Research progress on controlled release of various growth factors in bone regeneration_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

JI Lin ¹ , SONG Ziwei ² , ZENG Fuhai ¹ , HU Ming ² , CHEN Siqi ¹ , QIN Zhongjie ² ,  XIA Delin ²

1. Department of Burn and Plastic Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China;
2. Department of Oral and Maxillofacial Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China;

Corresponding author：

XIA Delin, Email: xiadelin@163.com

Keywords：

Growth factor; controlled release; bone regeneration; angiogenesis

DOI：

10.7507/1002-1892.201901116

Video：

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Objective To summarize the research progress of controlled release of angiogenic factors and osteogenic factors in bone tissue engineering. Methods The domestic and abroad literature on the controlled release structure of growth factors during bone regeneration in recent years was extensively reviewed and summarized. Results The sustained-release structure includes direct binding, microsphere-three-dimensional scaffold structure, core-shell structure, layer self-assembly, hydrogel, and gene carrier. A sustained-release system composed of different sustained-release structures combined with different growth factors can promote bone regeneration and angiogenesis. Conclusion Due to its controllability and persistence, the growth factor sustained-release system has become a research hotspot in bone tissue engineering and has broad application prospects.

Citation： JI Lin, SONG Ziwei, ZENG Fuhai, HU Ming, CHEN Siqi, QIN Zhongjie, XIA Delin. Research progress on controlled release of various growth factors in bone regeneration. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(6): 750-755. doi: 10.7507/1002-1892.201901116 Copy

