Advertisement

Current advances for bone regeneration based on tissue engineering strategies

  • Rui Shi
  • Yuelong Huang
  • Chi Ma
  • Chengai Wu
  • Wei Tian
Review

Abstract

Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration.

Keywords

bone tissue engineering stem cell bone scaffold growth factor bone regeneration 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 51673029, 81330043, and 81071499), Beijing Talent Fund (No. 2016000021223ZK34), and another fund (No. PXM2018_026275_000001).

References

  1. 1.
    Khan SN, Cammisa FPJr, Sandhu HS, Diwan AD, Girardi FP, Lane JM. The biology of bone grafting. J Am Acad Orthop Surg 2005; 13(1): 77–86PubMedCrossRefGoogle Scholar
  2. 2.
    Oryan A, Alidadi S, Moshiri A, Maffulli N. Bone regenerative medicine: classic options, novel strategies, and future directions. J Orthop Surg Re. 2014; 9(1): 18CrossRefGoogle Scholar
  3. 3.
    Swetha M, Sahithi K, Moorthi A, Srinivasan N, Ramasamy K, Selvamurugan N. Biocomposites containing natural polymers and hydroxyapatite for bone tissue engineering. Int J Biol Macromol 2010; 47(1): 1–4PubMedCrossRefGoogle Scholar
  4. 4.
    Hosseinkhani M, Mehrabani D, Karimfar MH, Bakhtiyari S, Manafi A, Shirazi R. Tissue engineered scaffolds in regenerative medicine. World J Plast Surg 2014; 3(1): 3–7PubMedPubMedCentralGoogle Scholar
  5. 5.
    Gómez S, Vlad MD, López J, Fernández E. Design and properties of 3D scaffolds for bone tissue engineering. Acta Biomate. 2016; 42: 341–350CrossRefGoogle Scholar
  6. 6.
    D’souza N, Rossignoli F, Golinelli G, Grisendi G, Spano C, Candini O, Osturu S, Catani F, Paolucci P, Horwitz EM, Dominici M. Mesenchymal stem/stromal cells as a delivery platform in cell and gene therapies. BMC Me. 2015; 13(1): 186CrossRefGoogle Scholar
  7. 7.
    Pittenger MF. Mesenchymal stem cells from adult bone marrow. Methods Mol Biol 2008; 449: 27–44PubMedGoogle Scholar
  8. 8.
    Wang ZG, Wang Y, Huang Y, Lu Q, Zheng L, Hu D, Feng WK, Liu YL, Ji KT, Zhang HY, Fu XB, Li XK, Chu MP, Xiao J. bFGF regulates autophagy and ubiquitinated protein accumulation induced by myocardial ischemia/reperfusion via the activation of th. PI3K/Akt/mTOR pathway. Sci Re. 2015; 5(1): 9287Google Scholar
  9. 9.
    Nguyen MK, Alsberg E. Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine. Prog Polym Sc. 2014; 39(7): 1235–1265CrossRefGoogle Scholar
  10. 10.
    Polo-Corrales L, Latorre-Esteves M, Ramirez-Vick JE. Scaffold design for bone regeneration. J Nanosci Nanotechnol 2014; 14(1): 15–56PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Porter JR, Ruckh TT, Popat KC. Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog 2009; 25(6): 1539–1560PubMedGoogle Scholar
  12. 12.
    Gong T, Xie J, Liao J, Zhang T, Lin S, Lin Y. Nanomaterials and bone regeneration. Bone Re. 2015; 3(1): 15029CrossRefGoogle Scholar
  13. 13.
    Tang D, Tare RS, Yang LY, Williams DF, Ou KL, Oreffo RO. Biofabrication of bone tissue: approaches, challenges and translation for bone regeneration. Biomaterials 2016; 83: 363–382PubMedCrossRefGoogle Scholar
  14. 14.
    Harris GM, Rutledge K, Cheng Q, Blanchette J, Jabbarzadeh E. Strategies to direct angiogenesis within scaffolds for bone tissue engineering. Curr Pharm De. 2013; 19(19): 3456–3465CrossRefGoogle Scholar
  15. 15.
    Fernandez-Yague MA, Abbah SA, McNamara L, Zeugolis DI, Pandit A, Biggs MJ. Biomimetic approaches in bone tissue engineering. Integrating biological and physicomechanical strategies. Adv Drug Deliv Re. 2015; 84: 1–29CrossRefGoogle Scholar
  16. 16.
    Li Y, Thula TT, Jee S, Perkins SL, Aparicio C, Douglas EP, Gower LB. Biomimetic mineralization of woven bone-like nanocomposites: role of collagen cross-links. Biomacromolecules 2012; 13(1): 49–59PubMedCrossRefGoogle Scholar
  17. 17.
    Venkatesan J, Kim SK. Nano-hydroxyapatite composite biomaterials for bone tissue engineering—a review. J Biomed Nanotechnol 2014; 10(10): 3124–3140PubMedCrossRefGoogle Scholar
  18. 18.
    Sang L, Huang J, Luo D, Chen Z, Li X. Bone-like nanocomposites based on self-assembled protein-based matrices with Ca2+ capturing capability. J Mater Sci Mater Me. 2010; 21(9): 2561–2568CrossRefGoogle Scholar
  19. 19.
    Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials 2000; 21(24): 2529–2543PubMedCrossRefGoogle Scholar
  20. 20.
    Osathanon T, Linnes ML, Rajachar RM, Ratner BD, Somerman MJ, Giachelli CM. Microporous nanofibrous fibrin-based scaffolds for bone tissue engineering. Biomaterials 2008; 29(30): 4091–4099PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Lin KF, He S, Song Y, Wang CM, Gao Y, Li JQ, Tang P, Wang Z, Bi L, Pei GX. Low-temperature additive manufacturing of biomimic three-dimensional hydroxyapatite/collagen scaffolds for bone regeneration. ACS Appl Mater Interfaces 2016; 8(11): 6905–6916PubMedCrossRefGoogle Scholar
  22. 22.
    Ryan GE, Pandit AS, Apatsidis DP. Porous titanium scaffolds fabricated using a rapid prototyping and powder metallurgy technique. Biomaterials 2008; 29(27): 3625–3635PubMedCrossRefGoogle Scholar
  23. 23.
    Patra S, Young V. A review of 3D printing techniques and the future in biofabrication of bioprinted tissue. Cell Biochem Biophy. 2016; 74(2): 93–98CrossRefGoogle Scholar
  24. 24.
    Brunello G, Sivolella S, Meneghello R, Ferroni L, Gardin C, Piattelli A, Zavan B, Bressan E. Powder-based 3D printing for bone tissue engineering. Biotechnol Ad. 2016; 34(5): 740–753CrossRefGoogle Scholar
  25. 25.
    Warnke PH, Seitz H, Warnke F, Becker ST, Sivananthan S, Sherry E, Liu Q, Wiltfang J, Douglas T. Ceramic scaffolds produced by computer-assisted 3D printing and sintering: characterization and biocompatibility investigations. J Biomed Mater Res B Appl Biomate. 2010; 93(1): 212–217Google Scholar
  26. 26.
    Xia Y, Zhou P, Cheng X, Xie Y, Liang C, Li C, Xu S. Selective laser sintering fabrication of nano-hydroxyapatite/poly-e-caprolactone scaffolds for bone tissue engineering applications. Int J Nanomedicine 2013; 8: 4197–4213PubMedPubMedCentralGoogle Scholar
  27. 27.
    Chia HN, Wu BM. Recent advances in 3D printing of biomaterials. J Biol En. 2015; 9(1): 4CrossRefGoogle Scholar
  28. 28.
    Mota C, Puppi D, Chiellini F, Chiellini E. Additive manufacturing techniques for the production of tissue engineering constructs. J Tissue Eng Regen Me. 2015; 9(3): 174–190CrossRefGoogle Scholar
  29. 29.
    Zhang LC, Attar H, Calin M, Eckert J. Review on manufacture by selective laser melting and properties of titanium based materials for biomedical applications. Mater Techno. 2016; 31(2): 66–76CrossRefGoogle Scholar
  30. 30.
    Körner C. Additive manufacturing of metallic components by selective electron beam melting—a review. Int Mater Re. 2016; 61(5): 361–367CrossRefGoogle Scholar
  31. 31.
