A startup claims it broke through a bottleneck that’s holding back LLMs

Miami-based AI startup Subquadratic came out of stealth mode last month with a huge claim. It announced that it had solved a mathematical bottleneck that had been holding back large language models for almost a decade.

The details were thin, and many people were unconvinced. But Subquadratic has started to bring the receipts, sharing the results of an independent evaluation of its new tech. The results suggest that the company’s claims might be worth paying attention to.

According to Subquadratic, it has developed a new kind of LLM, called SubQ, that is faster and cheaper and uses a lot less energy than any other model on the market. The company also claims that SubQ is able to process up to 12 times as much text at once than most other models, allowing it to carry out a range of data-heavy tasks, such as analyzing hundreds of documents or entire code bases.

What’s more, Subquadratic says, SubQ does this while more or less matching the performance of the best models put out by Google DeepMind, OpenAI, and Anthropic on key tasks like coding.

The problem was that the company at first provided little evidence for its claims beyond a handful of self-published test scores. And it has yet to make SubQ widely available for people to try out themselves.

So it’s no surprise that Subquadratic’s claims were met with skepticism. Dan McAteer, an artificial intelligence engineer, captured the overall response on X: “SubQ is either the biggest breakthrough since the Transformer … or it’s AI Theranos.”

A month on, the company has published more information about its model, including the results of additional independent tests run by third-party firm Appen.

“We expected healthy skepticism,” says Subquadratic cofounder and chief technology officer Alex Whedon. “In hindsight, releasing the third-party benchmarks alongside the initial announcement would have preempted much of the skepticism, which is why we’re taking the time to make sure any future results are fully verified before putting them out.”

Subquadratic asked Appen, which evaluates other companies’ models, to run its tests on SubQ. The results seem to back up a lot of Subquadratic’s claims. “That was really exciting to me, it validated their architecture,” says Jeanine Sinanan-Singh, Appen’s director of generative AI research.

“I was like, ‘Wow, this could be a game changer,’ because models struggle with speed and inefficiency,” she adds. “But when you have kind of shocking results, it’s really not as credible when you say it yourself.”

SubQ won’t replace existing top models across the board, but it could offer huge increases in speed at a fraction of the typical cost for certain tasks. Subquadratic insists that in the long run, though, its breakthrough could change how LLMs are built. “We hope we’re kicking off a new age of efficiency,” says Justin Dangel, the firm’s cofounder and CEO. “We don’t think anybody will be building on transformers in a few years.”

Attention!

To understand why Subquadratic’s claims are a big deal, let’s dig into how most LLMs work. The key mechanism inside an LLM is a type of neural network called a transformer, which runs a process known as dense attention. Today’s LLMs typically chain together multiple transformers. (The foundational paper of the LLM era, published by researchers at Google in 2017, was titled “Attention Is All You Need.”)

Dense attention works like this: When a transformer processes a chunk of text, it first encodes each word (or part of a word, known as a token) with a number. To capture the meaning of the full text, it then multiplies each of those numbers with every other number for that text. For example, a piece of text 10,000 words long would kick off almost 50 million individual multiplications. That’s a lot of computation and the main reason that LLMs are notorious power hogs.

“If you want to summarize The Great Gatsby, you have to look at the first word and the last word together, and then you have to look at every other combination,” says Dangel.

As the length of the text increases, the number of computations skyrockets. That’s because each additional number must be multiplied by all other previous numbers. Double the number of words, and you roughly quadruple the number of computations, a rate of increase known as a quadratic expansion.

(You can picture this yourself: Draw a circle and mark dots around its edge. Each dot is a token. Then draw lines between pairs of dots to represent the multiplication of those two tokens. A circle with five dots will have 10 lines crossing it. Make it 10 dots and you will have 45 lines, 20 dots and you will have 190 lines, and so on.)

Slashing costs

Subquadratic’s solution is to ditch dense attention, the core operation of a transformer, in favor of what’s known as sparse attention, which slashes the number of computations needed. Instead of multiplying the number assigned to each token by every other number, sparse attention selects just some of the numbers to multiply. The idea is that not all relationships between words in a piece of text matter.

“Sparse attention says not all of those relationships are important, because they’re not,” says Whedon. “If you’re reading a book, you’re not going to look at the first and second words, first and third—that’s insane.”

