The work is supported by grants to M.F. from the Japanese government MEXT KAKENHI (24592560, 15H04991, and 15K15624) and the Takeda Science Foundation to M.F. and the Jikei University Strategic Prioritizing Research Fund to H.J.O.

All experimental procedures were performed at the Jikei University, Tokyo Japan. Animal handling and experimental procedures were approved by The Institutional Animal Care and Use Committee of The Jikei University (Approval no: 26-060) and performed in accordance with the Institutional guidelines for use of laboratory animals at the Jikei University, which agree with the Guidelines for Proper Conduct of Animal Experiments by the Science Council of Japan (2006). Animal care was conducted in accordance with the recommendations of the Guide for...

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The volume of cochlear blood flow is extremely small, estimated to be in the order of 1/1,000,000 of the total cardiac output in humans, and access is limited by the presence of the blood-cochlea barrier which separates the inner ear from the general circulation19,20. For these reasons, drug or viral vector administration into the inner ear is favorable, not via systemic administration but rather by direct administration. In mouse and guinea pig experiments, vari...

Sensorineural hearing loss (SNHL) arises predominantly from damage or deficiency in the cochlea. Common causes of SNHL include aging (e.g. presbycusis), genetic defects, exposure to loud noise, infection, and ototoxic drugs1. The World Health Organization (WHO) estimated that over 360 million people, representing 5.3% of the world&#39;s population, suffer from hearing loss2. It is also estimated that 1 in 900 to 1 in 2,500 newborns have moderate, severe, and profound congenital permanent hearing loss, and around one in three adults older than 65 years have some degree of hearing loss3. However, there is no effective clinical treatment of hearing loss for these patients.
Hearing research has long been performed using rodent or guinea pig models, and many approaches, such as gene therapy and regenerative therapy, have been suggested as a new treatment for hearing loss. However, there is a large difference between humans and rodents in terms of the auditory system, and it is very difficult to translate animal models to human applications. The common marmoset (C. jacchus), a New World monkey originating from the Amazon, has become an attractive non-human primate model for various basic research studies for several reasons. First, its anatomy and physiology are more similar to those of the humans rather than rodents. Second, the basic biological information about this species, including diseases, neural networks, behavior, and the genome, is well characterized. Auditory and vocal processing, the cortical coding of periodicity, the representation of pitch, and the auditory-vocal interactions of common marmosets have also been reported4,5,6,7,8,9,10. In recent histological studies, researchers identified distinctive expression patterns of 20 deafness genes and anion exchangers in the cochlea of the common marmoset and found that five genes that are causative of progressive deafness, and three anion exchangers, had different expression patterns from those of rodents11,12. These profiles lead us to believe that the common marmoset is a powerful tool for hearing research.
The most marked attributes of the common marmoset as an experimental animal are as follows:
<ul>
	<li>Easy handling with a small body size compared to some species of Old World monkeys: Adult marmosets weigh 300 - 400 g and are approximately 60 cm in height, which is similar to rats.</li>
	<li>Highly reproductive primate: Marmosets attain sexual maturity at an age of 18 months and are able to bear twice a year and produce 4 to 6 offspring annually.</li>
	<li>Genetic modifications are available: Sasaki E et al. succeeded in creating transgenic13 and knock-out14 primates using marmosets by genetic modifications implicated in neurological disorders (e.g., Parkinson&#39;s disease and Alzheimer&#39;s disease).</li>
	<li>Both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have been established15,16. Though it is rather difficult to keep the same number of marmosets compared to rodents, the availability of stem cells or iPS cells provides in vitro assays which will reduce the number of in vivo assays required.</li>
</ul>
To facilitate better translational research in the field of deafness and its potential therapy, we established an imaging study protocol using CT and MRI, general anesthesia and hearing tests using auditory brain stem responses (ABRs). These experimental systems may provide us with better opportunities to obtain pre-clinical proof of concept studies which are essential for bridging the gaps between rodent studies and clinical trials. Here, we report a surgical method to administrate drugs to the inner ear of the common marmoset through the round window membrane. To obtain a clear view around the round window, without manipulating the tympanic membrane which might cause a conductive hearing loss, it is useful to approach from the mastoid cavity. Clinically, this approach, referred to as &#34;posterior tympanotomy&#34; is well established and usually used for cochlear implantation and cholesteatoma surgery. We believe that posterior tympanotomy allows us to perform the accurate administration of drugs without inducing hearing loss.

