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Researchers awarded $39m to develop living knee replacement



Biomedical engineers are collaborating with orthopaedic surgeons to build a living replacement knee which could be tested in clinical trials within the next five years.

A team of researchers from Columbia University Irving Medical Center (CUIMC) and Columbia Engineering has been awarded up to a $38.95 million contract from the Advanced Research Projects Agency for Health (ARPA-H) to build a living knee replacement from biomaterials and human stem cells, including a patient’s own cells.

ARPA-H is a federal funding agency that funds transformative biomedical and health research breakthroughs, rapidly translating research from the lab to applications in the marketplace.

The award, part of the ARPA-H’s Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO) program, will support the development of NOVAJoint, a revolutionary biocompatible, low-cost, patient-specific knee joint replacement.

This high-risk project builds upon more than two decades of collaborative musculoskeletal research at Columbia in engineering and medicine, and promises to offer a transformative solution for the more than 30 million people in the US who suffer from osteoarthritis. NITRO is the first Health Science Futures specific program under the new ARPA-H agency, established by the Biden Administration.

“ARPA-H is a hugely important endeavor that could bring about a breakthrough in personalised and patient-specific solutions,” said Shih-Fu Chang, Dean of Columbia Engineering.

“As society seeks to address the challenge of population aging, such collaborative approaches combining engineering and medicine will help improve conditions for those with osteoarthritis and many other musculoskeletal conditions.”

“We saw during the COVID pandemic just how fast science can move when teams of researchers are given the support and resources to work together,” said Katrina Armstrong, Dean of the Faculties of Health Sciences and the Vagelos College of Physicians and Surgeons, and Executive Vice President for Health and Biomedical Sciences, Columbia University.

“By focusing Columbia’s expertise in biomedical engineering and orthopaedic surgery onto a single goal, this funding from ARPA-H has the potential to rapidly revolutionize the way we treat osteoarthritis and the way we do biomedical research in the future.”

Impact of osteoarthritis

Osteoarthritis is a degenerative joint disease that is the most common type of arthritis. It gradually worsens over time as cartilage, the specialised connective tissue that covers the ends of bones, wears down, leading to pain, stiffness, and loss of mobility.

Osteoarthritis is already the third most common type of disability and has an estimated economic burden of more than $136 billion per year. It disproportionately affects women, the elderly, certain racial/ethnic minorities, and those with lower socioeconomic status. The prevalence of knee osteoarthritis has been rising due to aging of the population, increasing rates of joint injury, and, significantly, obesity.

The clinical gold standard treatment for knee joints ravaged by pervasive OA or traumatic injury is a total joint replacement using prosthetic implants made of metal and plastic. Although knee replacement is widely successful, there are some major drawbacks to these conventional materials.

There can be life-changing complications and limitations of current artificial knee replacements, including infection, loosening, hardware failure, stiffness, abnormal kinematics (i.e., the way a knee moves), instability, and persistent pain.

Historically, knee replacements have had a limited lifespan with a portion failing at 15 to 20 years due to plastic wear or implant loosening. This means that younger patients may need one or even two revision implants. The demand for total knee replacements is projected to grow by 673 per cent—3.48 million procedures from 2005 to 2030 —with total knee revisions projected to grow 601 per cent between 2005 to 2030.

NOVAJoint — a living solution to ravaged knees

With the ARPA-H award, the researchers propose to design NOVAJoint to address the urgent, unmet clinical need for a permanent solution for patients with advanced OA where a conventional knee replacement is indicated.

The project’s goal is to develop a replacement knee of regenerated living cartilage and bone that integrates seamlessly with the native bone and restores pain-free joint function. Since cells are required to regenerate and maintain this living implant, the team will create two versions of NOVAJoint: a version that uses patient’s own cells and one that uses donor cells.

The researchers expect NOVAJoint to substantially extend the implant life, reducing complications, and to become a permanent and final procedure for the treatment of osteoarthritis of the knee.  With an aggressive timeline, in the first two years, the team will create the first prototypes before moving into preclinical and clinical studies in the final three years, including a Phase 1 safety clinical trial in the final year.

Though the first NOVAJoint is still in development, many of the technologies and scientific discoveries necessary to create the joint have already been developed and validated by Columbia researchers through funding from the National Institutes of Health, National Science Foundation, Department of Defense, and institutional support.