    Bose S, Tarafder S, Bandyopadhyay A. Effect of chemistry on osteogenesis and angiogenesis towards bone tissue engineering using 3D printed scaffolds. Ann Biomed En. 2017; 45(1): 261–272CrossRefGoogle Scholar
  32. 32.
    Torres J, Tamimi F, Alkhraisat MH, Prados-Frutos JC, Rastikerdar E, Gbureck U, Barralet JE, López-Cabarcos E. Vertical bone augmentation with 3D-synthetic monetite blocks in the rabbit calvaria. J Clin Periodonto. 2011; 38(12): 1147–1153CrossRefGoogle Scholar
  33. 33.
    Tarafder S, Davies NM, Bandyopadhyay A, Bose S. 3D printed tricalcium phosphate scaffolds: effect o. SrO and MgO doping on in vivo osteogenesis in a rat distal femoral defect model. Biomater Sc. 2013; 1(12): 1250–1259CrossRefGoogle Scholar
  34. 34.
    Tamimi F, Torres J, Al-Abedalla K, Lopez-Cabarcos E, Alkhraisat MH, Bassett DC, Gbureck U, Barralet JE. Osseointegration of dental implants in 3D-printed synthetic onlay grafts customized according to bone metabolic activity in recipient site. Biomaterials 2014; 35(21): 5436–5445PubMedCrossRefGoogle Scholar
  35. 35.
    Castilho M, Dias M, Vorndran E, Gbureck U, Fernandes P, Pires I, Gouveia B, Armés H, Pires E, Rodrigues J. Application of a 3D printed customized implant for canine cruciate ligament treatment by tibial tuberosity advancement. Biofabricatio. 2014; 6(2): 025005CrossRefGoogle Scholar
  36. 36.
    Ronca A, Ambrosio L, Grijpma DW. Design of porous threedimensiona. PDLLA/nano-hap composite scaffolds using stereolithography. J Appl Biomater Funct Mate. 2012; 10(3): 249–258Google Scholar
  37. 37.
    Lan PX, Lee JW, Seol YJ, Cho DW. Development of 3. PPF/DEF scaffolds using micro-stereolithography and surface modification. J Mater Sci Mater Me. 2009; 20(1): 271–279CrossRefGoogle Scholar
  38. 38.
    Guo R, Lu S, Page JM, Merkel AR, Basu S, Sterling JA, Guelcher SA. Fabrication of 3D scaffolds with precisely controlled substrate modulus and pore size by templated-fused deposition modeling to direct osteogenic differentiation. Adv Healthc Mater 2015; 4(12): 1826–1832PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Nowicki MA, Castro NJ, Plesniak MW, Zhang LG. 3D printing of novel osteochondral scaffolds with graded microstructure. Nanotechnology 2016; 27(41): 414001PubMedCrossRefGoogle Scholar
  40. 40.
    Ostrowska B, Di Luca A, Szlazak K, Moroni L, Swieszkowski W. Influence of internal pore architecture on biological and mechanical properties of three-dimensional fiber deposited scaffolds for bone regeneration. J Biomed Mater Res. 2016; 104(4): 991–1001CrossRefGoogle Scholar
  41. 41.
    Xu N, Ye X, Wei D, Zhong J, Chen Y, Xu G, He D. 3D artificial bones for bone repair prepared by computed tomography-guided fused deposition modeling for bone repair. ACS Appl Mater Interfaces 2014; 6(17): 14952–14963PubMedCrossRefGoogle Scholar
  42. 42.
    Xuan Y, Tang H, Wu B, Ding X, Lu Z, Li W, Xu Z. A specific groove design for individualized healing in a canine partial sternal defect model by a polycaprolactone/hydroxyapatite scaffold coated with bone marrow stromal cells. J Biomed Mater Res. 2014; 102(10): 3401–3408CrossRefGoogle Scholar
  43. 43.
    Mehta M, Schmidt-Bleek K, Duda GN, Mooney DJ. Biomaterial delivery of morphogens to mimic the natural healing cascade in bone. Adv Drug Deliv Rev 2012; 64(12): 1257–1276PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Farokhi M, Mottaghitalab F, Shokrgozar MA, Ou KL, Mao C, Hosseinkhani H. Importance of dual delivery systems for bone tissue engineering. J Control Releas. 2016; 225: 152–169CrossRefGoogle Scholar
  45. 45.
    McFadden TM, Duffy GP, Allen AB, Stevens HY, Schwarzmaier SM, Plesnila N, Murphy JM, Barry FP, Guldberg RE, O’Brien FJ. The delayed addition of human mesenchymal stem cells to preformed endothelial cell networks results in functional vascularization of a collagen-glycosaminoglycan scaffold in vivo. Acta Biomater 2013; 9(12): 9303–9316PubMedCrossRefGoogle Scholar
  46. 46.
    Bayer EA, Gottardi R, Fedorchak MV, Little SR. The scope and sequence of growth factor delivery for vascularized bone tissue regeneration. J Control Release 2015; 219: 129–140PubMedCrossRefGoogle Scholar
  47. 47.
    Basmanav FB, Kose GT, Hasirci V. Sequential growth factor delivery from complexed microspheres for bone tissue engineering. Biomaterial. 2008; 29(31): 4195–4204CrossRefGoogle Scholar
  48. 48.
    Kim S, Kang Y, Krueger CA, Sen M, Holcomb JB, Chen D, Wenke JC, Yang Y. Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation. Acta Biomate. 2012; 8(5): 1768–1777CrossRefGoogle Scholar
  49. 49.
    Rothstein SN, Huber KD, Sluis-Cremer N, Little SR. In vitro characterization of a sustained-release formulation for enfuvirtide. Antimicrob Agents Chemother 2014; 58(3): 1797–1799PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Perez RA, Kim HW. Core-shell designed scaffolds for drug delivery and tissue engineering. Acta Biomater 2015; 21: 2–19PubMedCrossRefGoogle Scholar
  51. 51.
    Kempen DH, Lu L, Heijink A, Hefferan TE, Creemers LB, Maran A, Yaszemski MJ, Dhert WJ. Effect of local sequentia. VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterial. 2009; 30(14): 2816–2825CrossRefGoogle Scholar
  52. 52.
    Wu C, Fan W, Gelinsky M, Xiao Y, Chang J, Friis T, Cuniberti G. In situ preparation and protein delivery of silicate-alginate composite microspheres with core-shell structure. J R Soc Interface 2011; 8(65): 1804–1814PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Bai Y, Leng Y, Yin G, Pu X, Huang Z, Liao X, Chen X, Yao Y. Effects of combinations of BMP-2 with FGF-2 and/or VEGF on HUVECs angiogenesis in vitro and CAM angiogenesis in vivo. Cell Tissue Re. 2014; 356(1): 109–121CrossRefGoogle Scholar
  54. 54.
    Boanini E, Bigi A. Biomimetic gelatin-octacalcium phosphate core–shell microspheres. J Colloid Interface Sci 2011; 362(2):594–599PubMedCrossRefGoogle Scholar
  55. 55.
    Kim K, Lam J, Lu S, Spicer PP, Lueckgen A, Tabata Y, Wong ME, Jansen JA, Mikos AG, Kasper FK. Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. J Control Releas. 2013; 168(2): 166–178CrossRefGoogle Scholar
  56. 56.
    Lu S, Lam J, Trachtenberg JE, Lee EJ, Seyednejad H, van de Beucken JJJP, Tabata Y, Wong ME, Jansen JA, Mikos AG, Kasper FK. Dual growth factor delivery from bilayered, biodegradable hydrogel composites for spatially-guided osteochondral tissue repair. Biomaterial. 2014; 35(31): 8829–8839CrossRefGoogle Scholar
  57. 57.
    Shah NJ, Hyder MN, Quadir MA, Dorval Courchesne NM, Seeherman HJ, Nevins M, Spector M, Hammond PT. Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction. Proc Natl Acad Sci USA 2014; 111(35): 12847–12852PubMedCrossRefGoogle Scholar
  58. 58.
    DeMuth PC, Moon JJ, Suh H, Hammond PT, Irvine DJ. Releasable layer-by-layer assembly of stabilized lipid nanocapsules on microneedles for enhanced transcutaneous vaccine delivery. ACS Nano 2012; 6(9): 8041–8051PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Min J, Braatz RD, Hammond PT. Tunable staged release of therapeutics from layer-by-layer coatings with clay interlayer barrier. Biomaterials 2014; 35(8): 2507–2517PubMedCrossRefGoogle Scholar
  60. 60.
