3D-printed porous titanium changed femoral head repair growth patterns: osteogenesis and vascularisation in porous titanium

Clinical Applications of Biomaterials Original Research
Part of the following topical collections:
  1. Clinical Applications of Biomaterials


Osteonecrosis of the femoral head (ONFH) is a major cause of morbidity, and total hip arthroplasty is both traumatic and expensive. Here, we created a gelatine scaffold embedded in uniquely shaped, 3D-printed porous titanium parts, which could attract and promote the proliferation of osteoblasts as well as bone regeneration, as the extracellular matrix (ECM) does in vivo. Interestingly, after hybridisation with platelets, the scaffold exhibited a low yet considerable rate of stable, safe and long-term growth factor release. Additionally, a novel ONFH model was constructed and verified. Scaffolds implanted in this model were found to accelerate bone repair. In conclusion, our scaffold successfully simulates the ECM and considerably accelerates bone regeneration, in which platelets play an indispensable role. We believe that platelets should be emphasised as carriers that may be employed to transport drugs, cytokines and other small molecules to target locations in vivo. In addition, this novel scaffold is a useful material for treating ONFH.

Graphical Abstract

An overview of the novel scaffold mimicking the extracellular environment in bone repair. a and b: A gelatine scaffold was cross-linked and freeze-dried within 3D-printed porous titanium. c: Platelets were coated onto the gelatine microscaffold after freeze-drying platelet-rich plasma. d: The microscaffold supported the migration of cells into the titanium pores and their subsequent growth, while the platelets slowly released cell factors, exerting bioactivity. Open image in new window



We would like to express our sincere gratitude to the Central Laboratory and Laboratory Animal Centre of Peking Union Medical College Hospital and the National High-tech R&D Programme of China for the provided support (863 Programme) (2015AA020316, 2015AA033601). We would also like to thank Uppsala University in Sweden for the support provided in the preparation and verification of the scaffolds.

Author contributions

XW and ZW designed the research. WZ performed the in vitro experiments and manufactured the materials. YZ performed the animal research. WZ, QM and YW wrote the main manuscript and prepared the figures, which were reviewed by all authors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The animal experiments in this study were approved by the Ethical Inspection Committee of Peking Union Medical College Hospital (XHDW-2015-0034). All methods were performed in accordance with the relevant guidelines and regulations.

