Medical device maker Integra LifeSciences announced today it will purchase Acclarent, a leader in ear, nose and throat (ENT) technologies, from Johnson & Johnson’s Ethicon division for $275 million upfront plus future regulatory milestones. The deal values Acclarent at approximately 2.5 times sales, with the company generating $110 million in revenues during 2022.
For Integra, the acquisition provides an opportunity to significantly expand its footprint beyond neurosurgery and establish the company as a major player in the attractive ENT specialty devices segment. The global ENT market is projected to grow at a 5-6% clip annually, adding an estimated $1 billion in addressable market opportunity for Integra.
Acclarent brings to Integra pioneered balloon dilation platforms for treating chronic sinusitis as well as novel treatments for Eustachian tube dilations. Its flagship products are the only FDA-approved stents for maintaining sinus openings after surgery. Acclarent also provides image guidance systems to assist surgeons with minimally invasive procedures.
The company maintains strong brand awareness and deep clinical relationships after rebuilding its commercial presence following a period of declining sales between 2017-2020.
Integra management sees substantial room for additional share gains in ENT given Acclarent’s leadership in balloon dilation and the generally fragmented supplier landscape in ENT today. The global sinus dilation devices market alone is projected to reach $3.5 billion by 2030, providing a sizable growth pipeline for Acclarent’s portfolio.
Strategic and Financial Benefits
The acquisition furthers Integra’s strategy to complement its legacy strength in neurosurgery with scaled positions across faster-growth clinical applications adjacent to its core.
Integra aims to replicate its #1 share in dural repair for neuro procedures by becoming one of few dominant players in ENT. The company believes the combination of its commercial infrastructure and Acclarent’s innovative portfolio can support above-market growth for the foreseeable future.
Financially, Acclarent is being acquired at an attractive upfront valuation of 2.5 times sales. Integra management expects the deal will be immediately accretive to earnings per share after closing.
Acclarent generated gross margins in line with Integra’s overall company average in 2022, providing opportunities for further margin expansion from operating leverage as the business scales.
The transaction also comes at a time when medtech valuations have declined from their pandemic peaks, enabling Integra to obtain Acclarent at what it believes to be an opportunistic price.
Cultural and Portfolio Fit
Integra CEO Jan De Witte highlighted the cultural alignment between both organizations and focus on restoring patient lives as key rationales behind the deal.
De Witte said, “Acclarent’s culture of pioneering technologies aligns with Integra’s legacy of innovation to transform care and restore patients’ lives. We are looking forward to welcoming the Acclarent employees to the Integra team. Together, we can make a profound impact on the future of ENT and neurosurgery.”
Acclarent will operate as part of Integra’s $1.3 billion Codman Specialty Surgical division focused on neurosurgery. Integra sees substantial opportunities for its neurosurgery and ENT sales teams to collaborate on treating certain brain tumors by leveraging skull base surgical approaches.
Integra also gains access to a robust ENT product development pipeline, including next-generation surgical staplers, powered sinus surgery technologies, and potential new indications for Acclarent’s balloon dilation platforms.
Acclarent’s R&D and regulatory expertise will help accelerate Integra’s internal efforts to bring new generations of minimally invasive surgery products to market.
Smooth Post-Close Integration
Integra expects to retain Acclarent’s entire workforce as part of ensuring a smooth organizational transition after the deal closes. The company aims to operate Acclarent as an independent business unit during the near-term while integrating back-office functions.
Manufacturing operations will continue to be outsourced to third parties and Integra anticipates no supply chain disruptions to Acclarent’s product availability.
The transaction is projected to close by the second quarter of 2024, subject to customary antitrust and regulatory clearances globally. Transition services agreements will provide additional support for up to four years following deal closure.