    Derby B. Printing and prototyping of tissues and scaffolds. Scienc. 2012; 338(6109): 921–926CrossRefGoogle Scholar
  61. 61.
    Li J, Chen M, Fan X, Zhou H. Recent advances in bioprinting techniques: approaches, applications and future prospects. J Transl Me. 2016; 14(1): 271CrossRefGoogle Scholar
  62. 62.
    Kang HW, Lee SJ, Ko IK, Kengla C, Yoo JJ, Atala A. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat Biotechno. 2016; 34(3): 312–319CrossRefGoogle Scholar
  63. 63.
    Gudapati H, Dey M, Ozbolat I. A comprehensive review on droplet-based bioprinting: past, present and future. Biomaterial. 2016; 102: 20–42CrossRefGoogle Scholar
  64. 64.
    Cui X, Breitenkamp K, Finn MG, Lotz M, D’Lima DD. Direct human cartilage repair using three-dimensional bioprinting technology. Tissue Eng Part. 2012; 18(11–12): 1304–1312CrossRefGoogle Scholar
  65. 65.
    Cui X, Breitenkamp K, Lotz M, D’Lima D. Synergistic action of fibroblast growth factor-2 and transforming growth factor-ß1 enhances bioprinted human neocartilage formation. Biotechnol Bioen. 2012; 109(9): 2357–2368CrossRefGoogle Scholar
  66. 66.
    Cui X, Gao G, Qiu Y. Accelerated myotube formation using bioprinting technology for biosensor applications. Biotechnol Let. 2013; 35(3): 315–321CrossRefGoogle Scholar
  67. 67.
    Gao G, Schilling AF, Yonezawa T, Wang J, Dai G, Cui X. Bioactive nanoparticles stimulate bone tissue formation in bioprinted three-dimensional scaffold and human mesenchymal stem cells. Biotechnol J 2014; 9(10): 1304–1311PubMedCrossRefGoogle Scholar
  68. 68.
    Gao G, Yonezawa T, Hubbell K, Dai G, Cui X. Inkjet-bioprinted acrylated peptides and PEG hydrogel with human mesenchymal stem cells promote robust bone and cartilage formation with minimal printhead clogging. Biotechnol J 2015; 10(10): 1568–1577PubMedCrossRefGoogle Scholar
  69. 69.
    Gao G, Schilling AF, Hubbell K, Yonezawa T, Truong D, Hong Y, Dai G, Cui X. Improved properties of bone and cartilage tissue from 3D inkjet-bioprinted human mesenchymal stem cells by simultaneous deposition and photocrosslinking in PEG-GelMA. Biotechnol Let. 2015; 37(11): 2349–2355CrossRefGoogle Scholar
  70. 70.
    Mandrycky C, Wang Z, Kim K, Kim DH. 3D bioprinting for engineering complex tissues. Biotechnol Adv 2016; 34(4): 422–434PubMedCrossRefGoogle Scholar
  71. 71.
    Ozbolat IT, Hospodiuk M. Current advances and future perspectives in extrusion-based bioprinting. Biomaterial. 2016; 76: 321–343CrossRefGoogle Scholar
  72. 72.
    Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol 2014; 32(8): 773–785PubMedCrossRefGoogle Scholar
  73. 73.
    Lu CH, Chang YH, Lin SY, Li KC, Hu YC. Recent progresses in gene delivery-based bone tissue engineering. Biotechnol Adv 2013; 31(8): 1695–1706PubMedCrossRefGoogle Scholar
  74. 74.
    Carlier A, Skvortsov GA, Hafezi F, Ferraris E, Patterson J, Koç B, Van Oosterwyck H. Computational model-informed design and bioprinting of cell-patterned constructs for bone tissue engineering. Biofabricatio. 2016; 8(2): 025009CrossRefGoogle Scholar
  75. 75.
    Koch L, Gruene M, Unger C, Chichkov B. Laser assisted cell printing. Curr Pharm Biotechno. 2013; 14(1): 91–97Google Scholar
  76. 76.
    Jana S, Lerman A. Bioprinting a cardiac valve. Biotechnol Ad. 2015; 33(8): 1503–1521CrossRefGoogle Scholar
  77. 77.
    Catros S, Fricain JC, Guillotin B, Pippenger B, Bareille R, Remy M, Lebraud E, Desbat B, Amédée J, Guillemot F. Laser-assisted bioprinting for creating on-demand patterns of human osteoprogenitor cells and nano-hydroxyapatite. Biofabricatio. 2011; 3(2): 025001CrossRefGoogle Scholar
  78. 78.
    Ali M, Pages E, Ducom A, Fontaine A, Guillemot F. Controlling laser-induced jet formation for bioprinting mesenchymal stem cells with high viability and high resolution. Biofabricatio. 2014; 6(4): 045001CrossRefGoogle Scholar
  79. 79.
    Yao Q, Wei B, Guo Y, Jin C, Du X, Yan C, Yan J, Hu W, Xu Y, Zhou Z, Wang Y, Wang L. Design, construction and mechanical testing of digital 3D anatomical data-based PCL-HA bone tissue engineering scaffold. J Mater Sci Mater Me. 2015; 26(1): 51CrossRefGoogle Scholar
  80. 80.
    Pati F, Song TH, Rijal G, Jang J, Kim SW, Cho DW. Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. Biomaterials 2015; 37: 230–241PubMedCrossRefGoogle Scholar
  81. 81.
    Baranski JD, Chaturvedi RR, Stevens KR, Eyckmans J, Carvalho B, Solorzano RD, Yang MT, Miller JS, Bhatia SN, Chen CS. Geometric control of vascular networks to enhance engineered tissue integration and function. Proc Natl Acad Sci USA 2013; 110(19): 7586–7591PubMedCrossRefGoogle Scholar
  82. 82.
    Barabaschi GD, Manoharan V, Li Q, Bertassoni LE. Engineering pre-vascularized scaffolds for bone regeneration. Adv Exp Med Biol 2015; 881: 79–94PubMedCrossRefGoogle Scholar
  83. 83.
    Qin D, Xia Y, Whitesides GM. Soft lithography for micro- and nanoscale patterning. Nat Protoc 2010; 5(3): 491–502PubMedCrossRefGoogle Scholar
  84. 84.
    Nikkhah M, Eshak N, Zorlutuna P, Annabi N, Castello M, Kim K, Dolatshahi-Pirouz A, Edalat F, Bae H, Yang Y, Khademhosseini A. Directed endothelial cell morphogenesis in micropatterned gelatin methacrylate hydrogels. Biomaterial. 2012; 33(35): 9009–9018CrossRefGoogle Scholar
  85. 85.
    Raghavan S, Nelson CM, Baranski JD, Lim E, Chen CS. Geometrically controlled endothelial tubulogenesis in micropatterned gels. Tissue Eng Part A 2010; 16(7): 2255–2263PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Zheng Y, Chen J, Craven M, Choi NW, Totorica S, Diaz-Santana A, Kermani P, Hempstead B, Fischbach-Teschl C, López JA, Stroock AD. In vitro microvessels for the study of angiogenesis and thrombosis. Proc Natl Acad Sci U S. 2012; 109(24): 9342–9347CrossRefGoogle Scholar
  87. 87.
    Wray LS, Tsioris K, Gi ES, Omenetto FG, Kaplan DL. Slowly degradable porous silk microfabricated scaffolds for vascularized tissue formation. Adv Funct Mater 2013; 23(27): 3404–3412PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Miller JS, Stevens KR, Yang MT, Baker BM, Nguyen DH, Cohen DM, Toro E, Chen AA, Galie PA, Yu X, Chaturvedi R, Bhatia SN, Chen CS. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat Mater 2012; 11(9): 768–774PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Bertassoni LE, Cardoso JC, Manoharan V, Cristino AL, Bhise NS, Araujo WA, Zorlutuna P, Vrana NE, Ghaemmaghami AM, Dokmeci MR, Khademhosseini A. Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels. Biofabricatio. 2014; 6(2): 024105CrossRefGoogle Scholar
  90. 90.
    Kinstlinger IS, Yalacki DR, Miller JS. Engineered tissues with perfusable vascular networks created by sacrificial templating of laser sintered carbohydrates. Front Bioeng Biotechnol 2016; Conference Abstract: 10th World Biomaterials Congress. https://doi.org/10.3389/conf.FBIOE.2016.01.00491
  91. 91.