1.	Farokhi M, Mottaghitalab F, Shokrgozar MA, et al. Importance of dual delivery systems for bone tissue engineering. J Control Release, 2016, 225: 152-169.
2.	Bayer EA, Gottardi R, Fedorchak MV, et al. The scope and sequence of growth factor delivery for vascularized bone tissue regeneration. J Control Release, 2015, 219: 129-140.
3.	Larsen M, Willems WF, Pelzer M, et al. Augmentation of surgical angiogenesis in vascularized bone allotransplants with host-derived a/v bundle implantation, fibroblast growth factor-2, and vascular endothelial growth factor administration. J Orthop Res, 2010, 28(8): 1015-1021.
4.	Ren Q, Cai M, Zhang K, et al. Effects of bone morphogenetic protein-2(BMP-2) and vascular endothelial growth factor (VEGF) release from polylactide-poly (ethylene glycol)-polylactide (PELA) microcapsule-based scaffolds on bone. Braz J Med Biol Res, 2017, 51(2): e6520.
5.	Schindeler A, McDonald MM, Bokko P, et al. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol, 2008, 19(5): 459-466.
6.	Lienemann PS, Lutolf MP, Ehrbar M. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration. Adv Drug Deliv Rev, 2012, 64(12): 1078-1089.
7.	Kuttappan S, Mathew D, Jo JI, et al. Dual release of growth factor from a nanocomposite fibrous scaffold promotes vascularisation and bone regeneration in a rat critical sized calvarial defect. Acta Biomater, 2018, 78: 36-47.
8.	Liao H, Zhong Z, Liu Z, et al. Bone mesenchymal stem cells co-expressing VEGF and BMP-6 genes to combat avascular necrosis of the femoral head. Exp Ther Med, 2018, 15(1): 954-962.
9.	徐万林, 卢浩, 叶金海, 等. 载 VEGF₁₆₅ 多孔聚己内酯支架促进脂肪来源干细胞体内外成骨分化的实验研究. 中国修复重建外科杂志, 2018, 32(3): 270-275.
10.	Lee JH, Woo DK, Kim TH, et al. In vitro and long-term (2-year follow-up) in vivo osteogenic activities of human periosteum-derived osteoblasts seeded into growth factor-releasing polycaprolactone/pluronic F127 beads scaffolds. J Biomed Mater Res A, 2017, 105(2): 363-376.
11.	Bai Y, Bai L, Zhou J, et al. Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis. Cell Immunol, 2018, 323: 19-32.
12.	Marie PJ. Fibroblast growth factor signaling controlling bone formation: an update. Gene, 2012, 498(1): 1-4.
13.	Tengood JE, Ridenour R, Brodsky R, et al. Sequential delivery of basic fibroblast growth factor and platelet-derived growth factor for angiogenesis. Tissue Eng Part A, 2011, 17(9-10): 1181-1189.
14.	Bishop GB, Einhorn TA. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop, 2007, 31(6): 721-727.
15.	Deckers MM, van Bezooijen RL, van der Horst G, et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology, 2002, 143(4): 1545-1553.
16.	Phipps MC, Xu Y, Bellis SL, et al. Delivery of platelet-derived growth factor as a chemotactic factor for mesenchymal stem cells by bone-mimetic electrospun scaffolds. PLoS One, 2012, 7(7): e40831.
17.	Zara JN, Siu RK, Zhang X, et al. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng Part A, 2011, 17(9-10): 1389-1399.
18.	Wang Q, Zhang YX, Li B, et al. Controlled dual delivery of low doses of BMP-2 and VEGF in a silk fibroin-nanohydroxyapatite scaffold for vascularized bone regeneration. J Mater Chem B, 2017, 5(33): 6953-6972.
19.	Peng H, Wright V, Usas A, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest, 2002, 110(6): 751-759.
20.	Martino MM, Briquez PS, Maruyama K, et al. Extracellular matrix-inspired growth factor delivery systems for bone regeneration. Adv Drug Deliv Rev, 2015, 94: 41-52.
21.	Sharma S, Sapkota D, Xue Y, et al. Delivery of VEGFA in bone marrow stromal cells seeded in copolymer scaffold enhances angiogenesis, but is inadequate for osteogenesis as compared with the dual delivery of VEGFA and BMP2 in a subcutaneous mouse model. Stem Cell Res Ther, 2018, 9(1): 23.
22.	刘宁, 王佐林. 多因子释放系统在组织工程领域的应用. 口腔颌面外科杂志, 2016, 26(2): 135-139.
23.	唐功文, 赵蕴慧, 袁晓燕. 微球-三维支架复合体系控制释放生长因子的研究进展. 高分子通报, 2012, (12): 8-15.
24.	Eğri S, Eczacıoğlu N. Sequential VEGF and BMP-2 releasing PLA-PEG-PLA scaffolds for bone tissue engineering: I. Design and in vitro tests. Artif Cells Nanomed Biotechnol, 2017, 45(2): 321-329.