By maintaining continuity of strategy, personnel and manufacturing, Integra hopes to achieve targeted revenue and cost synergies from the integration of Acclarent, while continuing its above-market growth trajectory in the ENT segment. The addition of Acclarent’s portfolio and innovative roadmap makes this transaction an important step forward in Integra’s strategy to complement leadership in neurosurgery with scaled positions in some of medtech’s most attractive and fastest-growing markets.
Looming Behind Antibiotic Resistance is Another Bacterial Threat – Antibiotic Tolerance
Have you ever had a nasty infection that just won’t seem to go away? Or a runny nose that keeps coming back? You may have been dealing with a bacterium that is tolerant of, though not yet resistant to, antibiotics.
Antibiotic resistance is a huge problem, contributing to nearly 1.27 million deaths worldwide in 2019. But antibiotic tolerance is a covert threat that researchers have only recently begun to explore.
Antibiotic tolerance happens when a bacterium manages to survive for a long time after being exposed to an antibiotic. While antibiotic-resistant bacteria flourish even in the presence of an antibiotic, tolerant bacteria often exist in a dormant state, neither growing nor dying but putting up with the antibiotic until they can “reawaken” once the stress is gone. Tolerance has been linked to the spread of antibiotic resistance.
This article was republished with permission from The Conversation, a news site dedicated to sharing ideas from academic experts. It represents the research-based findings and thoughts of Megan Keller, Ph.D. Candidate in Microbiology, Cornell University.
I am a microbiologist who studies antibiotic tolerance, and I seek to uncover what triggers tolerant bacteria to enter a protective dormant slumber. By understanding why bacteria have the ability to become tolerant, researchers hope to develop ways to avoid the spread of this ability. The exact mechanism that sets tolerance apart from resistance has been unclear. But one possible answer may reside in a process that has been overlooked for decades: how bacteria create their energy.
Cholera and Antibiotic Tolerance
Many antibiotics are designed to break through the bacteria’s outer defenses like a cannonball through a stone fortress. Resistant bacteria are immune to the cannonball because they can either destroy it before it damages their outer wall or change their own walls to be able to withstand the impact.
Tolerant bacteria can remove their wall entirely and avoid damage altogether. No wall, no target for the cannonball to smash. If the threat goes away before too long, the bacterium can rebuild its wall to protect it from other environmental dangers and resume normal functions. However, it is still unknown how bacteria know the antibiotic threat is gone, and what exactly triggers their reawakening.
My colleagues and I at the Dörr Lab at Cornell University are trying to understand processes of activation and reawakening in the tolerant bacteria responsible for cholera, Vibrio cholerae. Vibrio is rapidly evolving resistance against various types of antibiotics, and doctors are concerned. As of 2010, Vibrio is already resistant to 36 different antibiotics, and this number is expected to continue rising.
To study how Vibrio develops resistance, we chose a strain that is tolerant to a class of antibiotics called beta-lactams. Beta-lactams are the cannonball sent to destroy the bacteria’s fortress, and Vibrio adapts by activating two genes that temporarily remove its cell wall. I witnessed this phenomenon using a microscope. After removing its cell wall, the bacteria activate even more genes that morph it into fragile globs that can survive the effects of the antibiotic. Once the antibiotic is removed or degraded, Vibrio returns to its normal rod shape and continues to grow.
In people, this process of tolerance is seen when a doctor prescribes an antibiotic, typically doxycycline, to a patient infected with cholera. The antibiotic temporarily seems to stop the infection. But then the symptoms start back up again because the antibiotics never fully cleared the bacteria in the first place.
The ability to revert back to normal and grow after the antibiotic is gone is the key to tolerant survival. Exposing Vibrio to an antibiotic for a long enough time would eventually kill it. But a standard course of antibiotics often isn’t long enough to get rid of all the bacteria even in their fragile state.
However, taking a medicine for a prolonged period can harm healthy bacteria and cells, causing further discomfort and illness. Additionally, misuse and extended exposure to antibiotics can increase the chances of other bacteria residing in the body becoming resistant.
