention of skeletal muscle atrophy.

Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing.

Implantable drug delivery devices offer many advantages over other routes of drug delivery. Most significantly, the delivery of lower doses of drug, thus, potentially reducing side-effects and improving patient compliance. Three dimensional (3D) printing is a flexible technique, which has been subject to increasing interest in the past few years, especially in the area of medical devices. The present work focussed on the use of 3D printing as a tool to manufacture implantable drug delivery devices to deliver a range of model compounds (methylene blue, ibuprofen sodium and ibuprofen acid) in two in vitro models. Five implant designs were produced, and the release rate varied, depending on the implant design and the drug properties. Additionally, a rate controlling membrane was produced, which further prolonged the release from the produced implants, signalling the potential use of these devices for chronic conditions.

Development of injectable and durable kefiran hydro-alcoholic gels

Injectable, in-situ forming kefiran gels have been developed for potential applications as implantable drug delivery devices or scaffolds for tissue regeneration. Concentrated solutions (4, 5 and 6%w) of kefiran, extracted from kefir grains, have been assessed in term of viscosity and injectability through G26 syringe needles, and for their ability to undergo gelation upon mixing with different alcohols. Propylene glycol (PG) has been selected as gelling agent because it ensures homogenous gelation in relatively short times (from few minutes up to 6 h). The investigation of the rheological behavior of kefiran/PG gels varying polymer concentration and temperature (25 °C and 37 °C) has provided interesting hints to support a possible gelation mechanism that accounts also for the observed influence of the alcohol type. Finally, the study of kefiran/PG gels has been complemented with the investigation on selected formulations of the swelling/degradation behavior upon immersion in isotonic buffer solution for up to 40 days at 37 °C; of the ability of the gels to retain and/or release two model molecules; and within vitro cell viability and cytotoxicity tests, to support the absence of toxic effects on cells induced by direct contact with the gels or by leached components from these gels.

Advanced implantable drug delivery technologies: transforming the clinical landscape of therapeutics for chronic diseases.

Chronic diseases account for the majority of all deaths worldwide, and their prevalence is expected to escalate in the next 10years. Because chronic disorders require long-term therapy, the healthcare system must address the needs of an increasing number of patients. The use of new drug administration routes, specifically implantable drug delivery devices, has the potential to reduce treatment-monitoring clinical visits and follow-ups with healthcare providers. Also, implantable drug delivery devices can be designed to maintain drug concentrations in the therapeutic window to achieve controlled, continuous release of therapeutics over extended periods, eliminating the risk of patient non-compliance to oral treatment. A higher local drug concentration can be achieved if the device is implanted in the affected tissue, reducing systemic adverse side effects and decreasing the challenges and discomfort of parenteral treatment. Although implantable drug delivery devices have existed for some time, interest in their therapeutic potential is growing, with a global market expected to reach over $12 billion USD by 2018. This review discusses implantable drug delivery technologies in an advanced stage of development or in clinical use and focuses on the state-of-the-art of reservoir-based implants including pumps, electromechanical systems, and polymers, sites of implantation and side effects, and deployment in developing countries.

Implantable Polymeric Drug Delivery Devices: Classification, Manufacture, Materials, and Clinical Applications.

The oral route is a popular and convenient means of drug delivery. However, despite its advantages, it also has challenges. Many drugs are not suitable for oral delivery due to: first pass metabolism; less than ideal properties; and side-effects of treatment. Additionally, oral delivery relies heavily on patient compliance. Implantable drug delivery devices are an alternative system that can achieve effective delivery with lower drug concentrations, and as a result, minimise side-effects whilst increasing patient compliance. This article gives an overview of classification of these drug delivery devices; the mechanism of drug release; the materials used for manufacture; the various methods of manufacture; and examples of clinical applications of implantable drug delivery devices.

Fabrication of Circular Obelisk-Type Multilayer Microneedles Using Micro-Milling and Spray Deposition.

