Drug Delivery To the Inner Ear For the Treatment Of Meniere's Disease
Summary
During my time at the Kysar Small Scale Mechanics Lab, I was part of a medical device research project between the Mechanical & Biomedical Engineering Departments and the Otolaryngology (ENT) department from Columbia Medical School. The project was to find a suitable method of delivering drugs to the Inner Ear for the treatment of Meniere’s disease. My role was to design and build a system that would effectively simulate the movement of drugs within the Human Ear. It involved 3D printing, prototyping and using off the shelf components that would integrate well to provide consistent data from the diffusion study. The design incorporated a side by side Franz cell arrangement that could enable sampling from the ports at regular intervals. The second part of the project included the incorporation of internal fluid pressure (as observed when creating holes in the Inner Ear) into the system. The constant pressure was created by having a water head difference maintained by a constant vacuum system, that was provided by a dust buster.
Background
Hearing Loss affects close to 300 million people worldwide. Meniere’s disease is one such inner ear disorder that causes episodes of vertigo (spinning). The existing treatments available for such hearing losses are very limited in their nature and not very successful.
Recently, intra-tympanic drug delivery showed some level of success. However, the RWM presented a barrier for the drugs to reach the inner ear efficiently. To obtain a greater understanding of how this experiment would benefit humans, diffusion tests are first carried out on the Round Window Membrane (RWM) of guinea pigs.
Guinea pigs are used as a standard animal model in hearing research and intra-tympanic drug delivery. And yes! I did have to cut open a dead guinea pig to extract its Round Window Membrane (as an initiation into this research)
The Franz cell usually uses a membrane that doesn’t have a hole in it.
Thus convection also comes into play due to the fluid pressure. In this regard, we intend to separate convection and diffusion in their roles in Concentration.
The aim is to establish a method where we can analyze the concentration from the convection of fluid across the RWM.
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Samples are obtained through the sampling port of the Franz cell via a micro-pipette.
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Sampling is carried out in regular intervals until the error reaches a minimum.
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This adapted Franz cell method thus provides a consistent and controlled means to study permeability of the RWM.
Individual magnetic stirrers are used to build a dual motor stage to enable the side-side Horizontal Franz cell Diffusion study.
Concept
The individual magnetic stirrers essentially power the dual motor stage built for the diffusion study
The pink stuff you see on the right cell (donor chamber) is Rhodamine B. The dye is used as it has a similar molecular weight and similar diffusion coefficient as Gentamicin, the drug administered for the treatment of Meniere's disease.
Samples are collected from the sampling port, and thanks to the Gen5 Data Analysis software (in the Biomedical Department), the concentration of Fluorescence is obtained. The size of the holes created on the membrane is obtained through an optical microscope and the image processing software ImageJ.
Testing being carried out in the video below.
Inner Ear with the Round Window Membrane
Horizontal side-by-side Franz cell
Magnetic stirrer stage
Laser printed washers to hold the magnets within the holders
Image converted to binary on ImageJ
Image callibration using an optical microscope
This data is required to be able to carry out tests on human inner ear membrane. Experimentation will begin in late January.
The project is carried out in collaboration with the doctors from Columbia University Medical Center (CUMC) and engineers from the Kysar Lab, Mechanical Engineering Department, Columbia University.
To maintain constant pressure head
Constant Vacuum Pressure System
With the working of the Franz Cell Diffusion system, a new challenge in the form of a constant pressure system needed to be overcome.
The human body has a myriad of fluids and parts that exert pressure.
Examples include the Arterial Blood pressure, Capillary blood pressure, Eye pressure (acqueous humor) and the like.
Similarly, the Perilymph liquid within the inner ear exerts a pressure, which needs to be accounted for within our study. The mean perilymphatic pressure for a Guinea Pig is 2.31 cm H2O. [1]
Water head ∆P has to be thus maintained at 2.31 cm between the donor and sampling ports.
Convection currents are set due to Pressure, and thus a possible change in concentration of the drugs delivered can be predicted due to this internal body pressure.
To account for this constant internal body pressure, a constant water head difference has to be maintained.
A constant exit and influx needs to be included in our study in order to maintain this constant water head difference. As seen below, Convection and Diffusion take place in opposite directions when we do account the pressure head within our set up.
Experimentation
Different techniques was employed to arrive at the best solution which would be reproducible and ensure efficient functioning.
Initially, a vacuum pump was used to create the suction to remove the fluid from the sampling chamber. The pump being too powerful for the system, a 12V Dustbuster was used as a source of vacuum for the Franz Cell System. The machine was reverse engineered to use it with a DC power supply in order to gain greater power as well as control over the system.
Throughout the experimentation it was noticed that the high pressure would be required to overcome the high Fluidic resistance as offered by the narrow, thin pipes that were being used.
This challenge was addressed by reducing the length of travel as well as increasing radius of the pipe as shown below by the Hagen–Poiseuille equation.
Consequently, with a few more iterations to the system, the resistance was greatly reduced to enable fluid movement into the water trap. Separate water traps were also used to ensure pressure head control for both the systems that were built for the Diffusion Study using Magnetic Stirrers.
The Pressure from the Dust-Buster was pivoted at the center to access both systems to overcome the first technique used, wherein we observed leakages and massive pressure losses for the second system
Final Design
Different stages of the design shown below.
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Middle Ear Side
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Where Drugs will be Administered
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Negative Pressure (perilymph)
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Influx of water via syringe pump
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Inner Ear Side
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Where Drugs will be Delivered
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Positive pressure (perilymph)
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Vacuum Suction
Where:
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∆P is the pressure loss
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L is the length of pipe
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ν is the dynamic viscosity
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Q is the volumetric flow rate
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r is the radius
