Creating a blueprint for optimized ear tubes and other implantable fluid-transporting devices

Date:
April 5, 2023
Source:
Wyss Institute for Biologically Inspired Engineering at Harvard
Summary:
A new study provides a complete design overhaul for IMCs by creating
a broadly applicable strategy that solves key challenges in the
design of ear tubes and other 'implantable medical conduits.' The
approach enables IMCs with predictable and effective uni- and
bi-directional fluid transport at the millimeter scale that resist
various contaminations.


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FULL STORY ========================================================================== Infections of the middle ear, the air-filled space behind the eardrum
that contains the tiny vibrating bones of hearing, annually affect
more than 700 million people worldwide. Children are especially prone
to ear infections, with 40% of them developing recurrent or chronic
infections that can lead to complications like impaired hearing,
speech and language delays, perforations in their eardrums, and even life-threatening meningitis.


==========================================================================
As a treatment, doctors may surgically insert ear tubes knowns as
"tympanostomy tubes" (TTs) into the eardrum to create an opening between
the ear canal and middle ear. Ideally, these conduits ventilate the middle
ear, provide a route for fluid to drain out, and allow antibiotic drops
to reach the infection- causing bacteria. But in reality, these small
hollow cylindrical devices made of plastic or metal function far from perfectly. Bacteria can lay down biofilms and local tissue can grow on
their surfaces, which blocks TTs' lumen and causes them to extrude. Also, antibiotic ear drops applied in the ear canal may not reach the site of infection anymore. These complications pose risks and result in the need
for frequent replacement surgeries, producing sizeable economic costs
to the health care system.

Importantly, problems affecting TTs also plague other fluid-transporting "implantable medical conduits" (IMCs), such as catheters, shunts, and
various small tubes with use in the brain, liver, eyes, and other organs
where a high- pressure barrier prevents fluids from flowing through the conduit. In the quest for superior devices, the fundamental challenge
faced by biomedical engineers is rooted in the conflict that reducing
IMC devices' size and invasiveness comes at the price of increasing
their risk of becoming blocked and malfunctioning.

Now, a multi-disciplinary research collaboration at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard John A.

Paulson School of Engineering and Applied Sciences (SEAS), and
Massachusetts Eye and Ear (MEE) in Boston provides a complete design
overhaul for IMCs by creating a broadly applicable strategy that solves
this challenge. Their approach enables IMCs with predictable and effective
uni- and bi-directional fluid transport at the millimeter scale that
resist various contaminations.

With the example of TTs fabricated from a liquid-infused material
(iTTs, short for "infused tympanostomy tubes"), they co-optimized difficult-to-reconcile functions, including fast drug delivery into
and drainage of fluids out of the middle ear, resistance against water
crossing from the outside into the middle ear, as well as the prevention
of bacterial and cell adhesion to tubes, by introducing a novel curved
lumen geometry of the tube. The findings are published in the recent
cover article of Science Translational Medicine.

"As a clinical otologist, I treat pediatric and adult patients with
recurrent ear infections on a daily basis and I routinely place
tympanostomy tubes, which in children is the most common surgical
procedure performed in the United States. Yet, TT medical device
technology has remained relatively unchanged for the past 50 years,"
said co-senior author Aaron Remenschneider, M.D., M.P.H.

"Given our findings, I do see hope on the horizon for patients with
chronic ear infections. Not only do our iTTs demonstrate a reduction
in cell adhesion and improved selective fluid transport, but we showed
how iTTs result in decreased scarring of the eardrum and preserved
hearing when compared to standard-of-care control TTs. iTTs could also
become an effective tool for delivering a range of drugs to the middle
ear." Remenschneider is a lecturer at Harvard Medical School (HMS), and
at MEE collaborates closely with co-author, MEE otologist- colleague,
and HMS Assistant Professor Elliott Kozin, M.D., who also investigates therapeutic approaches to ear disorders at MEE.

Material and clinical scientists listen closely -- together Preceding
this collaboration, co-senior author Joanna Aizenberg, Ph.D., who is an Associate Faculty member of the Wyss Institute and the Amy Smith Berylson Professor of Material Sciences at SEAS, has pioneered bio-inspired
materials with entirely new functionalities. These included SLIPS
(short for "Slippery Liquid-Infused Porous Surfaces"), which expose a
thin layer of oil-based liquid to prevent biofouling by various organisms
while enabling specific interactions with other fluids. Aizenberg's group
had applied SLIPS technology to different industrial and environmental "biofouling" problems and, in search of unmet needs in the medical
field that their materials could help address, they consulted with Remenschneider, Kozin and other physicians. A complete design overhaul
of TTs and other IMCs became the goal of a long-standing collaboration
driven by Aizenberg's group, and Remenschneider and Kozin, which also
included other researchers and clinicians. During its advancement,
the cross- institutional project was recognized as a Validation Project
at the Wyss Institute, which provided additional financial, technical,
and translational support.

