Direct Fabrication as a Patient-Targeted Therapeutic in a Clinical Environment

  • Dietmar W. HutmacherEmail author
  • Maria Ann Woodruff
  • Kevin Shakesheff
  • Robert E. Guldberg
Part of the Methods in Molecular Biology book series (MIMB, volume 868)


A paradigm shift is taking place in orthopaedic and reconstructive surgery. This transition from using medical devices and tissue grafts towards the utilization of a tissue engineering approach combines biodegradable scaffolds with cells and/or biological molecules in order to repair and/or regenerate tissues. One of the potential benefits offered by solid freeform fabrication (SFF) technologies is the ability to create such biodegradable scaffolds with highly reproducible architecture and compositional variation across the entire scaffold due to their tightly controlled computer-driven fabrication. Many of these biologically activated materials can induce bone formation at ectopic and orthotopic sites, but they have not yet gained widespread use due to several continuing limitations, including poor mechanical properties, difficulties in intraoperative handling, lack of porosity suitable for cellular and vascular infiltration, and suboptimal degradation characteristics. In this chapter, we define scaffold properties and attempt to provide some broad criteria and constraints for scaffold design and fabrication in combination with growth factors for bone engineering applications. Lastly, we comment on the current and future developments in the field, such as the functionalization of novel composite scaffolds with combinations of growth factors designed to promote cell attachment, cell survival, vascular ingrowth, and osteoinduction.

Key words

Tissue engineering Scaffolds Rapid prototyping Composites Mesenchymal stem cells Growth factors 