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		<col />
		<col />
		<col />
		<col />
	</colgroup>
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">common marmoset</td>
			<td style="width:92px;">CLEA Japan</td>
			<td style="width:160px;">EDM:C.Marmoset(Jic)</td>
			<td style="width:207px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">isoflurane</td>
			<td style="width:92px;">Phizer</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">medetomidine</td>
			<td style="width:92px;">ZENOAQ</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">midazolam</td>
			<td style="width:92px;">astellas</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">butorphanol</td>
			<td style="width:92px;">Meiji Seika</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="24">
			<td height="24" style="height:24px;width:216px;">ampicillin</td>
			<td style="width:92px;">Meiji Seika</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">lidocaine hydrochloride</td>
			<td style="width:92px;">AstraZeneca</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">&#160;6-0 absorbent thread</td>
			<td style="width:92px;">ETHICON</td>
			<td style="width:160px;">RD-1</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">atipamezole hydrochloride</td>
			<td style="width:92px;">ZENOAQ</td>
			<td style="width:160px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">phosphate buffered saline</td>
			<td style="width:92px;">Wako</td>
			<td style="width:160px;">045-29795</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Surge Wave</td>
			<td style="width:92px;">Morita</td>
			<td style="width:160px;">TR-900-OR</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Diamond Bar 006</td>
			<td style="width:92px;">Morita</td>
			<td style="width:160px;">14070057</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Diamond Bar 010</td>
			<td style="width:92px;">Morita</td>
			<td style="width:160px;">14070081</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">intensive care unit</td>
			<td style="width:92px;">Menix</td>
			<td style="width:160px;">P-100</td>
			<td></td>
		</tr>
	</tbody>
</table>

a surgical procedure for the administration of drugs to the inner ear in a non-human primate common marmoset (callithrix jacchus)

Hearing research has long been facilitated by rodent models, although in some diseases, human symptoms cannot be recapitulated. The common marmoset (Callithrix jacchus) is a small, easy-to-handle New World monkey which has a similar anatomy of the temporal bone, including the middle ear ossicular chains and inner ear to humans, than in comparison with that of rodents. Here, we report a reproducible, safe, and rational surgical approach to the cochlear round window niche for the drug delivery to the inner ear of the common marmoset. We adopted posterior tympanotomy, a procedure used clinically in human surgery, to avoid manipulation of the tympanic membrane that may cause conductive hearing loss. This surgical procedure did not lead to any significant hearing loss. This approach was possible due to the large bulla structure of the common marmoset, although the lateral semicircular canal and vertical portion of the facial nerve should be carefully considered. This surgical method allows us to perform the safe and accurate administration of drugs without hearing loss, which is of great importance in obtaining pre-clinical proof of concept for translational research.

Posterior tympanotomy was performed without any complication such as surgical site infection, bleeding with vascular injury, or vestibular dysfunction, which sometimes occurs with middle ear manipulation. We performed posterior tympanotomy on the right ear of 7-year-old common marmoset and administered 1 &#181;L of phosphate buffered saline to the round window niche. ABRs were measured before and two months after surgery (Figure 5A-B). Wavefo...

Watch this Scientific Journal Video about A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset Callithrix jacchus at JoVE.com

A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset Callithrix jacchus

We report a surgical method to administrate drugs to the inner ear of a non-human primate, the common marmoset (Callithrix jacchus), via the round window membrane.

A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset (Callithrix jacchus)

Hearing research has long been facilitated by rodent models, although in some diseases, human symptoms cannot be recapitulated. The common marmoset ...

