Tag Archives: Mark T. McClendon

New approach to cartilage regeneration

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Not long after announcing their new work on cartilage and ‘dancing molecules’, Samuel I. Stupp and his team at Northwestern University (Chicago, Illinois) have announced work with a new material that does not have dancing molecules in a study using animal models. It’s here in an August 5, 02024 Northwestern University news release (also on EurekAlert and on SciTechDaily and received by email) by Amanda Morris, Note: Links have been removed,

Northwestern University scientists have developed a new bioactive material that successfully regenerated high-quality cartilage in the knee joints of a large-animal model.

Although it looks like a rubbery goo, the material is actually a complex network of molecular components, which work together to mimic cartilage’s natural environment in the body. 

In the new study, the researchers applied the material to damaged cartilage in the animals’ knee joints. Within just six months, the researchers observed evidence of enhanced repair, including the growth of new cartilage containing the natural biopolymers (collagen II and proteoglycans), which enable pain-free mechanical resilience in joints.

With more work, the researchers say the new material someday could potentially be used to prevent full knee replacement surgeries, treat degenerative diseases like osteoarthritis and repair sports-related injuries like ACL [anterior cruciate ligament] tears.

The study will be published during the week of August 5 [2024] in the Proceedings of the National Academy of Sciences.

“Cartilage is a critical component in our joints,” said Northwestern’s Samuel I. Stupp, who led the study. “When cartilage becomes damaged or breaks down over time, it can have a great impact on people’s overall health and mobility. The problem is that, in adult humans, cartilage does not have an inherent ability to heal. Our new therapy can induce repair in a tissue that does not naturally regenerate. We think our treatment could help address a serious, unmet clinical need.”

A pioneer of regenerative nanomedicine, Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology and its affiliated center, the Center for Regenerative Nanomedicine. Stupp has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine. Jacob Lewis, a former Ph.D. student in Stupp’s laboratory, is the paper’s first author.

What’s in the material?

The new study follows recently published work from the Stupp laboratory, in which the team used “dancing molecules” to activate human cartilage cells to boost the production of proteins that build the tissue matrix. Instead of using dancing molecules, the new study evaluates a hybrid biomaterial also developed in Stupp’s lab. The new biomaterial comprises two components: a bioactive peptide that binds to transforming growth factor beta-1 (TGFb-1) — an essential protein for cartilage growth and maintenance — and modified hyaluronic acid, a natural polysaccharide present in cartilage and the lubricating synovial fluid in joints. 

“Many people are familiar with hyaluronic acid because it’s a popular ingredient in skincare products,” Stupp said. “It’s also naturally found in many tissues throughout the human body, including the joints and brain. We chose it because it resembles the natural polymers found in cartilage.”

Stupp’s team integrated the bioactive peptide and chemically modified hyaluronic acid particles to drive the self-organization of nanoscale fibers into bundles that mimic the natural architecture of cartilage. The goal was to create an attractive scaffold for the body’s own cells to regenerate cartilage tissue. Using bioactive signals in the nanoscale fibers, the material encourages cartilage repair by the cells, which populate the scaffold.

Clinically relevant to humans

To evaluate the material’s effectiveness in promoting cartilage growth, the researchers tested it in sheep with cartilage defects in the stifle joint, a complex joint in the hind limbs similar to the human knee. This work was carried out in the laboratory of Mark Markel in the School of Veterinary Medicine at the University of Wisconsin–Madison. 

According to Stupp, testing in a sheep model was vital. Much like humans, sheep cartilage is stubborn and incredibly difficult to regenerate. Sheep stifles and human knees also have similarities in weight bearing, size and mechanical loads.

“A study on a sheep model is more predictive of how the treatment will work in humans,” Stupp said. “In other smaller animals, cartilage regeneration occurs much more readily.”

In the study, researchers injected the thick, paste-like material into cartilage defects, where it transformed into a rubbery matrix. Not only did new cartilage grow to fill the defect as the scaffold degraded, but the repaired tissue was consistently higher quality compared to the control.

A lasting solution

In the future, Stupp imagines the new material could be applied to joints during open-joint or arthroscopic surgeries. The current standard of care is microfracture surgery, during which surgeons create tiny fractures in the underlying bone to induce new cartilage growth.

“The main issue with the microfracture approach is that it often results in the formation of fibrocartilage — the same cartilage in our ears — as opposed to hyaline cartilage, which is the one we need to have functional joints,” Stupp said. “By regenerating hyaline cartilage, our approach should be more resistant to wear and tear, fixing the problem of poor mobility and joint pain for the long term while also avoiding the need for joint reconstruction with large pieces of hardware.”

The study, “A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model,” was supported by the Mike and Mary Sue Shannon Family Fund for Bio-Inspired and Bioactive Materials Systems for Musculoskeletal Regeneration.

Here’s a link to and a citation for the paper,

A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model by Jacob A. Lewis, Brett Nemke, Yan Lu, Nicholas A. Sather, Mark T. McClendon, Michael Mullen, Shelby C. Yuan, Sudheer K. Ravuri, Jason A. Bleedorn, Marc J. Philippon, Johnny Huard, Mark D. Markel, and Samuel I. Stupp. Proceedings ot the National Academy of Sciences (PNAS) 121 (33) e2405454121 DOI: https://doi.org/10.1073/pnas.2405454121 August 6, 2024

This paper is behind a paywall.

Sugar in your bones might be better for you than you think

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These days sugar is often  viewed as leading to health problems but there is an instance where it may be useful—bone regeneration. From a June 19, 2017 news item on Nanowerk (Note: A link has been removed),

There hasn’t been a gold standard for how orthopaedic spine surgeons promote new bone growth in patients, but now Northwestern University scientists have designed a bioactive nanomaterial that is so good at stimulating bone regeneration it could become the method surgeons prefer.

