This study was funded by Central Michigan University Innovative Research Grant P421071 and Early Career Grant P622911.

The MRI images were provided by the Hamner Institutes for Health Sciences and the usage of these images was approved by the Virginia Commonwealth University institutional review board.
1. Image-Based Nasal Airway Preparation
<ol>
	<li>Acquire magnetic resonance (MR) images of a healthy non-smoking 53-year-old male (weight 73 kg and height 173 cm) that consist of 72 coronal cross-sections spaced 1.5 mm apart spanning the nostrils to the nasopharynx4.</li>
	<li>Open Imaging Program (e.g., MIMICS)
	<ol>
		<li>To import images, click &#34;File&#34;, &#34;Import images&#34;. Select the MR images and click &#34;Ok&#34;.</li>
		<li>To construct the 3-D model, click &#34;Segmentation&#34;, then &#34;Threshold&#34; to set the grey scale range between -1020 and -500. Click &#34;Segmentation&#34;, &#34;Calculate 3D&#34;.</li>
		<li>Click &#34;Segmentation&#34; and &#34;Calculate polylines&#34;. Select the 3-D body, and click &#34;Ok&#34; to generate the polylines that define the solid geometry. Export the polylines as an IGES file.</li>
	</ol>
	</li>
	<li>Open Model Development Software (e.g., Gambit)
	<ol>
		<li>Click &#34;File&#34;, &#34;Import&#34;, &#34;IGES&#34; to import the IGES file into the program. Click &#34;Edge command button&#34; on the right panel; click &#34;Create Edge&#34; and select &#34;NURBS&#34; to reconstruct smooth contours.</li>
		<li>Click &#34;Face command button&#34;, then click &#34;Form face&#34;. Select &#34;Wireframe&#34; to build a surface from edges. Continue to build all surfaces that cover the whole airway. Retain the nasal anatomical details such as the uvula, epiglottal fold, and laryngeal sinus (Figure 1). Click &#34;File&#34;, &#34;Export&#34; &#34;IGES&#34; to export the nasal airway model.</li>
	</ol>
	</li>
	<li>Open Meshing Software (e.g., ICEM CFD)
	<ol>
		<li>Click &#34;File&#34;, &#34;Import Geometry&#34;, &#34;Legacy&#34; and &#34;STEP/IES&#34; to import the nasal airway model. Click &#34;Create Parts&#34; to divide the airway surfaces into five different regions: nasal vestibule, nasal valve, turbinate region, olfactory, and nasopharynx.</li>
		<li>To generate computational mesh inside the airway, click &#34;Mesh&#34;, &#34;Global Mesh Setup&#34;. Specify the maximum mesh size as 0.1 mm and click &#34;Apply&#34;.</li>
		<li>To add a body-fitted mesh in the near-wall region, click &#34;Compute Mesh&#34;, &#34;Prism Mesh&#34;. Specify the number of layers as 5 and the expanding ratio as 1.25 and click &#34;Apply&#34;.</li>
	</ol>
	</li>
</ol>
2. Passive Control of Particles
<ol>
	<li>Vestibular Intubation: Front vs. Back
	<ol>
		<li>Open Model Development Software to develop the nasal model with front vestibular intubation. Click &#34;Volume&#34;, then &#34;Move/copy&#34; to change the location of the nebulizer catheter 5 mm into the vestibule from nostril tip. Click &#34;injection&#34; to release 60,000 particles (150 nm) into the nostril.</li>
		<li>Open the fluid simulation software (e.g., ANSYS Fluent) to compute particle deposition rates inside the nose. To compute the airflow field inside the airway, select the laminar flow model by clicking &#34;Define&#34;, &#34;Models&#34;, &#34;Viscous&#34;; chose &#34;Laminar&#34; under &#34;Viscous model&#34;.</li>
		<li>Select the &#34;Discrete Phase Model&#34; to track particle motions. Check &#34;Saffman Lift Force&#34; under &#34;Discrete Phase Model&#34;. Click &#34;Report&#34;, then choose &#34;Sample Trajectories&#34;; select &#34;nasal&#34; under &#34;Boundaries&#34; and click &#34;Compute&#34; to find the number of particles deposited in the predefined olfactory region. Calculate the deposition rate as the ratio of the amount of deposited particles to the amount of particles entering the nostrils.</li>
		<li>Repeat steps 2.1.2 for 1 &#181;m particles.</li>
		<li>Follow the step 2.1.1, insert the spray nozzle 5 mm into the vestibule from the back of the nostril. Repeat steps 2.1.2, and 2.1.3 to compute deposition rate for 150 nm particles. Repeat step 2.1.4 for 1 &#181;m particles (back-intubation).</li>
	</ol>
	</li>
	<li>Deep Intubation
	<ol>
