11:46am Sunday 28 May 2017

A Universal Solution for Regenerative Medicine

Revolutionary nanomaterials developed at Northwestern could make it possible to repair any part of the body.

When he came to Northwestern in 2008, Wellington Hsu, MD, was searching for a strategy to heal bone using materials science.

He turned to Samuel Stupp, PhD, director of Northwestern’s Louis A. Simpson and Kimberly K. Querrey Institute for BioNanotechnology (SQI). Stupp’s laboratory had engineered molecules able to self-assemble into nanofibers thousands of times thinner than a human hair that can mimic cell structures and biological signaling. The technology can be used to regenerate tissues and organs spanning from bone and cartilage to muscle and brain tissues. Hsu hoped it could rebuild bone in spine therapy.

“We learned we could help each other out: apply his technology to my clinical patients,” says Hsu, the Clifford C. Raisbeck, MD, Professor of Orthopaedic Surgery. “You can have the best technology in the world, but if you don’t know how to apply it or how to promote it, it can all be for naught.”

Spinal fusion is a surgery that “welds” vertebrae together in the spine so they heal into a single bone. The procedure is designed to imitate the normal healing process of broken bones and is used to eliminate pain caused by fractured bones, deformities or arthritis. During a spinal fusion procedure, a surgeon takes small pieces of bone or synthetic bone graft substitute and places them between the vertebrae to help them fuse.

While advances in technology and bone grafting substitutes have improved this process, better spine fusion rates with minimal side effects are still needed. With this in mind, Hsu and and his wife Erin Hsu, PhD, research assistant professor of Orthopaedic Surgery — both resident faculty in the SQI — sought to apply Stupp’s novel nanofibers to spinal fusion animal models.

Working together, the Stupp-Hsu team developed a new version of the nanofiber material that they believe will be a better bone graft substitute. Made from collagen and self-assembling nanofibers, their “nanoslurry” is a malleable paste that binds to the native growth factors in a patient’s own body, enhancing natural healing ability.

In challenging healing environments, this “slurry” can also deliver BMP-2, a growth factor protein critical in the regeneration of bone. The BMP-2 protein is then released over time to induce bone growth, so lower amounts of the protein are required for successful fusion, which could minimize side effects. In either iteration, this paste will allow surgeons to adapt the material to fill any size bone defect.

“We have these synthetic nanogels that we know can promote bone formation, but to work in the operating room, they have to be readily accessible and implant easily,” Erin Hsu says. “This slurry will allow the nanofiber gels to be used in a more universal fashion.”

Wellington Hsu adds, “Different applications for spine surgeries necessitate different characteristics of a product. Our collaborations can optimize the ability to define those characteristics, whether we want our product to be more soupy, or more like a toothpaste or more like a crouton.”

Next generation materials

Stupp’s research is based on supramolecular chemistry, which explores how molecules interact with each other and how they self-assemble and function. The underlying science behind the field was recognized in 1987 when Donald J. Cram, Jean-Marie Lehn and Charles J. Pedersen received the Nobel Prize in Chemistry.

Stupp spearheaded the study of “supramolecular biomaterials,” self-assembling materials that can be designed to interact specifically with cells. “What makes this field exciting is getting to use cutting-edge science — it’s new for everybody — and having an impact on lifespan and quality of life for people,” says Stupp, who is also a professor at Feinberg, the Weinberg College of Arts and Sciences, and the McCormick School of Engineering.

Stupp’s work focuses on developing materials that mimic the nanoscale architecture of extracellular matrices surrounding mammalian cells. These materials have the ability to display biological signals that can interact with receptors and cause cells to migrate, proliferate or differentiate.

The nanofibers that Stupp has engineered resemble collagen or fibronectin fibers, both structures of the extracellular matrix. They can be built from a combination of amino acids, nucleic acids, lipids and sugars, which allows them to degrade into nutrients for cells. The scientists believe they can incorporate any biological signal in these nanofibers to achieve a specific regenerative medicine target.

