Porous copper- and lithium-doped nano-hydroxyapatite composite scaffold promotes angiogenesis and bone regeneration in the repair of glucocorticoids-induced osteonecrosis of the femoral head

Glucocorticoids-induced osteonecrosis of the femoral head (GIONFH) is a common refractory disease. In the present study, we aimed to synthesize the nano-hydroxyapatite-copper-lithium (Cu-Li-nHA) composite porous scaffold to promote osteogenesis and angiogenesis functions to repair GIONFH by regulating the Wnt/β-catenin and HIF-1α/VEGF pathways. The physicochemical property of the scaffold was characterized and their osteogenic and angiogenic effects were tested through a serial of experiments in vitro and in vivo. Results showed that 0.25% Cu-Li-nHA scaffolds possessed the highest mechanical and biocompatibility in vitro. Then the 0.25% Cu-Li-nHA scaffolds significantly enhanced the new bone formation on defects in GIONFH rabbits in vivo. Moreover, the scaffold could increase the expression of osteogenic and angiogenic factors along with the activation of factors in Wnt/β-catenin and HIF-1α/VEGF pathways in vitro and in vivo. In conclusion, the 0.25% Cu-Li-nHA scaffold could improve the osteogenesis and angiogenesis by upregulating the Wnt/β-catenin and HIF-1α/VEGF pathways which benefited to repair the GIONFH in rabbit models.

[1]  Zhouyuan Yang,et al.  A bone regeneration strategy via dual delivery of demineralized bone matrix powder and hypoxia-pretreated bone marrow stromal cells using an injectable self-healing hydrogel. , 2020, Journal of materials chemistry. B.

[2]  Dewei Zhao,et al.  Application of biomaterials for the repair and treatment of osteonecrosis of the femoral head , 2020, Regenerative biomaterials.

[3]  K. Marycz,et al.  Lithium ions (Li+) and nanohydroxyapatite (nHAp) doped with Li+ enhance expression of late osteogenic markers in adipose-derived stem cells. Potential theranostic application of nHAp doped with Li+ and co-doped with europium (III) and samarium (III) ions. , 2019, Materials science & engineering. C, Materials for biological applications.

[4]  Lin Li,et al.  A novel composite scaffold of Cu-doped nano calcium-deficient hydroxyapatite/multi-(amino acid) copolymer for bone tissue regeneration , 2019, International journal of nanomedicine.

[5]  P. Kang,et al.  Porous, lithium-doped calcium polyphosphate composite scaffolds containing vascular endothelial growth factor (VEGF)-loaded gelatin microspheres for treating glucocorticoid-induced osteonecrosis of the femoral head , 2019, Biomedical materials.

[6]  Y. J. Kang,et al.  Copper affects the binding of HIF-1α to the critical motifs of its target genes. , 2019, Metallomics : integrated biometal science.

[7]  Wenjing Zhang,et al.  Copper affects the binding of HIF-1α to the critical motifs of its target genes. , 2018, Metallomics : integrated biometal science.

[8]  Y. Mishina,et al.  Pore size directs bone marrow stromal cell fate and tissue regeneration in nanofibrous macroporous scaffolds by mediating vascularization. , 2018, Acta biomaterialia.

[9]  Jinhai Zhao,et al.  Porous lithium-doped hydroxyapatite scaffold seeded with hypoxia-preconditioned bone-marrow mesenchymal stem cells for bone-tissue regeneration , 2018, Biomedical materials.

[10]  Jiang Chang,et al.  Bone tissue engineering strategy based on the synergistic effects of silicon and strontium ions. , 2018, Acta biomaterialia.

[11]  Zhouyuan Yang,et al.  Enhanced bone defect repairing effects in glucocorticoid-induced osteonecrosis of the femoral head using a porous nano-lithium-hydroxyapatite/gelatin microsphere/erythropoietin composite scaffold. , 2018, Biomaterials science.

[12]  R. Weinstein,et al.  The Pathophysiological Sequence of Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Male Mice , 2017, Endocrinology.

[13]  J. Weng,et al.  The synergistic effect of micro/nano-structured and Cu2+-doped hydroxyapatite particles to promote osteoblast viability and antibacterial activity , 2017, Biomedical materials.

[14]  Moustafa N. Aboushelib,et al.  Osteogenesis ability of CAD/CAM porous zirconia scaffolds enriched with nano-hydroxyapatite particles , 2017, International journal of implant dentistry.

[15]  Li Li,et al.  In vitro study on the degradation of lithium-doped hydroxyapatite for bone tissue engineering scaffold. , 2016, Materials science & engineering. C, Materials for biological applications.