		<li>Follow procedure 2.1.1 to insert the nebulizer catheter right beneath the olfactory region. Release 60,000 submicron particles (150 nm) from the nebulizer.</li>
		<li>Use fluid and simulation software to compute particle deposition rates inside the nose on both total and local basis by following similar procedures as listed in 2.1.2. Repeat this procedure for 1 &#181;m particles.</li>
		<li>Repeat the above procedures while exercising breathing-holding and exhalation, respectively. Click &#34;Define&#34;, then &#34;Boundary Conditions&#34; to open the boundary condition panel. Specify zero velocity at the two nostrils for breathing-holding. Specify vacuum pressure (200 Pa) at the nostrils and zero pressure at the outlet for exhalation.</li>
	</ol>
	</li>
</ol>
3. Active Control: Magnetophoretic Guidance
<ol>
	<li>Test in a Two-Plate Channel
	<ol>
		<li>Open magnetic particle tracking software (e.g., COMSOL). Click &#34;Geometry&#34;, and &#34;Rectangle&#34; to build the two-plate channel. Click &#34;Rectangle&#34; to build the magnets around the two-plate channel.</li>
		<li>Compute the particle trajectories and deposition rate. Click &#34;Model 1&#34;, &#34;Laminar flow&#34; and &#34;Inlet 1&#34;; specify the inlet velocity as 0.5 m/s. Click &#34;Model 1&#34;, &#34;Magnetic Fields&#34;, and &#34;Magnetic Flux Conservation&#34;, specify the strength of the three magnets (1 &#215; 105 A/m).</li>
		<li>Click &#34;Model 1&#34;, &#34;Particle Tracking for Fluid Flow&#34;, and &#34;Particle Properties&#34;; specify the particle diameter (15 &#181;m), density (1.78 g/cm3). Click &#34;Inlet&#34; to release 3,000 particles. Click &#34;Magnetophoretic Force&#34;, specify particle relative permeability (50). Click &#34;Compute&#34;.</li>
		<li>To find how many particles depositing in the selected area, click &#34;Results&#34;, &#34;1D Plot Group&#34; and &#34;Plot&#34;. Calculate the deposition rate as the ratio of the amount of particle deposited in certain area to the amount of particles entering the geometry.</li>
		<li>To adjust the magnet strength, click &#34;Model 1&#34;, then &#34;Magnetic Fields&#34;; choose &#34;Magnetic Flux Conservation&#34;, and change the magnet strength under &#34;Magnetization&#34;. Increase the magnet strength by an increment of 1 &#215; 104 A/m and click &#34;Compute&#34;.</li>
		<li>Repeat this procedure until the appropriate magnets arrangement was obtained for effective drug delivery to the olfactory region.</li>
	</ol>
	</li>
	<li>Test in the 2-D Idealized Nose Model
	<ol>
		<li>Apply the magnetic strengths obtained in 3.1 into a 2-D nose model by putting three magnets 1 mm above the nose. Click &#34;Model 1&#34;, &#34;Geometry 1&#34; to specify the size and position of the magnet. Click &#34;Model 1&#34;, &#34;Particle Tracking for Fluid Flow&#34;, &#34;Inlet&#34; to release 3,000 particles into the left nostril. Click &#34;Particle Properties&#34; to specify the particle size as 15 &#181;m.</li>
		<li>Simulate the particle trajectories and subsequent olfactory delivery efficiencies by following similar procedures as listed in 3.1.2.</li>
		<li>Adjust the magnet layout and strength to improve olfactory delivery efficiency. To adjust the magnet size and position, click &#34;Model 1&#34;, then &#34;Geometry 1&#34;; choose the magnet of interest, change the values of width, depth, height or x, y, z. Follow 3.1.5 to adjust the magnet strength.</li>
	</ol>
	</li>
	<li>Test in the 3-D Anatomically Accurate Nose Model
	<ol>
		<li>Import the 3-D nasal airway model into Magnetic Particle Tracking software. Follow the procedure 3.2.1, put four magnets 1 mm above the nose and release 3,000 particles of 15 &#181;m in diameter from one selected point only.</li>
		<li>Use Magnetic Particle Tracking software to track particle trajectories and compute olfactory delivery efficiencies by following similar procedures as listed in 3.2.1 - 3.2.3.</li>
		<li>Following 3.2.3, adjust the magnet layout and strength in the 3D model to improve the targeted delivery to the olfactory region.</li>
		<li>Test particle size ranging from 1 - 30 &#181;m to find the right particle size for optimal magnetophoretic guidance to the olfactory region.</li>
	</ol>
	</li>
</ol>

