Tissue engineering of bone: the reconstructive surgeon's point of view

Bone defects represent a medical and socioeconomic challenge. Different types of biomaterials are applied for reconstructive indications and receive rising interest. However, autologous bone grafts are still considered as the gold standard for reconstruction of extended bone defects. The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. Tissue engineering is, according to its historic definition, an “interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function”. It is based on the understanding of tissue formation and regeneration and aims to rather grow new functional tissues than to build new spare parts. While reconstruction of small to moderate sized bone defects using engineered bone tissues is technically feasible, and some of the currently developed concepts may represent alternatives to autologous bone grafts for certain clinical conditions, the reconstruction of largevolume defects remains challenging. Therefore vascularization concepts gain on interest and the combination of tissue engineering approaches with flap prefabrication techniques may eventually allow application of bone‐tissue substitutes grown in vivo with the advantage of minimal donor site morbidity as compared to conventional vascularized bone grafts. The scope of this review is the introduction of basic principles and different components of engineered bioartificial bone tissues with a strong focus on clinical applications in reconstructive surgery. Concepts for the induction of axial vascularization in engineered bone tissues as well as potential clinical applications are discussed in detail.

[1]  M. Ueda,et al.  Clinical case reports of injectable tissue-engineered bone for alveolar augmentation with simultaneous implant placement. , 2005, The International journal of periodontics & restorative dentistry.

[2]  G. Ahrendt,et al.  Angiogenic Growth Factors: A Review for Tissue Engineering , 1998 .

[3]  Thorsten Walles,et al.  Engineering of a vascularized scaffold for artificial tissue and organ generation. , 2005, Biomaterials.

[4]  R. Horch,et al.  The composite vastus medialis-patellar complex osseomuscular flap as a salvage procedure after complex trauma of the knee--an anatomical study and clinical application. , 2005, British journal of plastic surgery.

[5]  G. Stein,et al.  Development of the osteoblast phenotype: molecular mechanisms mediating osteoblast growth and differentiation. , 1995, The Iowa orthopaedic journal.

[6]  D Heinegård,et al.  Structure and biology of cartilage and bone matrix noncollagenous macromolecules , 1989, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  P. Madeddu Therapeutic angiogenesis and vasculogenesis for tissue regeneration , 2005, Experimental physiology.

[8]  Catalina Wong,et al.  Fibrin-based biomaterials to deliver human growth factors , 2003, Thrombosis and Haemostasis.

[9]  Yasuhiko Tabata,et al.  Tissue regeneration based on growth factor release. , 2003, Tissue engineering.

[10]  T. Einhorn Clinical applications of recombinant human BMPs: early experience and future development. , 2003, The Journal of bone and joint surgery. American volume.

[11]  J. Vacanti,et al.  Bone and cartilage reconstruction with tissue engineering approaches. , 1994, Otolaryngologic clinics of North America.

[12]  J. Beier,et al.  Y Chromosome Detection of Three-Dimensional Tissue-Engineered Skeletal Muscle Constructs in a Syngeneic Rat Animal Model , 2004, Cell transplantation.

[13]  S. Bruder,et al.  Terminal differentiation of osteogenic cells in the embryonic chick tibia is revealed by a monoclonal antibody against osteocytes. , 1990, Bone.

[14]  R. A. Forster,et al.  Alternatives to Autogenous Bone Graft: Efficacy and Indications , 1995, The Journal of the American Academy of Orthopaedic Surgeons.

[15]  D. Möbest,et al.  Differentiation of osteoblasts in three-dimensional culture in processed cancellous bone matrix: quantitative analysis of gene expression based on real-time reverse transcription-polymerase chain reaction. , 2005, Tissue engineering.

[16]  A. Reddi,et al.  Regulation of cartilage and bone differentiation by bone morphogenetic proteins. , 1992, Current opinion in cell biology.