It’s a simple approach, and Subquadratic is not the first to try it. “Pretty much everything under the sun has been attempted,” says Will Depue, an independent AI researcher who previously worked at OpenAI. “It’s not impossible, but it’s akin to running a four-minute mile.”

Previous techniques for selecting which numbers to multiply and which to ignore have not produced a mechanism that can capture the meaning of a document as well as dense attention can.

Subquadratic claims to have cracked the problem at last. It pitches SubQ as the first sparse-attention LLM that rivals mainstream dense-attention models in performance.

“Historically, most mechanisms have used fixed patterns, like always comparing the first word to the fifth,” says Whedon. “That’s pretty limiting. Language is too sophisticated for that. And so, one of the things that makes our mechanism unique is that we dynamically select which ones are important.”

The firm won’t say exactly how SubQ chooses which words to focus on, but the selection is calculated on the fly and differs for each piece of text the model is given. “That’s kind of where the secret sauce is,” says Whedon.

Testing, testing

The upshot is that for certain tasks, SubQ may be faster and cheaper to run than most other models. Appen evaluated SubQ on a handful of standard tests. In a straight-up speed test, which sets a baseline for how fast a model can operate in theory rather than assess what a model can actually do, Appen found that SubQ was 56 times faster than models using FlashAttention, a previous sparse-attention technique. 

On LiveCodeBench, a test that looks at how well models perform on competitive coding problems taken from real contests, SubQ scored 89.7%, putting it in the same ballpark as other top coding models. “This model continues to provide frontier-level performance in coding,” says Appen’s Sinanan-Singh.

Subquadratic’s claims about cost are harder to verify because SubQ is not yet widely available. According to Dangel, it costs $2600 to run Anthropic’s LLM Opus 4.6 through RULER 128, a test developed by Nvidia to assess a model’s ability to retrieve information from large data sets. And SubQ? “It cost us eight dollars,” he says.

SubQ does seem to be able to handle very large data sets. The model has a context window (roughly akin to a working memory) up to 12 million tokens long. Most top models today have context windows one million tokens long. In a demo that Whedon ran for me, he asked SubQ to perform a task that required it to reason about information contained in 400 documents. It responded in seconds. When he gave Perplexity—a popular LLM-powered search engine—the same task, it failed to load all 400 documents. 

Appen also ran the needle-in-a-haystack test, which assesses how well a model can retrieve specific information buried in a large amount of data. In its report, Appen states that SubQ scored 98% with context windows six million and 12 million tokens long, “sustaining near-perfect long-context retrieval at scales few models are tested at.”

Too good to be true?

Despite the high scores, benchmarks paint an incomplete picture of what a model can and cannot do. Testing under very specific conditions is not a substitute for running a model on a wide range of real tasks.

Subquadratic is offering SubQ as a model tailored to coding and to searching very large data sets. It says that tens of thousands of potential users have already signed up for early access, including more than 500 enterprise customers. But there’s a long waitlist, and the firm has given very few people access so far. Subquadratic’s response is that it is a new, small company with limited resources and cannot serve too many people at once.

Until more people get their hands on the model and try it out for themselves, some skepticism is justified. One nagging issue is that Subquadratic reused the weights (values set within a model during training that determine how it will behave) from a version of the Chinese open-source model Qwen to bootstrap SubQ, rather than training it from scratch. That’s a common thing for model makers to do, but it cuts across Subquadratic’s claim that it has fully reinvented how LLMs work.  

“They may have built something real and useful,” says Depue. “But the public evidence does not yet justify the stronger claim that they have solved the quadratic attention bottleneck.”

In the meantime, Subquadratic cofounder Whedon insists that making something different was his only option. If you want to build a competitive model, you have to have new ideas, he says: “We’re more up against it than OpenAI is.”

New hope in treating Huntington’s disease and a report card on RFK Jr.’s promises

On this week’s episode of “The Readout LOUD”: New hope for people living with Huntington’s disease, and a report card on RFK Jr.’s effort to remake health in America. 

The Food and Drug Administration reversed its opposition to a closely watched gene therapy for Huntington’s disease, clearing a path for its maker, the biotech company UniQure, to file for U.S. approval. Joining us to discuss this new development and what it means for the Huntington’s community is Lauren Holder, a Huntington’s disease advocate who is living with the early stages of the disease. 

