Ultrasound-Mediated Nanobiomaterial Delivery for Segmental Bone Fracture Repair
Abstract
Topic Area: This proposal addresses the topic area “Nanomaterials for Bone Regeneration” with the specific areas of encouragement of: (1) technologies addressing segmental/large bone defects in craniomaxillofacial and/or load-bearing regions and (2) the development of controlled release/extended release of growth factors for bone regeneration. Severe bone fractures constitute a complex medical condition. There are 11 to 15 million bone fractures in lower and upper limbs in the US, per year. Up to 12% of fractures fail to heal even with the best treatment, resulting in non-union. About 90% of the traumatic and nonunion fractures present a gap of 1-2 cm. A larger gap most often leads to amputation. Combat-related extremity injuries require the greatest use of resources for inpatient treatment during the initial post-injury period, cause the greatest number of disabled Soldiers, and have the greatest projected disability benefit costs. Current treatments include autografts (bone harvesting from the patient), allografts (bone harvesting from cadavers), the Ilizarov method based on special fixators applying tension to the fractured bone thus inducing gradual bone formation, or, less frequently used, the administration of so-called bone morphogenetic proteins to stimulate bone growth. All four methods have significant complications or side effects. Of these four methods, autografts represent the gold standard. We propose a “no bone graft” technology, which can create new bone. During the initial surgery to stabilize the bone fracture, a special scaffold is implanted in the injury site. During the following 14-day waiting period, the patient’s own stem cells invade this scaffold. Then, in an outpatient procedure, a DNA molecule, which encodes for bone morphogenetic protein, is injected with microbubbles into the scaffold. The microbubbles are activated using a special ultrasound pulse, to deliver the DNA to the cells, thus the name “SonoHeal” for our therapy. Complete healing has been shown in 59 minipigs (whose bone anatomy resembles that of humans most closely) within 8 weeks. This process entirely avoids the second surgery for autografts at both the donor and the repair sites. We have developed this treatment with components already approved by the Food and Drug Administration (FDA). The next step is to develop an investigational new drug application for approval by the FDA. To reach this objective, we will determine the optimal delivery device (syringe specification) for the microbubbles loaded with the DNA and the standard operating procedures for handling and mixing the final product at the clinical site. Furthermore, we will demonstrate the reproducibility and the accuracy of delivering this mixture to the target site. Lastly, we will also conduct a toxicology study using the proposed therapy to treat critical-size bone fractures. This study has the potential to advance a very promising therapy to the next stage toward clinical practice. It addresses the urgent need for highly effective and lower cost therapies for non-union and segmental fractures. Based on our very promising preliminary data, we anticipate that this study will lead to an investigational new drug approval and thus take the next step toward clinical practice. The benefits for Service members, Veterans, or civilians with non-union and segmental bone fractures will be better healing, faster healing, and shorter rehabilitation times enabling earlier return to duty or service. The current high cost associated with such bone fractures is likely to be lowered significantly during the recovery process and also long term, as it will require fewer operations, no bone grafts, and will reduce disability. We also anticipate that this research will trigger application in other bone fractures and in research to further optimize this breakthrough procedure.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810593
Entities
People
- Dan Gazit
Organizations
- Cedars-Sinai Medical Center
- United States Army