[17]  T. Himi,et al.  A prefabricated osteocutaneous flap for tracheal reconstruction. , 2003, Plastic and reconstructive surgery.

[18]  A. Reddi Initiation of fracture repair by bone morphogenetic proteins. , 1998, Clinical orthopaedics and related research.

[19]  Antonios G Mikos,et al.  Influence of the in vitro culture period on the in vivo performance of cell/titanium bone tissue-engineered constructs using a rat cranial critical size defect model. , 2003, Journal of biomedical materials research. Part A.

[20]  K. Leong,et al.  The design of scaffolds for use in tissue engineering. Part II. Rapid prototyping techniques. , 2002, Tissue engineering.

[21]  Jay R Lieberman,et al.  The role of growth factors in the repair of bone. Biology and clinical applications. , 2002, The Journal of bone and joint surgery. American volume.

[22]  J. Upton,et al.  Prefabrication of Composite Free Flaps Through Staged Microvascular Transfer: An Experimental and Clinical Study , 1991, Plastic and reconstructive surgery.

[23]  S Jepsen,et al.  Mandibular reconstruction with a prefabricated vascularized bone graft using recombinant human osteogenic protein-1: an experimental study in miniature pigs. Part I: Prefabrication. , 2001, International journal of oral and maxillofacial surgery.

[24]  H. Oztunç,et al.  Long-term results of the application of solvent-dehydrated bone xenograft and duramater xenograft for the healing of oroantral osseous defects: a pilot experimental study. , 2003, Dental traumatology : official publication of International Association for Dental Traumatology.

[25]  Marc A. Asher,et al.  Iliac Crest Bone Graft Harvest Donor Site Morbidity: A Statistical Evaluation , 1995, Spine.

[26]  R E Horch,et al.  Skeletal muscle tissue engineering , 2004, Journal of cellular and molecular medicine.

[27]  G. Mundy,et al.  Optimizing human demineralized bone matrix for clinical application. , 2000, Tissue engineering.

[28]  A. Reddi,et al.  Morphogenesis and tissue engineering of bone and cartilage: inductive signals, stem cells, and biomimetic biomaterials. , 2000, Tissue engineering.

[29]  T. Lim,et al.  Repair of calvarial defects with customized tissue-engineered bone grafts I. Evaluation of osteogenesis in a three-dimensional culture system. , 2003, Tissue engineering.

[30]  J. Buckwalter,et al.  Bone biology. I: Structure, blood supply, cells, matrix, and mineralization. , 1996, Instructional course lectures.

[31]  M. Owen,et al.  The origin of bone cells. , 1970, International review of cytology.

[32]  U. Kneser,et al.  Fibrin Gel-Immobilized Primary Osteoblasts in Calcium Phosphate Bone Cement: In vivo Evaluation with Regard to Application as Injectable Biological Bone Substitute , 2005, Cells Tissues Organs.

[33]  Daniel A Grande,et al.  Gene therapy and tissue engineering in repair of the musculoskeletal system , 2003, Journal of cellular biochemistry.

[34]  R. Schmelzeisen,et al.  Making bone: implant insertion into tissue-engineered bone for maxillary sinus floor augmentation-a preliminary report. , 2003, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[35]  C. Kaps,et al.  TISSUE ENGINEERING OF BONE FOR MANDIBULAR AUGMENTATION IN IMMUNOCOMPETENT MINIPIGS: PRELIMINARY STUDY , 2003, Scandinavian journal of plastic and reconstructive surgery and hand surgery.

[36]  G. Karsenty,et al.  Genetic control of cell differentiation in the skeleton. , 1998, Current opinion in cell biology.

[37]  T. Hefferan,et al.  Structure and molecular regulation of bone matrix proteins , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  H. Chambers,et al.  Complications of iliac crest bone graft harvesting. , 1996, Clinical orthopaedics and related research.

[39]  Antonios G Mikos,et al.  Biomimetic materials for tissue engineering. , 2003, Biomaterials.

