Application status of hypoxia mimetic agents in bone tissue engineering_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

REN Sicong , LIU Yiping , ZHU Yanlin , WANG Yingying , LIU Manxuan ,  ZHOU Yanmin

Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun Jilin, 130021, P.R.China;

Corresponding author：

ZHOU Yanmin, Email: zhouym1962@126.com

Keywords：

Bone tissue engineering; hypoxia mimetic agents; vascularization; bone repair

DOI：

10.7507/1002-1892.201911144

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the application status of hypoxia mimetic agents in bone tissue engineering.Methods The related literature about the hypoxia mimetic agents in bone tissue engineering was reviewed and analyzed. And the application status and progress of hypoxia mimetic agents in bone tissue engineering were retrospectively analyzed.Results Hypoxia mimetic agents have the same effect as hypoxia in up-regulating the level of hypoxia inducible factor 1α (HIF-1α). The combination of hypoxia mimetic agents and scaffolds can up-regulate the level of HIF-1α in bone tissue engineering, thus promoting early vascularization and bone regeneration of the bone defect area, which provides a new idea for using bone tissue engineering to repair bone defect. At present, the commonly used hypoxia mimetic agents include iron chelating agents, oxoglutarate competitive analogues, proline hydroxylase inhibitors, etc.Conclusion Hypoxia mimetic agents have a wide application prospect in bone tissue engineering, but they have been used in bone tissue engineering for a short time, more attention should be paid to their possible side effects. In the future research, the hypoxia mimetic agents should be developed in the direction of higher targeting specificity and safety, and the exact mechanism of hypoxia mimetic agents in promoting bone regeneration should be further explored.

Citation： REN Sicong, LIU Yiping, ZHU Yanlin, WANG Yingying, LIU Manxuan, ZHOU Yanmin. Application status of hypoxia mimetic agents in bone tissue engineering. Chinese Journal of Reparative and Reconstructive Surgery, 2020, 34(9): 1190-1194. doi: 10.7507/1002-1892.201911144 Copy