Supplementary material

10856_2017_5862_MOESM1_ESM.docx (62 kb)
Supplementary Table 1


  1. 1.
    Hollister SJ, Flanagan CL, Zopf DA, Morrison RJ, Nasser H, Patel JJ, et al. Design control for clinical translation of 3D printed modular scaffolds. Ann Biomed Eng. 2015;43:774–86. doi:10.1007/s10439-015-1270-2.CrossRefGoogle Scholar
  2. 2.
    Zhang S, Cheng X, Yao Y, Wei Y, Han C, Shi Y, et al. Porous niobium coatings fabricated with selective laser melting on titanium substrates: preparation, characterization, and cell behavior. Mater Sci Eng C Mater Biol Appl. 2015;53:50–9. doi:10.1016/j.msec.2015.04.005.CrossRefGoogle Scholar
  3. 3.
    Kim M, Kim G. 3D multi-layered fibrous cellulose structure using an electrohydrodynamic process for tissue engineering. J Colloid Interface Sci. 2015;457:180–7. doi:10.1016/j.jcis.2015.07.007.CrossRefGoogle Scholar
  4. 4.
    Li L, Zuo Y, Zou Q, Yang B, Lin L, Li J, et al. Hierarchical structure and mechanical improvement of an n-HA/GCO-PU composite scaffold for bone regeneration. ACS Appl Mater Interfaces. 2015;7:22618–29. doi:10.1021/acsami.5b07327.CrossRefGoogle Scholar
  5. 5.
    Flauder S, Gbureck U, Müller FA. Structure and mechanical properties of beta-TCP scaffolds prepared by ice-templating with preset ice front velocities. Acta Biomater. 2014;10:5148–55. doi:10.1016/j.actbio.2014.08.020.CrossRefGoogle Scholar
  6. 6.
    Wieding J, Wolf A, Bader R. Numerical optimization of open-porous bone scaffold structures to match the elastic properties of human cortical bone. J Mech Behav Biomed Mater. 2014;37:56–68. doi:10.1016/j.jmbbm.2014.05.002.CrossRefGoogle Scholar
  7. 7.
    Vaquette C, Ivanovski S, Hamlet SM, Hutmacher DW. Effect of culture conditions and calcium phosphate coating on ectopic bone formation. Biomaterials. 2013;34:5538–51. doi:10.1016/j.biomaterials.2013.03.088.CrossRefGoogle Scholar
  8. 8.
    Bsat S, Yavari SA, Munsch M, Valstar ER, Zadpoor AA. Effect of alkali-acid-heat chemical surface treatment on electron beam melted porous titanium and its apatite forming ability. Materials. 2015;8:1612–25. doi:10.3390/ma8041612.CrossRefGoogle Scholar
  9. 9.
    Ravindran S, Kotecha M, Huang CC, Ye A, Pothirajan P, Yin Z, et al. Biological and MRI characterization of biomimetic ECM scaffolds for cartilage tissue regeneration. Biomaterials. 2015;71:58–70. doi:10.1016/j.biomaterials.2015.08.030.CrossRefGoogle Scholar
  10. 10.
    Jhala D, Vasita R. A review on extracellular matrix mimicking strategies. a review on extracellular matrix mimicking strategies for an artificial stem cell niche. Polym Rev. 2015;55:561–95. doi:10.1080/15583724.2015.1040552.CrossRefGoogle Scholar
  11. 11.
    Kang Y, Kim S, Khademhosseini A, Yang Y. Creation of bony microenvironment with CaP and cell-derived ECM to enhance human bone-marrow MSC behavior and delivery of BMP-2. Biomaterials. 2011;32:6119–30. doi:10.1016/j.biomaterials.2011.05.015.CrossRefGoogle Scholar
  12. 12.
    Akar B, Jiang B, Somo SI, Appel AA, Larson JC, Tichauer KM, et al. Biomaterials with persistent growth factor gradients in vivo accelerate vascularized tissue formation. Biomaterials. 2015;72:61–73. doi:10.1016/j.biomaterials.2015.08.049.CrossRefGoogle Scholar
  13. 13.
    Chaudhary C, Garg T. Scaffolds: a novel carrier and potential wound healer. Crit Rev Ther Drug Carrier Syst. 2015;32:277–321. doi:10.1615/CritRevTherDrugCarrierSyst.2015011246.CrossRefGoogle Scholar
  14. 14.
    Bansiddhi A, Sargeant TD, Stupp SI, Dunand DC. Porous NiTi for bone implants: a review. Acta Biomater. 2008;4:773–82. doi:10.1016/j.actbio.2008.02.009.CrossRefGoogle Scholar
  15. 15.
    Wang Q, Zhang H, Li Q, Ye L, Gan H, Liu Y, et al. Biocompatibility and osteogenic properties of porous tantalum. Exp Ther Med. 2015;9:780–6. doi:10.3892/etm.2015.2208.Google Scholar
  16. 16.
    Briggs T, Matos J, Collins G, Arinzeh TL. Evaluating protein incorporation and release in electrospun composite scaffolds for bone tissue engineering applications. J Biomed Mater Res A. 2015;103:3117–27. doi:10.1002/jbm.a.35444.CrossRefGoogle Scholar
  17. 17.
    Sharmin F, Adams D, Pensak M, Dukas A, Lieberman J, Khan Y. Biofunctionalizing devitalized bone allografts through polymer-mediated short and long term growth factor delivery. J Biomed Mater Res A. 2015;103:2847–54. doi:10.1002/jbm.a.35435.CrossRefGoogle Scholar