In this study we present the fabrication of multilayer microneedles with circular obelisk and beveled-circular obelisk geometries, which have potential applications in implantable drug delivery devices. Micro-milling was adopted as an environmental-friendly and cost-effective way to fabricate primary metal microneedle masters. Polylactic acid (PLA) microneedles with sharp tips were then obtained by micromolding followed by oxygen plasma etching and used for preparing polydimethylsiloxane (PDMS) microneedle molds. A spray deposition process was employed for microneedle fabrication to facilitate the formation of multilayer microneedles while helping in maintenance of drug stability. Multilayer microneedles were successfully formed by sequential spraying of poly(lactic-co-glycolic acid) (PLGA) and polyvinylpyrrolidone (PVP) solutions into the mold. The fabricated PLGA-PVP multilayer microneedles penetrated the pig cadaver skin without breakage and released dyes in the skin at different rates, which reveals the potential for implantable microneedles enabling controlled release. Mechanical testing demonstrated that the obelisk-shaped microneedles were mechanically stronger than a pyramid-shaped microneedle and suggested that strong adhesion between PLGA and PVP layers was achieved as well. Structural stability and functionality of a model drug, horseradish peroxidase (HRP), upon spray deposition was examined using circular dichroism (CD) spectroscopy and enzyme activity assay. HRP retained its secondary structure and activity in PVP, whereas HRP in PLGA showed structural changes and reduced activity. Combination of micro-milling and spray deposition would be an attractive way of fabricating drug-containing polymer microneedles with various geometries while reducing prototyping time and process-induced drug instability.

Electrically Triggered Small Molecule Release from Poly( N-Isopropylacrylamide- co-Acrylic Acid) Microgel-Modified Electrodes.

A monolithic layer of poly( N-isopropylacrylamide- co-acrylic acid) microgels was deposited on an Au electrode and used for electrically triggered release of the small molecule crystal violet (CV), which was used as a model drug. CV was loaded into the surface-bound microgels by exposing them to a CV solution at pH 6.5, where the microgels are negatively charged and the CV is positively charged. The electrostatic attraction holds the CV inside of the microgels, while a decrease of the solution pH can neutralize the microgels and allow for CV release. In this investigation, we show that when CV-loaded microgels are deposited on the anode in an electrochemical cell and an appropriate voltage applied, there is a decrease in the solution pH near the anode surface that allows for CV release. We also show that removing the applied potential allows the solution pH near the anode to return to pH 6.5, which halts the release. We show that the release rate from the microgel-modified anodes could be controlled by the magnitude of the applied voltage and by pulsing the applied voltage or applying a continuous voltage. Furthermore, we showed that the microgel-modified anodes can be reloaded with CV and used to release CV to a system many times. Such devices could be used as implantable drug delivery devices, as well as for industrial applications, where small molecules need to be released to systems in response to their chemical status.

Miniaturized-electroneurostimulators and self-powered/rechargeable implanted devices for electrical-stimulation therapy

Advances in technology provide a path towards a new type of medicine that allows physicians to treat diseases with electricity rather than drugs. Recently, miniaturized-electroneurostimulators or electroceuticals which employ electrical-stimulation to affect and modify functions of the body have been attracting great attention. Since the nervous system is criss-crossing in our body to control many aspects of our organ function, bioelectronic implants can treat disease by stimulating nerves as an alternative to drugs. Miniaturized-electroneurostimulators provides a more-targeted approach to treat illness and alleviate pain, presenting a lucrative opportunity. In this review, we discussed on basic concept of electroceuticals or miniaturized-electroneurostimulators, electrical-neurostimulators and electrical-neurostimulation parameters such as amplitude, pulse width, pulse rate, electrode configuration and impedance. Importantly, we focus on self-powered/rechargeable implantable devices which are essential to avoid unnecessary infection or bleeding during repeated surgery. In addition, we summarized on self-powered artificial cardiac pacemaker, self-powered wound dressing, externally-powered dust，externally-powered implantable drug delivery device, wireless charging system in implanted tiny pacemaker, for treatment of diseases by electrical-stimulation and listed potential risks of implanted electrical-neurostimulation device. Miniaturized-electroneurostimulators are expected to play a profound role in implantable neural small devices that treat illnesses and support restore functions in injured or disabled nervous system and also used for monitoring the vital signs of a person.