25.	陈家磊, 刘明, 段鑫, 等. BMP-7/聚乳酸-羟基乙酸共聚物缓释微球对兔 BMSCs 增殖和成软骨分化的影响. 中国修复重建外科杂志, 2018, 32(4): 428-433.
26.	Kim S, Kang Y, Krueger CA, et al. Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation. Acta Biomater, 2012, 8(5): 1768-1777.
27.	Kempen DH, Lu L, Heijink A, et al. Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials, 2009, 30(14): 2816-2825.
28.	Lei L, Wang S, Wu H, et al. Optimization of release pattern of FGF-2 and BMP-2 for osteogenic differentiation of low-population density hMSCs. J Biomed Mater Res A, 2015, 103(1): 252-261.
29.	Wang Y, Wei Y, Zhang XH, et al. PLGA/PDLLA core-shell submicron spheres sequential release system: Preparation, characterization and promotion of bone regeneration in vitro and in vivo. Chemical Engineering Journal, 2015, 273: 490-501.
30.	Chen X, Xu J, Xiao L, et al. Double-layered microsphere based dual growth factor delivery system for guided bone regeneration. RSC Advances, 2018, 8(30): 16503-16512.
31.	Rinker TE, Philbrick BD, Temenoff JS. Core-shell microparticles for protein sequestration and controlled release of a protein-laden core. Acta Biomater, 2017, 56: 91-101.
32.	Shah NJ, Macdonald ML, Beben YM, et al. Tunable dual growth factor delivery from polyelectrolyte multilayer films. Biomaterials, 2011, 32(26): 6183-6193.
33.	Koutsopoulos S, Unsworth LD, Nagai Y, et al. Controlled release of functional proteins through designer self-assembling peptide nanofiber hydrogel scaffold. Proc Natl Acad Sci U S A, 2009, 106(12): 4623-4628.
34.	Müller S, Koeing G, Charpiot A, et al. VEGF-functionalized polyelectrolyte multilayers as proangiogenic prosthetic coatings. Advanced Functional Materials, 2010, 18(12): 1767-1775.
35.	Cai P, Xue ZY, Qi W, et al. Adsorbed BMP-2 in polyelectrolyte multilayer films for enhanced early osteogenic differentiation of mesenchymal stem cells. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2013, 434(19): 110-117.
36.	Yu X, Khalil A, Dang PN, et al. Multilayered inorganic microparticles for tunable dual growth factor delivery. Adv Funct Mater, 2014, 24(20): 3082-3093.
37.	Gronowicz G, Jacobs E, Peng T, et al. Calvarial bone regeneration is enhanced by sequential delivery of FGF-2 and BMP-2 from layer-by-layer coatings with a biomimetic calcium phosphate barrier layer. Tissue Engineering Part A, 2017, 23(23-24).
38.	余海湖, 秦麟卿, 周灵德, 等. 自组装聚电解质薄膜的低角度 X 射线衍射研究. 胶体与聚合物, 2002, 20(3): 18-20.
39.	Kim SK, Cho TH, Han JJ, et al. Comparative study of BMP-2 alone and combined with VEGF carried by hydrogel for maxillary alveolar bone regeneration. Tissue Eng Regen Med, 2016, 13(2): 171-181.
40.	Agrawal V, Sinha M. A review on carrier systems for bone morphogenetic protein-2. J Biomed Mater Res B Appl Biomater, 2017, 105(4): 904-925.
41.	Han F, Zhou F, Yang X, et al. A pilot study of conically graded chitosan-gelatin hydrogel/PLGA scaffold with dual-delivery of TGF-β1 and BMP-2 for regeneration of cartilage-bone interface. J Biomed Mater Res B Appl Biomater, 2015, 103(7): 1344-1353.
42.	Zhang W, Wang X, Wang S, et al. The use of injectable sonication-induced silk hydrogel for VEGF(165) and BMP-2 delivery for elevation of the maxillary sinus floor. Biomaterials, 2011, 32(35): 9415-9424.
43.	Barati D, Shariati SRP, Moeinzadeh S, et al. Spatiotemporal release of BMP-2 and VEGF enhances osteogenic and vasculogenic differentiation of human mesenchymal stem cells and endothelial colony-forming cells co-encapsulated in a patterned hydrogel. J Control Release, 2016, 223: 126-136.
44.	Zhang C, Meng C, Guan D, et al. BMP2 and VEGF165 transfection to bone marrow stromal stem cells regulate osteogenic potential in vitro. Medicine (Baltimore), 2018, 97(5): e9787.
45.	Zhang C, Liu HM, Li QW, et al. Construction of recombinant adenovirus vector containing hBMP2 and hVEGF165 genes and its expression in rabbit Bone marrow mesenchymal stem cells. Tissue Cell, 2014, 46(5): 311-317.

