Intracochlear drug delivery systems

Introduction: Advances in molecular biology and in the basic understanding of the mechanisms associated with sensorineural hearing loss and other diseases of the inner ear are paving the way towards new approaches for treatments for millions of patients. However, the cochlea is a particularly challenging target for drug therapy, and new technologies will be required to provide safe and efficacious delivery of these compounds. Emerging delivery systems based on microfluidic technologies are showing promise as a means for direct intracochlear delivery. Ultimately, these systems may serve as a means for extended delivery of regenerative compounds to restore hearing in patients suffering from a host of auditory diseases.

Areas covered: Recent progress in the development of drug delivery systems capable of direct intracochlear delivery is reviewed, including passive systems such as osmotic pumps, active microfluidic devices and systems combined with currently available devices such as cochlear implants. The aim of this article is to provide a concise review of intracochlear drug delivery systems currently under development and ultimately capable of being combined with emerging therapeutic compounds for the treatment of inner ear diseases.

Expert opinion: Safe and efficacious treatment of auditory diseases will require the development of microscale delivery devices, capable of extended operation and direct application to the inner ear. These advances will require miniaturization and integration of multiple functions, including drug storage, delivery, power management and sensing, ultimately enabling closed-loop control and timed-sequence delivery devices for treatment of these diseases.     

Drug delivery to the inner ear: strategies and their therapeutic implications for sensorineural hearing loss

Hearing aids or cochlear implants constitute almost exclusively the treatment options currently available to patients suffering from sensorineural hearing loss and related conditions, such as noise-induced hearing loss, ototoxicity or autoimmune inner ear disease. While some systemic treatments exist, they generally exert adverse secondary effects and their efficacy is hampered by the blood-cochlear barrier that limits drug access to the inner ear. Hence, the new therapies that are being developed for hearing loss focus on strategies for direct drug delivery to the inner ear. The passive and active methods for local delivery can be categorized into two general groups: intratympanic or intracochlear. The intratympanic approach is a non-invasive method that preserves hearing and takes advantage of the permeability of the round window to gain access to the cochlea. However, this technique is limited by not knowing the dose of the drug that reaches the cochlea, (a handicap which might be overcome by the use of tagged drugs). While direct access to the inner ear by intracochlear administration avoids this problem, this method requires surgery. Currently, laboratory animals are being used to explore which therapeutic approaches are best suited to address this problem. These include cochleostomy and the insertion of devices that pump drugs into the inner ear without inducing cochlear damage. In this article, we review the different techniques under evaluation in animal models of deafness, and their potential use for drug delivery and treatment of human inner ear diseases.     

Inner ear drug delivery for auditory applications

Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored.     

Local drug delivery to the inner ear using biodegradable materials

The lack of an effective method of drug delivery has been a considerable obstacle in the development of novel therapeutics for inner ear diseases. However, several strategies have been investigated to achieve drug delivery to the inner ear, particularly for local application. Here, we review recent advances in the development of inner ear drug-delivery systems, focusing on biodegradable materials. Both synthetic and natural biodegradable materials have shown efficacy for inner ear drug delivery, resulting in an attenuation of hearing loss in animal models. We expect the further development of such drug-delivery systems to help translate the findings of experimental studies to clinical applications.     

Methods for providing therapeutic agents to treat damaged spiral ganglion neurons

Sensorineural hearing loss, characterized by damage to sensory hair cells and/or associated nerve fibers is a leading cause of hearing disorders throughout the world. To date, treatment options are limited and there is no cure for damaged inner ear cells. Because the inner ear is a tiny organ housed in bone deep within the skull, access to the inner ear is limited, making delivery of therapeutic agents difficult. In recent years scientists have investigated a number of growth factors that have the potential to regulate survival or recovery of auditory neurons. Coinciding with the focus on molecules that may restore function are efforts to develop novel delivery methods. Researchers have been investigating the use of mini osmotic pumps, viral vectors and stem cells as a means of providing direct application of growth factors to the inner ear. This review summarizes recent findings regarding the molecules that may be useful for restoring damaged spiral ganglion neurons, as well as the advantages and disadvantages of various delivery systems.     