[40]  J. Folkman,et al.  SELF-REGULATION OF GROWTH IN THREE DIMENSIONS , 1973, The Journal of experimental medicine.

[41]  G. Mundy Regulation of bone formation by bone morphogenetic proteins and other growth factors. , 1996, Clinical orthopaedics and related research.

[42]  J. Aubin,et al.  Advances in the osteoblast lineage. , 1998, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[43]  Jeffrey Bonadio,et al.  Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration , 1999, Nature Medicine.

[44]  S. Shenaq,et al.  Prefabricated flaps: experimental and clinical review. , 1995, Plastic and reconstructive surgery.

[45]  M. Riminucci [Bone stem cells]. , 2005, Pathologica.

[46]  D. Benayahu,et al.  Single‐Colony Derived Strains of Human Marrow Stromal Fibroblasts Form Bone After Transplantation In Vivo , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[47]  U Kneser,et al.  Long-term differentiated function of heterotopically transplanted hepatocytes on three-dimensional polymer matrices. , 1999, Journal of biomedical materials research.

[48]  J. Schipper,et al.  [The preconditioning and prelamination of pedicled and free microvascular anastomised flaps with the technique of vacuum assisted closure]. , 2003, Laryngo- rhino- otologie.

[49]  A Kingman,et al.  In vivo bone formation by human bone marrow stromal cells: effect of carrier particle size and shape. , 2001, Biotechnology and bioengineering.

[50]  C. Perry,et al.  Bone repair techniques, bone graft, and bone graft substitutes. , 1999, Clinical orthopaedics and related research.

[51]  P. Giannoudis,et al.  Application of recombinant BMP-7 on persistent upper and lower limb non-unions. , 2005, Injury.

[52]  R. Schmelzeisen,et al.  Tissue-engineered bone for maxillary sinus augmentation. , 2004, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[53]  S. Govender,et al.  Staged reduction and stabilisation in chronic atlantoaxial rotatory fixation. , 2002, The Journal of bone and joint surgery. British volume.

[54]  J. Hubbell,et al.  Development of fibrin derivatives for controlled release of heparin-binding growth factors. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[55]  G. Hotz,et al.  Bone substitute with osteoinductive biomaterials--current and future clinical applications. , 1994, International journal of oral and maxillofacial surgery.

[56]  M J Glimcher,et al.  Bone biology. II: Formation, form, modeling, remodeling, and regulation of cell function. , 1996, Instructional course lectures.

[57]  R. Acland,et al.  The Osteocutaneous Scapular Flap for Mandibular and Maxillary Reconstruction , 1986, Plastic and reconstructive surgery.

[58]  J. Vacanti,et al.  Tissue engineering : Frontiers in biotechnology , 1993 .

[59]  A. O’Connor,et al.  Increasing the volume of vascularized tissue formation in engineered constructs: an experimental study in rats. , 2003, Plastic and reconstructive surgery.

[60]  G. Karsenty Minireview: transcriptional control of osteoblast differentiation. , 2001, Endocrinology.

[61]  P. Dean,et al.  Incorporation and Clinical Results of Large Allografts of the Extremities and Pelvis , 1994, Clinical orthopaedics and related research.

[62]  N. McDonald,et al.  Demineralized bone matrix graft: a scientific and clinical case study assessment. , 2005, The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons.

[63]  Banwart Jc,et al.  Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. , 1995 .

[64]  M. Sefton,et al.  Tissue engineering. , 1998, Journal of cutaneous medicine and surgery.

[65]  A. Ladd,et al.  Repair of five distal radius fractures with an investigational cancellous bone cement: a preliminary report. , 1997, Journal of orthopaedic trauma.

[66]  Lucie Germain,et al.  Inosculation of Tissue‐Engineered Capillaries with the Host's Vasculature in a Reconstructed Skin Transplanted on Mice , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[67]  K. Leong,et al.  The design of scaffolds for use in tissue engineering. Part I. Traditional factors. , 2001, Tissue engineering.