1. Farokhi M, Mottaghitalab F, Shokrgozar MA, et al. Importance of dual delivery systems for bone tissue engineering. J Control Release, 2016, 225: 152-169.
2. Bayer EA, Gottardi R, Fedorchak MV, et al. The scope and sequence of growth factor delivery for vascularized bone tissue regeneration. J Control Release, 2015, 219: 129-140.
3. Larsen M, Willems WF, Pelzer M, et al. Augmentation of surgical angiogenesis in vascularized bone allotransplants with host-derived a/v bundle implantation, fibroblast growth factor-2, and vascular endothelial growth factor administration. J Orthop Res, 2010, 28(8): 1015-1021.
4. Ren Q, Cai M, Zhang K, et al. Effects of bone morphogenetic protein-2(BMP-2) and vascular endothelial growth factor (VEGF) release from polylactide-poly (ethylene glycol)-polylactide (PELA) microcapsule-based scaffolds on bone. Braz J Med Biol Res, 2017, 51(2): e6520.
5. Schindeler A, McDonald MM, Bokko P, et al. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol, 2008, 19(5): 459-466.
6. Lienemann PS, Lutolf MP, Ehrbar M. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration. Adv Drug Deliv Rev, 2012, 64(12): 1078-1089.
7. Kuttappan S, Mathew D, Jo JI, et al. Dual release of growth factor from a nanocomposite fibrous scaffold promotes vascularisation and bone regeneration in a rat critical sized calvarial defect. Acta Biomater, 2018, 78: 36-47.
8. Liao H, Zhong Z, Liu Z, et al. Bone mesenchymal stem cells co-expressing VEGF and BMP-6 genes to combat avascular necrosis of the femoral head. Exp Ther Med, 2018, 15(1): 954-962.
9. 徐万林, 卢浩, 叶金海, 等. 载 VEGF₁₆₅ 多孔聚己内酯支架促进脂肪来源干细胞体内外成骨分化的实验研究. 中国修复重建外科杂志, 2018, 32(3): 270-275.
10. Lee JH, Woo DK, Kim TH, et al. In vitro and long-term (2-year follow-up) in vivo osteogenic activities of human periosteum-derived osteoblasts seeded into growth factor-releasing polycaprolactone/pluronic F127 beads scaffolds. J Biomed Mater Res A, 2017, 105(2): 363-376.
11. Bai Y, Bai L, Zhou J, et al. Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis. Cell Immunol, 2018, 323: 19-32.
12. Marie PJ. Fibroblast growth factor signaling controlling bone formation: an update. Gene, 2012, 498(1): 1-4.
13. Tengood JE, Ridenour R, Brodsky R, et al. Sequential delivery of basic fibroblast growth factor and platelet-derived growth factor for angiogenesis. Tissue Eng Part A, 2011, 17(9-10): 1181-1189.
14. Bishop GB, Einhorn TA. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop, 2007, 31(6): 721-727.
15. Deckers MM, van Bezooijen RL, van der Horst G, et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology, 2002, 143(4): 1545-1553.
16. Phipps MC, Xu Y, Bellis SL, et al. Delivery of platelet-derived growth factor as a chemotactic factor for mesenchymal stem cells by bone-mimetic electrospun scaffolds. PLoS One, 2012, 7(7): e40831.
17. Zara JN, Siu RK, Zhang X, et al. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng Part A, 2011, 17(9-10): 1389-1399.
18. Wang Q, Zhang YX, Li B, et al. Controlled dual delivery of low doses of BMP-2 and VEGF in a silk fibroin-nanohydroxyapatite scaffold for vascularized bone regeneration. J Mater Chem B, 2017, 5(33): 6953-6972.
19. Peng H, Wright V, Usas A, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest, 2002, 110(6): 751-759.
20. Martino MM, Briquez PS, Maruyama K, et al. Extracellular matrix-inspired growth factor delivery systems for bone regeneration. Adv Drug Deliv Rev, 2015, 94: 41-52.
21. Sharma S, Sapkota D, Xue Y, et al. Delivery of VEGFA in bone marrow stromal cells seeded in copolymer scaffold enhances angiogenesis, but is inadequate for osteogenesis as compared with the dual delivery of VEGFA and BMP2 in a subcutaneous mouse model. Stem Cell Res Ther, 2018, 9(1): 23.
22. 刘宁, 王佐林. 多因子释放系统在组织工程领域的应用. 口腔颌面外科杂志, 2016, 26(2): 135-139.
23. 唐功文, 赵蕴慧, 袁晓燕. 微球-三维支架复合体系控制释放生长因子的研究进展. 高分子通报, 2012, (12): 8-15.
24. Eğri S, Eczacıoğlu N. Sequential VEGF and BMP-2 releasing PLA-PEG-PLA scaffolds for bone tissue engineering: I. Design and in vitro tests. Artif Cells Nanomed Biotechnol, 2017, 45(2): 321-329.
