The technique allows the stem cells applied to break sites to experience some mechanical stress, as they do in developing embryos. These forces may help encourage stem cells to differentiate into cartilage and bone, as well as encourage other cells in the bone to regenerate.

Their findings are reported in the journal Science Translational Medicine.

Stem cells need environmental cues to differentiate into cells that make up unique tissues. Stem cells that give rise to bone and cartilage are subject to mechanical forces during development and healing, explained Eben Alsberg, the Richard and Loan Hill Professor of Bioengineering and Orthopaedics at the University of Illinois at Chicago and a senior author on the paper.

When a bone heals, stem cells in the marrow near the break site first become cartilage cells and later bone cells -- ultimately knitting together the break. When there are large gaps between broken or deformed bones, applying additional stem cells to break sites can help bones heal faster by either actively participating in the regenerative process or stimulating bone formation by neighboring cells.

But to use stem cells for bone regeneration, they need to be delivered to the defect site and differentiate appropriately to stimulate repair.

Alsberg and colleagues developed a unique preparation of the cells that can be handled and manipulated easily for implantation and that supports the cellular differentiation events that occur in embryonic bone development.

In Alsberg's preparation, stem cells are cultured so that they link to each other to form either sheets or plugs. The preparation also contains gelatin microparticles loaded with growth factors that help the stem cells differentiate. These sheets or plugs can be manipulated and implanted and reduce the tendency for cells to drift away. Alsberg calls these materials "condensates."

In previous studies, Alsberg and colleagues used condensates in a rodent model to help heal bone defects in the skull. They saw that the condensates stayed in place and were able to improve the rate and extent of bone regeneration.

More recently, Alsberg teamed up with Joel Boerckel, assistant professor of orthopedic surgery and bioengineering at Penn Medicine and a senior author on the paper, to take the idea one step further.

Boerckel has developed a unique, flexible "fixator." Fixators, as they are known to orthopedic surgeons, usually are stiff metal plates or bars that are used to stabilize bones at break sites. These kinds of fixators minimize the amount of mechanical stress breaks experience as they are healing.

Boerckel's flexible fixator would allow the cells in Alsberg's condensates to experience the compressive forces that are critical for stimulating enhanced cartilage and bone formation.

The researchers used a rat model to determine how the mechanical forces present within bone defects affected the ability of condensates to contribute to bone regeneration. When the researchers used condensate sheets together with a flexible fixator in rats with a defect in their femur, they saw that there was enhanced healing and the bones had better mechanical function compared with control rats that received condensates and stiff, traditional fixators.

"Devices and techniques we develop out of this research could also influence the way we implement physical therapy after injury," Boerckel said. "Our findings support the emerging paradigm of 'regenerative rehabilitation,' a concept that marries principles from physical therapy and regenerative medicine. Our goals are to understand how mechanical stimuli influence cell behavior to better impact patient outcomes without additional drugs or devices."

Anna McDermott, Devon Mason and Joseph Collins of the University of Pennsylvania; Samuel Herberg and Rui Tang of Case Western Reserve University; Hope Pearson and James Dawahare of the University of Notre Dame; Amit Patwa and Mark Grinstaff of Boston University, and Daniel Kelly of Trinity College Dublin are co-authors on the paper.

This research was supported by the Naughton Foundation; the Indiana Clinical and Translational Sciences Institute grant 16SDG31230034; the National Science Foundation grant 1435467; National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01 AR066193, R01 AR063194, and R01 AR069564; National Institute of Biomedical Imaging & Bioengineering grant R01 EB023907; National Institute of Dental and Craniofacial Research grant 5F32DE024712; National Heart, Lung, and Blood Institute award T3HL134622, and Ohio Biomedical Research Commercialization Program award TECG20150782.