[68]  A. Mikos,et al.  Growing new organs. , 1999, Scientific American.

[69]  C. H. Johnson,et al.  Free Fibula Donor-Site Morbidity: The Mayo Experience with 100 Consecutive Harvests , 2000, Journal of reconstructive microsurgery.

[70]  George K B Sándor,et al.  Histomorphometric evaluation of bone regeneration using allogeneic and alloplastic bone substitutes. , 2004, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[71]  Ulrich Kneser,et al.  Tissue engineering of cultured skin substitutes , 2005, Journal of cellular and molecular medicine.

[72]  S. Bernard,et al.  The Use of Coralline Hydroxyapatite in a “Biocomposite” Free Flap , 1991, Plastic and reconstructive surgery.

[73]  P. Warnke,et al.  Mandibular reconstruction with prefabricated vascularized bone grafts using recombinant human osteogenic protein-1: an experimental study in miniature pigs. Part II: transplantation. , 2001, International journal of oral and maxillofacial surgery.

[74]  J. Lee,et al.  Ex Vivo Gene Therapy to Produce Bone Using Different Cell Types , 2000, Clinical orthopaedics and related research.

[75]  Hollinger,et al.  Sustained release emphasizing recombinant human bone morphogenetic protein-2. , 1998, Advanced drug delivery reviews.

[76]  P. Ducy CBFA1: A molecular switch in osteoblast biology , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[77]  J. Gugenheim The Ilizarov method. Orthopedic and soft tissue applications. , 1998, Clinics in plastic surgery.

[78]  W. Winkelmann,et al.  Reconstruction of tibia by ipsilateral vascularized fibula and allograft. 12 cases with malignant bone tumors. , 1997, Acta orthopaedica Scandinavica.

[79]  B. Olsen,et al.  Bone development. , 2000, Annual review of cell and developmental biology.

[80]  K. Schlegel,et al.  PRP modulates expression of bone matrix proteins in vivo without long-term effects on bone formation. , 2006, Bone.

[81]  G. Stevens,et al.  The Influence of Extracellular Matrix on the Generation of Vascularized, Engineered, Transplantable Tissue , 2001, Annals of the New York Academy of Sciences.

[82]  A. Mikos,et al.  Effect of convection on osteoblastic cell growth and function in biodegradable polymer foam scaffolds. , 2001, Biomaterials.

[83]  J. Harmey,et al.  Angiogenic and cell survival functions of Vascular Endothelial Growth Factor (VEGF) , 2005, Journal of cellular and molecular medicine.

[84]  H. Spiegel,et al.  Cellular mechanisms of bone repair. , 1997, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[85]  L. Edsberg,et al.  Maxillary Sinus Elevation for Implant Placement Using Calcium Sulfate With and Without DFDBA: Six Cases , 2004, Implant dentistry.

[86]  Y. M. Elçin,et al.  Extensive in vivo angiogenesis following controlled release of human vascular endothelial cell growth factor: implications for tissue engineering and wound healing. , 2001, Artificial organs.

[87]  N. Kimura,et al.  Prefabricated Thin Flap Using the Transversalis Fascia as a Carrier , 2001, Plastic and reconstructive surgery.

[88]  Andreas Hess,et al.  Engineering of vascularized transplantable bone tissues: induction of axial vascularization in an osteoconductive matrix using an arteriovenous loop. , 2006, Tissue engineering.

[89]  I. Martin,et al.  Prefabricated Engineered Bone Flaps: An Experimental Model of Tissue Reconstruction in Plastic Surgery , 1998, Plastic and reconstructive surgery.

[90]  S. Kadiyala,et al.  What is This? Downloaded from , 2001 .

[91]  H. Eufinger,et al.  Growth and transplantation of a custom vascularised bone graft in a man , 2004, The Lancet.