Clark T. Hung, a groundbreaking researcher in musculoskeletal regeneration, who is leading the project, said: “The ARPA-H NITRO program has enabled us to leverage our innovative technologies and expertise to solve one of the most difficult challenges in biomedical engineering,”

The project is led by Clark T. Hung, Professor and Vice Chair of the Department of Biomedical Engineering and Professor of Orthopedic Science (in Orthopedic Surgery) at Columbia Engineering, and Nadeen O. Chahine, Associate Professor of Biomedical Engineering in the Department of Orthopedic Surgery at Columbia University Vagelos College of Physicians and Surgeons, leaders in tissue regeneration and orthopedic research.

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ChatGPT shows promise as medication management tool



Researchers have found that ChatGPT may hold promise as a tool to manage medication and polypharmacy—which could be particularly helpful in the care of older adults.

Polypharmacy, or the concurrent use of five or more medications, is common in older adults and increases the risk of adverse drug interactions. While de-prescribing unnecessary drugs can combat this risk, the decision-making process can be complex and time-consuming. Increasingly, there is a need for effective polypharmacy management tools that can support short-staffed primary care practitioners.

In a new study, researchers from the Mass General Brigham MESH Incubator found that ChatGPT, a generative artificial intelligence (AI) chatbot, showed promise as a tool to manage polypharmacy and de-prescription. The findings, published in the Journal of Medical Systems, demonstrate the first use case of AI models in medicine management.

To evaluate its utility, the investigators provided ChatGPT with different clinical scenarios and asked it a set of decision-making questions. Each scenario featured the same elderly patient taking a mixture of medications but included variations in cardiovascular disease history (CVD) and degree of impairment in activities of daily living (ADL).

When asked yes or no questions about reducing prescribed drugs, ChatGPT consistently recommended deprescribing medications in patients without a history of CVD. However, it was more cautious when overlying CVD was introduced, and more likely to keep the patient’s medication regimen unchanged. In both cases, the researchers observed that ADL impairment severity did not seem to affect decision outcomes.

The team also noted that ChatGPT had a tendency to disregard pain and favoured de-prescribing pain medications over other drug types like statins or antihypertensives. In addition, ChatGPT responses varied when presented with the same scenario in new chat sessions — which the authors suggest could reflect inconsistency in commonly reported clinical deprescribing trends on which the model was trained.

More than 40 per cent of older adults meet the criteria for polypharmacy. The rate of seniors on Medicare seeing more specialists on their care teams has increased in recent years, leaving primary care providers to oversee medication management. An effective AI tool could help aid this practice, according to the researchers.

“Our study provides the first use case of ChatGPT as a clinical support tool for medication management,” said senior corresponding author Marc Succi, MD, Associate Chair of Innovation and Commercialization at Mass General Brigham Radiology and Executive Director of the MESH Incubator.

“While caution should be taken to increase accuracy of such models, AI-assisted polypharmacy management could help alleviate the increasing burden on general practitioners. Further research with specifically trained AI tools may significantly enhance the care of aging patients.”

Arya Rao, lead author, MESH researcher and Harvard Medical student, added: “Our findings suggest that AI-based tools can play an important role in ensuring safe medication practices for older adults; it is imperative that we continue to refine these tools to account for the complexities of medical decision-making.”

Read more in the Journal of Medical Systems.

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Ageing fight revealed in new ‘muscle map’



The first comprehensive cell atlas of ageing human muscle reveals the intricate genetic and cellular processes behind muscle deterioration and mechanisms to counteract it.

How muscle changes with ageing, and tries to fight its effects, is now better understood at the cellular and molecular level with the first comprehensive atlas of ageing muscles in humans.

Researchers from the Wellcome Sanger Institute and their collaborators at Sun Yat-sen University, China applied single-cell technologies and advanced imaging to analyse human skeletal muscle samples from 17 individuals across the adult lifespan. By comparing the results, they shed new light on the many complex processes underlying age-related muscle changes.

The atlas uncovers new cell populations that may explain why some muscle fibres age faster than others. It also identifies compensatory mechanisms the muscles employ to combat ageing.

The findings offer avenues for future therapies and interventions to improve muscle health and quality of life as we age.

This study is part of the international Human Cell Atlas initiative to map every cell type in the human body, to transform understanding of health and disease.