Read the rest…

Historic Biotech IPO, Merck, Protillion’s AI Deal, Testing a Lassa–Rabies Vaccine

We are still talking about big pharma deals and biotech fundraising in this episode. The big news this week was Parabilis Medicines’s history-making IPO. We dive into the drug developer’s plans for the eye-popping $770.5 million that it raised. Next, we discuss the details of a collaboration between Merck and Protillion Biosciences to use artificial intelligence to discover multiple therapeutic candidates. Turning to some newly published research, we discuss the early results of a first-in-human clinical trial that is testing a dual vaccine against Lassa fever and rabies, a CRISPR system engineered to selectively trigger cancer cell death by chromatin shredding, and a novel mRNA delivery platform for delivering gene therapies starting with Duchenne muscular dystrophy.

 

 

Listed below are links to the GEN stories referenced in this episode of Touching Base:

StockWatch: Parabilis Medicines Makes Wall Street History with $770.5M IPO
By Alex Philippidis, GEN Edge, June 14, 2026

Merck, Protillion Launch AI Drug Discovery Collaboration with Up-to-$510M in Milestone Payments
By Alex Philippidis, GEN Edge, June 16, 2026

First-in-Human Trial Reports Promising Dual Lassa–Rabies Vaccine Data
GEN, June 9, 2026

CRISPR Shreds Undruggable Cancer Cells with Precision
By Fay Lin, PhD, GEN Edge, June 8, 2026

New mRNA Delivery Platform Restores Muscle Function in DMD Models
GEN, June 11, 2026

Touching Base Podcast
Hosted by Corinna Singleman, PhD

Behind the Breakthroughs
Hosted by Jonathan D. Grinstein, PhD

The post Historic Biotech IPO, Merck, Protillion’s AI Deal, Testing a Lassa–Rabies Vaccine appeared first on GEN – Genetic Engineering and Biotechnology News.

China Sets Framework for Advanced Therapeutic Development

China’s Order 818—Regulations on the Administration of Clinical Research and Clinical Translation and Application of Biomedical New Technologies—establishes a new commercialization pathway for cell and gene therapeutics, gene editing, and other advanced therapeutics. More importantly, it signals China’s intent to accelerate local innovation and standardize the drug development environment, thereby becoming a more important player in advanced therapy development and manufacturing.

Order 818 allows therapeutics whose mechanisms of action are at the cellular or molecular level to be clinically translated at 3A hospitals (tertiary care hospitals, of which there are approximately 1,700) without requiring National Medical Products Administration (NMPA) drug registration. Once translational approval is granted, hospitals may begin charging patients for these treatments.

A good move

While the move appears to be viewed positively by the biopharma industry, some details are still being ironed out. For example, boundary delineation guidelines still need to be issued to specify which technologies fall under Order 818 and which remain under the NMPA’s purview. Interpretations of the order generally suggest that therapies intended for mass manufacturing and wide distribution will be governed by the NMPA, while personalized therapeutics may use the Order 818 pathway.

“We definitely see this as a positive signal,” Boyang Wang, founder of Singapore-based global longevity fund Immortal Dragons, tells GEN. Because advanced therapeutics are intricate and often personalized, it’s quite difficult for them to use the standard NMPA pathway. Before Order 818 was enacted on May 1, “biomedical companies in China would initiate investigator-initiated trials and partner with any training medical institution of their choice.”

Order 818 provides a standardized structure that ensures only hospitals capable of advanced therapy development are involved. It also provides a one-to-five-year risk observation window before the technology can shift from the tech track to a drug track, Wang says. That effectively provides a level of Chinese exclusivity before the therapeutic developer can file for approval with regulators outside China.

Ramifications

For international firms partnering with Chinese companies to develop advanced therapeutics, the new regulatory pathway mainly triggers a review of existing contracts and milestone clauses.

The greatest disruption may be for Chinese companies that are in the midst of investigator-initiated trials for advanced therapies at smaller institutions. This affects contract research and manufacturing organizations, too, who are producing materials, such as stem cells, for investigator-initiated trials.

lab researchers
Boundary guidelines are pending, but Order 818 is expected to cover personalized therapies, while mass-market products remain under NMPA oversight. [STAP/Getty Images]

Speaking to GEN, Todd Liao, partner at Morgan Lewis & Bockius’s Singapore office, emphasizes the need for foreign companies invested in China to review their contracts.