    Kolesky DB, Truby RL, Gladman AS, Busbee TA, Homan KA, Lewis JA. 3D bioprinting of vascularized, heterogeneous cellladen tissue constructs. Adv Mater 2014; 26(19): 3124–3130PubMedCrossRefGoogle Scholar
  92. 92.
    Radtke CL, Nino-Fong R, Esparza Gonzalez BP, Stryhn H, McDuffee LA. Characterization and osteogenic potential of equine muscle tissue- and periosteal tissue-derived mesenchymal stem cells in comparison with bone marrow- and adipose tissue-derived mesenchymal stem cells. Am J Vet Res 2013; 74(5): 790–800PubMedCrossRefGoogle Scholar
  93. 93.
    Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cell. 2006; 24(5): 1294–1301CrossRefGoogle Scholar
  94. 94.
    Pantalone A, Antonucci I, Guelfi M, Pantalone P, Usuelli FG, Stuppia L, Salini V. Amniotic fluid stem cells: an ideal resource for therapeutic application in bone tissue engineering. Eur Rev Med Pharmacol Sc. 2016; 20(13): 2884–2890Google Scholar
  95. 95.
    Petridis X, Diamanti E, Trigas GCh, Kalyvas D, Kitraki E. Bone regeneration in critical-size calvarial defects using human dental pulp cells in an extracellular matrix-based scaffold. J Craniomaxillofac Sur. 2015; 43(4): 483–490CrossRefGoogle Scholar
  96. 96.
    Guan J, Zhang J, Li H, Zhu Z, Guo S, Niu X, Wang Y, Zhang C. Human urine derived stem cells in combination with ß-TCP can be applied for bone regeneration. PLoS On. 2015; 10(5): e0125253CrossRefGoogle Scholar
  97. 97.
    Illich DJ, Demir N, Stojkovic M, Scheer M, Rothamel D, Neugebauer J, Hescheler J, Zoller JE. Induced pluripotent stem(iPS) cells and lineage reprogramming: prospects for bone regeneration. Stem Cells 2011; 29(4): 555–563PubMedCrossRefGoogle Scholar
  98. 98.
    Chan CK, Seo EY, Chen JY, Lo D, McArdle A, Sinha R, Tevlin R, Seita J, Vincent-Tompkins J, Wearda T, Lu WJ, Senarath-Yapa K, Chung MT, Marecic O, Tran M, Yan KS, Upton R, Walmsley GG, Lee AS, Sahoo D, Kuo CJ, Weissman IL, Longaker MT. Identification and specification of the mouse skeletal stem cell. Cell 2015; 160(1–2): 285–298PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Aicher WK, Bühring HJ, Hart M, Rolauffs B, Badke A, Klein G. Regeneration of cartilage and bone by defined subsets of mesenchymal stromal cells—potential and pitfalls. Adv Drug Deliv Re. 2011; 63(4–5): 342–351CrossRefGoogle Scholar
  100. 100.
    Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM. Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS One 2014; 9(12): e115963PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Li YY, Cheng HW, Cheung KM, Chan D, Chan BP. Mesenchymal stem cell-collagen microspheres for articular cartilage repair: cell density and differentiation status. Acta Biomater 2014; 10(5): 1919–1929PubMedCrossRefGoogle Scholar
  102. 102.
    Mizuno H. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sc. 2009; 76(2): 56–66CrossRefGoogle Scholar
  103. 103.
    Levi B, Longaker MT. Concise review: adipose-derived stromal cells for skeletal regenerative medicine. Stem Cells 2011; 29(4): 576–582PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Markarian CF, Frey GZ, Silveira MD, Chem EM, Milani AR, Ely PB, Horn AP, Nardi NB, Camassola M. Isolation of adiposederived stem cells: a comparison among different methods. Biotechnol Let. 2014; 36(4): 693–702CrossRefGoogle Scholar
  105. 105.
    Baer PC, Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells In. 2012; 2012: 81Google Scholar
  106. 106.
    Lindroos B, Suuronen R, Miettinen S. The potential of adipose stem cells in regenerative medicine. Stem Cell Re. 2011; 7(2): 269–291CrossRefGoogle Scholar
  107. 107.
    Gharaibeh B, Lu A, Tebbets J, Zheng B, Feduska J, Crisan M, Péault B, Cummins J, Huard J. Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique. Nat Proto. 2008; 3(9): 1501–1509CrossRefGoogle Scholar
  108. 108.
    Wu X, Wang S, Chen B, An X. Muscle-derived stem cells: isolation, characterization, differentiation, and application in cell and gene therapy. Cell Tissue Re. 2010; 340(3): 549–567CrossRefGoogle Scholar
  109. 109.
    Nimura A, Muneta T, Koga H, Mochizuki T, Suzuki K, Makino H, Umezawa A, Sekiya I. Increased proliferation of human synovial mesenchymal stem cells with autologous human serum: comparisons with bone marrow mesenchymal stem cells and with fetal bovine serum. Arthritis Rheu. 2008; 58(2): 501–510CrossRefGoogle Scholar
  110. 110.
    Fan J, Varshney RR, Ren L, Cai D, Wang DA. Synovium-derived mesenchymal stem cells: a new cell source for musculoskeletal regeneration. Tissue Eng Part B Rev 2009; 15(1): 75–86PubMedCrossRefGoogle Scholar
  111. 111.
    Yamazaki H, Tsuneto M, Yoshino M, Yamamura K, Hayashi S. Potential of dental mesenchymal cells in developing teeth. Stem Cell. 2007; 25(1): 78–87CrossRefGoogle Scholar
  112. 112.
    Guan JJ, Niu X, Gong FX, Hu B, Guo SC, Lou YL, Zhang CQ, Deng ZF, Wang Y. Biological characteristics of human-urinederived stem cells: potential for cell-based therapy in neurology. Tissue Eng Part. 2014; 20(13–14): 1794–1806CrossRefGoogle Scholar
  113. 113.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282(5391): 1145–1147PubMedCrossRefGoogle Scholar
  114. 114.
    Hwang YS, Polak JM, Mantalaris A. In vitro direct osteogenesis of murine embryonic stem cells without embryoid body formation. Stem Cells De. 2008; 17(5): 963–970CrossRefGoogle Scholar
  115. 115.
    Ström S, Inzunza J, Grinnemo KH, Holmberg K, Matilainen E, Strömberg AM, Blennow E, Hovatta O. Mechanical isolation of the inner cell mass is effective in derivation of new human embryonic stem cell lines. Hum Repro. 2007; 22(12): 3051–3058CrossRefGoogle Scholar
  116. 116.
    Bielec B, Stojko R. Stem cells of umbilical blood cord — therapeutic use. Postepy Hig Med Dosw(Online. 2015; 69: 853–863(i. Polish)CrossRefGoogle Scholar
  117. 117.
    Fong CY, Chak LL, Biswas A, Tan JH, Gauthaman K, Chan WK, Bongso A. Human Wharton’s jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Re. 2011; 7(1): 1–16CrossRefGoogle Scholar
  118. 118.
    Huang P, Lin LM, Wu XY, Tang QL, Feng XY, Lin GY, Lin X, Wang HW, Huang TH, Ma L. Differentiation of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells into germlike cells in vitro. J Cell Bioche. 2010; 109(4): 747–754Google Scholar
  119. 119.
    De Coppi P, Bartsch G Jr, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechno. 2007; 25(1): 100–106CrossRefGoogle Scholar
  120. 120.
    Roubelakis MG, Pappa KI, Bitsika V, Zagoura D, Vlahou A, Papadaki HA, Antsaklis A, Anagnou NP. Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells. Stem Cells Dev 2007; 16(6): 931–952PubMedCrossRefGoogle Scholar
  121. 121.
    Trohatou O, Anagnou NP, Roubelakis MG. Human amniotic fluid stem cells as an attractive tool for clinical applications. Curr Stem Cell Res Ther 2013; 8(2): 125–132PubMedCrossRefGoogle Scholar
  122. 122.
    Gholizadeh-Ghaleh Aziz S, Pashaei-Asl F, Fardyazar Z, Pashaiasl M. Isolation, characterization, cryopreservation of human amniotic stem cells and differentiation to osteogenic and adipogenic cells. PLoS On. 2016; 11(7): e0158281CrossRefGoogle Scholar
  123. 123.