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The authors report no conflicts of interest in this work.

A coupled image-CFD method was presented in this study that incorporated the image-based model development, quality meshing, airflow simulation, and magnetic particle tracking. Multiple software modules were implemented to this aim, which included functions of segmentation of medical images, reconstruction/meshing of anatomically accurate airway models, and flow-particle simulations. Using this numerical method, performances of three intranasal delivery protocols were tested and compared. Compared to in vitro ex...

Drugs delivered to the olfactory region can bypass the blood-brain-barrier and directly enter the brain, leading to an efficient uptake and quick action onset of the drugs1,2. However, conventional nasal devices such as nasal pumps and sprays deliver extremely low doses to the olfactory region (&#60; 1%) via the nasal route3,4. It is primarily due to the complicated structure of the human nose which is composed of narrow, convoluted passageways (Figure 1). The olfactory region locates above the superior meatus, where only a very small fraction of inhaled air can reach5,6. Furthermore, conventional inhalation devices depend on aerodynamic forces to transport therapeutic agents to the target area7. There is no further control over the motions of particles after their release. Therefore, the transport and deposition of these particles predominately depend on their initial speeds and release positions. Due to the convoluted nasal passage as well as the lack of particle control, the majority of drug particles are trapped in the anterior nose and cannot reach the olfactory region8.
While there are many choices of nasal devices, those designed specifically for targeted olfactory delivery have rarely been reported7,9. One exception is Hoekman and Ho10 who developed an olfactory-preferential delivery device and demonstrated higher cortex-to-blood drug levels in rats as opposed to using a nose drop. However, scaling the deposition results in rats to humans is not straightforward, considering the vast anatomical and physiological differences between these two species11. Many limitations exist when using adapted versions of standard nasal devices for olfactory deliveries. One primary setback is that only a very small portion of medications can be delivered to the olfactory mucosa, through which the medications may enter the brain. Numerical modeling predicted that less than 0.5% of intranasally administered nanoparticles can deposit in the olfactory region3,5. The deposition rate is even lower (0.007%) for micrometer particles12. In order to make the nose-to-brain delivery clinically feasible, the olfactory deposition rate has to be significantly improved.
There exist several possible approaches to improve the olfactory delivery. One approach is the smart inhaler idea proposed by Kleinstreuer et al.13 As particles depositing in one region are mainly from one specific area at the inlet, it is possible to deliver particles to the target site by releasing them only from certain areas at the inlet. The smart delivery technique has been shown to generate a much more efficient lung delivery than conventional methods.13,14 It is hypothesized that this smart delivery idea can also be applied in intranasal drug delivery to improve dosages to the olfactory mucosa. By releasing particles into different positions at the nostril opening and from different depths within the nasal cavity, improved olfactory delivery efficiencies and reduced drug waste in the anterior nose are possible.
Another possible method is to actively control the particle motion within the nasal cavity using a variety of field forces, such as electric or magnetic force. Electric control of charged particles has been suggested for targeted drug delivery to the human nose and lungs15-17. Xi et al.18 numerically tested the performance of electric guidance of charged particles and predicted significantly improved olfactory doses. Similarly, guidance of ferromagnetic drug particles with an appropriate magnetic field also has the potential to target particles to the olfactory mucosa. Behaviors of inhaled agents, if ferromagnetic, can be altered by imposing appropriate magnetic forces19. Dames et al.20 demonstrated that it is practical to target ferromagnetic particles to specific areas in mouse lungs. By packaging therapeutic agents with superparamagnetic iron oxide nanoparticles, the deposition in one lung of a mouse under the influence of a strong magnetic field was significantly increased compared to the other lung20.
Particles were assumed to be spherical and ranged from 150 nm to 30 &#181;m in diameter. The governing equation is21: 
(1)<img alt="Equation 1" src="/files/ftp_upload/53902/53902eq1.jpg" />
The above equation describes the motion of a particle governed by drag force, gravitational force, Saffman lift force 22, Brownian force for nanoparticles, and magnetophoretic force if placed in a magnetic field. Here, vi is the particle velocity, ui is the flow velocity, &#964;p is the particle response time, Cc is the Cunningham correction factor, and &#945; is the air/particle density ratio. To effectively guide the intranasally administered drugs to the olfactory region, it is necessary for the applied magnetophoretic forces to overcome both the particle inertia and gravitational force. In this study, a composite of 20% maghemite (&#947;-Fe2O3, 4.9 g/cm3) and 80% active agent was assumed, which give a density of approximate 1.78 g/cm3 and a relative permeability of 50. The selection of &#947;-Fe2O3 was due to its low cytotoxic. Iron (3+) ions are widely found in human body and a slightly higher ion concentration will not cause significant side-effects23.