Self-powered therapeutic release from conducting polymer/graphene oxide films on magnesium

Magnesium's complete in vivo degradation is appealing for medical implant applications. Rapid corrosion and hydrogen bubble generation along with inflammatory host tissue response have limited its clinical use. Here we electropolymerized a poly (3,4-ethylenedioxythiophene) (PEDOT) and graphene oxide (GO) film directly on Mg surface. GO acted as nano-drug carrier to carry anti-inflammatory drug dexamethasone (Dex). PEDOT/GO/Dex coatings improved Mg corrosion resistance and decreased the rate of hydrogen production. Dex could be released driven by the electrical current generated from Mg corrosion. The anti-inflammatory activity of the released Dex was confirmed in microglia cultures. This PEDOT/GO/Dex film displayed the ability to both control Mg corrosion and act as an on demand release coating that delivers Dex at the corrosion site to minimize detrimental effects of corrosion byproducts. Such multi-functional smart coating will improve the clinical use of Mg implants. Furthermore, the PEDOT/GO/Drug/Mg system may be developed into self-powered implantable drug delivery devices.

Remote magnetic switch off microgate for nanofluidic drug delivery implants.

In numerous pathologies, implantable drug delivery devices provide advantages over conventional oral or parenteral approaches. Based on the site of implantation and release characteristics, implants can afford either systemic delivery or local administration, whereby the drug is delivered at or near the site of intended action. Unfortunately, current implantable drug delivery systems provide limited options for intervention in the case of an adverse reaction to the drug or the need for dosage adjustment. In the event that drug delivery must be terminated, an urgent surgical retrieval may be the only reliable option. This could be a time sensitive and costly effort, requiring access to trained professionals and emergency medical facilities. To address such limitations, here we demonstrate, in vitro and ex vivo, a novel microsystem for the rapid and effective switch off of drug delivery from an implantable nanofluidic system, by applying a safe external electromagnetic field in the FDA approved dose range. This study represents a proof of concept for a technology with potential for broad applicability to reservoir-based delivery implants for both complete interruption or remote titration of drug administration.

Advanced drug delivery and targeting technologies for the ocular diseases.

Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders. Methods: In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies. Results: On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies need to be further advanced to get better compliance and higher clinical impacts. Conclusion: Despite mankind successful battle on ocular diseases, our challenge will continue to battle the ocular disease that happen with aging. Yet, we need to understand the molecular aspects of eye diseases in a holistic way and develop ultimate treatment protocols preferably as non-invasive systems.

Development and in vivo evaluation of an implantable nano-enabled multipolymeric scaffold for the management of AIDS dementia complex (ADC)

This study reports the use of biocompatible and biodegradable polymers for the formulation and design of an implantable multipolymeric drug delivery device (MDDD) for the management of AIDS dementia complex (ADC), a debilitating condition affecting the cognitive, motor and behavioral systems in HIV+ individuals. A 3-factor Box-Behnken statistical design was employed for the optimization of nanoparticle and multipolymeric scaffold formulations. Fifteen formulations were generated using the Box-Behnken template, which were assessed for physicochemical and physicomechanical characterization. The optimised nanoparticle formulation yielded nanoparticles measuring 68.04nm in size and zeta potential (ZP) of −13.4mV was calculated for the colloidal system. In an attempt to further retard drug release and to formulate a device for implantation in the frontal lobe of the brain, nanoparticles were dispersed within a multipolymeric matrix. Matrix erosion was calculated at 28% for multipolymeric scaffold and a matrix resilience of 4.451% was observed 30 days post exposure to PBS, indicating slow degradation of the MDDD. In vivo studies showed 12.793ng/mL and 35.225ng/mL AZT level in plasma and CSF. In view of the physicomechanical properties, in vitro and in vivo drug release kinetics of MDDD makes it a potential candidate for the management of the ADC.

Validation of Ultrasound Elastography Imaging for Nondestructive Characterization of Stiffer Biomaterials.

Ultrasound elastography (UE) has been widely used as a "digital palpation" tool to characterize tissue mechanical properties in the clinic. UE benefits from the capability of noninvasively generating 2-D elasticity encoded maps. This spatial distribution of elasticity can be especially useful in the in vivo assessment of tissue engineering scaffolds and implantable drug delivery platforms. However, the detection limitations have not been fully characterized and thus its true potential has not been completely discovered. Characterization studies have focused primarily on the range of moduli corresponding to soft tissues, 20-600 kPa. However, polymeric biomaterials used in biomedical applications such as tissue scaffolds, stents, and implantable drug delivery devices can be much stiffer. In order to explore UE's potential to assess mechanical properties of biomaterials in a broader range of applications, this work investigated the detection limit of UE strain imaging beyond soft tissue range. To determine the detection limit, measurements using standard mechanical testing and UE on the same polydimethylsiloxane samples were compared and statistically evaluated. The broadest detection range found based on the current optimized setup is between 47 kPa and 4 MPa which exceeds the modulus of normal soft tissue suggesting the possibility of using this technique for stiffer materials' mechanical characterization. The detectable difference was found to be as low as 157 kPa depending on sample stiffness and experimental setup.