Novel drug delivery systems for inner ear protection and regeneration after hearing loss

BACKGROUND: A cochlear implant, the only current treatment for restoring auditory perception after severe or profound sensorineural hearing loss (SNHL), works by electrically stimulating spiral ganglion neurons (SGNs). However, gradual degeneration of SGNs associated with SNHL can compromise the efficacy of the device. OBJECTIVE: To review novel drug delivery systems for preserving and/or regenerating sensory cells in the cochlea after SNHL. METHODS: The effectiveness of traditional cochlear drug delivery systems is compared to newer techniques such as cell, polymer and gene transfer technologies. Special requirements for local drug delivery to the cochlea are discussed, such as protecting residual hearing and site-specific drug delivery for cell preservation and regeneration. RESULTS/CONCLUSIONS: Drug delivery systems with the potential for immediate clinical translation, as well as those that will contribute to the future of hearing preservation or cochlear cellular regeneration, are identified.     

BioMEMS in drug delivery

The drive to design micro-scale medical devices which can be reliably and uniformly mass produced has prompted many researchers to adapt processing technologies from the semiconductor industry. By operating at a much smaller length scale, the resulting biologically-oriented microelectromechanical systems (BioMEMS) provide many opportunities for improved drug delivery: Low-dose vaccinations and painless transdermal drug delivery are possible through precisely engineered microneedles which pierce the skin's barrier layer without reaching the nerves. Low-power, low-volume BioMEMS pumps and reservoirs can be implanted where conventional pumping systems cannot. Drug formulations with geometrically complex, extremely uniform micro- and nano-particles are formed through micromolding or with microfluidic devices. This review describes these BioMEMS technologies and discusses their current state of implementation. As these technologies continue to develop and capitalize on their simpler integration with other MEMS-based systems such as computer controls and telemetry, BioMEMS' impact on the field of drug delivery will continue to increase.     

Novel drug delivery systems for inner ear protection and regeneration after hearing loss

Background: A cochlear implant, the only current treatment for restoring auditory perception after severe or profound sensorineural hearing loss (SNHL), works by electrically stimulating spiral ganglion neurons (SGNs). However, gradual degeneration of SGNs associated with SNHL can compromise the efficacy of the device. Objective: To review novel drug delivery systems for preserving and/or regenerating sensory cells in the cochlea after SNHL. Methods: The effectiveness of traditional cochlear drug delivery systems is compared to newer techniques such as cell, polymer and gene transfer technologies. Special requirements for local drug delivery to the cochlea are discussed, such as protecting residual hearing and site-specific drug delivery for cell preservation and regeneration. Results/conclusions: Drug delivery systems with the potential for immediate clinical translation, as well as those that will contribute to the future of hearing preservation or cochlear cellular regeneration, are identified.     

Challenges and opportunities in developing targeted molecular imaging to determine inner ear defects of sensorineural hearing loss

The development of inner ear gene carriers and delivery systems has enabled genetic defects to be repaired and hearing to be restored in mouse models. Today, promising advances in translational therapies provide confidence that targeted molecular therapy for inner ear diseases will be developed. Unfortunately, the currently available non-invasive modalities, such as Computerized Tomography scan or Magnetic Resonance Imaging provide insufficient resolution to identify most pathologies of the human inner ear, even when the current generation of contrast agents is utilized. The development of targeted contrast agents may play a critical role in determining the cause of, and treatment for, sensorineural hearing loss. Such agents should be able to pass through the cochlea barriers, possess minimal cytotoxicity, and easily conjugate to a targeting agent, without distorting the anatomic details. This review focuses on a series of contrast agents which may fit these criteria for potential clinical application.     