<table><tbody><tr><td>MIMICS 13</td><td>Materialise Inc, Ann Arbor, MI</td><td>MR image segmentation</td><td></td></tr><tr><td>Gambit</td><td>ANSYS Inc, Canonsburg, PA&amp;nbsp;</td><td>Model development</td><td></td></tr><tr><td>ANSYS ICEMCFD</td><td>ANSYS Inc, Canonsburg, PA&amp;nbsp;</td><td>Meshing</td><td></td></tr><tr><td>ANSYS Fluent</td><td>ANSYS Inc, Canonsburg, PA&amp;nbsp;</td><td>Fluid and particle simulation</td><td></td></tr><tr><td>COMSOL Multiphsics</td><td>COMSOL Inc, Burlington, MA</td><td>Magnetic particle tracing</td><td></td></tr></tbody></table>

modeling and simulations of olfactory drug delivery with passive and active controls of nasally inhaled pharmaceutical aerosols

There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the extremely low delivery efficiency (&#60; 1%) to the olfactory mucosa that directly connects the brain. It is crucial to develop novel techniques to deliver neurological medications more effectively to the olfactory region. The objective of this study is to develop a numerical platform to simulate and improve intranasal olfactory drug delivery. A coupled image-CFD method was presented that synthetized the image-based model development, quality meshing, fluid simulation, and magnetic particle tracking. With this method, performances of three intranasal delivery protocols were numerically assessed and compared. Influences of breathing maneuvers, magnet layout, magnetic field strength, drug release position, and particle size on the olfactory dosage were also numerically studied.
From the simulations, we found that clinically significant olfactory dosage (up to 45%) were feasible using the combination of magnet layout and selective drug release. A 64 -fold higher delivery of dosage was predicted in the case with magnetophoretic guidance compared to the case without it. However, precise guidance of nasally inhaled aerosols to the olfactory region remains challenging due to the unstable nature of magnetophoresis, as well as the high sensitivity of olfactory dosage to patient-, device-, and particle-related factors.