  18. 18.
    Suliman S, Xing Z, Wu X, Xue Y, Pedersen TO, Sun Y, et al. Release and bioactivity of bone morphogenetic protein-2 are affected by scaffold binding techniques in vitro and in vivo. J Control Release. 2015;197:148–57. doi:10.1016/j.jconrel.2014.11.003.CrossRefGoogle Scholar
  19. 19.
    Shen J, Gao QF, Zhang Y, He YH. Autologous platelet-rich plasma promotes proliferation and chondrogenic differentiation of adipose-derived stem cells. Mol Med Rep. 2015;11:1298–303. doi:10.3892/mmr.2014.2875.Google Scholar
  20. 20.
    Passaretti F, Tia M, D’Esposito V, De Pascale M, Del Corso M, Sepulveres R, et al. Growth-promoting action and growth factor release by different platelet derivatives. Platelets. 2014;25:252–6. doi:10.3109/09537104.2013.809060.CrossRefGoogle Scholar
  21. 21.
    Sánchez-Ilárduya MB, Trouche E, Tejero R, Orive G, Reviakine I, Anitua E. Time-dependent release of growth factors from implant surfaces treated with plasma rich in growth factors. J Biomed Mater Res A. 2013;101:1478–88. doi:10.1002/jbm.a.34428.CrossRefGoogle Scholar
  22. 22.
    Lucarelli E, Beretta R, Dozza B, Tazzari P, O’Connell S, Ricci F, et al. A recently developed bifacial platelet-rich fibrin matrix. Eur Cells Mater. 2010;20:13–23. doi:10.22203/eCM.v020a02.CrossRefGoogle Scholar
  23. 23.
    Mont MA, Cherian JJ, Sierra RJ, Jones LC, Lieberman JR. Nontraumatic osteonecrosis of the femoral head: where do we stand today? A ten-year update. J Bone Joint Surg Am. 2015;97:1604–27. doi:10.2106/JBJS.O.00071.CrossRefGoogle Scholar
  24. 24.
    Papakostidis C, Tosounidis TH, Jones E, Giannoudis PV. The role of “cell therapy” in osteonecrosis of the femoral head: a systematic review of the literature and meta-analysis of 7 studies. Acta Orthop. 2016;87:72–8. doi:10.3109/17453674.2015.1077418.CrossRefGoogle Scholar
  25. 25.
    Wang C, Wang Y, Meng HY, Yuan XL, Xu XL, Wang AY, et al. Application of bone marrow mesenchymal stem cells to the treatment of osteonecrosis of the femoral head. Int J Clin Exp Med. 2015;8:3127–35..Google Scholar
  26. 26.
    Mont MA, Marulanda GA, Seyler TM, Plate JF, Delanois RE. Core decompression and nonvascularized bone grafting for the treatment of early stage osteonecrosis of the femoral head. Instr Course Lect. 2007;56:213–20..Google Scholar
  27. 27.
    Vadasz Z, Misselevich I, Norman D, Peled E, Boss JH. Localization of vascular endothelial growth factor during the early reparative phase of the rats’ vessels deprivation-induced osteonecrosis of the femoral heads. Exp Mol Pathol. 2004;77:145–8. doi:10.1016/j.yexmp.2004.06.002.CrossRefGoogle Scholar
  28. 28.
    Gu J, Wang T, Fan G, Ma J, Hu W, Cai X. Biocompatibility of artificial bone based on vancomycin loaded mesoporous silica nanoparticles and calcium sulfate composites. J Mater Sci Mater Med. 2016;27:64.CrossRefGoogle Scholar
  29. 29.
    Chen L, Zhang Y, Liu J, Wei L, Song B, Shao L. Exposure of the murine RAW 264.7 macrophage cell line to dicalcium silicate coating: assessment of cytotoxicity and pro-inflammatory effects. J Mater Sci Mater Med. 2016;27:59.CrossRefGoogle Scholar
  30. 30.
    Landesberg R, Roy M, Glickman RS. Quantification of growth factor levels using a simplified method of platelet-rich plasma gel preparation. J Oral Maxillofac Surg. 2000;58:297–300..CrossRefGoogle Scholar
  31. 31.
    Chang NJ, Lin CC, Shie MY, Yeh ML, Li CF, Liang PI, et al. Positive effects of cell-free porous PLGA implants and early loading exercise on hyaline cartilage regeneration in rabbits. Acta Biomater. 2015;28:128–37. doi:10.1016/j.actbio.2015.09.026.CrossRefGoogle Scholar
  32. 32.
    Wang ZX, Chen C, Zhou Q, Wang XS, Zhou G, Liu W, et al. The treatment efficacy of bone tissue engineering strategy for repairing segmental bone defects under osteoporotic conditions. Tissue Eng A. 2015;21:2346–55. doi:10.1089/ten.tea.2015.0071.CrossRefGoogle Scholar
  33. 33.
    Inzunza D, Covarrubias C, Von Marttens A, Leighton Y, Carvajal JC, Valenzuela F, et al. Synthesis of nanostructured porous silica coatings on titanium and their cell adhesive and osteogenic differentiation properties. J Biomed Mater Res A. 2014;102:37–48. doi:10.1002/jbm.a.34673.CrossRefGoogle Scholar