As we age, our muscles progressively weaken. This can affect our ability to perform everyday activities like standing up and walking. For some people, muscle loss worsens, leading to falls, immobility, a loss of autonomy and a condition called sarcopenia. The reasons why our muscles weaken over time have remained poorly understood.

In this new study, scientists from the Wellcome Sanger Institute and Sun Yat-sen University, China used both single-cell and single-nucleus sequencing techniques along with advanced imaging to analyse human muscle samples from 17 individuals aged 20 to 75.

The team discovered that genes controlling ribosomes, responsible for producing proteins, were less active in muscle stem cells from aged samples. This impairs the cells’ ability to repair and regenerate muscle fibres as we age. Further, non-muscle cell populations within these skeletal muscle samples produced more of a pro-inflammatory molecule called CCL2, attracting immune cells to the muscle and exacerbating age-related muscle deterioration.

Age-related loss of a specific fast-twitch muscle fibre subtype, key for explosive muscle performance, was also observed. However, they discovered for the first time several compensatory mechanisms from the muscles appearing to make up for the loss. These included a shift in slow-twitch muscle fibres to express genes characteristic of the lost fast-twitch subtype, and increased regeneration of remaining fast-twitch fibre subtypes.

The team also identified specialised nuclei populations within the muscle fibres that help rebuild the connections between nerves and muscles that decline with age. Knockout experiments in lab-grown human muscle cells by the team confirmed the importance of these nuclei in maintaining muscle function.

Veronika Kedlian, first author of the study from the Wellcome Sanger Institute, said: “Our unbiased, multifaceted approach to studying muscle ageing, combining different types of sequencing, imaging and investigation reveals previously unknown cellular mechanisms of ageing and highlights areas for further study.”

Professor Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, China, said: “In China, the UK and other countries, we have ageing populations, but our understanding of the ageing process itself is limited. We now have a detailed view into how muscles strive to maintain function for as long as possible, despite the effects of ageing.”

Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: “Through the Human Cell Atlas, we are learning about the body in unprecedented detail, from the earliest stages of human development through to old age.With these new insights into healthy skeletal muscle ageing, researchers all over the world can now explore ways to combat inflammation, boost muscle regeneration, preserve nerve connectivity, and more. Discoveries from research like this have huge potential for developing therapeutic strategies that promote healthier ageing for future generations.”

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UK body calls for more ageing research backing



The British Society for Research on Ageing (BSRA) is calling for more public backing in the UK for research to help people stay healthier for longer, as an alternative to charities that support research on diseases.

The greatest risk factor for disease is ageing, but we have very little charitable support for research into how to slow ageing, the organisation warns.

Many diseases such as cancers and heart disease tragically shorten lives far too early, or like Alzheimer’s and arthritis, destroy quality of life for patients and carers. There is understandably huge public charitable support for more research. However, the greatest risk factor for those diseases, and even infectious diseases like COVID, is ageing.

Yet in comparison there is currently very little support for research to understand how we can slow ageing to prevent disease. This approach may be more productive in the long term to fight disease. Furthermore, keeping people healthier for longer, or avoiding chronic diseases all together, would be the most favourable outcome.

The UK population is ageing fast, putting pressure on the NHS and the economy. Despite this pressing problem all around us, there is no accessible way for people to support research into ageing in the UK. The BSRA aims to change that.

With a very small budget and almost completely run by volunteers, the BSRA has successfully funded several small research projects but progress needs to be accelerated. More funding is needed because it takes years to see the effects of ageing, so studies are long. Also ageing affects individuals in different ways, meaning that large numbers of people must be studied to make firm conclusions.

Therefore, there is an urgency to get studies funded and the BSRA has decided to launch an ambitious fundraising campaign to boost research into ageing. Initially, the Society aims to fund a series of one year research projects at the Masters degree level at universities across the UK and with plans to raise much more in the future to support longer and more ambitious projects that will impact the lives of the general public.

Chair of the BSRA, Prof David Weinkove from Durham University, says “The time is now to really get behind research into the biology of ageing. We have fantastic researchers across the country, but they are held back by a lack of funding. Evidence-based research is needed to understand how we people can stay healthier for longer, and to then we must make that knowledge available to as many people as possible”.

Dr Jed Lye says “This is a great opportunity for the public to help, for corporations to contribute, or philanthropists wanting a large impact with a relatively small donation; every £20,000 we raise can fund an entire year of research into ageing and longevity, and gets a budding scientist their research qualification.”

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