[16]  B. Olsen,et al.  Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. , 2016, The Journal of clinical investigation.

[17]  Kunzheng Wang,et al.  Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and osteogenesis in rabbit femoral head osteonecrosis. , 2015, Bone.

[18]  N. Wang,et al.  Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey , 2015, Chinese medical journal.

[19]  Michael A Mont,et al.  Nontraumatic Osteonecrosis of the Femoral Head: Where Do We Stand Today? A Ten-Year Update. , 2015, The Journal of bone and joint surgery. American volume.

[20]  Kunzheng Wang,et al.  Lithium chloride attenuates the abnormal osteogenic/adipogenic differentiation of bone marrow-derived mesenchymal stem cells obtained from rats with steroid-related osteonecrosis by activating the β-catenin pathway , 2015, International journal of molecular medicine.

[21]  Michael A Mont,et al.  High-Dose Corticosteroid Use and Risk of Hip Osteonecrosis: Meta-Analysis and Systematic Literature Review , 2015, The Journal of Arthroplasty.

[22]  Di Chen,et al.  Combination Treatment of Biomechanical Support and Targeted Intra‐arterial Infusion of Peripheral Blood Stem Cells Mobilized by Granulocyte‐Colony Stimulating Factor for the Osteonecrosis of the Femoral Head: A Randomized Controlled Clinical Trial , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[23]  Zong-ke Zhou,et al.  Repairing defect and preventing collapse of femoral head in a steroid-induced osteonecrotic of femoral head animal model using strontium-doped calcium polyphosphate combined BM-MNCs , 2015, Journal of Materials Science: Materials in Medicine.

[24]  V. Fotopoulos,et al.  Steroid-induced femoral head osteonecrosis in immune thrombocytopenia treatment with osteochondral autograft transplantation , 2015, Knee Surgery, Sports Traumatology, Arthroscopy.

[25]  P. Tengvall,et al.  Hydroxyapatite coating affects the Wnt signaling pathway during peri-implant healing in vivo. , 2014, Acta biomaterialia.

[26]  Bin Zhang,et al.  Analyzing the behavior of a porous nano-hydroxyapatite/polyamide 66 (n-HA/PA66) composite for healing of bone defects , 2014, International journal of nanomedicine.

[27]  Jiake Xu,et al.  Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation , 2013, Cell Death and Disease.

[28]  E. Zelzer,et al.  HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development , 2012, Development.

[29]  R. Baron,et al.  Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. , 2012, The Journal of clinical investigation.

[30]  P. Gao,et al.  Vascular Endothelial Growth Factor–Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[31]  R. Tuan,et al.  Stem cell- and growth factor-based regenerative therapies for avascular necrosis of the femoral head , 2012, Stem Cell Research & Therapy.

[32]  Jennifer J Westendorf,et al.  Update on Wnt signaling in bone cell biology and bone disease. , 2012, Gene.

[33]  Jaebeom Lee,et al.  Various preparation methods of highly porous hydroxyapatite/polymer nanoscale biocomposites for bone regeneration. , 2011, Acta biomaterialia.

[34]  D. Zou,et al.  In vitro study of enhanced osteogenesis induced by HIF‐1α‐transduced bone marrow stem cells , 2011, Cell proliferation.

[35]  M. Celeste Simon,et al.  O2 regulates stem cells through Wnt/β-catenin signalling , 2010, Nature Cell Biology.

[36]  T. Pufe,et al.  Differential Expression of Vascular Endothelial Growth Factor in Glucocorticoid-related Osteonecrosis of the Femoral Head , 2009, Clinical orthopaedics and related research.

[37]  N. Sugano,et al.  Distribution of TRAP‐positive cells and expression of HIF‐1α, VEGF, and FGF‐2 in the reparative reaction in patients with osteonecrosis of the femoral head , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  Samuel I Stupp,et al.  Biomimetic systems for hydroxyapatite mineralization inspired by bone and enamel. , 2008, Chemical reviews.

[39]  S. Takagi,et al.  In-situ hardening hydroxyapatite-based scaffold for bone repair , 2005, Journal of materials science. Materials in medicine.

[40]  G. Camenisch,et al.  Copper-dependent activation of hypoxia-inducible factor ( HIF ) – 1 : implications for ceruloplasmin regulation , 2005 .

[41]  V A Marker,et al.  Implant materials, designs, and surface topographies: their effect on osseointegration. A literature review. , 2000, The International journal of oral & maxillofacial implants.