Intracochlear Drug Administration
Intracochlear administration is a route of administration in which medicinal substances or medications are administered to the inner ear using a variety of techniques, such as osmotic pumps, active microfluidic devices, and systems coupled with gadgets like cochlear implants[1]. There are several ways to administer drugs, however the cochlea has proven difficult due to structural obstacles that must be overcome. The most frequent cause of hearing loss is an inner ear disorder, and intracochlear medicine delivery systems can help patients with auditory illnesses regain their hearing.
Cochlea are a Challenge for Drug Delivery
Researchers have made advancements in their understanding of the biology of the inner ear as a result of the rising prevalence of inner ear illnesses. Stem cells, gene therapy, and RNA interference-based systems are a few of the methods developed to assist treat internal diseases[2][3]. The fundamental problem with all of these treatments is that the blood-cochlear barrier frequently prevents oral drugs from working[2][3]. Intracochlear delivery devices have largely consisted of micropumps with active and passive control to get past this problem. Using a delivery system with a cochlear implant has been investigated as a different approach.[1]
Application of Intracochlear local drug delivery
1. Extracochlear medication application with the goal of protection before exposure or after exposure for therapeutic intervention to the damaged inner ear.[4]
2. Use of intracochlear technology for the treatment of inner ear illnesses using drugs, cells, or genes.[4]
3. Using passive middle ear implants along with additional and intracochlear applications.[4]
4. Using an auditory prosthesis in conjunction with extracochlear and intracochlear applications.[4]
Intracochlear Diseases that could benefit from Intracochlear Drug Delivery
A type of hearing loss known as sensorineural hearing loss affects the inner ear, sensory systems such as the cochlea, or the vestibular nerve. 90% of hearing loss is due to sensorineural deafness. Due to the size of the patient population, prolonged chemical delivery may be necessary.[1]
-A timed-sequenced administration is necessary for the patient population with Noise-induced hearing loss, which is expanding. The Department of Defense gave this a high priority. Exposure to overly loud noises is the source of this.[1]
-Sudden Sensorineural Hearing loss is also known as sudden deafness and is when there is unexplained rapid loss of hearing. This is due to something wrong with sensory organs of the inner ear.[1]
-A tiny number of people suffer from the inner ear inflammation known as autoimmune inner ear disease. It occurs when the immune system targets inner ear cells that it misidentifies as viruses.[1]
-An issue with the inner ear called Ménière's disease can result in vertigo and hearing loss. It can occur at any age and typically only affects one ear.[1]
-When a person hears ringing or other disturbances in one or both ears, it is known as Tinnitus. A patient with tinnitus may struggle to focus or experience anxiety as a result of a continual clicking or humming sound.[1]
Potential Advantages of local delivery to the inner ear
-The ability to bypass the blood brain barrier since there will be a direct insertion to the inner ear.[4]
-There will be the ability to have a higher drug concentration in the inner ear as the drug can bypass the barrier and be directly inserted.[4]
-There will be a reduction of adverse systematic effects including fever, headache, body aches, fatigue, etc.[4]
-When there is local delivery to the inner ear, a lower drug dose is necessary since more of the drug reaches the inner ear.[4]
Challenges of Inner-Ear Drug Delivery
It is difficult to access the inner ear anatomically and pharmacologically. Access to the cochlea is restricted by the blood-cochlear barrier[5]. By administering medications directly to the cochlear fluids, this barrier can be overcome. Moreover, the round window and middle ear can both receive the medication[6]. The distribution device would have to be compact, flexible enough, and biodegradable[5]. Because of the cochlea's size and location, direct infusion is challenging. The tympanic duct has a maximum cross sectional size of a few millimeters, making access through the RWM or cochleostomy necessary. The Corti organ's hair cells are likewise extremely fragile and susceptible to damage from mechanical and fluidic forces[7].
