While bone tissues have regenerative capabilities that enable self-repair of fractures, in extreme cases in which the extent of bone loss or damage is excessive, complete regeneration will not occur. Such bone defects in the craniofacial complex are often a result of birth defects, trauma or cancer surgery. Oral cancer is a major reason for mandibulectomy and maxillectomy;an estimated 34,000 Americans and over 400,000 people world-wide will be diagnosed this year. In addition, approximately 1,600,000 bone grafts are performed each year to regenerated bone lost due to trauma or disease, of which 6% (96,000) are craniomaxillofacial in nature. Unfortunately, the long-term results of these craniomaxillofacial reconstructions are poor due to the overwhelming tissue fibrosis and scarring that occurs following surgery. This inflammatory, foreign body response to the grafted biomaterial remains one of the great challenges in treating patients with birth defects, traumatic injuries or cancers in the head and mouth. To address these issues, this multi-institutional investigative team, comprised of immunologists, musculoskeletal scientists, tissue engineers and clinicians, has sustained a long term collaboration that produced several advances in this field. Most recently, we have achieved extraordinary success in treating several patients with facture non-unions non- surgically with recombinant parathyroid hormone (PTH, teriparatide), in whom it appears that fibrous tissue was induced to form a boney union. Based on this, we initiated a pre-clinical study to evaluate the effects of teriparatide in our established murine femur model of massive allografting. Our preliminary results indicate that in contrast to normal allograft healing, PTH: 1) prevents the formation of type 3 collagen (Col3) rich fibrotic tissue around the cortical surface of the allograft, 2) decreases inflammation and vascularity around the allograft, and 3) induces copious amounts of osteoblastic bone formation on and in structural allografts. As such we found that this PTH response closely resembles """"""""scarless"""""""" healing of live autografts. Based on this we hypothesize that: 1) PTH therapy acts on undifferentiated mesenchymal stem cells (MSC) recruited to the surgical site, rendering them refractory to the inflammatory-fibrotic signals that normally induce scar formation;and 2) PTH therapy can be used as an adjuvant to increase intramembranous ossification at the allograft host junctions, increase new bone formation in and around the allograft, and decrease inflammation, vascularization and scaring. To test these hypotheses we will: define biomarkers that are significantly affected by PTH therapy during scarless allograft healing;and determine the cellular target(s) of PTH-induced scarless healing with genetic loss and gain of function studies.
Although approximately 100,000 bone grafts are performed each year to regenerated bone lost due to trauma or disease that are craniomaxillofacial in nature, the long-term results of these reconstructions are poor due to the overwhelming tissue fibrosis and scarring that occurs following surgery. This inflammatory, foreign body response to the grafted biomaterial remains one of the great challenges in treating patients with birth defects, traumatic injuries or cancers in the head and mouth. Recently, we have observed remarkable effects of the osteoporosis drug teriparatide (recombinant parathyroid hormone, PTH) in treating patients with fracture non-unions and animal models of bone grafting, in which the drug appears to resolve the fibrotic tissue and prevent the foreign body reaction. Here we propose to formally demonstrate that PTH has these effects and could be used as an adjuvant therapy during craniomaxillofacial reconstructive surgery.
|Cohn Yakubovich, Doron; Sheyn, Dmitriy; Bez, Maxim et al. (2017) Systemic administration of mesenchymal stem cells combined with parathyroid hormone therapy synergistically regenerates multiple rib fractures. Stem Cell Res Ther 8:51|
|Zhang, Longze; Wang, Tao; Chang, Martin et al. (2017) Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model. J Bone Miner Res 32:1870-1883|
|Schwarz, Edward M (2017) Confirmation of Sexual Dimorphisms in Metal Hypersensitivity and Joint Pain Following Total Joint Arthroplasty: Commentary on an article by Marco S. Caicedo, PhD, et al.: ""Females with Unexplained Joint Pain Following Total Joint Arthroplasty Exhibit a H J Bone Joint Surg Am 99:e41|
|Wang, Tao; Zhang, Xinping; Bikle, Daniel D (2017) Osteogenic Differentiation of Periosteal Cells During Fracture Healing. J Cell Physiol 232:913-921|
|Zhang, Longze; Chang, Martin; Beck, Christopher A et al. (2016) Analysis of new bone, cartilage, and fibrosis tissue in healing murine allografts using whole slide imaging and a new automated histomorphometric algorithm. Bone Res 4:15037|
|Sheyn, Dmitriy; Shapiro, Galina; Tawackoli, Wafa et al. (2016) PTH Induces Systemically Administered Mesenchymal Stem Cells to Migrate to and Regenerate Spine Injuries. Mol Ther 24:318-330|
|Antebi, Ben; Zhang, Longze; Sheyn, Dmitriy et al. (2016) Controlling Arteriogenesis and Mast Cells Are Central to Bioengineering Solutions for Critical Bone Defect Repair Using Allografts. Bioengineering (Basel) 3:|
|Cohn Yakubovich, Doron; Tawackoli, Wafa; Sheyn, Dmitriy et al. (2015) Computed Tomography and Optical Imaging of Osteogenesis-angiogenesis Coupling to Assess Integration of Cranial Bone Autografts and Allografts. J Vis Exp :e53459|
|Dhillon, Robinder S; Zhang, Longze; Schwarz, Edward M et al. (2014) The murine femoral bone graft model and a semiautomated histomorphometric analysis tool. Methods Mol Biol 1130:45-59|
|Nishitani, Kohei; Schwarz, Edward M (2014) Regenerative medicine: Cartilage transplants hold promise for challenging bone defects. Nat Rev Rheumatol 10:129-30|
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