Control Case: 
Figure 3 displays the airflow field and particle deposition in the nasal airway with standard nasal devices. It clearly shows that airflow from the front nostril is ventilated to the upper passage and airflow from the back nostril is directed towards the nasal floor (Figure 3A). Aerosol particles are observed to move faster in the median passages and slower near the walls, forming an aerosol front in the mean flow dire...

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Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

This manuscript reviews the modeling and simulations of different protocols to deliver medications to the olfactory region in image-based nasal airway models. Multiple software modules are used to develop the anatomically accurate nose model, generate computational mesh, simulate nasal airflows, and predict particle deposition at the olfactory region.

There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the ...

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Research

JoVE Journal

Medicine

10.9K Views.  California Baptist University. This manuscript reviews the modeling and simulations of different protocols to deliver medications to the olfactory region in image-based nasal airway models. Multiple software modules are used to develop the anatomically accurate nose model, generate computational mesh, simulate nasal airflows, and predict particle deposition at the olfactory region. 

Video: Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to stimulate microcirculation. The choice of delivery method for these agents is important because the route of administration profoundly affects the bioactivity and efficacy of these agents1,2. In this article, we demonstrate how to locally administer a substance in ischemic hindlimbs by using a catheterized osmotic pump. This pump can deliver a fixed volume of aqueous solution continuously for an allotted period of time. We also present our mouse model of unilateral hindlimb ischemia induced by ligation of the common femoral artery proximal to the origin of profunda femoris and epigastrica arteries in the left hindlimb. Lastly, we describe the in vivo cannulation and ligation of the infrarenal abdominal aorta and perfusion of the hindlimb vasculature with Microfil, a silicone radiopaque casting agent. Microfil can perfuse and fill the entire vascular bed (arterial and venous), and because we have ligated the major vascular conduit for exit, the agent can be retained in the vasculature for future ex vivo imaging with the use of small specimen micro-CT3.

We show here the in vivo insertion of an osmotic pump for constant local drug delivery and the creation of hindlimb ischemia in a mouse model. Moreover, the hindlimb vasculature is perfused with Microfil, a silicone radiopaque agent, to prepare for micro-computed tomography (micro-CT) imaging.

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to ...

Controlled Odor Mimic Permeation Systems for Olfactory Training and Field Testing

The Controlled Odor Mimic Permeation System (COMPS) was developed to provide a convenient field testing method of odor delivery at controlled and reproducible rates. COMPS are composed of an odorant of interest on an absorbent material sealed inside of a permeable polymer bag. The permeable layer allows for a constant release of the odorant over a given amount of time. The permeable bag is further stored in a secondary, impermeable bag. The double-containment procedure allows for equilibration of the odorant from the permeable bag but within the impermeable outer layer, resulting in an instant and reproducible source of odorant vapor upon removal from the outer packaging. COMPS are used in both olfactory testing for experimental scenarios and for olfactory detection training, such as with detection canines. COMPS can be used to contain a wide range of odorants (e.g., narcotics powders) and provide a controlled release of the associated odorants. Odor availability from COMPS is expressed in terms of permeation rate (i.e., the rate of the odorant vapor released from a COMPS per unit time) and is typically measured by gravimetric means. The permeation rate for a given mass or volume of odorant can be adjusted as needed by varying the bag thickness, surface area, and/or polymer type. The available odor concentration from a COMPS can also be measured by headspace analysis techniques such as solid phase microextraction with gas chromatography/mass spectrometry (SPME-GC/MS).

The Controlled Odor Mimic Permeation System is a simple, field-portable, low-cost method of odor delivery for olfactory testing and training. It is constructed of an odorant retained on an adsorbent material and contained inside of a permeable polymer bag allowing controlled release of the odorant vapor over time.

The Controlled Odor Mimic Permeation System (COMPS) was developed to provide a convenient field testing method of odor delivery at controlled and ...