[92]  W A Morrison,et al.  Formation of new tissue from an arteriovenous loop in the absence of added extracellular matrix. , 2000, Tissue engineering.

[93]  Swee Hin Teoh,et al.  Repair of calvarial defects with customised tissue-engineered bone grafts II. Evaluation of cellular efficiency and efficacy in vivo. , 2003, Tissue engineering.

[94]  T. Takano-Yamamoto,et al.  Molecular events caused by mechanical stress in bone. , 2000, Matrix biology : journal of the International Society for Matrix Biology.

[95]  A. Keçi̇k,et al.  Osteocutaneous Flap Prefabrication Based on the Principle of Vascular Induction: An Experimental and Clinical Study , 2000, Plastic and reconstructive surgery.

[96]  J. Upton,et al.  Principles of flap prefabrication. , 1992, Clinics in plastic surgery.

[97]  W A Morrison,et al.  Vascularisation of tissue-engineered grafts: the regulation of angiogenesis in reconstructive surgery and in disease states. , 2002, British journal of plastic surgery.

[98]  A. Hess,et al.  Intrinsic versus extrinsic vascularization in tissue engineering. , 2006, Advances in experimental medicine and biology.

[99]  K. Shea,et al.  Microvascularized free fibular grafts for reconstruction of skeletal defects after tumor resection. , 1997, Journal of pediatric orthopedics.

[100]  G. Stein,et al.  Transcriptional control of osteoblast growth and differentiation. , 1996, Physiological reviews.

[101]  J. V. D. van den Bergh,et al.  Maxillary sinus floor augmentation using a beta-tricalcium phosphate (Cerasorb) alone compared to autogenous bone grafts. , 2005, The International journal of oral & maxillofacial implants.

[102]  J. Hurley,et al.  The prefabrication of a bone graft in a rat model. , 1998, The Journal of hand surgery.

[103]  V. Hentz,et al.  Tissue engineering for reconstruction of the thumb. , 2001, The New England journal of medicine.

[104]  A. Ladd,et al.  Norian SRS cement compared with conventional fixation in distal radial fractures. A randomized study. , 2003, The Journal of bone and joint surgery. American volume.

[105]  M. Spira,et al.  New Capillary Bed Formation with a Surgically Constructed Arteriovenous Fistula , 1980, Surgical forum.

[106]  T. Billiar,et al.  Gene therapy and tissue engineering. , 1999, Clinics in plastic surgery.

[107]  R. Horch,et al.  Composition and characteristics of an autologous thrombocyte gel. , 2004, The Journal of surgical research.

[108]  R. Bizios,et al.  Engineering bone: challenges and obstacles , 2005, Journal of cellular and molecular medicine.

[109]  R Langer,et al.  Functional arteries grown in vitro. , 1999, Science.

[110]  K G Greene,et al.  Development of Technologies Aiding Large‐Tissue Engineering , 1998, Biotechnology progress.

[111]  S. Bruder,et al.  Tissue engineering of bone. Cell based strategies. , 1999, Clinical orthopaedics and related research.

[112]  H Terheyden,et al.  Prefabrication of vascularized bone grafts using recombinant human osteogenic protein-1--part 3: dosage of rhOP-1, the use of external and internal scaffolds. , 2004, International journal of oral and maxillofacial surgery.

[113]  M. Urist,et al.  Bone cell differentiation and growth factors. , 1983, Science.

[114]  S. Green Ilizarov method. , 1992, Clinical orthopaedics and related research.

[115]  Thomas A Einhorn,et al.  Recombinant human bone morphogenetic proteins in the treatment of fractures. , 2005, Foot and ankle clinics.

[116]  L. Bonassar,et al.  Replacement of an avulsed phalanx with tissue-engineered bone. , 2001, The New England journal of medicine.