    Lee JM, Jung J, Lee HJ, Jeong SJ, Cho KJ, Hwang SG, Kim GJ. Comparison of immunomodulatory effects of placenta mesenchymal stem cells with bone marrow and adipose mesenchymal stem cells. Int Immunopharmacol 2012; 13(2): 219–224PubMedCrossRefGoogle Scholar
  124. 124.
    Fazekasova H, Lechler R, Langford K, Lombardi G. Placentaderived MSCs are partially immunogenic and less immunomodulatory than bone marrow-derived MSCs. J Tissue Eng Regen Me. 2011; 5(9): 684–694CrossRefGoogle Scholar
  125. 125.
    Zhong ZN, Zhu SF, Yuan AD, Lu GH, He ZY, Fa ZQ, Li WH. Potential of placenta-derived mesenchymal stem cells as seed cells for bone tissue engineering: preliminary study of osteoblastic differentiation and immunogenicity. Orthopedics 2012; 35(9): 779–788PubMedCrossRefGoogle Scholar
  126. 126.
    Semenov OV, Koestenbauer S, Riegel M, Zech N, Zimmermann R, Zisch AH, Malek A. Multipotent mesenchymal stem cells from human placenta: critical parameters for isolation and maintenance of stemness after isolation. Am J Obstet Gynecol 2010; 202(2): 193. e1–193. e13PubMedCrossRefGoogle Scholar
  127. 127.
    Lange-Consiglio A, Corradetti B, Meucci A, Perego R, Bizzaro D, Cremonesi F. Characteristics of equine mesenchymal stem cells derived from amnion and bone marrow: in vitro proliferative and multilineage potential assessment. Equine Vet. 2013; 45(6): 737–744CrossRefGoogle Scholar
  128. 128.
    Violini S, Gorni C, Pisani LF, Ramelli P, Caniatti M, Mariani P. Isolation and differentiation potential of an equine amnion-derived stromal cell line. Cytotechnolog. 2012; 64(1): 1–7CrossRefGoogle Scholar
  129. 129.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cel. 2006; 126(4): 663–676CrossRefGoogle Scholar
  130. 130.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cel. 2007; 131(5): 861–872CrossRefGoogle Scholar
  131. 131.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318(5858): 1917–1920PubMedCrossRefGoogle Scholar
  132. 132.
    Jung Y, Bauer G, Nolta JA. Concise review. Induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products. Stem Cell. 2012; 30(1): 42–47CrossRefGoogle Scholar
  133. 133.
    Grellier M, Bordenave L, Amédée J. Cell-to-cell communication between osteogenic and endothelial lineages: implications for tissue engineering. Trends Biotechno. 2009; 27(10): 562–571CrossRefGoogle Scholar
  134. 134.
    Nakasa T, Ishida O, Sunagawa T, Nakamae A, Yasunaga Y, Agung M, Ochi M. Prefabrication of vascularized bone graft using a combination of fibroblast growth factor-2 and vascular bundle implantation into a novel interconnected porous calcium hydroxyapatite ceramic. J Biomed Mater Res. 2005; 75(2): 350–355CrossRefGoogle Scholar
  135. 135.
    Kawamura K, Yajima H, Ohgushi H, Tomita Y, Kobata Y, Shigematsu K, Takakura Y. Experimental study of vascularized tissue-engineered bone grafts. Plast Reconstr Sur. 2006; 117(5): 1471–1479CrossRefGoogle Scholar
  136. 136.
    Sun H, Qu Z, Guo Y, Zang G, Yang B. In vitro and in vivo effects of rat kidney vascular endothelial cells on osteogenesis of rat bone marrow mesenchymal stem cells growing on polylactide-glycoli acid(PLGA) scaffolds. Biomed Eng Onlin. 2007; 6: 41CrossRefGoogle Scholar
  137. 137.
    Xue Y, Xing Z, Bolstad AI, Van Dyke TE, Mustafa K. Co-culture of human bone marrow stromal cells with endothelial cells alters gene expression profiles. Int J Artif Organs 2013; 36(9): 650–662PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Nesti LJ, Caterson EJ, Li WJ, Chang R, McCann TD, Hoek JB, Tuan RS. TGF-ß1 calcium signaling in osteoblasts. J Cell Biochem 2007; 101(2): 348–359PubMedCrossRefGoogle Scholar
  139. 139.
    Stahl A, Wenger A, Weber H, Stark GB, Augustin HG, Finkenzeller G. Bi-directional cell contact-dependent regulation of gene expression between endothelial cells and osteoblasts in a three-dimensional spheroidal coculture model. Biochem Biophys Res Commu. 2004; 322(2): 684–692CrossRefGoogle Scholar
  140. 140.
    Santos MI, Unger RE, Sousa RA, Reis RL, Kirkpatrick CJ. Crosstalk between osteoblasts and endothelial cells co-cultured on a polycaprolactone-starch scaffold and the in vitro development of vascularization. Biomaterials 2009; 30(26): 4407–4415PubMedCrossRefGoogle Scholar
  141. 141.
    Dohle E, Fuchs S, Kolbe M, Hofmann A, Schmidt H, Kirkpatrick CJ. Sonic hedgehog promotes angiogenesis and osteogenesis in a coculture system consisting of primary osteoblasts and outgrowth endothelial cells. Tissue Eng Part A 2010; 16(4): 1235–1237PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Colnot C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Re. 2009; 24(2): 274–282CrossRefGoogle Scholar
  143. 143.
    Chen D, Zhang X, He Y, Lu J, Shen H, Jiang Y, Zhang C, Zeng B. Co-culturing mesenchymal stem cells from bone marrow and periosteum enhances osteogenesis and neovascularization of tissue-engineered bone. J Tissue Eng Regen Me. 2012; 6(10): 822–832CrossRefGoogle Scholar
  144. 144.
    Chen D, Shen H, He Y, Chen Y, Wang Q, Lu J, Jiang Y. Synergetic effects of hBMSCs and hPCs in osteogenic differentiation and their capacity in the repair of critical-sized femoral condyle defects. Mol Med Re. 2015; 11(2): 1111–1119CrossRefGoogle Scholar
  145. 145.
    Park JS, Park KH. Light enhanced bone regeneration in an athymic nude mouse implanted with mesenchymal stem cells embedded i. PLGA microspheres. Biomater Re. 2016; 20(1): 4CrossRefGoogle Scholar
  146. 146.
    Wu L, Zhao X, He B, Jiang J, Xie XJ, Liu L. The possible roles of biological bone constructed with peripheral blood derived EPCs and BMSCs in osteogenesis and angiogenesis. Biomed Res Int. 2016; 2016: 8168943PubMedPubMedCentralGoogle Scholar
  147. 147.
    Fisher JN, Peretti GM, Scotti C. Stem cells for bone regeneration: from cell-based therapies to decellularised engineered extracellular matrices. Stem Cells Int 2016. 2016: 9352598Google Scholar
  148. 148.
    Dmitrieva RI, Minullina IR, Bilibina AA, Tarasova OV, Anisimov SV, Zaritskey AY. Bone marrow- and subcutaneous adipose tissuederived mesenchymal stem cells: differences and similarities. Cell Cycle 2012; 11(2): 377–383PubMedCrossRefGoogle Scholar
  149. 149.
    Brocher J, Janicki P, Voltz P, Seebach E, Neumann E, Mueller-Ladner U, Richter W. Inferior ectopic bone formation of mesenchymal stromal cells from adipose tissue compared to bone marrow: rescue by chondrogenic pre-induction. Stem Cell Re. 2013; 11(3): 1393–1406CrossRefGoogle Scholar
  150. 150.
    Sándor GK, Numminen J, Wolff J, Thesleff T, Miettinen A, Tuovinen VJ, Mannerström B, Patrikoski M, Seppänen R, Miettinen S, Rautiainen M, Öhman J. Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects. Stem Cells Transl Me. 2014; 3(4): 530–540CrossRefGoogle Scholar
  151. 151.
    Kuhn LT, Liu Y, Boyd NL, Dennis JE, Jiang X, Xin X, Charles LF, Wang L, Aguila HL, Rowe DW, Lichtler AC, Goldberg AJ. Developmental-like bone regeneration by human embryonic stem cell-derived mesenchymal cells. Tissue Eng Part A 2014; 20(1–2): 365–377PubMedCrossRefGoogle Scholar
  152. 152.