Chemistry

Disposable Dosators for Pulmonary Insufflation of Therapeutic Agents to Small Animals

Development of new therapeutic products requires efficacy testing in an animal model. The pulmonary route of administration can be utilized to deliver drugs locally and systemically. Evaluation of dry powder aerosols necessitates an efficient dispersion mechanism to maintain high concentrations in an exposure chamber or for direct endotracheal administration. While solutions exist to expose animals by passive inhalation to dry powder aerosols, most require masses of powder in large excess of the dose delivered. This precludes conducting early feasibility studies as insufficient drug is available at the research or early development stage to support the dose delivery requirements for conventional aerosol delivery systems. When designing an aerosol drug product, aerodynamic performance can relate directly to delivery efficiency and efficacy. Dispersion of powder into an aerosol requires energy input sufficient to overcome interparticulate forces, and particle engineering approaches can substantially improve aerosol performance. We have developed a dispersion system (dosator) which can aerosolize engineered dry powder aerosols efficiently for the purpose of direct pulmonary insufflation, dispersion into an exposure system or generation for analytical purposes.

During development of drugs for pulmonary delivery, it is necessary to evaluate pharmacokinetics and efficacy in an animal model. We present a method to build a disposable aerosol dispersion system from of-the-shelf components that can be used to administer intrapulmonary dry powder aerosol to rodents.

Development of new therapeutic products requires efficacy testing in an animal model. The pulmonary route of administration can be utilized to deliver ...

Dry Powder and Nebulized Aerosol Inhalation of Pharmaceuticals Delivered to Mice Using a Nose-only Exposure System

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and bronchodilator drugs. Despite the availability of multiple treatments, both diseases are growing public health concerns. The majority of asthma patients are well controlled on current inhaled therapies but a substantial number of patients with severe asthma are not. Asthma affects an estimated 300 million people worldwide and approximately 20 percent have a severe form of the disease. In contrast to asthma, there are few effective therapies for COPD. An estimated 10% of the population has COPD and the trend in death rates is increasing for COPD while decreasing for other major diseases. Although developing drugs for inhaled delivery is challenging, the nose-only inhalation unit enables direct delivery of novel drugs to the lung of rodents for pre-clinical efficacy and safety/toxicology studies. Inhaled drug delivery has multiple advantages for respiratory diseases, where high concentration in the lung improves efficacy and minimizes systemic side effects. Inhaled corticosteroids and bronchodilators benefit from these advantages and inhaled delivery may also hold potential for future biologic therapies. The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs of rodents, key data required before initiating clinical development.

The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs; key data enabling clinical inhaled drug development.

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and ...

Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models

Development of targeted therapies for pulmonary diseases is limited by the availability of preclinical testing methods with the ability to predict regional aerosol delivery. Leveraging 3D printing to generate patient-specific lung models, we outline the design of a high-throughput, in vitro experimental setup for quantifying lobular pulmonary deposition. This system is made with a combination of commercially available and 3D printed components and allows the flow rate through each lobe of the lung to be independently controlled. Delivery of fluorescent aerosols to each lobe is measured using fluorescence microscopy. This protocol has the potential to promote the growth of personalized medicine for respiratory diseases through its ability to model a wide range of patient demographics and disease states. Both the geometry of the 3D printed lung model and the air flow profile setting can be easily modulated to reflect clinical data for patients with varying age, race, and gender. Clinically relevant drug delivery devices, such as the endotracheal tube shown here, can be incorporated into the testing setup to more accurately predict a device&#8217;s capacity to target therapeutic delivery to a diseased region of the lung. The versatility of this experimental setup allows it to be customized to reflect a multitude of inhalation conditions, enhancing the rigor of preclinical therapeutic testing.

We present a high-throughput, in vitro method for quantifying regional pulmonary deposition at the lobe level using CT scan-derived, 3D printed lung models with tunable air flow profiles.

Development of targeted therapies for pulmonary diseases is limited by the availability of preclinical testing methods with the ability to predict ...