[117]  R. Horch,et al.  Präkonditionierung und Prälaminierung gestielter und mikrovaskulär anastomosierter Lappenplastiken mit der Vakuumtherapie , 2003 .

[118]  K. Satomura,et al.  Pedicled bone flap formation using transplanted bone marrow stromal cells. , 2001, Archives of surgery.

[119]  G. Stein,et al.  Relationship of cell growth to the regulation of tissue‐specific gene expression during osteoblast differentiation , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[120]  J. Lane,et al.  Current understanding of osteoconduction in bone regeneration. , 1998, Clinical orthopaedics and related research.

[121]  A. Meunier,et al.  Tissue-engineered bone regeneration , 2000, Nature Biotechnology.

[122]  U Kneser,et al.  Modulation of in vitro angiogenesis in a three-dimensional spheroidal coculture model for bone tissue engineering. , 2004, Tissue engineering.

[123]  R. Mülhaupt,et al.  Lysineurethanedimethacrylate--a novel generation of amino acid based monomers for bone cements and tissue repair. , 2002, Biomaterials.

[124]  J. L. Russell,et al.  Donor age and gender effects on osteoinductivity of demineralized bone matrix. , 2004, Journal of biomedical materials research. Part B, Applied biomaterials.

[125]  J. Block,et al.  Augmenting local bone with Grafton demineralized bone matrix for posterolateral lumbar spine fusion: avoiding second site autologous bone harvest. , 2000, Orthopedics.

[126]  U A Stock,et al.  Tissue engineering: current state and prospects. , 2001, Annual review of medicine.

[127]  S. Chang,et al.  Cranial repair using BMP-2 gene engineered bone marrow stromal cells. , 2004, The Journal of surgical research.

[128]  Jane Sottile,et al.  Regulation of angiogenesis by extracellular matrix. , 2004, Biochimica et biophysica acta.

[129]  S. Santavirta,et al.  Recombinant Human Bone Morphogenetic Protein-2 for Treatment of Open Tibial Fractures: A Prospective, Controlled, Randomized Study of Four Hundred and Fifty Patients , 2002, The Journal of bone and joint surgery. American volume.

[130]  J. Mulliken,et al.  The healing of bone and cartilage. , 1990, Clinics in plastic surgery.

[131]  P. Claudio,et al.  Use of autologous platelet-rich plasma (PRP) in periodontal defect treatment after extraction of impacted mandibular third molars. , 2005, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[132]  N. Ebraheim,et al.  Bone‐Graft Harvesting From Iliac and Fibular Donor Sites: Techniques and Complications , 2001, The Journal of the American Academy of Orthopaedic Surgeons.

[133]  M. Agarwal,et al.  Reconstructing Tumour Defects: Lyophilised, Irradiated Bone Allografts , 2004, Cell and Tissue Banking.

[134]  S. Bruder,et al.  Mesenchymal stem cells in bone development, bone repair, and skeletal regenaration therapy , 1994 .

[135]  A. Reddi,et al.  Role of morphogenetic proteins in skeletal tissue engineering and regeneration , 1998, Nature Biotechnology.

[136]  Donald E. Ingber,et al.  The structural and mechanical complexity of cell-growth control , 1999, Nature Cell Biology.

[137]  Antonios G Mikos,et al.  In vitro cytotoxicity of injectable and biodegradable poly(propylene fumarate)-based networks: unreacted macromers, cross-linked networks, and degradation products. , 2003, Biomacromolecules.

[138]  G. B. Stark,et al.  Tissue engineering of bone , 2002, Minimally invasive therapy & allied technologies : MITAT : official journal of the Society for Minimally Invasive Therapy.

[139]  Y. Matsuyama,et al.  Highly efficient transfection of human marrow stromal cells by nucleofection. , 2005, Transplantation proceedings.

[140]  G. Lewis,et al.  Properties of acrylic bone cement: state of the art review. , 1997, Journal of biomedical materials research.