Targeted Bone Regeneration via Activation of Resident Stem Cells

Severe bone fractures constitute a complex medical condition. Between 11 and 15 million bone fractures occur in the United States each year, and up to 12% of these fractures fail to heal with currently available medical strategies. Such fractures result in frequent hospitalizations, multiple surgeries, extended pain and reduced quality of life. The lead collaborators on this project have developed a biological therapy that can regenerate bone without the need for more complex surgical procedures, such as bone grafts and bone transport. This novel therapy recruits the patient’s own stem cells to the fracture site, which are subsequently activated to induce bone regeneration. The goal of this project is to develop the preclinical data necessary to enable first-in-human clinical trials to treat severe bone fractures.

Scientific Synopsis

More than 1 million severe bone fractures each year fail to heal, resulting in non-union. Current treatments include the use of autografts or bone transport. Limitations associated with autografts — harvesting bone from elsewhere in the patient’s body for use at the site of injury — include the need for an additional surgical procedure with the associated morbidity, increased bleeding and operating room time, acute pain during the procedure, and chronic pain post-implant. Bone transport requires an external circular, modular fixator that is fixed to the broken bone via heavy-gauge wires. The fixator allows partial weight bearing while applying tension to the fractured bone, inducing gradual bone regeneration. Its disadvantages include pain, multiple surgeries, poor patient compliance, inconvenience of the frame, risk of inducing bone malalignment, and a complicated procedure for the surgeon.

An alternative approach is the use of bone morphogenetic protein (BMP) to induce bone regeneration. An existing therapy uses BMP-2, but it is used mainly for spinal surgery rather than repair of long bones. Recombinant proteins have short half-lives, requiring large doses that can lead to inflammation and other unwanted side effects. To overcome the limitations of current treatments, the lead collaborators developed a new technology, called SonoHeal, that attracts and activates endogenous tissue stem cells to regenerate bone and heal fractures. First, a biodegradable scaffold is implanted into the fracture site, which recruits the patient’s own mesenchymal stem cells (MSCs). At a second step, BMP-6 plasmid is delivered to the MSCs via sonoporation — the use of transcutaneous ultrasound to transfer plasmid DNA across the cell membrane — resulting in BMP-6 protein expression at a physiological level to induce cell differentiation and promote the formation of new bone and fracture healing.

Lead Collaborators

Cedars-Sinai Medical Center, Los Angeles, CA
Dan Gazit, D.M.D., Ph.D.
Gadi Pelled, D.M.D., Ph.D.

Public Health Impact

More than 1 million severe bone fractures fail to heal each year in the United States, and most long bone fractures occur in people younger than 50 years of age. In addition to the chronic pain and reduced quality of life for patients, a substantial burden of related medical costs is associated with fracture repair, as well as disability and lost work productivity of the working-age population and their employers.


BrIDGs scientists have initiated a preclinical development campaign to advance the SonoHeal technology to clinical evaluation. Planned activities include development of bioanalytical methods, in vivo efficacy and biodistribution studies, manufacture and characterization of the injectable drug product, and the toxicology studies needed to support an Investigational New Drug application.