Other Bacteria Developing Tolerance
Vibrio isn’t the only species to exhibit tolerance. In fact, researchers have recently identified many infectious bacteria that have developed tolerance. A bacteria family called Enterobacteriaceae, which include major food-borne disease pathogens Salmonella, Shigella and E. coli, are just a few of the many types of bacteria that are capable of antibiotic tolerance.
As every bacterium is unique, the way one develops tolerance seems to be as well. Some bacteria, like Vibrio, erase their cell walls. Others can alter their energy sources, increase their ability to move or simply pump out the antibiotic.
I recently found that a bacterium’s metabolism, or the way it breaks down “food” to make energy, may play a significant role in its ability to become tolerant. Different structures within a bacterium, including its outer wall, are made of specific building blocks like proteins. Stopping the bacterium’s ability to craft these pieces weakens its wall, making it more likely to take damage from the outside environment before it can take the wall down.
Tolerance and Resistance are Connected
Although there has been considerable research on how bacteria develop tolerance, a key piece of the puzzle that has been neglected is how tolerance leads to resistance.
In 2016, researchers discovered how to make bacteria tolerant in the laboratory. After repeated exposure to different antibiotics, E. coli cells were able to adapt and survive. DNA, the genetic material containing instructions for cell function, is a fragile molecule. When DNA is damaged rapidly by stress, such as antibiotic exposure, the cell’s repair mechanisms tend to mess up and cause mutations that can create resistance and tolerance. Because E. coli is similar to many different types of bacteria, these researchers’ findings revealed that, ironically, essentially any bacteria can develop tolerance if pushed to their limits by the antibiotics meant to kill them.
Another recent key discovery was that the longer bacteria remain tolerant, the more likely they are to develop mutations leading to resistance. Tolerance allows bacteria to develop a resistance mutation that reduces their chances of being killed during antibiotic treatment. This is especially relevant to bacterial communities often seen in biofilms that tend to coat high-touch surfaces in hospitals. Biofilms are slimy layers of bacteria that ooze a protective jelly that makes antibiotic treatment difficult and DNA sharing between microbes easy. They can induce bacteria to evolve resistance. These conditions are thought to mimic what could be happening during antibiotic-treated infections, in which many bacteria are living next to one another and sharing DNA.
Researchers are calling for more research into antibiotic tolerance with the hope that it will lead to more robust treatments in both infectious diseases and cancers. And there is reason to be hopeful. In one promising development, a mouse study found that decreasing tolerance also reduced resistance.
Meanwhile, there are steps everyone can take to aid in the battle against antibiotic tolerance and resistance. You can do this by taking an antibiotic exactly as prescribed by a doctor and finishing the entire bottle. Brief, inconsistent exposure to a medicine primes bacteria to become tolerant and eventually resistant. Smarter use of antibiotics by everyone can stop the evolution of tolerant bacteria.
A team of scientists at the Whitehead Institute for Biomedical Research and the Broad Institute of MIT and Harvard has systematically evaluated the functions of over 5,000 essential human genes using a novel, pooled, imaged-based screening method. Their analysis harnesses CRISPR-Cas9 to knock out gene activity and forms a first-of-its-kind resource for understanding and visualizing gene function in a wide range of cellular processes with both spatial and temporal resolution. The team’s findings span over 31 million individual cells and include quantitative data on hundreds of different parameters that enable predictions about how genes work and operate together. The new study appears in the Nov. 7 online issue of the journal Cell.
“For my entire career, I’ve wanted to see what happens in cells when the function of an essential gene is eliminated,” says MIT Professor Iain Cheeseman, who is a senior author of the study and a member of Whitehead Institute. “Now, we can do that, not just for one gene but for every single gene that matters for a human cell dividing in a dish, and it’s enormously powerful. The resource we’ve created will benefit not just our own lab, but labs around the world.”
