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Researchers at the University of Nebraska Medical Center (UNMC) and University of Nebraska–Lincoln (UNL) designed a unique nanofiber-based scaffold that regenerates bone by guiding bone marrow stem cells to defects caused by trauma, surgery or osteoporosis.
“So far, we haven’t found any scaffolds that can perform better than ours,” said Jingwei Xie, Ph.D., Professor of Surgery at UNMC and Courtesy Professor of Mechanical and Materials Engineering at UNL. “The structure is the key.”
Biomaterials that promote tissue repair and regeneration on their own — without the need for cells or other therapeutics — have emerged as a potentially powerful paradigm for regenerative medicine, wrote Dr. Xie and his team of researchers in a study published in the journal Science Advances.
“Our approach shows great promise for the development of the next generation of cell- and therapeutic agent–free biomaterials for effective endogenous bone repair,” they noted.
Calculated Improvement
Dr. Xie’s research expanded on 2D nanofiber implants that are aligned to form pores, which are then filled by bone marrow stem cells to form tissue with a similar structure to nearby native bone. This standard scaffold design limits the size and organization of the pores, thereby preventing stem cells from passing through consistently enough to form new bone.
“It has been technically challenging to develop three-dimensional nanofiber scaffolds with controlled fiber alignment,” Dr. Xie said. “Previous studies reported a radially aligned nanofiber scaffold, but the thickness of the scaffold was limited to hundreds of microns.”
His lab initially developed a gas-foaming method to expand electrospun nanofiber membranes and form nanofiber sponges and foams. “That’s when we got the idea to fabricate cylinder-shaped nanofiber objects based on the gas-foaming expansion and the solids-of-revolution mathematical concept,” he said.
The math concept demonstrates that a rectangle, circle and triangle can be rotated around an axis point to form a cylinder, cone and sphere.
Dr. Xie used the concept to construct 3D scaffolds that featured larger, more organized pores that bone marrow stem cells can easily pass through to establish new bone growth. “These cylindrical scaffolds show unique radially aligned or longitudinally aligned structures,” he said.
The finding led to the development of the new scaffold’s signature radial design. Dr. Xie believed the design would cause numerous types of cells to form around an injury site and move toward the center of the scaffold.
His assumption proved correct when the research team implanted the scaffolds into divots of missing bone in the skulls of rats. The experiment was part of a study designed to explore whether a 3D scaffold made up of radially and vertically aligned nanofibers could promote and guide the formation of bone marrow stem cells.
The radial scaffolds generated bone that covered more of the divots than collagen sponges implanted in the control group of rats at four- and eight-week follow-ups.
“We found that the radially aligned nanofibers enhance bone regeneration in this scenario, especially with cranial bone,” Dr. Xie said. “During the first four weeks, we saw a significant difference. The scaffold promoted bone regeneration within a very short timeframe.”
A burr hole resulting from neurosurgery could be filled with the scaffold to speed regeneration of cranial bone, according to Dr. Xie. “The implant could also be used for repairing cranial maxillofacial injuries and long bone or spinal fusion defects,” he added.
Appealing Alternative
The implant developed by Dr. Xie and his team consists of extracellular matrix (ECM), which mimics nanofibers with controlled alignment and porosity. This design element provides nanotopographic cues to enhance the migration of osteoprogenitor and vascular progenitor cells from surrounding tissues to the bone defect.
“Our implant could potentially be loaded with various factors — including biochemical and genetic cues — to further promote new bone formation and angiogenesis,” Dr. Xie said.
The implant promoted bone regeneration without the use of sourced stem cells or growth factors, which generate healing but present stringent regulatory approval hurdles and increase the risk of side effects such as tissue inflammation or excess scar tissue formation.
The regenerated bone was dense and thick and contained the minerals, including calcium, that are needed to form healthy bone. It also grew radially in the shape of the scaffold, suggesting that its growth followed the shape of the scaffold’s pores.
It also contained higher levels of numerous growth factors — including bone morphogenetic protein 2, or BMP-2 — that stimulate bone growth and have been used in regenerative medicine techniques. Dr. Xie’s design, however, reportedly outperformed other 3D-printed scaffolds, aerogels and injectable hydrogels.
Mechanical stress tests indicated the regenerated bone could withstand compressive forces as well as healthy bone.
The implant could provide an appealing alternative to traditional allografts and autografts in practice settings, according to Dr. Xie. Treating bone defects without harvesting cells from donors or patients’ bodies through multiple surgeries is considered clinically beneficial.
Dr. Xie was surprised that an implant consisting solely of radially aligned nanofibers and without any growth factors or living cells showed a high bone regeneration efficacy.
“We could optimize the structure and composition to further improve its performance in bone regeneration,” he said. “Further, we could add biochemical and genetic cues to the implant to enhance its bone regeneration abilities.”
Planning for Approval
Dr. Xie is applying for an NIH grant to test the implant in a large animal model, and seeking industry partners to enhance and commercialize the technology. He also wants to secure sponsorship from industry partners to move the research forward with trials involving large bones such as the femur and clavicle.
He is confident the scaffold will gain regulatory clearance and said it could go down the FDA 510(k) pathway. The implant does not have loading growth factors and living cells and is made of polycaprolactone (PCL) electrospun nanofibers, a class of biomaterial already used in FDA-cleared implants and sutures. PCL fully resorbs in 18 to 24 months, a gradual and predictable profile that matches the stages of natural bone healing.
That the biodegradable implant stimulates bone growth on its own could appeal to FDA regulators — Dr. Xie plans to submit the technology for clearance in the next three to five years.
In the meantime, he and his research team are refining the scaffold’s structure. “We’re still trying to optimize its design,” he said. “It can enhance bone regeneration, but I think we still can improve it in certain ways.”
