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Erickson CB, Newsom JP, Fletcher NA, et al. Anti-VEGF antibody delivered locally reduces bony bar formation following physeal injury in rats. J Orthop Res. 2020;39(8):1658-1668doi: 10.1002/jor.24907.
Erickson, C. B., Newsom, J. P., Fletcher, N. A., Yu, Y., Rodriguez-Fontan, F., Weatherford, S. A., Hadley-Miller, N., Krebs, M. D., & Payne, K. A. (2021). Anti-VEGF antibody delivered locally reduces bony bar formation following physeal injury in rats. Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 39(8), 1658-1668. https://doi.org/10.1002/jor.24907
Erickson, Christopher B, et al. "Anti-VEGF antibody delivered locally reduces bony bar formation following physeal injury in rats." Journal of orthopaedic research : official publication of the Orthopaedic Research Society vol. 39,8 (2021): 1658-1668. doi: https://doi.org/10.1002/jor.24907
Erickson CB, Newsom JP, Fletcher NA, Yu Y, Rodriguez-Fontan F, Weatherford SA, Hadley-Miller N, Krebs MD, Payne KA. Anti-VEGF antibody delivered locally reduces bony bar formation following physeal injury in rats. J Orthop Res. 2021 Aug;39(8):1658-1668. doi: 10.1002/jor.24907. Epub 2020 Nov 24. PMID: 33179297.
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J Orthop Res. 2021 Aug;39(8):1658-1668. doi: 10.1002/jor.24907. Epub 2020 Nov 24.

Anti-VEGF antibody delivered locally reduces bony bar formation following physeal injury in rats.

Journal of orthopaedic research : official publication of the Orthopaedic Research Society

Christopher B Erickson, Jake P Newsom, Nathan A Fletcher, Yangyi Yu, Francisco Rodriguez-Fontan, Shane A Weatherford, Nancy Hadley-Miller, Melissa D Krebs, Karin A Payne

Affiliations

  1. Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  2. Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  3. Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado, USA.
  4. Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  5. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

PMID: 33179297 DOI: 10.1002/jor.24907

Abstract

Physeal injuries can result in the formation of a "bony bar" which can lead to bone growth arrest and deformities in children. Vascular endothelial growth factor (VEGF) has been shown to play a role in bony bar formation, making it a potential target to inhibit bony repair tissue after physeal injury. The goal of this study was to investigate whether the local delivery of anti-VEGF antibody (α-VEGF; 7.5 μg) from alginate:chitosan hydrogels to the tibial physeal injury site in rats prevents bony bar formation. We tested the effects of quick or delayed delivery of α-VEGF using both 90:10 and 50:50 ratio alginate:chitosan hydrogels, respectively. Male and female 6-week-old Sprague-Dawley rats received a tibial physeal injury and the injured site injected with alginate-chitosan hydrogels: (1) 90:10 (Quick Release); (2) 90:10 + α-VEGF (Quick Release + α-VEGF); (3) 50:50 (Slow Release); (4) 50:50 +  α-VEGF (Slow Release +  α-VEGF); or (5) Untreated. At 2, 4, and 24 weeks postinjury, animals were euthanized and tibiae assessed for bony bar and vessel formation, repair tissue type, and limb lengthening. Our results indicate that Quick Release + α-VEGF reduced bony bar and vessel formation, while also increasing cartilage repair tissue. Further, the quick release of α-VEGF neither affected limb lengthening nor caused deleterious side-effects in the adjacent, uninjured physis. This α-VEGF treatment, which inhibits bony bar formation without interfering with normal bone elongation, could have positive implications for children suffering from physeal injuries.

© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.