The overall goal of this surgical procedure is to evaluate the effects of specific drugs of interest on the hearing function of non-human primate common marmoset through their safe administration into the inner ear without inducing hearing loss. This method can help answer key questions about inner ear drug delivery, including how to open the master cavity and where to deliver the drug. The main advantage of this technique is that the inner ear can be a plus without complications, which is critical for evaluating the efficiency of inner ear treatments in primates.The implications of this technique extend towards the study of potential therapies for human deafness, as the auditory system of the marmoset is quite similar to that of humans. The masteration of this method is critical and the posture and anatomy is difficult to learn and require that small window to be created in the narrow space without damaging the facial knob or the ossicular chain. Confirm the appropriate level of sedation by toe pinch and place the animal in the supine position on a heating mat with the head and neck extended.Fix maxilla to the table with nylon thread and pull out the tongue. Insert an endotracheal tube along the laryngeal surface of the epiglottis. Check the entitle carbon dioxide level in the endotracheal tube to confirm that the tube has been properly placed within the trachea and secure the tube to the animal's face.Incline the head to the 30 to 45 degree angle toward the non-operative side and shave the postauricular region of the operative side of the animal Then disinfect the postauricular region and the external auditory canal with povidone iodine and cover the animal with a surgical drape sheet with a round opening over the surgical area. Before opening the skin inject 1%of lidocaine hydrochloride subcutaneously to the incision site. Then, using a surgical microscope and a number 15 round shaped blade, make an incision into the postauricular skin and apply pressure to the bleeding area with a gauze soaked in one to 5, 000 diluted epinephrine.Open the soft tissue of the postauricular region so that the auricular cartilage and the postauricular muscle can be identified and expose the external auditory canal bone deep within the cartilage. To confirm the depth of the tympanic membrane, expose the bony part of the tympanic rim and peel the postauricular muscles toward the caudal aspect to separate the muscles from the temporal bone. Expose the lateral surface of the temporal bone and use a one millimeter diamond burr to make a hole approximately five millimeters behind the external auditory canal.Drill further to enlarge the hole as appropriate and locate the horizontal semi-circular canal, which bulges toward the mastoid cavity. Then drill and remove any bone septa as necessary to obtain a clear view of the facial recess, located at the center of the triangular area between the facial nerve and the corded tympany. Using a 0.6 millimeter diameter diamond burr at 1, 000 rpm, drill a small hole between the vertical section of the facial nerve, which appears as a pink line through the thinned bone and the tympanic rim.Stop the drilling just before the nerve is exposed as a white line structure and confirm that the round window niche can be visualized through the hold. Using a 25 gauge or thinner needle, deliver the drugs of interest into the niche and cover the niche with an appropriate miscues solution to ensure the drug is retained. Confirm that hemostasis is securely controlled and use six o absorbent threads to close the epidermal and dermal layers with simple, interrupted sutures.Then place a piece of gauze onto the surgical wound, fix the gauze in place with a bandage, and allow the marmoset to recover in an intensive care unit at 37 degrees Celsius in 30%oxygen until complete arousal. In these graphs, the auditory brain stem responses of a seven year old common marmoset before and two months after the delivery of one microliter of PBS to the round window niche, as just demonstrated, are shown. Comparison of these wave forms and thresholds to a previous study demonstrated no changes in these parameters before or after the surgery, confirming that posterior tympanotomy is a safe and useful procedure for drug administration to the round window niche of the common marmoset.Once mastered, this technique can be completed in an hour, including the anesthesia and induction, if it's performed properly. While attempting this procedure, it's important to remember not to damage the ossicle or the facial knob which can result in conductive hearing loss or facial paralysis respectively. After its development, this technique paved the way for researchers in the field of the translation research to test potential new therapies for hearing loss.After watching this video, you should have a good understanding of how to approach the inner ear of the common marmoset safely and to administer the drug into round window niche properly.

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Research

JoVE Journal

Medicine

8.5K visualizações.  Jikei University School of Medicine. The overall goal of this surgical procedure is to evaluate the effects of specific drugs of interest on the hearing function of non-human primate common marmoset through their safe administration into the inner ear without inducing hearing loss. This method can help answer key questions about inner ear drug delivery, including how to open the master cavity and where to deliver the drug. The main advantage of this technique is that the inner ear can be a plus without complications, which is cr...