Research Areas

Targeting of Endogenous Stem Cells for Segmental Bone Fracture Repair

Graphic representation of the ultrasound-mediated gene therapy for segmental bone repair. (1) Non-union bone fracture. (2) Collagen sponge insertion. (3) Stem cell migration into the sponge (4) Injection of microbubbles and therapeutic gene. (5) Sonoporation/Ultrasound application.

Bone tissue, which provides major structural and supportive connective tissue to the body, can be lost due to cancer or trauma. When the edges of a fracture are close to each other, bone repair cells are capable of healing the injury. However, when a large piece of bone is missing, these cells cannot bridge the necessary gap for healing, resulting in the need for bone grafting—the current gold-standard therapy.

Bone grafting can be complicated, as bone cells are not always available and their harvest, usually from the pelvic bone, can lead to prolonged pain. The Gazit Laboratory is developing a novel approach for the treatment of bone fractures without the need for bone grafting. Stem cells are recruited to the fracture site using a collagen matrix and then a bone-forming gene is directly delivered to the stem cells using an ultrasound pulse. This proposed therapy has the potential to generate rapid healing of segmental bone fractures and significantly decrease patient hospitalization, loss of working days and significant healthcare costs. In addition, this therapeutic intervention can be repeated several times when needed in order to deal with severe cases of bone loss. The research is supported by a grant from National Institutes of Health (NIH)/National Institute of Biomedical Imaging and Bioengineering (#R01EB026094) entitled "Ultrasound-Guided DNA Delivery for Regenerative Medicine" and Department of Defense (#W81XWH-18-1-0593) entitled "Ultrasound-Mediated Nanobiomaterial Delivery for Segmental Bone Fracture Repair."

Representative μCT slices of the fractures eight weeks after surgery. Asterisks represent new bone formation within the fracture. Arrows point to cortical discontinuity indicating nonunion within the fracture. Published in Bez M et al. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci Transl Med. 2017 May 17; 9(390):pii:eaal3128.

Noninvasive Method for Diagnosing Low Back Pain

More than 85 percent of the United States population suffers from low back pain, much of which is caused by intervertebral disc degeneration. Disc degeneration is a progressive condition, resulting in chronic pain in the back and neck. For some patients, degeneration can occur for years before pain sets in, presenting symptoms, while others are affected almost immediately. Currently, identifying the exact disc that is the source of pain involves painful and invasive diagnostic procedures, in which physicians inject a contrast agent or non-toxic dye into patients’ spinal discs.

Study design: three groups having four degenerate intervertebral discs (in orange) and timepoints of the MRI and pH measurements for each group, at 2, 6 and 10 weeks, respectively. Published in Bez M et al. Molecular pain markers correlate with pH-sensitive MRI signal in a pig model of disc degeneration. Sci Rep. 2018 Nov;8(1):17363

Representative images of IVDs and corresponding exchange rate maps in one pig. (a) T2-weighted image in the sagittal plane. (b) Axial anatomical images of corresponding IVDs. (c) Exchange rate maps of corresponding IVDs. The IVDs with lower pH tend to have a higher exchange rate. Published in Zhou Z, et al. Quantitative chemical exchange saturation transfer MRI of intervertebral disc in a porcine model. Magn Reson Med. 2016 Dec;76(6):1677-1683.

Knee Cartilage Resurfacing Utilizing Bio-Scaffolds

Healthy articular knee cartilage can be observed in the left image and osteoarthritic lesion is depicted in the right image.

The use of implanted devices in orthopedics to alleviate pain and restore joint function has grown dramatically in recent times. Driven by worldwide aging populations and increasing prevalence of physically active lifestyles, the clinical need for orthopedic implants continues to increase.

Knee osteoarthritis continues to pose a major clinical challenge. The Gazit Lab proposes to expand the usability of meniscal allograft-based arthroplasty (MABA) to knee cartilage resurfacing in order to elucidate some of the cellular processes mediating the therapeutic effect of MABA. By improving our understanding of these processes, the Gazit Lab could potentially improve current clinical practice and develop novel therapeutic approaches to treat arthritis, eliminate pain and restore joint function.

Reconstruction of Massive Bone Loss in the Jaws Utilizing Bone Allografts and a Recombinant Hormone

Massive craniofacial bone loss poses a clinical challenge to neurosurgeons and maxillofacial surgeons alike. Structural bone allografts are readily available at tissue banks but are rarely used in such cases due to a high failure rate. Previous studies showed that intermittent administration of recombinant parathyroid hormone (rPTH) enhanced integration of allografts in a murine model of calvarial bone defect. Our studies aim to assess the hypothesis that rPTH would enhance integration of a mandibular allograft in a clinically relevant model of mandibulectomy in a large animal. Porcine bone allografts are generated at a veterinary tissue bank and implanted in a 5-cm-long noncontinuous bone defect that had been created in the mandible of minipigs. To date, our results showed formation of more bone in the animals treated with rPTH, all biomechanical properties of bone were higher in the rPTH group. This is an ongoing study, but at this point we can affirm that a daily dose of rPTH induced integration of mandibular allografts in a large animal model of mandibulectomy.

High Resolution X-ray Images of Right Hemimandibles. A Faxitron scanner was used to image surgically treated hemimandibles after the animals had been euthanized. Mandible allografts are seen at the defect site with variable amounts of new bone surrounding them.

3D Micro-CT Images of Treated Bone Defects. Upper: 3D micro-CT scan of a mandibular allograft prior to implantation. Following, hemimandibles were trimmed and scanned using a micro-CT system. Allografts are highlighted in yellow, new bone in red, and host bone in blue. Note the signs of remodeling in two allografts in the Allo+PTH group and advanced resorption of one allograft in the Allo+PBS group.

Human Induced Pluripotent Stem Cells (iPSC) Can Be Differentiated into Notochordal Cells that Reduce Intervertebral Disc Degeneration in a Porcine Model

In a recently published paper, the Gazit Lab reports a stepwise differentiation method to generate notochordal cells (iNCs) from human iPSCs. These cells not only demonstrate a sustainable notochordal cell phenotype in vitro and in vivo, but also show the functionality of notochordal cells and have protective effect in case of induced disc degeneration and prevent the change in the pH level of the injected intervertebral discs (IVD).

Porcine IVD Degenerated and Injected with iNCs: Imaging Analysis. Three levels of IVDs were subjected to annular puncture with a 14G needle under fluoroscopic guidance. The degeneration process was imaged using MRI. The first image was obtained before induction of degeneration and shows all healthy IVDs. Subsequent images were taken 4, 8 or 12 weeks after annular puncture. Yellow arrows indicate injured IVDs and white arrows indicate healthy IVDs. Four weeks after induction of degeneration, DiI-labeled iNCs, bone marrow mesenchymal stem cells (BM-MSC), or hydrogel alone were injected into the Nucleus Pulposus. qCEST imaging that was previously correlated to the pH measured inside the disc. Published in Sheyn D, et al. Human iPSCs can be differentiated into notochordal cells that reduce intervertebral disc degeneration in a porcine model. Theranostics. 2019 Oct 12;9(25):7506-7524.

Contact the Gazit Lab

8700 Beverly Blvd.
Advanced Health and Sciences Pavilion, Room 8304
Los Angeles, CA 90048