Cochlear Implants
The creation of drug-releasing electrode carriers aims to enhance cochlear implant rehabilitation. Glucocorticosteroids, antiapoptotic agents, or neurotrophins are the medications for administration.[4]. By preventing insertion stress to neuronal structures, minimizing inner ear fibrosis, and promoting neuronal structure growth in the electrode orientation, cochlear implants can be made better[4]. Controlled drug release following extracochlear or intracochlear application with cochlear implants provides the protection. Drug therapy for the inner ear in the treatment and prevention of hearing loss in mice[8]. A ventral technique was used to expose the mouse bulla and cauterize the stapedial artery[8]. The auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) have cochlear responses[8]. With the cochleostomy hole properly positioned, researchers have been able to deliver directly[4]
Objectives of drug application in combination with cochlear implants
When using pharmacological administrations in conjunction with cochlear implants, there are numerous goals, including a reduction in insertion trauma, a reduction in immune reactivity, and a reduction in the likelihood of infection. When drugs are delivered, they frequently result in the loss of spiral ganglion cells and auditory neurons; however, when cochlear implants are used, this effect is lessened. The decrease of fibrosis, ossification, and channel interaction are further goals. Since there is less stimulation of nonauditory brain structures when drugs are delivered in combination, the frequency spectrum of auditory implants is improved.[4]
Delivery Methods
There are three delivery methods with a cochlear implant which include being incorporated in the CI electrode carrier itself, an electrode carrier coated with the substance, or an electrode carrier can be equipped with a delivery channel.[4]
Measuring Drug Distribution through Fluorescence
For the development of local delivery techniques, it is crucial to measure the drug's distribution in the inner ear. The concentration of drugs in cochlear fluids has also been measured using other sampling techniques, however these techniques do not directly reveal how the drugs are distributed throughout the cochlear tissues. Fluorescent indicators that, upon intracochlear drug delivery to the cochlea's scala tympani compartment, induce drug distribution in the organ of Corti[9][10]. Other fluorescent markers used include FITC-dextran, Qtracker 655, gentamicin Texas-Red, and FM 1-43 FX[10][9]. The development of microelectromechanical systems technologies, which improve intracochlear delivery systems, also made this conceivable. Pharmacokinetic evaluation of the spatiotemporal drug distribution is required for the optimization of these devices' delivery parameters.
Dexamethasone drug delivery for the Inner Ear
Widely used steroid dexamethasone has an anti-inflammatory effect[11][12]. The preferred method of treatment for idiopathic abrupt sensorineural hearing loss is steroids[11]. The fundamental justification for the administration of steroids in this region is the cochlear glucocorticoid receptor. Both local and systemic administration of dexamethasone are possible. Anti-inflammatory medications can lessen the damage and inflammation that cochlear implantation surgery causes to the inner ear[11]. It has been studied to release dexamethasone over an extended period of time and at a specific dose. As evidenced by the decreased inflammatory cytokines, increased hair cell survival, and less severe intracochlear fibrosis and ossification concurrently observed in the local delivery group compared to the systemic group, residual hearing was better preserved with local dexamethasone administration[13]. The findings show that local dexamethasone delivery can lessen intracochlear inflammation and preserve residual hearing more effectively than dexamethasone given systemically[13]. A high concentration of medication in the inner ear would arise from direct intracochlear administration. The only direct intracochlear delivery is through a cochleostomy or by puncturing the round window membrane during cochlear implant surgery[11][13]. A local approach reduces the systemic side effects. They can nonetheless leave the cochlea damaged and induce hearing loss. Systematic administration of dexamethasone does not ensure that it will effectively cross the blood-labyrinth barrier and reach the inner ear.