“Legacy agreements were written for a single-pathway world that no longer fully describes the Chinese landscape. If milestones are defined solely by NMPA events, a licensee commercializing [a therapeutic] through hospitals may never trigger them.” The solution, he says, “is to redefine milestones around clinical and commercial outcomes [such as] ‘first fee-paying patient’ rather than ‘first NMPA-approved commercial sale.’”

Liao says he expects “a wave of proactive contract amendments. It becomes contentious only if ignored.” Any disputes, he adds, will most likely be tried internationally rather than in Chinese courts.

To succeed under this dual-pathway system, Liao advises multinational corporations to define success by what happens in the clinic and the market, not the regulatory pathway. Therefore, he says:

  • Use pathway-agnostic milestone language
  • Require the Chinese partner to notify you before selecting the translation pathway so you can assess the global intellectual property (IP) and data implications
  • Address human genetic resources’ joint IP requirements upfront to maintain global commercial control

“The overall regulatory direction is actually loosening, not tightening,” Liao says, citing new, “centralized oversight for clinical research and clinical transformation applications of biomedical new technologies.”

As he elaborates, “Notably, on May 8, 2026, the National Health Commission released a consultation draft that proposes to exclude pure clinical data, imaging data, and protein data from human genetic resources restrictions entirely, limiting the scope to nucleic acid sequence data only. It also introduces same-day filing confirmations for international clinical trials.”

Unless and until that proposal is enacted, export controls for Chinese human genetic resources remain strict, which may affect data-sharing arrangements for non-Chinese companies seeking to license or acquire Chinese cell and gene therapies. Basically, under current laws, Wang says, human genetic resource data “can never leave Chinese soil.” Analyses based on that data may be less restricted, and the differences can be subtle. Understandably, the close collaborations with 3A hospitals required under Order 181 could complicate data export decisions.

pharma vials
Advanced therapies such as CAR T, cell therapy, and gene therapy require highly coordinated systems—regulatory clarity, manufacturing standards, hospital infrastructure, quality oversight, and predictable development pathways. [Zorazhuang/Getty Images]

Additionally, the applicability of Order 818 to free trade zones has not yet been specified. Currently, the 2024 Foreign Investment Negative List prohibits multinational companies from investing in China’s cell and gene therapy development at a national level. Such investment is allowed, however, within the free trade zones of Beijing, Shanghai, Guangdong, and Hainan, but only under the NMPA product registration pathway. The so-called Negative List has not yet been updated to reflect the Order 818 pathway.

“Advanced therapies such as CAR T, cell therapy, and gene therapy require highly coordinated systems—regulatory clarity, manufacturing standards, hospital infrastructure, quality oversight, and predictable development pathways,” Jeremy Levin, PhD, chairman of Ovid Therapeutics and Opthera, chairman Emeritus of BIO, and author of the recently released Biotech in the Balance: Saving a Strategic Industry in an Age of Distrust, points out. “China is clearly trying to standardize and industrialize that environment.”

“If implemented consistently, that could make China a more attractive environment for advanced therapeutics development, and potentially accelerate local innovation, manufacturing, and partnerships,” Levin says. “China intends to compete at the highest levels of biotechnology over the long term.”

While some of the points of Order 818 are being refined in terms of their interrelationships with other trade regulations, “the clear signal is that biotech, healthcare, and biomedical technologies are at the top of senior government officials’ priority list,” Wang says. “They want to develop this sector. They want investment, and they want to leverage international capital and expertise. If any of the terms of this [order] will stifle innovation development, they will likely make modifications.”

 

The post China Sets Framework for Advanced Therapeutic Development appeared first on GEN – Genetic Engineering and Biotechnology News.

Nirrin Technologies and S.T. Japan Partner on Next-Gen Protein Quantitation Tech

Nirrin Technologies appointed S.T. Japan as its exclusive distribution partner for the TALOSTM protein quantitation system in Japan. The Japanese company will purchase a TALOS demonstration system, establishing local evaluation capabilities that will allow prospective customers throughout Japan to assess the technology using their own samples and workflows.