A remotely operated drug delivery system with an electrolytic pump and a thermo-responsive valve

Implantable drug delivery devices are becoming attractive due to their abilities of targeted and controlled dose release. Currently, two important issues are functional lifetime and non-controlled drug diffusion. In this work, we present a drug delivery device combining an electrolytic pump and a thermo-responsive valve, which are both remotely controlled by an electromagnetic field (40.5 mT and 450 kHz). Our proposed device exhibits a novel operation mechanism for long-term therapeutic treatments using a solid drug in reservoir approach. Our device also prevents undesired drug liquid diffusions. When the electromagnetic field is on, the electrolysis-induced bubble drives the drug liquid towards the Poly (N-Isopropylacrylamide) (PNIPAM) valve that consists of PNIPAM and iron micro-particles. The heat generated by the iron micro-particles causes the PNIPAM to shrink, resulting in an open valve. When the electromagnetic field is turned off, the PNIPAM starts to swell. In the meantime, the bubbles are catalytically recombined into water, reducing the pressure inside the pumping chamber, which leads to the refilling of the fresh liquid from outside the device. A catalytic reformer is included, allowing more liquid refilling during the limited valve's closing time. The amount of body liquid that refills the drug reservoir can further dissolve the solid drug, forming a reproducible drug solution for the next dose. By repeatedly turning on and off the electromagnetic field, the drug dose can be cyclically released, and the exit port of the device is effectively controlled.

Self-assembly of carrageenin–CaCO3 hybrid microparticles on bacterial cellulose films for doxorubicin sustained delivery

Stereospecific nucleation of mesoporous hybrid microspheres composed of CaCO3 and carrageenan was appended to one side of bacterial cellulose membrane synthesized in static cultures of Gluconacetobacter hansenii to develop an implantable drug delivery device. The synthesis of the hybrid microparticles proceeds by self-assembly mechanism in the presence of calcium and contains tailorable amounts of doxorubicin. However, in the absence of the particles, doxorubicin was distributed along the BC film, but without control release of drug. Infrared spectroscopy, confocal and scanning electron microscopies analyses demonstrate that the doxorubicin is entrapped inside the hybrid particles with approximately 80% drug loading compared to the 11% obtained for native bacterial cellulose. Doxorubicin content in the hybrid particles can be increased by a factor of 10 (from 258.6 to 2586.3nmolml−1), and also by the quantities of particles regulated by the CaCO3–carrageenan content and the physicochemical microenvironment. The hybrid BC system can be considered as smart device since the kinetic release of doxorubicin from the hybrid cellulose system rise from 1.50 to 2.75μg/membrane/day when the pH decreases from 7.4 to 5.8 at 37°C, a pathologic simulated environment. The hybrid microparticle system can be potentially used as an implantable drug delivery system for personalized oncological therapies.

Wireless implantable chip with integrated nitinol-based pump for radio-controlled local drug delivery.

We demonstrate an active, implantable drug delivery device embedded with a microfluidic pump that is driven by a radio-controlled actuator for temporal drug delivery. The polyimide-packaged 10 × 10 × 2 mm(3) chip contains a micromachined pump chamber and check valves of Parylene C to force the release of the drug from a 76 μL reservoir by wirelessly activating the actuator using external radio-frequency (RF) electromagnetic fields. The rectangular-shaped spiral-coil actuator based on nitinol, a biocompatible shape-memory alloy, is developed to perform cantilever-like actuation for pumping operation. The nitinol-coil actuator itself forms a passive 185 MHz resonant circuit that serves as a self-heat source activated via RF power transfer to enable frequency-selective actuation and pumping. Experimental wireless operation of fabricated prototypes shows successful release of test agents from the devices placed in liquid and excited by radiating tuned RF fields with an output power of 1.1 W. These tests reveal a single release volume of 219 nL, suggesting a device's capacity of ~350 individual ejections of drug from its reservoir. The thermal behavior of the activated device is also reported in detail. This proof-of-concept prototype validates the effectiveness of wireless RF pumping for fully controlled, long-lasting drug delivery, a key step towards enabling patient-tailored, targeted local drug delivery through highly miniaturized implants.