Systematically disrupting the function of essential genes is not a new concept, but conventional methods have been limited by various factors, including cost, feasibility, and the ability to fully eliminate the activity of essential genes. Cheeseman, who is the Herman and Margaret Sokol Professor of Biology at MIT, and his colleagues collaborated with MIT Associate Professor Paul Blainey and his team at the Broad Institute to define and realize this ambitious joint goal. The Broad Institute researchers have pioneered a new genetic screening technology that marries two approaches — large-scale, pooled, genetic screens using CRISPR-Cas9 and imaging of cells to reveal both quantitative and qualitative differences. Moreover, the method is inexpensive compared to other methods and is practiced using commercially available equipment.
“We are proud to show the incredible resolution of cellular processes that are accessible with low-cost imaging assays in partnership with Iain’s lab at the Whitehead Institute,” says Blainey, a senior author of the study, an associate professor in the Department of Biological Engineering at MIT, a member of the Koch Institute for Integrative Cancer Research at MIT, and a core institute member at the Broad Institute. “And it’s clear that this is just the tip of the iceberg for our approach. The ability to relate genetic perturbations based on even more detailed phenotypic readouts is imperative, and now accessible, for many areas of research going forward.”
Cheeseman adds, “The ability to do pooled cell biological screening just fundamentally changes the game. You have two cells sitting next to each other and so your ability to make statistically significant calculations about whether they are the same or not is just so much higher, and you can discern very small differences.”
Cheeseman, Blainey, lead authors Luke Funk and Kuan-Chung Su, and their colleagues evaluated the functions of 5,072 essential genes in a human cell line. They analyzed four markers across the cells in their screen — DNA; the DNA damage response, a key cellular pathway that detects and responds to damaged DNA; and two important structural proteins, actin and tubulin. In addition to their primary screen, the scientists also conducted a smaller, follow-up screen focused on some 200 genes involved in cell division (also called “mitosis”). The genes were identified in their initial screen as playing a clear role in mitosis but had not been previously associated with the process. These data, which are made available via a companion website, provide a resource for other scientists to investigate the functions of genes they are interested in.
“There’s a huge amount of information that we collected on these cells. For example, for the cells’ nucleus, it is not just how brightly stained it is, but how large is it, how round is it, are the edges smooth or bumpy?” says Cheeseman. “A computer really can extract a wealth of spatial information.”
Flowing from this rich, multi-dimensional data, the scientists’ work provides a kind of cell biological “fingerprint” for each gene analyzed in the screen. Using sophisticated computational clustering strategies, the researchers can compare these fingerprints to each other and construct potential regulatory relationships among genes. Because the team’s data confirms multiple relationships that are already known, it can be used to confidently make predictions about genes whose functions and/or interactions with other genes are unknown.
There are a multitude of notable discoveries to emerge from the researchers’ screening data, including a surprising one related to ion channels. Two genes, AQP7 and ATP1A1, were identified for their roles in mitosis, specifically the proper segregation of chromosomes. These genes encode membrane-bound proteins that transport ions into and out of the cell. “In all the years I’ve been working on mitosis, I never imagined ion channels were involved,” says Cheeseman.
He adds, “We’re really just scratching the surface of what can be unearthed from our data. We hope many others will not only benefit from — but also build upon — this resource.”
This work was supported by grants from the U.S. National Institutes of Health as well as support from the Gordon and Betty Moore Foundation, a National Defense Science and Engineering Graduate Fellowship, and a Natural Sciences and Engineering Research Council Fellowship.
A team of scientists at the Whitehead Institute for Biomedical Research and the Broad Institute of MIT and Harvard has systematically evaluated the functions of over 5,000 essential human genes using a novel, pooled, imaged-based screening method. Their analysis harnesses CRISPR-Cas9 to knock out gene activity and forms a first-of-its-kind resource for understanding and visualizing gene function in a wide range of cellular processes with both spatial and temporal resolution. The team’s findings span over 31 million individual cells and include quantitative data on hundreds of different parameters that enable predictions about how genes work and operate together. The new study appears in the Nov. 7 online issue of the journal Cell.