Automated Drug Delivery through to bypass the pharmacokinetic barrier
Direct medication administration to cochlear fluids avoids pharmacokinetic obstacles and reduces toxicity. Several doses must be administered manually due to the anatomical features. Treatments for hair-cell regeneration are required for the automated system. Drug administration to the inner ear is mechanized and controlled using a micropump[14]. This is an implanted or wearable delivery system for long-term use. Several difficulties are reduced by including a medication reservoir and all fluidic parts into the pump's microfluidic structure. Maintaining a controlled distribution at a low, safe pace and avoiding increasing the fluid amount are difficult tasks. Because of the cochlea's limited volume of fluid and sensitivity, automated distribution requires extremely accurate fluid control[14]. The human inner ear has 150–200 microliters of perilymph, of which 50 are located in the scala tympani. Given that it is implanted close to the cochlea, the delivery system must also be portable[14]. One type of micropump that has been utilized with a cochleostomy but cannot be turned off are osmotic pumps. The Round Window Microcatheter with a Panomat micropump was another micropump that was tested, but the system was too big.[14]
Microfluidic Drug Delivery through Microelectromechanical Systems
MicroElectroMechanical Systems (MEMS) devices may perform the same tasks as traditional sensors and actuators while taking up a fraction of the space[6][7]. These gadgets combine mechanical and electrical operations. They can be placed close to the organ being treated, in this case the cochlea because they are small enough[6][7]. They can be made to react in a closed-loop manner to sensor input or physiological measurements[6][7]. The medications are kept in concentrated, stable form and delivered to the perilymph by a micropump that is controlled by a microprocessor. Since the inner ear fluid can circulate without needing to be refilled, this supply system serves as both an inlet and an outlet[6][7]. Less occlusion is possible with reciprocating delivery. Another benefit is that the perilymph in the pump is guaranteed to be compatible with the perilymph's fluid. The perilymph proteins' potential involvement in harmful processes including drug metabolism[6] is a drawback.
Basal Turn Cochleostomy and Posterior Semicircular Canal Colostomy for Drug Delivery
A canalostomy is an exit hole in the posterior semicircular canal, whereas a cochleostomy is a basal turn scala tympani infusion.[15][16][17]. Cochleosomy can result in damage or trauma and is known to trigger the release of inflammatory cytokines, which can cause hair cells to die[15][17]. Direct access to cochlear structures with a potent basal-to-apical medication concentration gradient is made possible by basal turn cochleostomy. The gradient restricts the range of doses by limiting the effectiveness of therapeutic strategies for apical structures[15][16][17]. The concentration gradient is lessened when a posterior semicircular canal canalostomy combined with a basal turn cochleostomy is used. A preferred perfusion flow pattern would be created in the scala tympani from base to apex through the helicotrema if both canalostomy and cochleostomy were present[15][17]. The flow would be affected by the relative fluidic resistances of the path that includes the cochlear aqueduct and interscalar transfer[15][16][17]
Round Window Membrane Intracochlear Drug Delivery
The round window has three layers of cells and is typically not accessible to other bodily fluids. These layers feature tight connections in two of them. Hearing aids have less of an impact when therapeutic substances are delivered to the inner ear via the round window membrane[6]. A novel strategy that facilitates in the distribution of substances throughout the inner ear is induced advection[6]. Using a bullaostomy, polyimide microtubing was positioned close to the circular window. Using a bullaostomy with a canalostomy demonstrated more precise medication administration and more effective pharmacological efficacy at lower frequencies[6][15][17]. It is unnecessary to directly access the cochlea when drugs are delivered to the round window membrane niche in the middle ear, preventing long-term hearing impairments. The vestibular system's canalostomy preserves the advantages of round window membrane delivery while facilitating the transportation of substances across the membrane throughout the cochlea[17]. As nanoparticles may easily traverse the RWM and incorporate into the membranes and cells of the cortical organ, they have been employed in medication administration through the round window[6]. It has been demonstrated that the success depends on the size. The degree of variability in the round window membrane's thickness is one disadvantage of this approach[6]. The RWM is covered by an auxiliary membrane, the presence of which can vary, and this can result in rates of drug-containing fluid leakage into the eustachian tube.[6]
Transtympanic Delivery
Three techniques are available for transtympanic drug delivery: sustained or intermittent microcatheter delivery, implantation of stabilizing matrices with circular windows, and blind injection into the middle ear cavity through the tympanic membrane[18][15]. They all depend on transport through the round window. The different techniques show no clinically significant differences. Gentamicin has been administered successfully to treat Meniere's disease with uncontrollable vertigo using transtympanic administration with absorption through the round window membrane. Transtympanic administration of glucocorticoids has been reported to treat idiopathic acute sensorineural hearing loss. Dexamethasone, lidocaine, and gentamicin are used to treat tinnitus. Injection into the round window is made possible using a chitosan-glycerophosphate hydrogel, and stabilization matrices have demonstrated improvements in transtympanic administration[18][15].