25. 陈家磊, 刘明, 段鑫, 等. BMP-7/聚乳酸-羟基乙酸共聚物缓释微球对兔 BMSCs 增殖和成软骨分化的影响. 中国修复重建外科杂志, 2018, 32(4): 428-433.
26. Kim S, Kang Y, Krueger CA, et al. Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation. Acta Biomater, 2012, 8(5): 1768-1777.
27. Kempen DH, Lu L, Heijink A, et al. Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials, 2009, 30(14): 2816-2825.
28. Lei L, Wang S, Wu H, et al. Optimization of release pattern of FGF-2 and BMP-2 for osteogenic differentiation of low-population density hMSCs. J Biomed Mater Res A, 2015, 103(1): 252-261.
29. Wang Y, Wei Y, Zhang XH, et al. PLGA/PDLLA core-shell submicron spheres sequential release system: Preparation, characterization and promotion of bone regeneration in vitro and in vivo. Chemical Engineering Journal, 2015, 273: 490-501.
30. Chen X, Xu J, Xiao L, et al. Double-layered microsphere based dual growth factor delivery system for guided bone regeneration. RSC Advances, 2018, 8(30): 16503-16512.
31. Rinker TE, Philbrick BD, Temenoff JS. Core-shell microparticles for protein sequestration and controlled release of a protein-laden core. Acta Biomater, 2017, 56: 91-101.
32. Shah NJ, Macdonald ML, Beben YM, et al. Tunable dual growth factor delivery from polyelectrolyte multilayer films. Biomaterials, 2011, 32(26): 6183-6193.
33. Koutsopoulos S, Unsworth LD, Nagai Y, et al. Controlled release of functional proteins through designer self-assembling peptide nanofiber hydrogel scaffold. Proc Natl Acad Sci U S A, 2009, 106(12): 4623-4628.
34. Müller S, Koeing G, Charpiot A, et al. VEGF-functionalized polyelectrolyte multilayers as proangiogenic prosthetic coatings. Advanced Functional Materials, 2010, 18(12): 1767-1775.
35. Cai P, Xue ZY, Qi W, et al. Adsorbed BMP-2 in polyelectrolyte multilayer films for enhanced early osteogenic differentiation of mesenchymal stem cells. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2013, 434(19): 110-117.
36. Yu X, Khalil A, Dang PN, et al. Multilayered inorganic microparticles for tunable dual growth factor delivery. Adv Funct Mater, 2014, 24(20): 3082-3093.
37. Gronowicz G, Jacobs E, Peng T, et al. Calvarial bone regeneration is enhanced by sequential delivery of FGF-2 and BMP-2 from layer-by-layer coatings with a biomimetic calcium phosphate barrier layer. Tissue Engineering Part A, 2017, 23(23-24).
38. 余海湖, 秦麟卿, 周灵德, 等. 自组装聚电解质薄膜的低角度 X 射线衍射研究. 胶体与聚合物, 2002, 20(3): 18-20.
39. Kim SK, Cho TH, Han JJ, et al. Comparative study of BMP-2 alone and combined with VEGF carried by hydrogel for maxillary alveolar bone regeneration. Tissue Eng Regen Med, 2016, 13(2): 171-181.
40. Agrawal V, Sinha M. A review on carrier systems for bone morphogenetic protein-2. J Biomed Mater Res B Appl Biomater, 2017, 105(4): 904-925.
41. Han F, Zhou F, Yang X, et al. A pilot study of conically graded chitosan-gelatin hydrogel/PLGA scaffold with dual-delivery of TGF-β1 and BMP-2 for regeneration of cartilage-bone interface. J Biomed Mater Res B Appl Biomater, 2015, 103(7): 1344-1353.
42. Zhang W, Wang X, Wang S, et al. The use of injectable sonication-induced silk hydrogel for VEGF(165) and BMP-2 delivery for elevation of the maxillary sinus floor. Biomaterials, 2011, 32(35): 9415-9424.
43. Barati D, Shariati SRP, Moeinzadeh S, et al. Spatiotemporal release of BMP-2 and VEGF enhances osteogenic and vasculogenic differentiation of human mesenchymal stem cells and endothelial colony-forming cells co-encapsulated in a patterned hydrogel. J Control Release, 2016, 223: 126-136.
44. Zhang C, Meng C, Guan D, et al. BMP2 and VEGF165 transfection to bone marrow stromal stem cells regulate osteogenic potential in vitro. Medicine (Baltimore), 2018, 97(5): e9787.
45. Zhang C, Liu HM, Li QW, et al. Construction of recombinant adenovirus vector containing hBMP2 and hVEGF165 genes and its expression in rabbit Bone marrow mesenchymal stem cells. Tissue Cell, 2014, 46(5): 311-317.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress on controlled release of various growth factors in bone regeneration

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