  34. 34.
    Xiao X, Wang W, Liu D, Zhang H, Gao P, Geng L, et al. The promotion of angiogenesis induced by three-dimensional porous beta-tricalcium phosphate scaffold with different interconnection sizes via activation of PI3K/Akt pathways. Sci Rep. 2015;5:9409 doi:10.1038/srep09409.CrossRefGoogle Scholar
  35. 35.
    Yang J, Kang Y, Browne C, Jiang T, Yang Y. Graded porous β-tricalcium phosphate scaffolds enhance bone regeneration in mandible augmentation. J Craniofac Surg. 2015;26:e148–53. doi:10.1097/SCS.0000000000001383.CrossRefGoogle Scholar
  36. 36.
    Hoshiba T, Kawazoe N, Tateishi T, Chen G. Development of extracellular matrices mimicking stepwise adipogenesis of mesenchymal stem cells. Adv Mater. 2010;22:3042–7. doi:10.1002/adma.201000038.CrossRefGoogle Scholar
  37. 37.
    Mukhatyar V, Karumbaiah L, Yeh J, Bellamkonda R. Tissue engineering strategies designed to realize the endogenous regenerative potential of peripheral nerves. Adv Mater. 2009;21:4670–9.Google Scholar
  38. 38.
    Wang Y, Zhao Q, Zhang H, Yang S, Jia X. A novel poly(amido amine)-dendrimer-based hydrogel as a mimic for the extracellular matrix. Adv Mater. 2014;26:4163–7. doi:10.1002/adma.201400323.CrossRefGoogle Scholar
  39. 39.
    Zhang AP, Qu X, Soman P, Hribar KC, Lee JW, Chen S, et al. Rapid fabrication of complex 3D extracellular microenvironments by dynamic optical projection stereolithography. Adv Mater. 2012;24:4266–70. doi:10.1002/adma.201202024.CrossRefGoogle Scholar
  40. 40.
    Donda RS, Wironen JF, Seid C. Obtaining growth factors from tissue for use in repairing a wound, defect or injury comprises obtaining tissue and extracting one or more growth factors. WO200157082-A2; US2001041792-A1; AU200136632-A; WO200157082-A3.Google Scholar
  41. 41.
    Lindner R, Moosmann A, Dietrich A, Böttinger H, Kontermann R, Siemann-Herzberg M. Process development of periplasmatically produced single chain fragment variable against epidermal growth factor receptor in Escherichia coli. J Biotechnol. 2014;192:136–45. doi:10.1016/j.jbiotec.2014.10.003.CrossRefGoogle Scholar
  42. 42.
    Vetillard J, Herodin F, Caterini R. Culture chamber for growing animal cells, useful for transplantation and genetic transformation, provides optimum growing conditions and recycle of growth factors. EP1174497-A1; WO200206441-A1; AU200178542-A; EP1301586-A1; CN1460122-A; JP2004504023-W; US2004132175-A1; EP1174497-B1; DE60013585-E; DE60013585-T2; CN1258588-C.Google Scholar
  43. 43.
    Grasman JM, Do DM, Page RL, Pins GD. Rapid release of growth factors regenerates force output in volumetric muscle loss injuries. Biomaterials. 2015;72:49–60. doi:10.1016/j.biomaterials.2015.08.047.CrossRefGoogle Scholar
  44. 44.
    Park KE, Kim BS, Kim MH, You HK, Lee J, Park WH. Basic fibroblast growth factor-encapsulated PCL nano/microfibrous composite scaffolds for bone regeneration. Polymer. 2015;76:8–16. doi:10.1016/j.polymer.2015.08.024.CrossRefGoogle Scholar
  45. 45.
    Bai R, Liu W, Zhao A, Zhao Z, Jiang D. Nitric oxide content and apoptosis rate in steroid-induced avascular necrosis of the femoral head. Exp Ther Med. 2015;10:591–7. doi:10.3892/etm.2015.2521.Google Scholar
  46. 46.
    Qin L, Zhang G, Sheng H, Yeung KW, Yeung HY, Chan CW, et al. Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone. Bone. 2006;39:863–71. doi:10.1016/j.bone.2006.04.018.CrossRefGoogle Scholar
  47. 47.
    Zhang M, Wang GL, Zhang HF, Hu XD, Shi XY, Li S, et al. Repair of segmental long bone defect in a rabbit radius nonunion model: comparison of cylindrical porous titanium and hydroxyapatite scaffolds. Artif Organs. 2014;38:493–502. doi:10.1111/aor.12208.CrossRefGoogle Scholar
  48. 48.
    Thomas CV, McMillan KG, Jeynes P, Martin T, Parmar S. Use of a titanium cutting guide to assist raising the composite radial forearm free flap. Int J Oral Maxillofac Surg. 2013;42:1414–7. doi:10.1016/j.ijom.2013.06.015.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Orthopaedics, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
  2. 2.Beijing Key Laboratory for Genetic Research of Bone and Joint Disease, Central Laboratory, Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijingP.R. China

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