First-authors Haritosh Patel, a graduate engineering student in the
Aizenberg lab, and Ida Pavlichenko, Ph.D., a former Wyss Technology
Development Fellow began to develop the first iTT prototypes, using
materials with liquid-infused surfaces and the 3D printing expertise of co-author Jennifer Lewis, Sd.D. at SEAS. "As a mother of a child who had experienced recurrent ear infections and some of their pain and harmful consequences, I could immediately relate to the clinical problem, and
felt strongly compelled to spearhead a project with the potential to
solve it," said Pavlichenko. "We soon began to investigate geometry as
a possible solution for solving IMCs' fundamental design challenge.

Surprisingly, only cylindrical TTs with straight internal lumen channels existed. We hypothesized that introducing specific curvatures into iTTs' channels could allow them to discriminate between different fluids at
a small scale." While focusing on iTTs as a first application, the
team developed a much more broadly applicable modeling-enabled design
process that can be applied to IMCs with different tasks and locations
in the body. Based on the physical parameters of liquids, materials, and
size, it starts with the fluid dynamics- based prediction of specific geometries for millimeter-sized IMCs fabricated with liquid-infused
surfaces to control the directional transport of different liquids through them. "Besides validating the predicted transport of fluids through
rationally designed and fabricated iTT prototypes in in vitromodels of
the middle ear, we also demonstrated their resistance against adhesion
by the five most common bacterial strains causing ear infection in
children," said Patel. The strains were directly isolated from patients
with chronic middle ear infections by co-author Paulo Bispo, Ph.D.,
another MEE collaborator on the project and an Assistant Professor at HMS.

Moving closer to the human ear To investigate the performance of their
iTTs in comparison with conventional TTs in an in vivo model with
relevance to the human ear, the collaborators tested their approach
on the ears of chinchillas, the gold-standard for studying middle
ear diseases and treatment approaches. Chinchillas have a tympanic
membrane about the same size of that of humans and a similar frequency
range of hearing, and Remenschneider and Kozin had routinely used them
in their MEE research lab. "Checking off all essential boxes, iTTs,
when implanted into chinchillas' eardrum, kept out environmental water, prevented infectious buildup, reduced scarring, and remained clear for
aeration and pressure equalization," said Patel. Pavlichenko added, "Importantly, they preserved hearing and enabled more easy and reliable
dosing of antibiotic ear drops to the middle ear compared to conventional
TTs, which is particularly exciting." According to Remenschneider,
"reliable dosing of medications to the middle ear through iTTs opens the
door to rethinking our management of middle and even inner ear conditions,
like hearing loss." "Based on our excellent safety and efficacy results,
iTTs could next be tested in a clinical trial in human patients. But
what equally excites us is to extend our patented design approach to
other important IMCs, for example, as shunts for the brain, eye, and
bile duct. The technology and fabrication process would even enable
the creation of personalized devices optimized for specific patients' characteristics and needs," said Aizenberg. "We envision that iTTs'
and other IMCs' material and geometrical properties in the future could
be reverse-engineered to adapt them to different drug formulations
and make them a part of the drug discovery process for an efficient
topical delivery of therapeutics and treatment of various diseases."
"This is wonderful example of what can happen when you have innovative materials scientists, engineers, and clinicians working together hand
in hand to devise a new approach to meet specific patients' needs,"
said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the
Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital, and the Hansjo"rg Wyss Professor of Bioinspired Engineering
at SEAS.

Other authors on the study are Alison Grinthal, Cathy Zhang, Jack
Alvarenga, Michael Kreder, James Weaver, Qin Ji, Christopher Ling, Joseph
Choy, Zihan Li, and Nicole Black. The study has been funded by the Wyss Institute for Biologically Inspired Engineering at Harvard University,
National Science Foundation (under award# DMR-2011754), and National
Institutes of Health (under award# R43DC019318 and K08DC018575).

* RELATED_TOPICS
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========================================================================== Story Source: Materials provided
by Wyss_Institute_for_Biologically_Inspired_Engineering_at
Harvard. Original written by Benjamin Boettner. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Haritosh Patel, Ida Pavlichenko, Alison Grinthal, Cathy T. Zhang,
Jack
Alvarenga, Michael J. Kreder, James C. Weaver, Qin Ji, Christopher
W. F.

Ling, Joseph Choy, Zihan Li, Nicole L. Black, Paulo J. M. Bispo,
Jennifer A. Lewis, Elliott D. Kozin, Joanna Aizenberg, Aaron
K. Remenschneider.

Design of medical tympanostomy conduits with selective fluid
transport properties. Science Translational Medicine, 2023; 15
(690) DOI: 10.1126/ scitranslmed.add9779 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/04/230405161310.htm

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