Bioengineering

Real-time In Vitro Monitoring of Odorant Receptor Activation by an Odorant in the Vapor Phase

Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition follows a combinatorial coding scheme, where one OR can be activated by a set of odorants and one odorant can activate a combination of ORs. Through such combinatorial coding, organisms can detect and discriminate between a myriad of volatile odor molecules. Thus, an odor at a given concentration can be described by an activation pattern of ORs, which is specific to each odor. In that sense, cracking the mechanisms that the brain uses to perceive odor requires the understanding odorant-OR interactions. This is why the olfaction community is committed to &#34;de-orphanize&#34;&#160;these receptors. Conventional in vitro systems used to identify odorant-OR interactions have utilized incubating cell media with odorant, which is distinct from the natural detection of odors via vapor odorants dissolution into nasal mucosa before interacting with ORs. Here, we describe a new method that allows for real-time monitoring of OR activation via vapor-phase odorants. Our method relies on measuring cAMP release by luminescence using the Glosensor assay. It bridges current gaps between in vivo and in vitro approaches and provides a basis for a biomimetic volatile chemical sensor.

Physiologically, odorant receptors are activated by odorant molecules inhaled in the vapor phase. However, most in vitro systems utilize liquid phase odorant stimulation. Here, we present a method that allows real-time in vitro monitoring of odorant receptor activation upon odorant stimulation in vapor phase.

Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition ...

Neuroscience

Novel Methods for Intranasal Administration Under Inhalation Anesthesia to Evaluate Nose-to-Brain Drug Delivery

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain barrier. However, there have been few reports regarding not only the quantitative analysis but also optimal administration conditions and dosing regimens for investigations of nose-to-brain delivery. The limited progress in research on nose-to-brain pathway mechanisms using rodents represents a significant impediment in terms of designing nose-to-brain delivery systems for candidate drugs.
To gain some headway in this regard, we developed and evaluated two novel methods of stable intranasal administration under inhalation anesthesia for experimental animals. We also describe a method for the evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radio-labeled [14C]-inulin (molecular weight: 5,000) as a model substrate of water-soluble macromolecules.
Initially, we developed a pipette-based intranasal administration protocol using temporarily openable masks, which enabled us to perform reliable administration to animals under stable anesthesia. Using this system, [14C]-inulin could be delivered to the brain with little experimental error.
We subsequently developed an intranasal administration protocol entailing reverse cannulation from the airway side through the esophagus, which was developed to minimize the effects of mucociliary clearance (MC). This technique led to significantly higher levels of [14C]-inulin, which was quantitatively detected in the olfactory bulb, cerebrum, and medulla oblongata, than the pipette method. This appears to be because retention of the drug solution in the nasal cavity was substantially increased by active administration using a syringe pump in a direction opposite to the MC into the nasal cavity.
In conclusion, the two methods of intranasal administration developed in this study can be expected to be extremely useful techniques for evaluating pharmacokinetics in rodents. The reverse cannulation method, in particular, could be useful for evaluating the full potential of nose-to-brain delivery of drug candidates.

Here, we describe two novel methods of stable intranasal administration under inhalation anesthesia with minimal physical stress for experimental animals. We also describe a method for quantitative evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radiolabeled [14C]-inulin as a model substrate of water-soluble macromolecules.

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain ...

Effect of Odor on Brain Excitability Assessed by a Breath-Synchronized Olfactometer

Combining a Breath-Synchronized Olfactometer with Brain Simulation to Study the Impact of Odors on Corticospinal Excitability and Effective Connectivity

It is widely accepted that olfactory stimulation elicits motor behaviors, such as approaching pleasant odorants and avoiding unpleasant ones, in animals and humans. Recently, studies using electroencephalography and transcranial magnetic stimulation (TMS) have demonstrated a strong link between processing in the olfactory system and activity in the motor cortex in humans. To better understand the interactions between the olfactory and the motor systems and to overcome some of the previous methodological limitations, we developed a new method combining an olfactometer that synchronizes the random order presentation of odorants with different hedonic values and the TMS (single- and dual-coil) triggering with nasal breathing phases. This method allows probing the modulations of corticospinal excitability and effective ipsilateral connectivity between the dorsolateral prefrontal cortex and the primary motor cortex that could occur during pleasant and unpleasant odor perception. The application of this method will allow for objectively discriminating the pleasantness value of an odorant in a given participant, indicating the biological impact of the odorant on brain effective connectivity and excitability. In addition, this could pave the way for clinical investigations in patients with neurological or neuropsychiatric disorders who may exhibit&#160;odor hedonic alterations and maladaptive approach-avoidance behaviors.