“Japan is one of the world’s leading centers for biopharmaceutical innovation and manufacturing,” according to Bryan Hassell, PhD, CEO of Nirrin Technologies. “S.T. Japan has built a strong reputation for helping customers adopt advanced analytical technologies through deep technical expertise and exceptional support.”

TALOS is designed to replace traditional variable pathlength UV workflows with a simpler fixed-path near-infrared measurement approach, noted Hassell. By directly measuring absorption from the peptide backbone, TALOS enables rapid protein quantitation across a wide concentration range without dilution, protein-specific calibration models, extinction coefficient determination, or manual pathlength adjustment, he explained.

“TALOS represents a unique advancement in protein quantitation, enabling rapid, consistent measurements with operational simplicity. These capabilities make it particularly well-suited for modern bioprocessing workflows, from early process development through GMP manufacturing,” said Takao Nakagawa, president, S. T. Japan. “As Japan’s biopharmaceutical industry continues to expand and evolve, TALOS has the potential to make a significant impact, driving efficiencies and reducing complexity across the drug development and manufacturing continuum.”

The post Nirrin Technologies and S.T. Japan Partner on Next-Gen Protein Quantitation Tech appeared first on GEN – Genetic Engineering and Biotechnology News.

Six of the biggest health news stories today

Want to stay on top of the science and politics driving biotech today? Sign up to get our biotech newsletter in your inbox.

Good morning. There’s a lot of great reporting to share today, so be sure to read all the way through the newsletter. We won’t have a newsletter tomorrow, Juneteenth, so I’ll talk to you again on Monday.

Read the rest…

STAT+: In pancreatic cancer, Patrick Soon-Shiong makes promises he has not kept

This is the online version of Adam’s Biotech Scorecard, a subscriber-only newsletter. STAT+ subscribers can sign up here to get it delivered to their inbox.

I am entirely enthralled by the World Cup. I am watching a ton of soccer on TV. I love the Tartan Army that has invaded Boston for Scotland’s games at Gillette Stadium. Tiny Cape Verde drawing mighty Spain was incredible. Messi, 39, playing in his sixth (!) World Cup, is still the GOAT. 

And England still hasn’t played but will in a couple of hours, as I get this newsletter finished on Wednesday afternoon. Olé!

Programming note: This newsletter is taking a holiday next week but will be back in your inboxes July 2.

What Soon-Shiong says vs. what he has delivered

I’ve taken a good bit of heat (and hate) from online fans of Patrick Soon-Shiong who view the billionaire physician as a selfless scientist/entrepreneur trying to rid the world of cancer. That’s a laudable goal, of course, except Soon-Shiong’s proclamations are mostly fluff, financially self-serving and have led to FDA wrist-slapping.

A wide gap exists between what Soon-Shiong says his cancer drugs can achieve and what they actually do, based on real clinical evidence.

Pancreatic cancer is an instructive and presently relevant example. Long before Soon-Shiong became rich and famous, he treated diabetic patients with pancreas transplants and performed surgery on patients with pancreatic cancer. A desire to transform the treatment of pancreatic cancer with novel immunotherapies inspired Soon-Shiong’s “Bioshield” mission, according to his own treatise.

Continue to STAT+ to read the full story…

Geoengineering still faces major practical challenges

Solar geoengineering is often portrayed as a sort of emergency brake. Something along the lines of Pull in case of climate emergency to scatter light-reflecting particles to bounce sunlight out of the atmosphere and cool the planet.

But it might be less like a simple brake and more like a complicated, entirely unsolved puzzle.

Some researchers are starting to look into how nations or companies would go about trying to cool the planet—and there’s a lot to figure out. My colleague James Temple dug into these engineering challenges in his latest feature story. My biggest takeaway? This all might be a lot harder than I thought.

I’ll admit, I’ve always thought of geoengineering as a relatively low-tech solution. That’s partly because over the years we’ve seen some companies do their own low-cost guerrilla “experiments,” tossing balloons up into the atmosphere and claiming to have made some small dent in climate change.

But to actually actively cool the planet in a significant way, and to make sure we understand exactly what effect we’re having, there’s a lot that researchers still need to learn. 

First, there’s the problem of getting up into the atmosphere. Generally, the target for solar geoengineering efforts is the stratosphere, since the air there is drier and more stable, so particles deposited there would stay aloft and move around the planet, lowering temperatures over a wider area and for a longer time.