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Borenstein, Jeffrey T (September 2011). "Intracochlear drug delivery systems". Expert Opinion on Drug Delivery. 8 (9): 1161–1174. doi:10.1517/17425247.2011.588207. ISSN 1742-5247. PMC 3159727. PMID 21615213.
- ↑ 2.0 2.1 Chin, Oliver Y.; Diaz, Rodney C. (October 2019). "State-of-the-art methods in clinical intracochlear drug delivery". Current Opinion in Otolaryngology & Head & Neck Surgery. 27 (5): 381–386. doi:10.1097/MOO.0000000000000566. ISSN 1068-9508. PMID 31460985. Unknown parameter
|s2cid=ignored (help) - ↑ 3.0 3.1 Peppi, M.; Marie, A.; Belline, C.; Borenstein, J. T. (2018-04-03). "Intracochlear drug delivery systems: a novel approach whose time has come". Expert Opinion on Drug Delivery. 15 (4): 319–324. doi:10.1080/17425247.2018.1444026. ISSN 1742-5247. PMID 29480039. Unknown parameter
|s2cid=ignored (help) - ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 Plontke, S. K.; Götze, G.; Rahne, T.; Liebau, A. (January 2017). "Intracochlear drug delivery in combination with cochlear implants: Current aspects". HNO. 65 (S1): 19–28. doi:10.1007/s00106-016-0285-9. ISSN 0017-6192. PMC 5281641. PMID 27933352.
- ↑ 5.0 5.1 Lehner, Eric; Menzel, Matthias; Gündel, Daniel; Plontke, Stefan K.; Mäder, Karsten; Klehm, Jessica; Kielstein, Heike; Liebau, Arne (January 2022). "Microimaging of a novel intracochlear drug delivery device in combination with cochlear implants in the human inner ear". Drug Delivery and Translational Research. 12 (1): 257–266. doi:10.1007/s13346-021-00914-9. ISSN 2190-393X. PMC 8677643 Check
|pmc=value (help). PMID 33543398 Check|pmid=value (help). - ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 Sewell, William F.; Borenstein, Jeffrey T.; Chen, Zhiqiang; Fiering, Jason; Handzel, Ophir; Maria; Kim, Ernest S.; Sharon G.; Michael J.; Mark M.; Murphy, Brian; Leary Swan, Erin E.; Peppi, Marcello; Tao, Sarah (2009). "Development of a Microfluidics-Based Intracochlear Drug Delivery Device". Audiology and Neurotology. 14 (6): 411–422. doi:10.1159/000241898. ISSN 1420-3030. PMC 2820330. PMID 19923811.
- ↑ 7.0 7.1 7.2 7.3 7.4 Kim, Ernest S.; Gustenhoven, Erich; Mark J.; Leary Pararas, Erin E.; Smith, Kim A.; Spencer, Abigail J.; Tandon, Vishal; Borenstein, Jeffrey T.; Fiering, Jason (2014). "A microfluidic reciprocating intracochlear drug delivery system with reservoir and active dose control". Lab Chip. 14 (4): 710–721. doi:10.1039/C3LC51105G. ISSN 1473-0197. PMC 3902088. PMID 24302432.
- ↑ 8.0 8.1 8.2 Chen, Zhiqiang; Mikulec, Anthony A.; Michael J.; Sewell, William F.; Kujawa, Sharon G. (January 2006). "A method for intracochlear drug delivery in the mouse". Journal of Neuroscience Methods. 150 (1): 67–73. doi:10.1016/j.jneumeth.2005.05.017. PMID 16043228. Unknown parameter
|s2cid=ignored (help) - ↑ 9.0 9.1 Ayoob, Andrew M.; Peppi, Marcello; Tandon, Vishal; Langer, Robert; Borenstein, Jeffrey T. (January 2019). "Intracochlear drug delivery: Fluorescent tracer evaluation for quantification of distribution in the cochlear partition". European Journal of Pharmaceutical Sciences. 126: 49–58. doi:10.1016/j.ejps.2018.09.007. PMID 30195649. Unknown parameter
|s2cid=ignored (help) - ↑ 10.0 10.1 Ayoob, Andrew M.; Peppi, Marcello; Tandon, Vishal; Langer, Robert; Borenstein, Jeffrey T. (October 2018). "A fluorescence-based imaging approach to pharmacokinetic analysis of intracochlear drug delivery". Hearing Research. 368: 41–48. doi:10.1016/j.heares.2018.03.026. PMID 29661614. Unknown parameter
|s2cid=ignored (help) - ↑ 11.0 11.1 11.2 11.3 Astolfi, Laura; Guaran, Valeria; Marchetti, Nicola; Olivetto, Elena; Simoni, Edi; Cavazzini, Alberto; Jolly, Claude; Martini, Alessandro (February 2014). "Cochlear implants and drug delivery: In vitro evaluation of dexamethasone release". Journal of Biomedical Materials Research Part B: Applied Biomaterials. 102 (2): 267–273. doi:10.1002/jbm.b.33004. ISSN 1552-4973. PMID 23997036.
