Samuel Herberg1, Galina Kondrikova1, Sudharsan Periyasamy-Thandavan1, R Nicole Howie2, Mohammed E Elsalanty3, Lee Weiss4, Phil Campbell5, William D Hill6, James J Cray7. 1. Department of Cellular Biology and Anatomy, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA. 2. Department of Oral Biology, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA. 3. Department of Oral Biology, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA; The Institute for Regenerative and Reparative Medicine, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA. 4. The Robotics Institute, Carnegie Mellon University, 5000 Forbes Ave., Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, 450 Technology Drive, Pittsburgh, PA, USA. 5. The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave., Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, 450 Technology Drive, Pittsburgh, PA, USA. 6. Department of Cellular Biology and Anatomy, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA; Department of Orthopaedic Surgery, Georgia Regents University, 1120 15th St., Augusta, GA, USA; The Institute for Regenerative and Reparative Medicine, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA. 7. Department of Cellular Biology and Anatomy, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA; Department of Oral Biology, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA; Department of Orthopaedic Surgery, Georgia Regents University, 1120 15th St., Augusta, GA, USA; Department of Orthodontics and Surgery, Division of Plastic Surgery, Georgia Regents University, 1120 15th St., Augusta, GA, USA; The Institute for Regenerative and Reparative Medicine, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA, USA. Electronic address: crayj@musc.edu.
Abstract
BACKGROUND: A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. METHODS: Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1β (SDF-1β), transforming growth factor-β1 (TGF-β1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1β co-delivery enhances BMP-2 and TGF-β1-driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. RESULTS: Our data showed that BMP-2 bioprinted in low-doses induced significant new bone formation by four weeks post-operation. TGF-β1 was less effective compared to BMP-2, and SDF-1β therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2+SDF-1β was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-β1+SDF-1β decreased bone healing compared to TGF-β1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. CONCLUSIONS: Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1β augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGF-β1-driven osteogenesis, its effect on osteogenesis is not universal.
BACKGROUND: A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. METHODS: Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1β (SDF-1β), transforming growth factor-β1 (TGF-β1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1β co-delivery enhances BMP-2 and TGF-β1-driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. RESULTS: Our data showed that BMP-2 bioprinted in low-doses induced significant new bone formation by four weeks post-operation. TGF-β1 was less effective compared to BMP-2, and SDF-1β therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2+SDF-1β was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-β1+SDF-1β decreased bone healing compared to TGF-β1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. CONCLUSIONS: Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1β augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGF-β1-driven osteogenesis, its effect on osteogenesis is not universal.
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