Haydn Scherry

Introduction:  Bone is a highly vascularized tissue that is susceptible to damage due to hypoxia.  Conditions such as osteonecrosis arise when regions of the bone lose the blood supply that brings them nutrients and oxygen, resulting in cell death.  Osteonecrosis (ON) is the cause of ~10% of the 500,000 total joint replacements performed every year.¹  Different causes are responsible for impeding blood flow, it can be due to trauma, infection, emboli, or fracture/dislocation that results in sheering of the blood vessel.¹  Regenerating the compromised blood supply to the hypoxic region of bone could reverse the effects of ON and result in healthy, viable bone.  Growth factors are involved in the body’s innate ability to form new blood vessels (neovascularization), some of the most notable are VEGF and IGF. Hypoxia-inducible factor 1 (HIF-1) is a chemical that the tissues produce when they are hypoxic, and its expression can be increased by IGF which leads to increased levels of VEGF.^2,3  IGF and VEGF have a dual role: promote both bone and endothelial development.⁴  Implanting these growth factors into a 3D printed gel biomaterial would be implanted into areas of ON and regenerate the blood supply as well as form new bone.  Methods:  Researchers used a bone-mimetic hydrogel scaffold that contains octacalcium phosphate (OCP), human umbulical vein endothelial cells (HUVEC), and gelatin methacrylate (GelMA) to promote capillary vasculogenisis.⁵ OCP is a precursor to hydroxyapatite which is the compound that gives bone its strength and durability.  HUVEC serve as the endothelial progenitor cells which become the walls of the new blood vessels. GelMA functions as the scaffold that holds everything in an organized manner.  The OCP was cultured and then 3D printed onto the GelMA and then crosslinked via photopolymerization.  Cells were cultured with the gel for 14 days and then analyzed to see if they promoted osteogenesis and angiogenesis.⁵  Results:  The experiment showed that the GelMA at a concentration of 5% produced the most capillary vasculogenisis at 14 days after polymerization.  The OCP in the GelMA promoted osteoblastic differentiation of mesenchymal stem cells and the HUVEC generated new capillary networks.^5,6 Conclusion:  This experiment showed the effectiveness of these compounds for promoting osteoblast differentiation, as well as, neovascularization.  Using this method and also incorporating IGF and VEGF could give this biomaterial an additive effect for the treatment of ON.

1. Mankin HJ: Nontraumatic Necrosis of Bone (Osteonecrosis). New England Journal of Medicine. 1992; 326:1473-1479.
2. Ceradini DJ, Gurtner GC. Homing to Hypoxia: HIF-1 as a Mediator of Progenitor Cell Recruitment to Injured Tissue. Trends in Cardiovascular Medicine. 2005;15(2):57-63.
3. Piecewicz SM, Pandey A, Roy B, Xiang SH, Zetter BR, Sengupta S. Insulin-Like Growth Factors Promote Vasculogenesis in Embryonic Stem Cells. PLoS ONE. 2012;7(2).
4. Ferretti C, Vozzi G, Falconi M, et al. Role of IGF1 and IGF1/VEGF on Human Mesenchymal Stromal Cells in Bone Healing: Two Sources and Two Fates. Tissue Engineering Part A. 2014;20(17-18):2473-2482.
5. Anada T, Pan C-C, Stahl A, et al. Vascularized Bone-Mimetic Hydrogel Constructs by 3D Bioprinting to Promote Osteogenesis and Angiogenesis. International Journal of Molecular Sciences. 2019;20(5):1096.
6. Lambertini E, Penolazzi L, Angelozzi M, et al. Hypoxia Preconditioning of Human MSCs: a Direct Evidence of HIF-1α and Collagen Type XV Correlation. Cellular Physiology and Biochemistry. 2018;51(5):2237-2249.