You can release the particles in balloons, but balloons may not go where you want them to. And at a large scale, you’d be leaving a lot of litter all over the planet. That leaves aircraft, but conventional planes aren’t suited to fly around in the stratosphere. (Commercial aircraft generally fly at around 12 kilometers above the Earth’s surface, while geoengineering would require reaching roughly 20 kilometers.) The air is thinner higher up, so aircraft with massive wings would probably fare better than more conventional designs.

One design, from a startup called Iris Aero, shows just how much rethinking of our current flight technologies might be needed—the plane is almost unsettling in its proportions. Its wings are so long, on a stubby little body. It reminds me of a water strider, those bugs that have super-long legs to scurry around on a pond’s surface.

And that’s just the beginning. There’s also the question of what, exactly, would be best to scatter up in the stratosphere. The idea behind geoengineering comes from volcanoes—after an eruption, sulfuric acid ends up floating around in the atmosphere, and it can temporarily cool the planet. But that chemical is sticky and would be heavy to carry, so scattering some sort of precursor to sulfuric acid would probably be better. Researchers, including some at the University of Chicago, one of the leading institutions in this field, are working to figure out the best formula. 

I’m struck by how complicated this turns out to be, and I’m also left with a big question: As research turns from modeling and simulations to the practical aspects of this incredibly controversial technology, what does it mean to be doing this work?

There are major concerns about what effects might come from large-scale attempts to cool the planet. The effects could be positive for some parts of the globe and negative for others. Established weather patterns, like the monsoon season in South Asia, could shift. There are major questions about what the governance for the use of geoengineering should look like, and who gets to decide whether to go ahead. 

Experts who champion research in geoengineering often draw a line between a desire to support learning more about the technology and a call to deploy it. Many would argue that we should understand it better, so we can make informed decisions.

But to me, there’s a clear difference between atmospheric modeling and detailed engineering work on an aircraft. If there’s public research that essentially amounts to a set of practical instructions, I can’t help but feel like it could enable any number of individual actors or nations to take geoengineering into their own hands. It also might normalize the idea of using the technology. 

Some experts shared concerns along these lines with James, arguing that the shift to practical engineering work requires more oversight. Some called research in this area dangerous.

One alternative perspective I found interesting came from Shuchi Talati, executive director of the nonprofit Alliance for Just Deliberation on Solar Geoengineering.

Rather than further practical research making a slippery slope slipperier, it could have the opposite effect, she told James. “The actual practice of R&D will be a sticky slope, because there will be more real-world problems that come up that we haven’t even thought of yet,” she says. Engineering research could challenge the “idealized notions” of how easy the technology would actually be, she adds.

It’s hard to argue against better understanding potential tools to address climate change. But if we draw a map towards a potential future, it might become difficult to control who follows it. 

This article is from The Spark, MIT Technology Review’s weekly climate newsletter. To receive it in your inbox every Wednesday, sign up here. 

Personalized Cartilage Graft Developed for Life-Threatening Infant Airway Narrowing

A study led by researchers at Children’s Hospital of Philadelphia (CHOP) demonstrated a new method of using decellularized cartilage with patient-specific cells to help enlarge the pediatric airways narrowed as a result of severe subglottic stenosis (SGS). The condition is a narrowing of the airway below the vocal cords and above the trachea, and affects an estimated 20,000 infants per year.

Researchers demonstrated in a preclinical model that this new method of airway reconstruction was faster, more effective, and able to overcome issues, such as donor site morbidity, insufficient tissue volume and delayed timeline, associated with the current standard grafts used for laryngotracheal reconstruction (LTR).

Riccardo Gottardi, PhD, assistant professor with the Perelman School of Medicine at the University of Pennsylvania and leader of the Bioengineering and Biomaterials (Bio2) lab, and Ian Jacobs, MD, medical director of the Center for Pediatric Airway Disorders in the Division of Otolaryngology (ENT) at CHOP, co-led the research, which is reported in Nature Communications, in a paper titled “A translational approach to airway reconstruction leveraging decellularized meniscus and cartilage progenitor cells.” In their paper the team said, “This technology has the potential to revolutionize the field of pediatric LTR.”