1.	Laschke MW, Harder Y, Amon M, et al. Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng, 2006, 12(8): 2093-2104.
2.	Auger FA, Gibot L, Lacroix D. The pivotal role of vascularization in tissue engineering. Annu Rev Biomed Eng, 2013, 15: 177-200.
3.	Moon JJ, West JL. Vascularization of engineered tissues: approaches to promote angiogenesis in biomaterials. Curr Top Med Chem, 2008, 8(4): 300-310.
4.	殷建, 王斌, 朱超, 等. 局部注射促血管生成素 2 调控自噬促进体内组织工程人工骨早期血管化和骨缺损修复的研究. 中国修复重建外科杂志, 2018, 32(9): 1150-1156.
5.	Maes C, Carmeliet G, Schipani E. Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol, 2012, 8(6): 358-366.
6.	Sun X, Wei Y. The role of hypoxia-inducible factor in osteogenesis and chondrogenesis. Cytotherapy, 2009, 11(3): 261-267.
7.	葛礼豪, 于德水, 苏瑞超, 等. 缺氧诱导因子 1α 对人羊膜间充质干细胞耐受缺氧能力影响的实验研究. 中国修复重建外科杂志, 2018, 32(3): 264-269.
8.	Zhu J, Tang Y, Wu Q, et al. HIF-1α facilitates osteocyte-mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro. J Cell Physiol, 2019, 234(11): 21182-21192.
9.	Zhang Y, Huang J, Wang C, et al. Application of HIF-1α by gene therapy enhances angiogenesis and osteogenesis in alveolar bone defect regeneration. J Gene Med, 2016, 18(4-6): 57-64.
10.	张丹, 任利玲. 缺氧诱导因子 1α 在组织工程成骨和成血管中的作用. 中国修复重建外科杂志, 2016, 30(4): 504-508.
11.	于鹏杰, 燕速. 体外模拟低氧微环境对人胃癌细胞侵袭、迁移及 Ras/MAPK/NF-κB 通路的影响. 中国临床研究, 2019, 32(7): 907-910, 914.
12.	李玢, 程辰, 李华, 等. 低氧模拟剂预处理提高预构皮瓣成活率的实验研究. 组织工程与重建外科杂志, 2019, 15(3): 142-145, 151.
13.	Saito T, Tabata Y. Hypoxia-induced angiogenesis is increased by the controlled release of deferoxiamine from gelatin hydrogels. Acta Biomater, 2014, 10(8): 3641-3649.
14.	郑胜武, 杜子婧, 黄雄梅, 等. 去铁胺促进 BMSCs 靶向归巢和血管新生的实验研究. 中国修复重建外科杂志, 2019, 33(1): 85-92.
15.	Guzey S, Aykan A, Ozturk S, et al. The effects of desferroxamine on bone and bone graft healing in critical-size bone defects. Ann Plast Surg, 2016, 77(5): 560-568.
16.	Sun Y, Jiang Y, Liu Q, et al. Biomimetic engineering of nanofibrous gelatin scaffolds with noncollagenous proteins for enhanced bone regeneration. Tissue Eng Part A, 2013, 19(15-16): 1754-1763.
17.	Yao Q, Liu Y, Tao J, et al. Hypoxia-mimicking nanofibrous scaffolds promote endogenous bone regeneration. ACS Appl Mater Interfaces, 2016, 8(47): 32450-32459.
18.	Yao Q, Liu Y, Selvaratnam B, et al. Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering. J Control Release, 2018, 279: 69-78.
19.	皮偲. 改良式给药方式应用于输血相关性铁过载的临床疗效分析. 中国处方药, 2020, 18(3): 138-139.
20.	Drager J, Ramirez-GarciaLuna JL, Kumar A, et al. Hypoxia biomimicry to enhance monetite bone defect repair. Tissue Eng Part A, 2017, 23(23-24): 1372-1381.
21.	Hadidi L, Constantin J, Dalisson B, et al. Biodegradable hypoxia biomimicry microspheres for bone tissue regeneration. J Biomater Appl, 2020, 34(7): 1028-1037.
22.	Leonard SS, Harris GK, Shi X. Metal-induced oxidative stress and signal transduction. Free Radic Biol Med, 2004, 37(12): 1921-1942.
23.	Wu C, Zhou Y, Fan W, et al. Hypoxia-mimicking mesoporous bioactive glass scaffolds with controllable cobalt ion release for bone tissue engineering. Biomaterials, 2012, 33(7): 2076-2085.
24.	Yoshizawa S, Brown A, Barchowsky A, et al. Magnesium ion stimulation of bone marrow stromal cells enhances osteogenic activity, simulating the effect of magnesium alloy degradation. Acta Biomater, 2014, 10(6): 2834-2842.
25.	Fu OY, Hou MF, Yang SF, et al. Cobalt chloride-induced hypoxia modulates the invasive potential and matrix metalloproteinases of primary and metastatic breast cancer cells. Anticancer Res, 2009, 29(8): 3131-3138.
26.	Kulanthaivel S, Roy B, Agarwal T, et al. Cobalt doped proangiogenic hydroxyapatite for bone tissue engineering application. Mater Sci Eng C Mater Biol Appl, 2016, 58: 648-658.
27.	Quinlan E, Partap S, Azevedo MM, et al. Hypoxia-mimicking bioactive glass/collagen glycosaminoglycan composite scaffolds to enhance angiogenesis and bone repair. Biomaterials, 2015, 52: 358-366.
28.	Stähli C, Muja N, Nazhat SN. Controlled copper ion release from phosphate-based glasses improves human umbilical vein rndothelial cell survival in a reduced nutrient environment. Tissue Eng Pt A, 2013, 19(3-4): 548-557.