  1. 1.
    Hutmacher DW, Cool S (2007) Concepts of scaffold-based tissue engineering – the rationale to use solid free-form fabrication techniques. J Cell Mol Med 11(4):654–669CrossRefGoogle Scholar
  2. 2.
    Lam CXF, Teoh SH, Hutmacher DW (2007) Comparison of degradation of PCL and PCL-TCP scaffolds in alkaline medium. Polym Int 6:718–728CrossRefGoogle Scholar
  3. 3.
    Vacanti CA (2006) The history of tissue engineering. J Cell Mol Med 10:569–576CrossRefGoogle Scholar
  4. 4.
    Hutmacher DW, Sittinger M, Risbud MV (2004) Scaffold-based tissue engineering: rationale for computer-aided design and solid free-form fabrication systems. Trends Biotechnol 22:354–362CrossRefGoogle Scholar
  5. 5.
    Bach AD, Arkudas A, Tjiawi J, Polykandriotis E, Kneser U, Horch RE, Beier JP (2006) A new approach to tissue engineering of vascularized skeletal muscle. J Cell Mol Med 10:716–726CrossRefGoogle Scholar
  6. 6.
    Kneser U, Stangenberg L, Ohnolz J, Buettner O, Stern-Straeter J, Mobest D, Horch RE, Stark GB, Schaefer DJ (2006) Evaluation of processed bovine cancellous bone matrix seeded with syngenic osteoblasts in a critical size calvarial defect rat model. J Cell Mol Med 10:695–670CrossRefGoogle Scholar
  7. 7.
    Zhou Y, Chen F, Ho ST, Woodruff MA, Lim TM, Hutmacher DW (2007) Combined marrow stromal cell-sheet techniques and high-strength biodegradable composite scaffolds for engineered functional bone grafts. Biomaterials 28:814–824CrossRefGoogle Scholar
  8. 8.
    Hollister SJ (2005) Porous scaffold design for tissue engineering. Nat Mater 4:518–524CrossRefGoogle Scholar
  9. 9.
    Oest ME, Dupont KM, Kong H-J, Mooney DJ, Guldberg RE (2005) Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res 17415756 (P,S,E,B,D)Google Scholar
  10. 10.
    Rai B, Teoh SH, Hutmacher DW, Cao T, Ho KH (2005) Novel PCL-based honeycomb scaffolds as drug delivery systems for rhBMP-2. Biomaterials 26:3739–3748CrossRefGoogle Scholar
  11. 11.
    Suciati T, Howard D, Barry J et al (2006) Zonal release of proteins within tissue engineering scaffolds J Mater Sci Mater Med 17(11):1049–1056Google Scholar
  12. 12.
    Kanczler JM, Barry J, Ginty P et al (2007) Supercritical carbon dioxide generated vascular endothelial growth factor encapsulated poly(DL-lactic acid) scaffolds induce angiogenesis in vitro. Biochem Biophys Res Commun 352:135–141Google Scholar
  13. 13.
    Kain MS, Einhorn TA (2005) Recombinant human bone morphogenetic proteins in the treatment of fractures. Foot Ankle Clin 10:639–650, viiiGoogle Scholar
  14. 14.
    Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A,Wisniewski T (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84-A:2123–2134Google Scholar
  15. 15.
    De Long WG, Jr., Einhorn TA, Koval K, McKee M, Smith W, Sanders R, Watson T (2007) Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. J Bone Joint Surg Am 89:649–658Google Scholar
  16. 16.
    Hutmacher DW, Woodruff MA (2008) Design, fabrication and characterisation of scaffolds via solid free form fabrication techniques. In: Chu PK, Liu X (eds) Handbook of fabrication and processing of biomaterials. CRC Press/Taylor and Francis Group, pp 45–68Google Scholar
  17. 17.
    Hutmacher, Dietmar W, Woodruff, Maria A (2007) Composite scaffolds for bone engineering. In: Fakirov S, Bhattacharyya D (eds) Handbook of engineering biopolymers: homopolymers, blends and composites. Hanser Gardner, Germany, Munich, pp 773–798Google Scholar
  18. 18.
    Schantz JT, Lim TC, Ning C, Teoh SH, Tan KC, Wang SC, Hutmacher DW (2006) Cranioplasty after trephination using a novel biodegradable burr hole cover: technical case report. Neurosurgery 58:ONS-E176; discussion ONS-E176Google Scholar
  19. 19.
    Zhou YF, Sae-Lim V, Chou AM, Hutmacher DW, Lim TM (2006) Does seeding density affect in vitro mineral nodules formation in novel composite scaffolds? J Biomed Mater Res A 78:183–193Google Scholar
  20. 20.
    Mohan S, Baylink DJ (1991) Bone growth factors. Clin Orthop Relat Res 263:30–48Google Scholar
  21. 21.
    Hutmacher DW, Garcia AJ (2005) Scaffold-based bone engineering but using genetically modified cells. Gene 347:1–10CrossRefGoogle Scholar
  22. 22.
    Cuevas P, de Paz V, Cuevas B, Marin-Martinez J, Picon-Molina M, Fernandez-Pereira A, Gimenez-Gallego G (1997) Osteopromotion for cranioplasty: an experimental study in rats using acidic fibroblast growth factor. Surg Neurol 47:242–246CrossRefGoogle Scholar
  23. 23.
    Tabata Y (2008) Current status of regenerative medical therapy based on drug delivery technology. Reprod Biomed Online 16(1):70–80CrossRefGoogle Scholar
  24. 24.
    Gruber R, Koch H, Doll BA, Tegtmeier F, Einhorn TA, Hollinger JO (2006) Fracture healing in the elderly patient. Exp Gerontol 41(11):1080–1093CrossRefGoogle Scholar
  25. 25.
    SSIB, AREJ (2004) Bone defect repair in rat tibia by TGF-beta1 and IGF-1 released from hydrogel scaffold. Cell Tissue Bank 5:223–230.136Google Scholar
  26. 26.
    Giannoudis PV, Einhorn TA, Marsh D (2007) Fracture healing: the diamond concept. Injury 38(Suppl 4):S3–S6CrossRefGoogle Scholar
  27. 27.
    S, Ryder J, Shemilt I, Mugford M, Harvey I, Song F (2007) Clinical effectiveness and costeffectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess 11(30):1–150, iii–ivGoogle Scholar
  28. 28.
    Robinson Y, Heyde CE, Tschöke SK, Mont MA, Seyler TM, Ulrich SD (2008) Evidence supporting the use of bone morphogenetic proteins for spinal fusion surgery. Expert Rev Med Devices 5(1):75–84CrossRefGoogle Scholar
  29. 29.
    Shakesheff KM, France RM, Quirk RA Porous matrix, inventors. International Patent WO2004084968-A1, GB2415142-A, EP1605984-A1, Regentec LTDGoogle Scholar
  30. 30.
    Pratoomsoot C et al (2008) A thermoreversible hydrogel as a biosynthetic bandage for corneal wound repair. Biomaterials 29(3):272–281CrossRefGoogle Scholar
  31. 31.
    Howdle SM, Watson MS, Whitaker MJ, Popov VK, Davies MC, Mandel FS, Don WJ, Shakesheff KM et al (2001) Supercritical fluid mixing: preparation of thermally sensitive polymer composites containing bioactive materials. Chem Commun 1:109–110CrossRefGoogle Scholar
  32. 32.
    Whitaker MJ et al (2005) The production of protein-loaded microparticles by supercritical fluid enhanced mixing and spraying. J Control Release 101(1–3):85–92CrossRefGoogle Scholar
  33. 33.
    Suciati T, Daniel H, Barry J, Everitt N, Shakesheff K, Rose F (2006) Zonal release of proteins within tissue engineering scaffolds. J Mater Sci Mater Med 17:1049CrossRefGoogle Scholar
  34. 34.
    Kanczler JM et al (2007) Supercritical carbon dioxide generated vascular endothelial growth factor encapsulated poly(DL-lactic acid) scaffolds induce angiogenesis in vitro. Biochem Biophys Res Commun 352(1):135–141CrossRefGoogle Scholar
  35. 35.
    Oest ME, Dupont KM, Kong HJ, Mooney DJ, Guldberg RE (2007) Quantitative assessment of scaffold and growth factor mediated repair of critically-sized bone defects. J Orthop Res 25(7):941–950CrossRefGoogle Scholar
  36. 36.
    Rai B, Oest ME, Dupont KM, Ho KH, Teoh SH, Guldberg RE (2007) Combination of platelet rich plasma with polycaprolactone-tricalcium phosphate scaffolds for segmental bone defect repair. J Biomed Mater Res 81(4):888–899CrossRefGoogle Scholar
  37. 37.
    Peng H et al (2005) Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Bone Miner Res 20:2017CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Dietmar W. Hutmacher
    • 1
    Email author
  • Maria Ann Woodruff
    • 2
  • Kevin Shakesheff
    • 3
  • Robert E. Guldberg
    • 4
  1. 1.Regenerative Medicine, Institute of Health and Biomedical InnovationQueensland University of TechnologyKelvin GroveAustralia
  2. 2.Biomaterials and Tissue Morphology Group, Institute of Health and Biomedical InnovationQueensland University of TechnologyKelvin GroveAustralia
  3. 3.School of Pharmacy, Wolfson Centre for Stem Cells, Tissue Engineering, and Modelling (STEM), Centre for Biomolecular Sciences (CBS)University of NottinghamNottinghamUK
  4. 4.Parker H. Petit Institute for Bioengineering and Bioscience, George W. Woodruff School of Mechanical EngineeringGeorgia Institute of TechnologyAtlantaUSA

Personalised recommendations