- ↑ Astolfi, Laura; Guaran, Valeria; Marchetti, Nicola; Olivetto, Elena; Simoni, Edi; Cavazzini, Alberto; Jolly, Claude; Martini, Alessandro (February 2014). "Cochlear implants and drug delivery: In vitro evaluation of dexamethasone release". Journal of Biomedical Materials Research Part B: Applied Biomaterials. 102 (2): 267–273. doi:10.1002/jbm.b.33004. ISSN 1552-4973. PMID 23997036.
- ↑ 13.0 13.1 13.2 Lyu, Ah-Ra; Kim, Dong Hyun; Lee, Seung Hun; Shin, Dong-Sik; Shin, Sun-Ae; Park, Yong-Ho (2018-03-30). Eshraghi, Adiren A., ed. "Effects of dexamethasone on intracochlear inflammation and residual hearing after cochleostomy: A comparison of administration routes". PLOS ONE. 13 (3): e0195230. Bibcode:2018PLoSO..1395230L. doi:10.1371/journal.pone.0195230. ISSN 1932-6203. PMC 5877881. PMID 29601595.
- ↑ 14.0 14.1 14.2 14.3 Tandon, Vishal; Kang, Woo Seok; Robbins, Tremaan A.; Spencer, Abigail J.; Kim, Ernest S.; Michael J.; Sharon G.; Jason; Pararas, Erin E. L.; Mark J.; Sewell, William F.; Borenstein, Jeffrey T. (2016). "Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing". Lab on a Chip. 16 (5): 829–846. doi:10.1039/C5LC01396H. ISSN 1473-0197. PMC 4766044. PMID 26778829.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 Borkholder, David A.; Zhu, Xiaoxia; Frisina, Robert D. (January 2014). "Round window membrane intracochlear drug delivery enhanced by induced advection". Journal of Controlled Release. 174: 171–176. doi:10.1016/j.jconrel.2013.11.021. PMC 3925065. PMID 24291333.
- ↑ 16.0 16.1 16.2 Borkholder, David A.; Zhu, Xiaoxia; Hyatt, Brad T.; Archilla, Alfredo S.; Livingston, William J.; Frisina, Robert D. (September 2010). "Murine intracochlear drug delivery: Reducing concentration gradients within the cochlea". Hearing Research. 268 (1–2): 2–11. doi:10.1016/j.heares.2010.04.014. PMC 2933796. PMID 20451593.
- ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 Borkholder, David A (October 2008). "State-of-the-art mechanisms of intracochlear drug delivery". Current Opinion in Otolaryngology & Head & Neck Surgery. 16 (5): 472–477. doi:10.1097/MOO.0b013e32830e20db. ISSN 1068-9508. PMC 6457114. PMID 18797291.
- ↑ 18.0 18.1 Zhang, Zipei; Li, Xiyu; Yang, Rong; Cullion, Kathleen; Prugneau, Laura; Kohane, Daniel S. (2023-02-06). "Enhancement of Trans-Tympanic Drug Delivery by Pharmacological Induction of Inflammation". Molecular Pharmaceutics. 20 (2): 1375–1381. doi:10.1021/acs.molpharmaceut.2c00959. ISSN 1543-8384. PMID 36633440 Check
|pmid=value (help). Unknown parameter|s2cid=ignored (help)
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