29.	Ewald A, Käppel C, Vorndran E, et al. The effect of Cu (Ⅱ)-loaded brushite scaffolds on growth and activity of osteoblastic cells. J Biomed Mater Res A, 2012, 100(9): 2392-2400.
30.	Rigiracciolo DC, Scarpelli A, Lappano R, et al. Copper activates HIF-1α/GPER/VEGF signalling in cancer cells. Oncotarget, 2015, 6(33): 34158-34177.
31.	Urso E, Maffia M. Behind the link between copper and angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J Vasc Res, 2015, 52(3): 172-196.
32.	Li Y, Wang J, Wang Y, et al. Transplantation of copper-doped calcium polyphosphate scaffolds combined with copper (Ⅱ) preconditioned bone marrow mesenchymal stem cells for bone defect repair. J Biomater Appl, 2018, 32(6): 738-753.
33.	王松, 杨函, 杨剑, 等. 多孔磷酸钙/骨基质明胶复合骨水泥修复兔腰椎骨缺损的实验研究. 中国修复重建外科杂志, 2017, 31(12): 1462-1467.
34.	崔鑫涛, 杨显声, 迟志永, 等. 聚磷酸钙纤维增强磷酸钙骨水泥复合骨髓间充质干细胞构建人工骨. 中国组织工程研究, 2019, 23(1): 74-78.
35.	Zhang W, Chang Q, Xu L, et al. Graphene oxide-copper nanocomposite-coated porous CaP scaffold for vascularized bone regeneration via activation of Hif-1α. Adv Healthc Mater, 2016, 5(11): 1299-1309.
36.	Wu C, Zhou Y, Xu M, et al. Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. Biomaterials, 2013, 34(2): 422-433.
37.	Wang W, Liu Y, Yang C, et al. Mesoporous bioactive glass combined with graphene oxide scaffolds for bone repair. Int J Biol Sci, 2019, 15(10): 2156-2169.
38.	El-Fiqi A, Kim TH, Kim M, et al. Capacity of mesoporous bioactive glass nanoparticles to deliver therapeutic molecules. Nanoscale, 2012, 4(23): 7475-7488.
39.	Li Y, Han W, Wu Y, et al. Stabilization of hypoxia inducible factor-1α by dimethyloxalylglycine oromotes recovery from acute spinal cord injury by inhibiting neural apoptosis and enhancing axon regeneration. J Neurotrauma, 2019, 36(24): 3394-3409.
40.	张磊, 龚跃昆, 赵学凌, 等. 低氧与低氧模拟剂对 BMSCs 成骨分化影响的对比研究. 中国修复重建外科杂志, 2016, 30(7): 903-908.
41.	Jahangir S, Hosseini S, Mostafaei F, et al. 3D-porous β-tricalcium phosphate-alginate-gelatin scaffold with DMOG delivery promotes angiogenesis and bone formation in rat calvarial defects. J Mater Sci Mater Med, 2018, 30(1): 1.
42.	Eslaminejad MB, Mirzadeh H, Mohamadi Y, et al. Bone differentiation of marrow-derived mesenchymal stem cells using beta-tricalcium phosphate-alginate-gelatin hybrid scaffolds. J Tissue Eng Regen Med, 2007, 1(6): 417-424.
43.	Wu C, Zhou Y, Chang J, et al. Delivery of dimethyloxallyl glycine in mesoporous bioactive glass scaffolds to improve angiogenesis and osteogenesis of human bone marrow stromal cells. Acta Biomater, 2013, 9(11): 9159-9168.
44.	Kim SY, Yang EG. Recent advances in developing inhibitors for hypoxia-inducible factor prolyl hydroxylases and their therapeutic implications. Molecules, 2015, 20(11): 20551-20568.
45.	Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol, 2016, 11(6): 982-991.
46.	Zhou M, Hou J, Li Y, et al. The pro-angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo tissue engineering chamber model. Sci Rep, 2019, 9(1): 6035.
47.	Thirunavukkarasu M, Selvaraju V, Dunna NR, et al. Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF-1alpha)-prolyl-4-hydroxylase 3(PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat. Int J Cardiol, 2013, 168(3): 2474-2480.
48.	Yu WL, Sun TW, Qi C, et al. Enhanced osteogenesis and angiogenesis by mesoporous hydroxyapatite microspheres-derived simvastatin sustained release system for superior bone regeneration. Sci Rep, 2017, 7: 44129.
49.	Tan B, Luo Z, Yue Y, et al. Effects of FTY720 (Fingolimod) on proliferation, differentiation, and migration of brain-derived neural stem cells. Stem Cells Int, 2016, 2016: 9671732.
50.	Li S, Song C, Yang S, et al. Supercritical CO₂ foamed composite scaffolds incorporating bioactive lipids promote vascularized bone regeneration via Hif-1alpha upregulation and enhanced type H vessel formation. Acta Biomater, 2019, 94: 253-267.
51.	Chen X, Gu S, Chen BF, et al. Nanoparticle delivery of stable miR-199a-5p agomir improves the osteogenesis of human mesenchymal stem cells via the HIF1a pathway. Biomaterials, 2015, 53: 239-250.