While studied in an animal model of spinal fusion, the method for promoting new bone growth could translate readily to humans, the researchers say, where an aging but active population in the U.S. is increasingly receiving this surgery to treat pain due to disc degeneration, trauma and other back problems. Many other procedures could benefit from the nanomaterial, ranging from repair of bone trauma to treatment of bone cancer to bone growth for dental implants.

“Regenerative medicine can improve quality of life by offering less invasive and more successful approaches to promoting bone growth,” said Samuel I. Stupp, who developed the new nanomaterial. “Our method is very flexible and could be adapted for the regeneration of other tissues, including muscle, tendons and cartilage.”

Stupp is director of Northwestern’s Simpson Querrey Institute for BioNanotechnology and the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering.

For the interdisciplinary study, Stupp collaborated with Dr. Wellington K. Hsu, associate professor of orthopaedic surgery, and Erin L. K. Hsu, research assistant professor of orthopaedic surgery, both at Northwestern University Feinberg School of Medicine. The husband-and-wife team is working to improve clinically employed methods of bone regeneration.

Sugar molecules on the surface of the nanomaterial provide its regenerative power. The researchers studied in vivo the effect of the “sugar-coated” nanomaterial on the activity of a clinically used growth factor, called bone morphogenetic protein 2 (BMP-2). They found the amount of protein needed for a successful spinal fusion was reduced to an unprecedented level: 100 times less of BMP-2 was needed. This is very good news, because the growth factor is known to cause dangerous side effects when used in the amounts required to regenerate high-quality bone, and it is expensive as well.

A June 19, 2017 Northwestern University news release by Megan Fellman, which originated the news item, tells the rest of the story,

Stupp’s biodegradable nanomaterial functions as an artificial extracellular matrix, which mimics what cells in the body usually interact with in their surroundings. BMP-2 activates certain types of stem cells and signals them to become bone cells. The Northwestern matrix, which consists of tiny nanoscale filaments, binds the protein by molecular design in the way that natural sugars bind it in our bodies and then slowly releases it when needed, instead of in one early burst, which can contribute to side effects.

To create the nanostructures, the research team led by Stupp synthesized a specific type of sugar that closely resembles those used by nature to activate BMP-2 when cell signaling is necessary for bone growth. Rapidly moving flexible sugar molecules displayed on the surface of the nanostructures “grab” the protein in a specific spot that is precisely the same one used in biological systems when it is time to deploy the signal. This potentiates the bone-growing signals to a surprising level that surpasses even the naturally occurring sugar polymers in our bodies.

In nature, the sugar polymers are known as sulfated polysaccharides, which have super-complex structures impossible to synthesize at the present time with chemical techniques. Hundreds of proteins in biological systems are known to have specific domains to bind these sugar polymers in order to activate signals. Such proteins include those involved in the growth of blood vessels, cell recruitment and cell proliferation, all very important biologically in tissue regeneration. Therefore, the approach of the Stupp team could be extended to other regenerative targets.

Spinal fusion is a common surgical procedure that joins adjacent vertebra together using a bone graft and growth factors to promote new bone growth, which stabilizes the spine. The bone used in the graft can come from the patient’s pelvis — an invasive procedure — or from a bone bank.

“There is a real need for a clinically efficacious, safe and cost-effective way to form bone,” said Wellington Hsu, a spine surgeon. “The success of this nanomaterial makes me excited that every spine surgeon may one day subscribe to this method for bone graft. Right now, if you poll an audience of spine surgeons, you will get 15 to 20 different answers on what they use for bone graft. We need to standardize choice and improve patient outcomes.”

In the in vivo portion of the study, the nanomaterial was delivered to the spine using a collagen sponge. This is the way surgeons currently deliver BMP-2 clinically to promote bone growth.

The Northwestern research team plans to seek approval from the Food and Drug Administration to launch a clinical trial studying the nanomaterial for bone regeneration in humans.

“We surgeons are looking for optimal carriers for growth factors and cells,” Wellington Hsu said. “With its numerous binding sites, the long filaments of this new nanomaterial is more successful than existing carriers in releasing the growth factor when the body is ready. Timing is critical for success in bone regeneration.”

In the new nanomaterial, the sugars are displayed in a scaffold built from self-assembling molecules known as peptide amphiphiles, first developed by Stupp 15 years ago. These synthetic molecules have been essential in his work on regenerative medicine.

“We focused on bone regeneration to demonstrate the power of the sugar nanostructure to provide a big signaling boost,” Stupp said. “With small design changes, the method could be used with other growth factors for the regeneration of all kinds of tissues. One day we may be able to fully do away with the use of growth factors made by recombinant biotechnology and instead empower the natural ones in our bodies.”

Here’s a link to and a citation for the paper,

Sulfated glycopeptide nanostructures for multipotent protein activation by Sungsoo S. Lee, Timmy Fyrner, Feng Chen, Zaida Álvarez, Eduard Sleep, Danielle S. Chun, Joseph A. Weiner, Ralph W. Cook, Ryan D. Freshman, Michael S. Schallmo, Karina M. Katchko, Andrew D. Schneider, Justin T. Smith, Chawon Yun, Gurmit Singh, Sohaib Z. Hashmi, Mark T. McClendon, Zhilin Yu, Stuart R. Stock, Wellington K. Hsu, Erin L. Hsu, & Samuel I. Stupp. Nature Nanotechnology 12, 821–829 (2017) doi:10.1038/nnano.2017.109 Published online 19 June 2017

This paper is behind a paywall.