Severe subglottic stenosis (SGS) develops in children almost exclusively as a response to intubation, and affects nearly 1.5% of the over 200,000 infants in intensive care units each year in the United States, the authors explained. The most severe cases require laryngotracheal reconstruction (LTR), an open airway surgery that is used to enlarge the airway by implanting cartilage taken from a rib cage. While LTR is used to successfully treat thousands of children with subglottic stenosis, in many cases, young children often lack enough costal cartilage—the cartilage connecting our ribs to the sternum—for these grafts.

As a result, operations often need to be delayed, leaving the child attached to a tracheostomy tube until they are older and grown enough to supply sufficiently sized cartilage for an effective LTR, and there is a higher risk of needing follow-up surgery because the airway is at risk of narrowing again. “In adults, LTR has a 90% success rate with low rates of revision,” the team stated. “However, in children, success rates significantly drop, and the incidence of restenosis requiring revision surgery increases to over 24%.”

To improve this process and reduce the risk of these potential complications, Gottardi and Jacobs and colleagues have been looking at tissue engineering a laryngotracheal graft. Tissue engineering, the team wrote, could provide “an ideal alternative to autologous cartilage grafts to alleviate unnecessary comorbidities as well as reduce surgical time.” However, the complexity of the trachea prevents the use of conventional cartilage engineering techniques for this procedure.

“We needed something that could be equivalent to a piece of cartilage, integrate well with the surrounding tissue, be well tolerated by the patient, behave like native tissues and regrow and be part of the airway,” Gottardi said. “This required quite a bit of creative thinking because of the additional challenges in children who are so small and still growing.”

To overcome the limitations of existing methods, the researchers, led by former Gottardi lab member Paul Gehret, PhD, created a first-of-its-kind scaffold based on porcine meniscal cartilage decellularization (MEND – MENiscus Decellularization). They realized that if the cells, elastin, and blood vessels present in the meniscus are “digested” away, the meniscal cartilage becomes amenable to recellularization and integration while being less likely to provoke an immune response. In their paper the researchers explained, “Building on the strengths of previous decellularized therapies, we established an innovative approach that leverages the selective enzymatic removal of the elastin fibers and blood vessels uniquely present in the fibro-elastic cartilage of the meniscus to create microchannels, which support cellular invasion while substantially preserving native structure.”

Using ear-derived cartilage progenitor cells (eCPCs), which can mature into cartilage-producing chondrocytes, the researchers demonstrated that MEND can be recellularized after the removal of elastin and blood vessels and suitable for implantation in less than a month. “Notably, porcine menisci, such as those used in this study, are a highly abundant cartilage source, being easily available as a waste product of the food industry, which can ensure no shortage of material for surgeons to shape into an ideal implant,” the team noted.

Importantly, the new method needed to work in a clinically relevant timeframe. In a real-world scenario, clinicians may only have one or two months to be able to perform the procedure when it can still benefit the patient. Harvesting seed cells within days and creating a scaffold within three to four weeks is significantly less time than the six months that was typically needed for engineered cartilage. “Here we demonstrate that MEND can be fully recellularized in three days with ear-derived cartilage progenitor cells and reaches structural and functional maturation suitable for implant within three weeks of chondrogenic differentiation, a time frame compatible with clinical translation,” the authors stated.

They validated their technology in a preclinical rabbit in vivo model, and demonstrated better performance than costal cartilage, the standard of care, with no instances of adverse events reported. “Our results demonstrate airway expansion, graft reepithelialization, neocartilage formation, and integration with adjacent native laryngotracheal cartilage at three months,” the team stated. “Notably, MEND implants perform better in all outcomes than autologous costal cartilage, the standard of care.”

These findings will be further validated prior to proposing the procedure for patients suffering from severe subglottic stenosis. “These results demonstrate the feasibility of our translational tissue engineering approach to laryngotracheal reconstruction and could overcome the autograft-associated limitations in pediatric patients, decreasing the need for invasive revision surgery,” the investigators concluded.

“This research shows really promising data that suggests this novel approach could overcome the autograft-associated limitations we sometimes encounter when attempting laryngotracheal reconstruction in infants,” Jacobs said. “With more research, we expect this could decrease the need for invasive surgery, and we may be able to apply the technology to other conditions that require a cartilage graft.”

The post Personalized Cartilage Graft Developed for Life-Threatening Infant Airway Narrowing appeared first on GEN – Genetic Engineering and Biotechnology News.