1. Laschke MW, Harder Y, Amon M, et al. Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng, 2006, 12(8): 2093-2104.
2. Auger FA, Gibot L, Lacroix D. The pivotal role of vascularization in tissue engineering. Annu Rev Biomed Eng, 2013, 15: 177-200.
3. Moon JJ, West JL. Vascularization of engineered tissues: approaches to promote angiogenesis in biomaterials. Curr Top Med Chem, 2008, 8(4): 300-310.
4. 殷建, 王斌, 朱超, 等. 局部注射促血管生成素 2 调控自噬促进体内组织工程人工骨早期血管化和骨缺损修复的研究. 中国修复重建外科杂志, 2018, 32(9): 1150-1156.
5. Maes C, Carmeliet G, Schipani E. Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol, 2012, 8(6): 358-366.
6. Sun X, Wei Y. The role of hypoxia-inducible factor in osteogenesis and chondrogenesis. Cytotherapy, 2009, 11(3): 261-267.
7. 葛礼豪, 于德水, 苏瑞超, 等. 缺氧诱导因子 1α 对人羊膜间充质干细胞耐受缺氧能力影响的实验研究. 中国修复重建外科杂志, 2018, 32(3): 264-269.
8. Zhu J, Tang Y, Wu Q, et al. HIF-1α facilitates osteocyte-mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro. J Cell Physiol, 2019, 234(11): 21182-21192.
9. Zhang Y, Huang J, Wang C, et al. Application of HIF-1α by gene therapy enhances angiogenesis and osteogenesis in alveolar bone defect regeneration. J Gene Med, 2016, 18(4-6): 57-64.
10. 张丹, 任利玲. 缺氧诱导因子 1α 在组织工程成骨和成血管中的作用. 中国修复重建外科杂志, 2016, 30(4): 504-508.
11. 于鹏杰, 燕速. 体外模拟低氧微环境对人胃癌细胞侵袭、迁移及 Ras/MAPK/NF-κB 通路的影响. 中国临床研究, 2019, 32(7): 907-910, 914.
12. 李玢, 程辰, 李华, 等. 低氧模拟剂预处理提高预构皮瓣成活率的实验研究. 组织工程与重建外科杂志, 2019, 15(3): 142-145, 151.
13. Saito T, Tabata Y. Hypoxia-induced angiogenesis is increased by the controlled release of deferoxiamine from gelatin hydrogels. Acta Biomater, 2014, 10(8): 3641-3649.
14. 郑胜武, 杜子婧, 黄雄梅, 等. 去铁胺促进 BMSCs 靶向归巢和血管新生的实验研究. 中国修复重建外科杂志, 2019, 33(1): 85-92.
15. Guzey S, Aykan A, Ozturk S, et al. The effects of desferroxamine on bone and bone graft healing in critical-size bone defects. Ann Plast Surg, 2016, 77(5): 560-568.
16. Sun Y, Jiang Y, Liu Q, et al. Biomimetic engineering of nanofibrous gelatin scaffolds with noncollagenous proteins for enhanced bone regeneration. Tissue Eng Part A, 2013, 19(15-16): 1754-1763.
17. Yao Q, Liu Y, Tao J, et al. Hypoxia-mimicking nanofibrous scaffolds promote endogenous bone regeneration. ACS Appl Mater Interfaces, 2016, 8(47): 32450-32459.
18. Yao Q, Liu Y, Selvaratnam B, et al. Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering. J Control Release, 2018, 279: 69-78.
19. 皮偲. 改良式给药方式应用于输血相关性铁过载的临床疗效分析. 中国处方药, 2020, 18(3): 138-139.
20. Drager J, Ramirez-GarciaLuna JL, Kumar A, et al. Hypoxia biomimicry to enhance monetite bone defect repair. Tissue Eng Part A, 2017, 23(23-24): 1372-1381.
21. Hadidi L, Constantin J, Dalisson B, et al. Biodegradable hypoxia biomimicry microspheres for bone tissue regeneration. J Biomater Appl, 2020, 34(7): 1028-1037.