Author Spotlight: Exploring Olfactory Influences on Corticospinal Excitability - Insights and Innovations in Neurological Research 

This paper describes using a breath-synchronized olfactometer to trigger single- and dual-coil transcranial magnetic stimulation (TMS) during odorant presentation synchronized to human nasal breathing. This combination allows us to objectively investigate how pleasant and unpleasant odors impact corticospinal excitability and brain-effective connectivity in a given individual.

It is widely accepted that olfactory stimulation elicits motor behaviors, such as approaching pleasant odorants and avoiding unpleasant ones, in animals ...

Customizable Disposable Dosators to Deliver Dry Powder Aerosol Drugs to Mice

Disposable Dosators Intended for Dry Powder Delivery to Mice

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus metering and dosing, and a propellant-free dispersal mechanism. To develop pharmaceutical dry powder aerosol products, robust in vivo testing is essential. Typically, initial studies involve using a murine model for preliminary evaluation before conducting formal studies in larger animal species. However, a significant limitation in this approach is the lack of suitable device technology to accurately and reproducibly deliver dry powders to small animals, hindering such models&#39; utility. To address these challenges, disposable syringe dosators were developed specifically for intrapulmonary delivery of dry powders in doses appropriate for mice. These dosators load and deliver a predetermined amount of powder obtained from a uniform bulk density powder bed. This discrete control is achieved by inserting a blunt needle to a fixed depth (tamping) into the powder bed, removing a fixed quantity each time. Notably, this dosing pattern has proven effective for a range of spray-dried powders. In experiments involving four different model spray-dried powders, the dosators demonstrated the ability to achieve doses within the range of 30 to 1100 &#181;g. The achieved dose was influenced by factors such as the number of tamps, the size of the dosator needle, and the specific formulation used. One of the key benefits of these dosators is their ease of manufacturing, making them accessible and cost-effective for delivering dry powders to mice during initial proof-of-concept studies. The disposable nature of the dosators facilitates use in animal procedure rooms, where cleaning and refilling reusable systems and weighing materials is inconvenient. Thus, developing disposable syringe dosators has addressed a significant hurdle in murine dry powder delivery for proof-of-concept studies, enabling researchers to conduct more accurate and reproducible preliminary studies in small animal models for pulmonary drug delivery.

Author Spotlight: Developing a Disposable Dosator for Preclinical Testing of Dry Powder Inhalers in Small Animal Models 

Pharmaceutical dry powder development necessitates reliable in vivo testing, often using a murine model. Device technology for accurately and reproducibly delivering dry powder aerosols to mice is restricted. This study presents disposable dosators for pulmonary drug delivery at mouse-relevant doses, aiding initial proof-of-concept research.

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus ...

A Technique to Generate and Deliver Drug Aerosols Directly to Mouse Lungs

Source: Phillips, J. E. et al., <a href="https://app.jove.com/v/55454">Dry Powder and Nebulized Aerosol Inhalation of Pharmaceuticals Delivered to Mice Using a Nose-only Exposure System.</a>&#160;J. Vis. Exp. (2017)
This video demonstrates the generation of drug aerosols and the targeted nose-only delivery of these aerosols to mice using an inhalation unit equipped with an aerosol generator. The mouse is restrained in a nose-only restrainer and connected to the inhalation unit, which delivers the drug directly into the mouse&#39;s nasal cavity. Subsequently, the drug passes through the trachea and enters the lungs.

All procedures involving animal models have been reviewed by the local institutional animal care committee and the JoVE veterinary review board.
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Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

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