    Levi B, Hyun JS, Montoro DT, Lo DD, Chan CK, Hu S, Sun N, Lee M, Grova M, Connolly AJ, Wu JC, Gurtner GC, Weissman IL, Wan DC, Longaker MT. In vivo directed differentiation of pluripotent stem cells for skeletal regeneration. Proc Natl Acad Sci U S. 2012; 109(50): 20379–20384CrossRefGoogle Scholar
  153. 153.
    Mathieu M, Rigutto S, Ingels A, Spruyt D, Stricwant N, Kharroubi I, Albarani V, Jayankura M, Rasschaert J, Bastianelli E, Gangji V. Decreased pool of mesenchymal stem cells is associated with altered chemokines serum levels in atrophic nonunion fractures. Bon. 2013; 53(2): 391–398CrossRefGoogle Scholar
  154. 154.
    Yamada Y, Nakamura S, Ito K, Sugito T, Yoshimi R, Nagasaka T, Ueda M. A feasibility of useful cell-based therapy by bone regeneration with deciduous tooth stem cells, dental pulp stem cells, or bone-marrow-derived mesenchymal stem cells for clinical study using tissue engineering technology. Tissue Eng Part. 2010; 16(6): 1891–1900CrossRefGoogle Scholar
  155. 155.
    Balmayor ER. Targeted delivery as key for the success of small osteoinductive molecules. Adv Drug Deliv Rev 2015; 94: 13–27PubMedCrossRefGoogle Scholar
  156. 156.
    Maßsagué J, Wotton D. Transcriptional control by the TGF-ß/Smad signaling system. EMBO. 2000; 19(8): 1745–1754CrossRefGoogle Scholar
  157. 157.
    Joyce ME, Jingushi S, Bolander ME. Transforming growth factor- ß in the regulation of fracture repair. Orthop Clin North Am 1990; 21(1): 199–209PubMedGoogle Scholar
  158. 158.
    Lind M, Schumacker B, Søballe K, Keller J, Melsen F, Bünger C. Transforming growth factor-ß enhances fracture healing in rabbit tibiae. Acta Orthop Scan. 1993; 64(5): 553–556CrossRefGoogle Scholar
  159. 159.
    Critchlow MA, Bland YS, Ashhurst DE. The effect of exogenous transforming growth factor-ß 2 on healing fractures in the rabbit. Bone 1995; 16(5): 521–527PubMedCrossRefGoogle Scholar
  160. 160.
    Tamai N, Myoui A, Hirao M, Kaito T, Ochi T, Tanaka J, Takaoka K, Yoshikawa H. A new biotechnology for articular cartilage repair: subchondral implantation of a composite of interconnected porous hydroxyapatite, synthetic polymer(PLA-PEG), and bone morphogenetic protein-2(rhBMP-2). Osteoarthritis Cartilag. 2005; 13(5): 405–417CrossRefGoogle Scholar
  161. 161.
    Vrijens K, Lin W, Cui J, Farmer D, Low J, Pronier E, Zeng FY, Shelat AA, Guy K, Taylor MR, Chen T, Roussel MF. Identification of small molecule activators o. BMP signaling. PLoS On. 2013; 8(3): e59045CrossRefGoogle Scholar
  162. 162.
    Bandyopadhyay A, Yadav PS, Prashar P. BMP signaling in development and diseases: a pharmacological perspective. Biochem Pharmaco. 2013; 85(7): 857–864CrossRefGoogle Scholar
  163. 163.
    Bergeron E, Leblanc E, Drevelle O, Giguère R, Beauvais S, Grenier G, Faucheux N. The evaluation of ectopic bone formation induced by delivery systems for bone morphogenetic protein-9 or its derived peptide. Tissue Eng Part. 2012; 18(3–4): 342–352CrossRefGoogle Scholar
  164. 164.
    Takahashi Y, Yamamoto M, Yamada K, Kawakami O, Tabata Y. Skull bone regeneration in nonhuman primates by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue En. 2007; 13(2): 293–300CrossRefGoogle Scholar
  165. 165.
    Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cel. 2002; 13(12): 4279–4295CrossRefGoogle Scholar
  166. 166.
    Wang J, Zheng Y, Zhao J, Liu T, Gao L, Gu Z, Wu G. Low-dose rhBMP2/7 heterodimer to reconstruct peri-implant bone defects: a micro-CT evaluation. J Clin Periodonto. 2012; 39(1): 98–105CrossRefGoogle Scholar
  167. 167.
    He X, Liu Y, Yuan X, Lu L. Enhanced healing of rat calvarial defects with MSCs loaded on BMP-2 releasing chitosan/alginate/ hydroxyapatite scaffolds. PLoS On. 2014; 9(8): e104061CrossRefGoogle Scholar
  168. 168.
    Li J, Hong J, Zheng Q, Guo X, Lan S, Cui F, Pan H, Zou Z, Chen C. Repair of rat cranial bone defects with nHAC/PLLA and BMP- 2-related peptide or rhBMP-2. J Orthop Re. 2011; 29(11): 1745–1752CrossRefGoogle Scholar
  169. 169.
    Lind M. Growth factor stimulation of bone healing. Effects on osteoblasts, osteomies, and implants fixation. Acta Orthop Scand Supp. 1998; 283: 2–37Google Scholar
  170. 170.
    Kato T, Kawaguchi H, Hanada K, Aoyama L, Hiyama Y, Nakamura T, Kuzutani K, Tamura M, Kurokawa T, Nakamura K. Single local injection of re-combinant fibroblast growth factor-2 stimulates healing of segmental bone defects in rabbits. J Orthop Re. 1998; 16: 654–659CrossRefGoogle Scholar
  171. 171.
    Liu Z, Lavine KJ, Hung IH, Ornitz DM. FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 2007; 302(1): 80–91PubMedCrossRefGoogle Scholar
  172. 172.
    Schmid GJ, Kobayashi C, Sandell LJ, Ornitz DM. Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn 2009; 238(3): 766–774PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Behr B, Leucht P, Longaker MT, Quarto N. Fgf-9 is required for angiogenesis and osteogenesis in long bone repair. Proc Natl Acad Sci U S. 2010; 107(26): 11853–11858CrossRefGoogle Scholar
  174. 174.
    Bak B, Jørgensen PH, Andreassen TT. Dose response of growth hormone on fracture healing in the rat. Acta Orthop Scan. 1990; 61(1): 54–57CrossRefGoogle Scholar
  175. 175.
    Thaller SR, Dart A, Tesluk H. The effects of insulin-like growth factor-1 on critical-size calvarial defects in Sprague-Dawley rats. Ann Plast Sur. 1993; 31(5): 429–433CrossRefGoogle Scholar
  176. 176.
    Segar CE, Ogle ME, Botchwey EA. Regulation of angiogenesis and bone regeneration with natural and synthetic small molecules. Curr Pharm Des 2013; 19(19): 3403–3419PubMedCrossRefGoogle Scholar
  177. 177.
    Street J, Bao M, de Guzman L, Bunting S, Peale FVJr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA 2002; 99(15): 9656–9661PubMedCrossRefGoogle Scholar
  178. 178.
    Bouletreau PJ, Warren SM, Spector JA, Peled ZM, Gerrets RP, Greenwald JA, Longaker MT. Hypoxia an. VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. Plast Reconstr Sur. 2002; 109(7): 2384–2397CrossRefGoogle Scholar
  179. 179.
    Zelzer E, McLean W, Ng YS, Fukai N, Reginato AM, Lovejoy S, D’Amore PA, Olsen BR. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Developmen. 2002; 129(8): 1893–1904Google Scholar
  180. 180.
    Cui F, Wang X, Liu X, Dighe AS, Balian G, Cui Q. VEGF and BMP-6 enhance bone formation mediated by cloned mouse osteoprogenitor cells. Growth Factor. 2010; 28(5): 306–317CrossRefGoogle Scholar
  181. 181.
    Bab I, Gazit D, Chorev M, Muhlrad A, Shteyer A, Greenberg Z, Namdar M, Kahn A. Histone H4-related osteogenic growth peptide(OGP): a novel circulating stimulator of osteoblastic activity. EMBO J 1992; 11(5): 1867–1873PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Gabarin N, Gavish H, Muhlrad A, Chen YC, Namdar-Attar M, Nissenson RA, Chorev M, Bab I. Mitogenic G(i) protein-MAP kinase signaling cascade in MC3T3-E1 osteogenic cells: activation by C-terminal pentapeptide of osteogenic growth peptide [OGP(10–14)] and attenuation of activation by cAMP. J Cell Bioche. 2001; 81(4): 594–603CrossRefGoogle Scholar
  183. 183.