22. Leonard SS, Harris GK, Shi X. Metal-induced oxidative stress and signal transduction. Free Radic Biol Med, 2004, 37(12): 1921-1942.
23. Wu C, Zhou Y, Fan W, et al. Hypoxia-mimicking mesoporous bioactive glass scaffolds with controllable cobalt ion release for bone tissue engineering. Biomaterials, 2012, 33(7): 2076-2085.
24. Yoshizawa S, Brown A, Barchowsky A, et al. Magnesium ion stimulation of bone marrow stromal cells enhances osteogenic activity, simulating the effect of magnesium alloy degradation. Acta Biomater, 2014, 10(6): 2834-2842.
25. Fu OY, Hou MF, Yang SF, et al. Cobalt chloride-induced hypoxia modulates the invasive potential and matrix metalloproteinases of primary and metastatic breast cancer cells. Anticancer Res, 2009, 29(8): 3131-3138.
26. Kulanthaivel S, Roy B, Agarwal T, et al. Cobalt doped proangiogenic hydroxyapatite for bone tissue engineering application. Mater Sci Eng C Mater Biol Appl, 2016, 58: 648-658.
27. Quinlan E, Partap S, Azevedo MM, et al. Hypoxia-mimicking bioactive glass/collagen glycosaminoglycan composite scaffolds to enhance angiogenesis and bone repair. Biomaterials, 2015, 52: 358-366.
28. Stähli C, Muja N, Nazhat SN. Controlled copper ion release from phosphate-based glasses improves human umbilical vein rndothelial cell survival in a reduced nutrient environment. Tissue Eng Pt A, 2013, 19(3-4): 548-557.
29. Ewald A, Käppel C, Vorndran E, et al. The effect of Cu (Ⅱ)-loaded brushite scaffolds on growth and activity of osteoblastic cells. J Biomed Mater Res A, 2012, 100(9): 2392-2400.
30. Rigiracciolo DC, Scarpelli A, Lappano R, et al. Copper activates HIF-1α/GPER/VEGF signalling in cancer cells. Oncotarget, 2015, 6(33): 34158-34177.
31. Urso E, Maffia M. Behind the link between copper and angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J Vasc Res, 2015, 52(3): 172-196.
32. Li Y, Wang J, Wang Y, et al. Transplantation of copper-doped calcium polyphosphate scaffolds combined with copper (Ⅱ) preconditioned bone marrow mesenchymal stem cells for bone defect repair. J Biomater Appl, 2018, 32(6): 738-753.
33. 王松, 杨函, 杨剑, 等. 多孔磷酸钙/骨基质明胶复合骨水泥修复兔腰椎骨缺损的实验研究. 中国修复重建外科杂志, 2017, 31(12): 1462-1467.
34. 崔鑫涛, 杨显声, 迟志永, 等. 聚磷酸钙纤维增强磷酸钙骨水泥复合骨髓间充质干细胞构建人工骨. 中国组织工程研究, 2019, 23(1): 74-78.
35. Zhang W, Chang Q, Xu L, et al. Graphene oxide-copper nanocomposite-coated porous CaP scaffold for vascularized bone regeneration via activation of Hif-1α. Adv Healthc Mater, 2016, 5(11): 1299-1309.
36. Wu C, Zhou Y, Xu M, et al. Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. Biomaterials, 2013, 34(2): 422-433.
37. Wang W, Liu Y, Yang C, et al. Mesoporous bioactive glass combined with graphene oxide scaffolds for bone repair. Int J Biol Sci, 2019, 15(10): 2156-2169.
38. El-Fiqi A, Kim TH, Kim M, et al. Capacity of mesoporous bioactive glass nanoparticles to deliver therapeutic molecules. Nanoscale, 2012, 4(23): 7475-7488.