Keywords: VEGF; alginate; chitosan; growth plate; physis

References

  1. Kronenberg HM . Developmental regulation of the growth plate. Nature. 2003;423:332-336. - PubMed
  2. Shaw N , Erickson C , Bryant SJ , et al. Regenerative medicine approaches for the treatment of pediatric physeal injuries. Tissue Eng Part B: Rev. 2017;24(2):85-97. - PubMed
  3. Peterson HA , Madhok R , Benson JT , Ilstrup DM , Melton LJ . Physeal fractures: part 1. Epidemiology in Olmsted County, Minnesota, 1979-1988. J Pediatr Orthop. 1994;14:423-430. - PubMed
  4. Young EY , Stans AA . Distal femoral physeal fractures. J Knee Surg. 2018;31:486-489. - PubMed
  5. Arkader A , Warner Jr. WC , Horn BD , Shaw R.N. , Wells L. 2007. Predicting the outcome of physeal fractures of the distal femur. J Pediatr Orthop 27:703-708. - PubMed
  6. Langenskiöld A , Heikel H , Nevalainen T , et al. 1989. Regeneration of the growth plate. Cells, Tissues, Organs 134:113-123. - PubMed
  7. Hosseinzadeh P , Milbrandt T . The normal and fractured physis: an anatomic and physiologic overview. J Pediatr Orthop Part B. 2015;25:385-392. - PubMed
  8. Foster BK , John B , Hasler C . Free fat interpositional graft in acute physeal injuries: the anticipatory Langenskiold procedure. J Pediatr Orthop. 2000;20:282-285. - PubMed
  9. Mizuta T , Benson WM , Foster BK , Morris LL . Statistical analysis of the incidence of physeal injuries. J Pediatr Orthop. 1987;7:518-523. - PubMed
  10. Hasler CC , Foster BK . Secondary tethers after physeal bar resection: a common source of failure? Clin Orthop Relat Res. 2002;405:242-249. - PubMed
  11. Chung R , Xian CJ . Recent research on the growth plate: mechanisms for growth plate injury repair and potential cell-based therapies for regeneration. J Mol Endocrinol. 2014;53:T45-T61. - PubMed
  12. Einhorn TA , Gerstenfeld LC . Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11:45-54. - PubMed
  13. Ogden JA . Anatomy and physiology of skeletal development. In: Ogden JA , ed. Skeletal injury in the child. New York City: Springer; 2000:1-37. - PubMed
  14. Fischerauer E , Heidari N , Neumayer B , Deutsch A , Weinberg AM . The spatial and temporal expression of VEGF and its receptors 1 and 2 in post-traumatic bone bridge formation of the growth plate. J Mol Histol. 2011;42:513-522. - PubMed
  15. Xian CJ , Zhou FH , McCarty RC , Foster BK . Intramembranous ossification mechanism for bone bridge formation at the growth plate cartilage injury site. J Orthop Res. 2004;22:417-426. - PubMed
  16. Arasapam G , Scherer M , Cool JC , Foster BK , Xian CJ . Roles of COX-2 and iNOS in the bony repair of the injured growth plate cartilage. J Cell Biochem. 2006;99:450-461. - PubMed
  17. Sivaraj KK , Adams RH . Blood vessel formation and function in bone. Development. 2016;143:2706-2715. - PubMed
  18. Michigami T . Regulatory mechanisms for the development of growth plate cartilage. Cell Mol Life Sci. 2013;70:4213-4221. - PubMed
  19. Bahney CS , Hu DP , Miclau III T , Marcucio RS . The multifaceted role of the vasculature in endochondral fracture repair. Front Endocrinol. 2015;6:4. - PubMed
  20. Percival CJ , Richtsmeier JT . Angiogenesis and intramembranous osteogenesis. Dev Dyn. 2013;242:909-922. - PubMed
  21. Hu DP , Ferro F , Yang F , et al. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;144:221-234. - PubMed
  22. Hall AP , Westwood FR , Wadsworth PF . Review of the effects of anti-angiogenic compounds on the epiphyseal growth plate. Toxicol Pathol. 2006;34:131-147. - PubMed
  23. Hankenson KD , Gagne K , Shaughnessy M . Extracellular signaling molecules to promote fracture healing and bone regeneration. Adv Drug Deliv Rev. 2015;94:3-12. - PubMed
  24. Yang YQ , Tan YY , Wong R , Wenden A , Zhang LK , Rabie ABM . The role of vascular endothelial growth factor in ossification. Int J Oral Sci. 2012;4:64-68. - PubMed
  25. Zelzer E , Glotzer DJ , Hartmann C , et al. Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech Dev. 2001;106:97-106. - PubMed
  26. Geiger F , Bertram H , Berger I , et al. Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects. J Bone Miner Res. 2005;20:2028-2035. - PubMed
  27. Street J , Bao M , Bunting S , et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA. 2002;99:9656-9661. - PubMed