Disposition of nanoparticle-based delivery system via inner ear administration

The inner ear is difficult to access by conventional systemic drug delivery due to formidable physiological and anatomic barriers. There is an increasing interest in the treatment of inner ear disorders by topical application of drugs to the inner ear. One of the most important issues to overcome before full clinical application is the development of smart delivery systems for drugs to the target sites and controlled release in the inner ear. This is an area where nanoparticles will play an extremely important role. These submicron particles have exhibited improved biocompatibility, in vivo stability, target specificity, and cell/tissue uptake and internalization of the encapsulated therapeutic agents, leading to a decrease in the dose required and a decrease in side effects. This unique combination of properties makes nanoparticles a novel delivery device, which fulfils the requirements for inner ear application. This review will summarize recent findings and applications of various nanoparticle-based systems like poly (D, L-lactic/glycolic acid) nanoparticles, magnetic nanoparticles, lipid nanoparticles, liposomes, polymersomes, hydroxyapatite nanoparticles, and silica nanoparticles in the field of inner ear drug delivery. Moreover, the review will provide an insight into the future strategies of nanoparticle-based cochlear drug delivery. In conjunction, physiological considerations related to inner ear administration will be highlighted. The routes and applications for local inner-ear drug delivery will also be mentioned. In closing, this review will give an overview of the potential future development in inner ear administration with nanoparticles.     

Use of the biodegradable polymer chitosan as a vehicle for applying drugs to the inner ear

Development of efficient local delivery systems for the auditory organ has an important role in clinical practice for the management of inner ear disorders using pharmacological means. Chitosan, a biodegradable polymer, is a good drug carrier with bioadhesive properties. The aim of this study was to investigate the feasibility of using chitosan to deliver drugs to the inner ear across the round window membrane (RWM).Three structurally different chitosans loaded with a tracer drug, neomycin, were injected into the middle ear cavity of albino guinea pigs (n = 35). After 7 days the effect of chitosans and neomycin was compared among the treatment groups. The hearing organ was analysed for hair cell loss and the RWM evaluated in term of thickness.All tested chitosan formulations successfully released the loaded neomycin which then diffused across the RWM, and exerted ototoxic effect on the cochlear hair cells in a degree depending on the concentrations used. Chitosans per se had no noxious effect on the cochlear hair cells. It is concluded that the chitosans, and especially glycosylated derivative, are safe and effective carriers for inner ear therapy.     

Cell therapy for inner ear diseases

Degeneration of inner ear cells, especially sensory hair cells and associated neurons, results in hearing impairment and balance disorders. These disabilities are incurable because loss of hair cells and associated neurons is currently irreversible. Protection or regeneration of hair cells and associated neurons is an important area of research for developing an effective treatment for inner ear diseases. Cell therapy is a rapidly growing area of research and has potential applications in the treatment of inner ear disorders. The first attempts to examine the feasibility of cell therapy in the treatment of inner ear disorders have been performed using neural stem cells (NSCs). Grafted NSCs can survive in the inner ear and differentiate into neural, glial and/or hair cell-phenotypes, making NSC transplantation for the restoration of inner ear cells a potentially viable treatment. Further studies have suggested embryonic stem cells (ESCs), dorsal ganglion cells and cell lines derived from fetal inner ear cells could be used to restore damaged inner ear cells. Cell transplantation has also been suggested as a strategy for drug delivery into the inner ear, and the ability of NSC-derived cells to produce neurotrophins in the inner ear has been demonstrated. Results from studies using autologous bone marrow stromal cells (MSCs) indicate a high survival and migration potential suggesting that MSCs can be used as a drug delivery vehicle to the inner ear. These cell transplantation findings provide a sound foundation for the development of therapies to treat inner ear disorders.     