    An G, Xue Z, Zhang B, Deng QK, Wang YS, Lv SC. Expressing osteogenic growth peptide in the rabbit bone mesenchymal stem cells increased alkaline phosphatase activity and enhanced the collagen accumulation. Eur Rev Med Pharmacol Sci 2014; 18(11): 1618–1624PubMedGoogle Scholar
  184. 184.
    Brager MA, Patterson MJ, Connolly JF, Nevo Z. Osteogenic growth peptide normally stimulated by blood loss and marrow ablation has local and systemic effects on fracture healing in rats. J Orthop Re. 2000; 18(1): 133–139CrossRefGoogle Scholar
  185. 185.
    Shuqiang M, Kunzheng W, Xiaoqiang D, Wei W, Mingyu Z, Daocheng W. Osteogenic growth peptide incorporated into PLGA scaffolds accelerates healing of segmental long bone defects in rabbits. J Plast Reconstr Aesthet Sur. 2008; 61(12): 1558–1560CrossRefGoogle Scholar
  186. 186.
    Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermitten. PTH. Bon. 2007; 40(6): 1434–1446CrossRefGoogle Scholar
  187. 187.
    Manabe T, Mori S, Mashiba T, Kaji Y, Iwata K, Komatsubara S, Seki A, Sun YX, Yamamoto T. Human parathyroid hormone(1–34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys. Bon. 2007; 40(6): 1475–1482CrossRefGoogle Scholar
  188. 188.
    Komatsu DE, Brune KA, Liu H, Schmidt AL, Han B, Zeng QQ, Yang X, Nunes JS, Lu Y, Geiser AG, M. YL, Wolos JA, Westmore MS, Sato M. Longitudinal in vivo analysis of the region-specific efficacy of parathyroid hormone in a rat cortical defect model. Endocrinolog. 2009; 150(4): 1570–1579CrossRefGoogle Scholar
  189. 189.
    Jung RE, Cochran DL, Domken O, Seibl R, Jones AA, Buser D, Hammerle CH. The effect of matrix bound parathyroid hormone on bone regeneration. Clin Oral Implants Res 2007; 18(3): 319–325PubMedCrossRefGoogle Scholar
  190. 190.
    Kaback LA, Soung Y, Naik A, Geneau G, Schwarz EM, Rosier RN, O’Keefe RJ, Drissi H. Teriparatide(1–34 human PTH) regulation of osterix during fracture repair. J Cell Bioche. 2008; 105(1): 219–226CrossRefGoogle Scholar
  191. 191.
    Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, García-Hernández PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Re. 2010; 25(2): 404–414CrossRefGoogle Scholar
  192. 192.
    Reynolds DG, Shaikh S, Papuga MO, Lerner AL, O’Keefe RJ, Schwarz EM, Awad HA. muCT-based measurement of cortical bone graft-to-host union. J Bone Miner Res 2009; 24(5): 899–907PubMedCrossRefGoogle Scholar
  193. 193.
    Manton KJ, Leon DFM, Cool SM, Nurcombe V. Disruption of heparan and chondroitin sulfate signaling enhances mesenchymal stem cell-derived osteogenic differentiation via bone morphogenetic protein signaling pathways. Stem Cell. 2007; 25(11): 2845–2854CrossRefGoogle Scholar
  194. 194.
    Choi YJ, Lee JY, Park JH, Park JB, Suh JS, Choi YS, Lee SJ, Chung CP, Park YJ. The identification of a heparin binding domain peptide from bone morphogenetic protein-4 and its role on osteogenesis. Biomaterials 2010; 31(28): 7226–7238PubMedCrossRefGoogle Scholar
  195. 195.
    Lee JY, Choo JE, Park HJ, Park JB, Lee SC, Jo I, Lee SJ, Chung CP, Park YJ. Injectable gel with synthetic collagen-binding peptide for enhanced osteogenesis in vitro and in vivo. Biochem Biophys Res Commun 2007; 357(1): 68–74PubMedCrossRefGoogle Scholar
  196. 196.
    Yewle JN, Puleo DA, Bachas LG. Bifunctional bisphosphonates for deliverin. PTH(1–34) to bone mineral with enhanced bioactivity. Biomaterial. 2013; 34(12): 3141–3149CrossRefGoogle Scholar
  197. 197.
    Rezania A, Healy KE. Biomimetic peptide surfaces that regulate adhesion, spreading, cytoskeletal organization, and mineralization of the matrix deposited by osteoblast-like cells. Biotechnol Prog 1999; 15(1): 19–32PubMedCrossRefGoogle Scholar
  198. 198.
    Lo KW, Ashe KM, Kan HM, Laurencin CT. The role of small molecules in musculoskeletal regeneration. Regen Med 2012; 7(4): 535–549PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Tai IC, Wang YH, Chen CH, Chuang SC, Chang JK, Ho ML. Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation. Int J Nanomedicine 2015; 10: 5881–5894PubMedPubMedCentralGoogle Scholar
  200. 200.
    Ruiz-Gaspa S, Nogues X, Enjuanes A, Monllau JC, Blanch J, Carreras R, Mellibovsky L, Grinberg D, Balcells S, Díez-Perez A, Pedro-Botet J. Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. J Cell Bioche. 2007; 101(6): 1430–1438CrossRefGoogle Scholar
  201. 201.
    Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Todo M, Takao Y, Koyano K. Local application of fluvastatin improves peri-implant bone quantity and mechanical properties: a rodent study. Acta Biomate. 2010; 6(4): 1610–1618CrossRefGoogle Scholar
  202. 202.
    Lo KW, Ulery BD, Kan HM, Ashe KM, Laurencin CT. Evaluating the feasibility of utilizing the small molecule phenamil as a novel biofactor for bone regenerative engineering. J Tissue Eng Regen Med 2014; 8(9): 728–736PubMedCrossRefGoogle Scholar
  203. 203.
    Balmayor ER. Targeted delivery as key for the success of small osteoinductive molecules. Adv Drug Deliv Rev 2015; 94: 13–27PubMedCrossRefGoogle Scholar
  204. 204.
    Park KW, Waki H, Kim WK, Davies BS, Young SG, Parhami F, Tontonoz P. The small molecule phenamil induces osteoblast differentiation and mineralization. Mol Cell Bio. 2009; 29(14): 3905–3914CrossRefGoogle Scholar
  205. 205.
    Zhao J, Ohba S, Shinkai M, Chung UI, Nagamune T. Icariin induces osteogenic differentiation in vitro in a BMP- and Runx2- dependent manner. Biochem Biophys Res Commu. 2008; 369(2): 444–448CrossRefGoogle Scholar
  206. 206.
    Nakajima K, Komiyama Y, Hojo H, Ohba S, Yano F, Nishikawa N, Ihara S, Aburatani H, Takato T, Chung UI. Enhancement of bone formation ex vivo and in vivo by a helioxanthin-derivative. Biochem Biophys Res Commun 2010; 395(4): 502–508PubMedCrossRefGoogle Scholar
  207. 207.
    Salazar VS, Gamer LW, Rosen V. BMP signalling in skeletal development, disease and repair. Nat Rev Endocrino. 2016; 12(4): 203–221CrossRefGoogle Scholar
  208. 208.
    Wu X, Ding S, Ding Q, Gray NS, Schultz PG. A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J Am Chem Soc 2002; 124(49): 14520–14521PubMedCrossRefGoogle Scholar
  209. 209.
    Corcoran RB, Scott MP. Oxysterols stimulat. Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci US. 2006; 103(22): 8408–8413CrossRefGoogle Scholar
  210. 210.
    James AW. Review of signaling pathways governin. MSC osteogenic and adipogenic differentiation. Scientifica(Cairo. 2013; 2013: 684736Google Scholar
  211. 211.
    Sinha S, Chen JK. Purmorphamine activates th. Hedgehog pathway by targeting Smoothened. Nat Chem Bio. 2006; 2(1): 29–30CrossRefGoogle Scholar
  212. 212.
    Gellynck K, Shah R, Parkar M, Young A, Buxton P, Brett P. Small molecule stimulation enhances bone regeneration but not titanium implant osseointegration. Bon. 2013; 57(2): 405–412CrossRefGoogle Scholar
  213. 213.