39. Li Y, Han W, Wu Y, et al. Stabilization of hypoxia inducible factor-1α by dimethyloxalylglycine oromotes recovery from acute spinal cord injury by inhibiting neural apoptosis and enhancing axon regeneration. J Neurotrauma, 2019, 36(24): 3394-3409.
40. 张磊, 龚跃昆, 赵学凌, 等. 低氧与低氧模拟剂对 BMSCs 成骨分化影响的对比研究. 中国修复重建外科杂志, 2016, 30(7): 903-908.
41. Jahangir S, Hosseini S, Mostafaei F, et al. 3D-porous β-tricalcium phosphate-alginate-gelatin scaffold with DMOG delivery promotes angiogenesis and bone formation in rat calvarial defects. J Mater Sci Mater Med, 2018, 30(1): 1.
42. Eslaminejad MB, Mirzadeh H, Mohamadi Y, et al. Bone differentiation of marrow-derived mesenchymal stem cells using beta-tricalcium phosphate-alginate-gelatin hybrid scaffolds. J Tissue Eng Regen Med, 2007, 1(6): 417-424.
43. Wu C, Zhou Y, Chang J, et al. Delivery of dimethyloxallyl glycine in mesoporous bioactive glass scaffolds to improve angiogenesis and osteogenesis of human bone marrow stromal cells. Acta Biomater, 2013, 9(11): 9159-9168.
44. Kim SY, Yang EG. Recent advances in developing inhibitors for hypoxia-inducible factor prolyl hydroxylases and their therapeutic implications. Molecules, 2015, 20(11): 20551-20568.
45. Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol, 2016, 11(6): 982-991.
46. Zhou M, Hou J, Li Y, et al. The pro-angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo tissue engineering chamber model. Sci Rep, 2019, 9(1): 6035.
47. Thirunavukkarasu M, Selvaraju V, Dunna NR, et al. Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF-1alpha)-prolyl-4-hydroxylase 3(PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat. Int J Cardiol, 2013, 168(3): 2474-2480.
48. Yu WL, Sun TW, Qi C, et al. Enhanced osteogenesis and angiogenesis by mesoporous hydroxyapatite microspheres-derived simvastatin sustained release system for superior bone regeneration. Sci Rep, 2017, 7: 44129.
49. Tan B, Luo Z, Yue Y, et al. Effects of FTY720 (Fingolimod) on proliferation, differentiation, and migration of brain-derived neural stem cells. Stem Cells Int, 2016, 2016: 9671732.
50. Li S, Song C, Yang S, et al. Supercritical CO₂ foamed composite scaffolds incorporating bioactive lipids promote vascularized bone regeneration via Hif-1alpha upregulation and enhanced type H vessel formation. Acta Biomater, 2019, 94: 253-267.
51. Chen X, Gu S, Chen BF, et al. Nanoparticle delivery of stable miR-199a-5p agomir improves the osteogenesis of human mesenchymal stem cells via the HIF1a pathway. Biomaterials, 2015, 53: 239-250.

Chinese Journal of Reparative and Reconstructive Surgery

Application status of hypoxia mimetic agents in bone tissue engineering

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