Connexins in hearing loss: a comprehensive overview

Connexins are a family of transmembrane proteins that form gap junctions between adjacent cells and allow intercellular communication. Connexin proteins are involved in pathological conditions in humans, mainly in hearing loss, neurodegenerative disorders and skin diseases. The association between connexin proteins and the inner ear is well established. The abundant expression of connexins in the auditory system of the inner ear demonstrates their importance in inner ear development and the hearing process. Most compelling, there are over 100 mutations in genes encoding connexins that are associated with deafness. Most prominent is the remarkable involvement of connexin 26 in hearing loss. Mutations in the gene GJB2, encoding connexin 26, are responsible for around 50% of genetic cases of severe to profound non-syndromic hearing loss in some parts of the world. Learning more about the connexin family in general and about connexin 26 in particular can shed light on the pathogenesis of the inner ear and bring us closer to finding clinical solutions for the hearing impaired.     

Viral protein complexed liposomes for intranasal delivery of hepatitis B surface antigen

Nanoparticle-mediated drug delivery represents the future in terms of treating inner ear diseases. Lipid core nanocapsules (LNCs), 50 nm in size, were shown to pass though the round window membrane (RWM) and reached the spiral ganglion cells and nerve fibers, among other cell types in the inner ear. The present study aimed to evaluate the toxicity of the LNCs in vitro and in vivo, utilizing intact round window membrane delivery in rats. The primary cochlear cells and mouse fibroblast cells treated with LNCs displayed dosage dependant toxicity. In vivo study showed that administration of LNCs did not cause hearing loss, nanoparticle application-related cell death, or morphological changes in the inner ear, at up to 28 days of observation. The cochlear neural elements, such as synaptophysin, ribbon synapses, and S-100, were not affected by the administration of LNCs. However, expression of neurofilament-200 decreased in SGCs and in cochlear nerve in osseous spiral lamina canal after LNC delivery, a phenomenon that requires further investigation. LNCs are potential vectors for the delivery of drugs to the inner ear.     

Recent advances in therapeutics and drug delivery for the treatment of inner ear diseases: a patent review (2011-2015)

Introduction: Inner ear disorders such as hearing loss, tinnitus, and Ménière’s disease significantly impact the quality of life of affected individuals. Treatment of such disorders is an ongoing challenge. Current clinical approaches relieve symptoms but do not fully restore hearing, and the search for more effective therapeutic methods represents an area of urgent current interest.

Areas covered: Thirty four patents and patent applications published from 2011 to 2015 were selected from the database of the U.S. Patent and Trademark Office (USPTO) and World Intellectual Property Organization (WIPO), covering new approaches for the treatment of inner ear disorders described in the patent literature: 1) identification of new therapeutic agents, 2) development of sustained release formulations, and 3) medical devices that facilitate delivery of such agents to the inner ear.

Expert opinion: The search for effective treatments of inner ear disorders is ongoing. Increased understanding of the molecular mechanisms of hearing loss, Ménière’s disease, and tinnitus is driving development of new therapeutic agents. However, delivery of these agents to the inner ear is a continuing challenge. At present, combination of a suitable drug with an appropriate mode of drug delivery is the key focus of innovative research to cure inner ear disorders.     

Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery

Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced.     

Developments in delivery of medications for inner ear disease

Introduction: Hearing loss, tinnitus and balance disturbance represent common diseases that have tremendous impact on quality of life. Despite the high incidence of inner ear disease in the general population, there are currently no dedicated pharmacologic interventions available to treat these problems.

Areas covered: This review will focus on how treatment of inner ear disease is moving toward local delivery at the end organ level. The authors will discuss current practice, ongoing clinical trials and potential areas of development such as hair cell regeneration and neurotrophin therapy.

Expert opinion: The inner ear is accessible through the middle ear via the oval and round windows allowing diffusion of drugs into the perilymph. With a better understanding of the physiology of the inner ear and the underlying molecular causes of inner ear disease there is great potential for the development of novel therapeutics that can be locally administered. At present, there is a rapid development of drugs to target diverse inner ear diseases that cause sensorineural hearing loss and balance dysfunction.     