Cross-disciplinary team science

The ability to fine-tune the nanofibers to any target has allowed Stupp to establish collaborations across the medical school, including with John Kessler, MD, Ken and Ruth Davee Professor of Stem Cell Biology, to regenerate the nervous system in the spinal cord, and with Susan Quaggin, MD, chief of Nephrology, and Guillermo Oliver, PhD, Thomas D. Spies Professor of Lymphatic Metabolism, to target vascular regeneration.

An embryonic neural cell derived from a mouse spinal cord and cultured on a synthetic nanofiber gel is pictured on day 0 (left) and day 5 (right). By mimicking the environment of spinal cord tissue, the nanofibers (about 10nm in diameter) encouraged the neuron to re-establish a network with other cells. The material could be used to repair spinal cord injuries. Images courtesy of Mark McClendon and Zaida Pinto, PhD.

An embryonic neural cell derived from a mouse spinal cord and cultured on a synthetic nanofiber gel is pictured on day 0 (left) and day 5 (right). By mimicking the environment of spinal cord tissue, the nanofibers (about 10nm in diameter) encouraged the neuron to re-establish a network with other cells. The material could be used to repair spinal cord injuries. Images courtesy of Mark McClendon and Zaida Pinto, PhD.

“One of the projects is the great possibility of using supramolecular materials to target plaque in arteries to reverse plaque formation,” Stupp says. He’s collaborating with Shad Thaxton, ’04 MD, ’07 PhD, associate professor of Urology, and Melina Kibbe, MD, ’03 GME, adjunct professor of Surgery, on that work.

In work published in Nature Materials, his lab showed how the length of nanofibers is critical to the survival and proliferation of mammalian cells.

“The group demonstrated that cells could actually distinguish between different lengths of nanofibers even though the nanofibers were identical in their other properties,” Stupp says.

Furthermore, in a paper published in Science, Stupp’s lab developed a new type of nanofiber that combines two kinds of polymers, those formed with covalent bonds and others formed with non-covalent bonds. The strongly bonded covalent polymer acts as a skeleton for structure and the weakly bonded non-covalent polymer forms a compartment that is soft like a gel. This soft component can be altered, removed, or regenerated by adding small molecules, allowing the hybrid polymer to have different features.

“These new unprecedented materials could be used as therapeutic agents to deliver drugs to cells over long periods of time or to affect cell behavior,” he says.

Stupp’s group has also used super resolution microscopy to illustrate that nanofibers are capable of rearranging their structures dynamically and can adapt to the receptor patterns on cells. This work was recently published in Nature Communications.

A paste made of collagen and nanofibers can enhance the growth factors in bone to promote spine fusion

A paste made of collagen and nanofibers can enhance the growth factors in bone to promote spine fusion

“This particular finding implies that highly bioactive nanoscale filaments will be possible in the future to address the most difficult regenerative targets,” Stupp says.

In future work, Stupp’s group plans to develop new materials capable of displaying signals that can be turned on and off by adding certain molecules to cell cultures.

“This means that stem cells could be manipulated with one signal to promote their proliferation, and then that signal could be turned off when the cells are ready to differentiate and a new signal could be introduced for differentiation,” Stupp says.

He also plans to collaborate with Northwestern newcomer John Rogers, PhD, a materials scientist who arrived from the University of Illinois at Urbana-Champaign last September. A pioneer in the field of bio-integrated electronic devices, Rogers will lead the new Center for Bio-Integrated Electronics within the Simpson Querrey Institute for BioNanotechnology.

Stupp’s lab, with focus on self-assembled structures, complements Rogers’ research on electronic materials that integrate with the surfaces of the body.

“We sensed an area of opportunity for collaboration,” Rogers says. “With our vision to bring our two areas of expertise together, we realized we could do even more significant things in medicine.”

NORTHWESTERN UNIVERSITY


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