“For my entire career, I’ve wanted to see what happens in cells when the function of an essential gene is eliminated,” says MIT Professor Iain Cheeseman, who is a senior author of the study and a member of Whitehead Institute. “Now, we can do that, not just for one gene but for every single gene that matters for a human cell dividing in a dish, and it’s enormously powerful. The resource we’ve created will benefit not just our own lab, but labs around the world.”
Systematically disrupting the function of essential genes is not a new concept, but conventional methods have been limited by various factors, including cost, feasibility, and the ability to fully eliminate the activity of essential genes. Cheeseman, who is the Herman and Margaret Sokol Professor of Biology at MIT, and his colleagues collaborated with MIT Associate Professor Paul Blainey and his team at the Broad Institute to define and realize this ambitious joint goal. The Broad Institute researchers have pioneered a new genetic screening technology that marries two approaches — large-scale, pooled, genetic screens using CRISPR-Cas9 and imaging of cells to reveal both quantitative and qualitative differences. Moreover, the method is inexpensive compared to other methods and is practiced using commercially available equipment.
“We are proud to show the incredible resolution of cellular processes that are accessible with low-cost imaging assays in partnership with Iain’s lab at the Whitehead Institute,” says Blainey, a senior author of the study, an associate professor in the Department of Biological Engineering at MIT, a member of the Koch Institute for Integrative Cancer Research at MIT, and a core institute member at the Broad Institute. “And it’s clear that this is just the tip of the iceberg for our approach. The ability to relate genetic perturbations based on even more detailed phenotypic readouts is imperative, and now accessible, for many areas of research going forward.”
Cheeseman adds, “The ability to do pooled cell biological screening just fundamentally changes the game. You have two cells sitting next to each other and so your ability to make statistically significant calculations about whether they are the same or not is just so much higher, and you can discern very small differences.”
Cheeseman, Blainey, lead authors Luke Funk and Kuan-Chung Su, and their colleagues evaluated the functions of 5,072 essential genes in a human cell line. They analyzed four markers across the cells in their screen — DNA; the DNA damage response, a key cellular pathway that detects and responds to damaged DNA; and two important structural proteins, actin and tubulin. In addition to their primary screen, the scientists also conducted a smaller, follow-up screen focused on some 200 genes involved in cell division (also called “mitosis”). The genes were identified in their initial screen as playing a clear role in mitosis but had not been previously associated with the process. These data, which are made available via a companion website, provide a resource for other scientists to investigate the functions of genes they are interested in.
“There’s a huge amount of information that we collected on these cells. For example, for the cells’ nucleus, it is not just how brightly stained it is, but how large is it, how round is it, are the edges smooth or bumpy?” says Cheeseman. “A computer really can extract a wealth of spatial information.”
Flowing from this rich, multi-dimensional data, the scientists’ work provides a kind of cell biological “fingerprint” for each gene analyzed in the screen. Using sophisticated computational clustering strategies, the researchers can compare these fingerprints to each other and construct potential regulatory relationships among genes. Because the team’s data confirms multiple relationships that are already known, it can be used to confidently make predictions about genes whose functions and/or interactions with other genes are unknown.
There are a multitude of notable discoveries to emerge from the researchers’ screening data, including a surprising one related to ion channels. Two genes, AQP7 and ATP1A1, were identified for their roles in mitosis, specifically the proper segregation of chromosomes. These genes encode membrane-bound proteins that transport ions into and out of the cell. “In all the years I’ve been working on mitosis, I never imagined ion channels were involved,” says Cheeseman.
He adds, “We’re really just scratching the surface of what can be unearthed from our data. We hope many others will not only benefit from — but also build upon — this resource.”
This work was supported by grants from the U.S. National Institutes of Health as well as support from the Gordon and Betty Moore Foundation, a National Defense Science and Engineering Graduate Fellowship, and a Natural Sciences and Engineering Research Council Fellowship.