  28. Shum L , Rabie A , Hägg U . Vascular endothelial growth factor expression and bone formation in posterior glenoid fossa during stepwise mandibular advancement. Am J Orthod Dentofacial Orthop. 2004;125:185-190. - PubMed
  29. Gerber HP , Vu TH , Ryan AM , Kowalski J , Werb Z , Ferrara N . VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5:623-628. - PubMed
  30. Hu K , Olsen BR . Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest. 2016;126:509-526. - PubMed
  31. Chung R , Foster BK , Xian CJ . The potential role of VEGF-induced vascularisation in the bony repair of injured growth plate cartilage. J Endocrinol. 2014;221:63-75. - PubMed
  32. Liechty WB , Kryscio DR , Slaughter BV , Peppas NA . Polymers for drug delivery systems. Annu Rev Chem Biomol Eng. 2010;1:149-173. - PubMed
  33. Fletcher NA , Von Nieda EL , Krebs MD . Cell-interactive alginate-chitosan biopolymer systems with tunable mechanics and antibody release rates. Carbohydr Polym. 2017;175:765-772. - PubMed
  34. Fletcher NA , Babcock LR , Murray EA , Krebs MD . Controlled delivery of antibodies from injectable hydrogels. Mat Sci Eng: C. 2016;59:801-806. - PubMed
  35. Fletcher NA , Krebs MD . Sustained delivery of anti-VEGF from injectable hydrogel systems provides a prolonged decrease of endothelial cell proliferation and angiogenesis in vitro. RSC Adv. 2018;8:8999-9005. - PubMed
  36. Xia W , Liu W , Cui L , et al. Tissue engineering of cartilage with the use of chitosan-gelatin complex scaffolds. J Biomed Mater Res B Appl Biomater. 2004;71:373-380. - PubMed
  37. Lee KY , Mooney DJ . Alginate: properties and biomedical applications. Prog Polym Sci. 2012;37:106-126. - PubMed
  38. Li Z , Zhang M . Chitosan-alginate as scaffolding material for cartilage tissue engineering. J Biomed Mater Res A. 2005;75:485-493. - PubMed
  39. Rowley JA , Madlambayan G , Mooney DJ . Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials. 1999;20:45-53. - PubMed
  40. Erickson CB , Shaw N , Hadley-Miller N , Riederer MS , Krebs MD , Payne KA . A rat tibial growth plate injury model to characterize repair mechanisms and evaluate growth plate regeneration strategies. J Vis Exp. 2017;125:55571. - PubMed
  41. Doube M , Kłosowski MM , Arganda-Carreras I , et al. BoneJ: free and extensible bone image analysis in ImageJ. Bone. 2010;47:1076-1079. - PubMed
  42. Martin E , Ritman E , Turner R . Time course of epiphyseal growth plate fusion in rat tibiae. Bone. 2003;32:261-267. - PubMed
  43. Coleman RM , Phillips JE , Lin A , Schwartz Z , Boyan BD , Guldberg RE . Characterization of a small animal growth plate injury model using microcomputed tomography. Bone. 2010;46:1555-1563. - PubMed
  44. Su YW , Chung R , Ruan CS , et al. Neurotrophin-3 induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats. J Bone Miner Res. 2016;31:1258-1274. - PubMed
  45. Hunziker E , Schenk R . Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats. J Physiol. 1989;414:55-71. - PubMed
  46. Lampl M , Schoen M . How long bones grow children: mechanistic paths to variation in human height growth. Am J Hum Biol. 2017;29:29. - PubMed
  47. Sider KL , Song J , Davies JE . A new bone vascular perfusion compound for the simultaneous analysis of bone and vasculature. Microsc Res Tech. 2010;73:665-672. - PubMed
  48. Li SK , Liddell MR , Wen H . Effective electrophoretic mobilities and charges of anti-VEGF proteins determined by capillary zone electrophoresis. J Pharm Biomed Anal. 2011;55:603-607. - PubMed
  49. Hamilton JL , Nagao M , Levine BR , Chen D , Olsen BR , Im HJ . Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. J Bone Miner Res. 2016;31:911-924. - PubMed
  50. Centola M , Abbruzzese F , Scotti C , et al. Scaffold-based delivery of a clinically relevant anti-angiogenic drug promotes the formation of in vivo stable cartilage. Tissue Eng Part A. 2013;19:1960-1971. - PubMed
  51. Nagai T , Sato M , Kutsuna T , et al. Intravenous administration of anti-vascular endothelial growth factor humanized monoclonal antibody bevacizumab improves articular cartilage repair. Arthritis Res Ther. 2010;12:1. - PubMed

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