Using zebrafish as a model to study the role of epigenetics in hearing loss

Introduction: The rapid progress of bioinformatics and high-throughput screening techniques in recent years has led to the identification of many candidate genes and small-molecule drugs that have the potential to make significant contributions to our understanding of the developmental and pathological processes of hearing, but it remains unclear how these genes and regulatory factors are coordinated. Increasing evidence suggests that epigenetic mechanisms are essential for establishing gene expression profiles and likely play an important role in the development of inner ear and in the pathology of hearing-associated diseases. Zebrafish are a valuable and tractable in vivo model organism for monitoring changes in the epigenome and for identifying new epigenetic processes and drug molecules that can influence vertebrate development.

Areas covered: In this review, the authors focus on zebrafish as a model to summarize recent findings concerning the roles of epigenetics in the development, regeneration, and protection of hair cells.

Expert opinion: Using the zebrafish model in combination with high-throughput screening and genome-editing technologies to investigate the function of epigenetics in hearing is crucial to help us better understand the molecular and genetic mechanisms of auditory development and function. It will also contribute to the development of new strategies to restore hearing loss.     

The design and screening of drugs to prevent acquired sensorineural hearing loss

Introduction: Sensorineural hearing loss affects a high percentage of the population. Ototoxicity is a serious and pervasive problem in patients treated with cisplatin. Strategies to ameliorate ototoxicity without compromising on antitumor activity of treatments are urgently needed. Similar problems occur with aminoglycoside antibiotic therapy for infections. Noise-induced hearing loss affects a large number of people. The use of ear protection is not always possible or effective. The prevention of hearing loss with drug therapy would have a huge impact in reducing the number of people with hearing loss from these major causes. Areas covered: This review discusses significant research findings dealing with the use of protective agents against hearing loss caused by cisplatin, aminoglycoside antibiotics and noise trauma. The efficacy in animal studies and the application of these protective agents in clinical trials that are ongoing are presented. Expert opinion: The reader will gain new insights into current and projected future strategies to prevent sensorineural hearing loss from cisplatin chemotherapy, aminoglycoside antibiotic therapy and noise exposure. The future appears to offer numerous agents to prevent hearing loss caused by cisplatin, aminoglycoside antibiotics and noise. Novel delivery systems will provide ways to guide these protective agents to the desired target areas in the inner ear and circumvent problems with therapeutic interference of antitumor and antibiotics agents as well as minimize undesired side effects.     

Sustained-release ophthalmic drug delivery systems for treatment of macular disorders: present and future applications

Macular disease currently poses the greatest threat to vision in aging populations. Historically, most of this pathology could only be dealt with surgically, and then only after much damage to the macula had already occurred. Current pathophysiological insights into macular diseases have allowed the development of effective new pharmacotherapies. The field of drug delivery systems has advanced over the last several years with emphasis placed on controlled release of drug to specific areas of the eye. Its unique location and tendency toward chronic disease make the macula an important and attractive target for drug delivery systems, especially sustained-release systems. This review evaluates the current literature on the research and development of sustained-release posterior segment drug delivery systems that are primarily intended for macular disease with an emphasis on age-related macular degeneration.Current effective therapies include corticosteroids and anti-vascular endothelial growth factor compounds. Recent successes have been reported using anti-angiogenic drugs for therapy of age-related macular degeneration. This review also includes information on implantable devices (biodegradable and non-biodegradable), the use of injected particles (microspheres and liposomes) and future enhanced drug delivery systems, such as ultrasound drug delivery. The devices reviewed show significant drug release over a period of days or weeks. However, macular disorders are chronic diseases requiring years of treatment. Currently, there is no 'gold standard' for therapy and/or drug delivery. Future studies will focus on improving the efficiency and effectiveness of drug delivery to the posterior chamber. If successful, therapeutic modalities will significantly delay loss of vision and improve the quality of life for patients with chronic macular disorders.