    Amantea CM, Kim WK, Meliton V, Tetradis S, Parhami F. Oxysterol-induced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signaling. J Cell Bioche. 2008; 105(2): 424–436CrossRefGoogle Scholar
  214. 214.
    Aghaloo TL, Amantea CM, Cowan CM, Richardson JA, Wu BM, Parhami F, Tetradis S. Oxysterols enhance osteoblast differentiation in vitro and bone healing in vivo. J Orthop Re. 2007; 25(11): 1488–1497CrossRefGoogle Scholar
  215. 215.
    Stappenbeck F, Xiao W, Epperson M, Riley M, Priest A, Huang D, Nguyen K, Jung ME, Thies RS, Farouz F. Novel oxysterols activate the Hedgehog pathway and induce osteogenesis. Bioorg Med Chem Let. 2012; 22(18): 5893–5897CrossRefGoogle Scholar
  216. 216.
    Siddappa R, Martens A, Doorn J, Leusink A, Olivo C, Licht R, van Rijn L, Gaspar C, Fodde R, Janssen F, van Blitterswijk C, de Boer J. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. Proc Natl Acad Sci USA 2008; 105(20): 7281–7286PubMedCrossRefGoogle Scholar
  217. 217.
    Lo KWH, Kan HM, Ashe KM, Laurencin CT. The small molecule PKA-specific cyclic AMP analogue as an inducer of osteoblast-like cells differentiation and mineralization. J Tissue Eng Regen Me. 2012; 6(1): 40–48CrossRefGoogle Scholar
  218. 218.
    Lo KW, Kan HM, Gagnon KA, Laurencin CT. One-day treatment of small molecule 8-bromo-cycli. AMP analogue induces cellbased VEGF production for in vitro angiogenesis and osteoblastic differentiation. J Tissue Eng Regen Me. 2016; 10(10): 867–875CrossRefGoogle Scholar
  219. 219.
    Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 2009; 458(7237): 524–528PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Petrie Aronin CE, Sefcik LS, Tholpady SS, Tholpady A, Sadik KW, Macdonald TL, Peirce SM, Wamhoff BR, Lynch KR, Ogle RC, Botchwey EA. FTY720 promotes local microvascular network formation and regeneration of cranial bone defects. Tissue Eng Part. 2010; 16(6): 1801–1809CrossRefGoogle Scholar
  221. 221.
    Petrie Aronin CE, Shin SJ, Naden KB, Rios PDJr, Sefcik LS, Zawodny SR, Bagayoko ND, Cui Q, Khan Y, Botchwey EA. The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterial. 2010; 31(25): 6417–6424CrossRefGoogle Scholar
  222. 222.
    Gellynck K, Neel EA, Li H, Mardas N, Donos N, Buxton P, Young AM. Cell attachment and response to photocured, degradable bone adhesives containing tricalcium phosphate and purmorphamine. Acta Biomater 2011; 7(6): 2672–2677PubMedCrossRefGoogle Scholar
  223. 223.
    Qi Y, Zhao T, Yan W, Xu K, Shi Z, Wang J. Mesenchymal stem cell sheet transplantation combined with locally released simvastatin enhances bone formation in a rat tibia osteotomy model. Cytotherap. 2013; 15(1): 44–56CrossRefGoogle Scholar
  224. 224.
    Maeda Y, Hojo H, Shimohata N, Choi S, Yamamoto K, Takato T, Chung UI, Ohba S. Bone healing by sterilizable calcium phosphate tetrapods eluting osteogenic molecules. Biomaterial. 2013; 34(22): 5530–5537CrossRefGoogle Scholar
  225. 225.
    Ohba S, Nakajima K, Komiyama Y, Kugimiya F, Igawa K, Itaka K, Moro T, Nakamura K, Kawaguchi H, Takato T, Chung UI. A novel osteogenic helioxanthin-derivative acts in. BMP-dependent manner. Biochem Biophys Res Commu. 2007; 357(4): 854–860CrossRefGoogle Scholar
  226. 226.
    Chatterjea A, LaPointe VL, Alblas J, Chatterjea S, van Blitterswijk CA, de Boer J. Suppression of the immune system as a critical step for bone formation from allogeneic osteoprogenitors implanted in rats. J Cell Mol Me. 2014; 18(1): 134–142CrossRefGoogle Scholar
  227. 227.
    Ghadakzadeh S, Mekhail M, Aoude A, Hamdy R, Tabrizian M. Small players ruling the hard game: siRNA in bone regeneration. J Bone Miner Re. 2016; 31(3): 475–487CrossRefGoogle Scholar
  228. 228.
    Hong L, Wei N, Joshi V, Yu Y, Kim N, Krishnamachari Y, Zhang Q, Salem AK. Effects of glucocorticoid receptor small interferin. RNA delivered using poly lactic-co-glycolic acid microparticles on proliferation and differentiation capabilities of human mesenchymal stromal cells. Tissue Eng Part. 2012; 18(7–8): 775–784CrossRefGoogle Scholar
  229. 229.
    Wang Y, Tran KK, Shen H, Grainger DW. Selective local delivery o. RANK siRNA to bone phagocytes using bone augmentation biomaterials. Biomaterial. 2012; 33(33): 8540–8547CrossRefGoogle Scholar
  230. 230.
    Zhang Y, Wei L, Miron RJ, Shi B, Bian Z. Anabolic bone formation via a site-specific bone-targeting delivery system by interfering with semaphorin 4D expression. J Bone Miner Re. 2015; 30(2): 286–296CrossRefGoogle Scholar
  231. 231.
    Zhang Y, Wei L, Miron RJ, Zhang Q, Bian Z. Prevention of alveolar bone loss in an osteoporotic animal model via interference of semaphorin 4d. J Dent Re. 2014; 93(11): 1095–1100CrossRefGoogle Scholar
  232. 232.
    Jackson AL, Linsley PS. Recognizing and avoiding siRNA offtarget effects for target identification and therapeutic application. Nat Rev Drug Discov 2010; 9(1): 57–67PubMedCrossRefGoogle Scholar
  233. 233.
    Hankenson KD, Dishowitz M, Gray C, Schenker M. Angiogenesis in bone regeneration. Injur. 2011; 42(6): 556–561CrossRefGoogle Scholar
  234. 234.
    Ozdemir T, Higgins AM, Brown JL. Osteoinductive biomaterial geometries for bone regenerative engineering. Curr Pharm Des 2013; 19(19): 3446–3455PubMedCrossRefGoogle Scholar
  235. 235.
    Mandal BB, Grinberg A, Gil ES, Panilaitis B, Kaplan DL. Highstrength silk protein scaffolds for bone repair. Proc Natl Acad Sci USA 2012; 109(20): 7699–7704PubMedCrossRefGoogle Scholar
  236. 236.
    O’Brien FJ, Harley BA, Yannas IV, Gibson LJ. The effect of pore size on cell adhesion in collagen-GAG scaffolds. Biomaterial. 2005; 26(4): 433–441CrossRefGoogle Scholar
  237. 237.
    Sicchieri LG, Crippa GE, de Oliveira PT, Beloti MM, Rosa AL. Pore size regulates cell and tissue interactions wit. PLGA-CaP scaffolds used for bone engineering. J Tissue Eng Regen Me. 2012; 6(2): 155–162CrossRefGoogle Scholar
  238. 238.
    Zajac AL, Discher DE. Cell differentiation through tissue elasticity-coupled, myosin-driven remodeling. Curr Opin Cell Biol 2008; 20(6): 609–615PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Yousefi AM, Hoque ME, Prasad RG, Uth N. Current strategies in multiphasic scaffold design for osteochondral tissue engineering: a review. J Biomed Mater Res. 2015; 103(7): 2460–2481CrossRefGoogle Scholar
  240. 240.
    Chapanian R, Amsden BG. Combined and sequential delivery of bioactiv. VEGF165 and HGF from poly(trimethylene carbonate) based photo-cross-linked elastomers. J Control Releas. 2010; 143(1): 53–63CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Rui Shi
    • 1
  • Yuelong Huang
    • 2
  • Chi Ma
    • 1
  • Chengai Wu
    • 1
  • Wei Tian
    • 1
    • 2
  1. 1.Institute of Traumatology and Orthopaedics, Beijing Laboratory of Biomedical MaterialsBeijing Jishuitan HospitalBeijingChina
  2. 2.Department of Spine Surgery of Beijing Jishuitan HospitalThe Fourth Clinical Medical College of Peking UniversityBeijingChina

Personalised recommendations