Engineered decellularized matrices to instruct bone regeneration processes.

Despite the significant progress in the field of bone tissue engineering, cell-based products have not yet reached the stage of clinical adoption. This is due to the uncertain advantages from the standard-of-care, combined with challenging cost-and regulatory-related issues. Novel therapeutic approaches could be based on exploitation of the intrinsic regenerative capacity of bone tissue, provided the development of a deeper understanding of its healing mechanisms. While it is well-established that endogenous progenitors can be activated toward bone formation by overdoses of single morphogens, the challenge to stimulate the healing processes by coordinated and controlled stimulation of specific cell populations remains open. Here, we review the recent approaches to generate osteoinductive materials based on the use of decellularized extracellular matrices (ECM) as reservoirs of multiple factors presented at physiological doses and through the appropriate ligands. We then propose the generation of customized engineered and decellularized ECM (i) as a tool to better understand the processes of bone regeneration and (ii) as safe and effective "off-the-shelf" bone grafts for clinical use. This article is part of a Special Issue entitled Stem Cells and Bone.

[1]  Fa-Ming Chen,et al.  Homing of endogenous stem/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives. , 2011, Biomaterials.

[2]  Stephen F Badylak,et al.  An overview of tissue and whole organ decellularization processes. , 2011, Biomaterials.

[3]  E. Mackenzie,et al.  Impact of Smoking on Fracture Healing and Risk of Complications in Limb-Threatening Open Tibia Fractures , 2005, Journal of orthopaedic trauma.

[4]  Eleftherios Tsiridis,et al.  Current concepts of molecular aspects of bone healing. , 2005, Injury.

[5]  Mark E. Bolander,et al.  Regulation of Fracture Repair by Growth Factors , 1992, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[6]  Donald O Freytes,et al.  Reprint of: Extracellular matrix as a biological scaffold material: Structure and function. , 2015, Acta biomaterialia.

[7]  Mrignayani Kotecha,et al.  Biomimetic extracellular matrix-incorporated scaffold induces osteogenic gene expression in human marrow stromal cells. , 2012, Tissue engineering. Part A.

[8]  Ivan Martin,et al.  Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis , 2014, Proceedings of the National Academy of Sciences.

[9]  D. Carnes,et al.  Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation is dependent on donor age but not gender. , 1998, Journal of periodontology.

[10]  C. Colnot,et al.  Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. , 2010, Bone.

[11]  J. Hollinger,et al.  Demineralized bone matrix in bone repair: History and use☆ , 2012, Advanced Drug Delivery Reviews.

[12]  Mikaël M. Martino,et al.  Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing , 2014, Science.

[13]  P. Bourgine,et al.  Tissue decellularization by activation of programmed cell death. , 2013, Biomaterials.

[14]  Huipin Yuan,et al.  Osteoinductive ceramics as a synthetic alternative to autologous bone grafting , 2010, Proceedings of the National Academy of Sciences.

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

[16]  Dietmar Werner Hutmacher,et al.  State of the art and future directions of scaffold‐based bone engineering from a biomaterials perspective , 2007, Journal of tissue engineering and regenerative medicine.

[17]  M. Mohammadi,et al.  A protein canyon in the FGF-FGF receptor dimer selects from an à la carte menu of heparan sulfate motifs. , 2005, Current opinion in structural biology.

[18]  Arpita Tiwari,et al.  Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion , 2013, Annals of Internal Medicine.

[19]  P. Bourgine,et al.  Engineering of a functional bone organ through endochondral ossification , 2013, Proceedings of the National Academy of Sciences.

[20]  E. Woo Adverse Events After Recombinant Human BMP2 in Nonspinal Orthopaedic Procedures , 2013, Clinical orthopaedics and related research.

[21]  Petros Lenas,et al.  Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part I: from three-dimensional cell growth to biomimetics of in vivo development. , 2009, Tissue engineering. Part B, Reviews.

[22]  S. Lundgren,et al.  Donor site morbidity in two different approaches to anterior iliac crest bone harvesting. , 2003, Clinical implant dentistry and related research.

[23]  A. Kundu,et al.  Extracellular matrix remodeling, integrin expression, and downstream signaling pathways influence the osteogenic differentiation of mesenchymal stem cells on poly(lactide-co-glycolide) substrates. , 2009, Tissue engineering. Part A.

[24]  J. Wozney,et al.  The bone morphogenetic protein family and osteogenesis , 1992, Molecular reproduction and development.

[25]  Petros Lenas,et al.  Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part II: from genes to networks: tissue engineering from the viewpoint of systems biology and network science. , 2009, Tissue engineering. Part B, Reviews.

[26]  Jos Malda,et al.  Extracellular matrix scaffolds for cartilage and bone regeneration. , 2013, Trends in biotechnology.

[27]  S. Sen,et al.  Matrix Elasticity Directs Stem Cell Lineage Specification , 2006, Cell.

[28]  T. Barker,et al.  Emerging concepts in engineering extracellular matrix variants for directing cell phenotype. , 2009, Regenerative medicine.

[29]  E. Deutsch The use of stem cell synthesized extracellular matrix for bone repair , 2009 .

[30]  P. Bourgine,et al.  Combination of immortalization and inducible death strategies to generate a human mesenchymal stromal cell line with controlled survival. , 2014, Stem cell research.

[31]  Ivan Martin,et al.  Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering , 2010, Proceedings of the National Academy of Sciences.

[32]  K. Koval,et al.  Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. , 2007, The Journal of bone and joint surgery. American volume.

[33]  H. Hutter,et al.  Conservation and novelty in the evolution of cell adhesion and extracellular matrix genes. , 2000, Science.

[34]  V. Goldberg,et al.  In vivo osteochondrogenic potential of cultured cells derived from the periosteum. , 1990, Clinical orthopaedics and related research.

[35]  A. Mikos,et al.  Osteogenic differentiation of mesenchymal stem cells on pregenerated extracellular matrix scaffolds in the absence of osteogenic cell culture supplements. , 2010, Tissue engineering. Part A.

[36]  Ian Harvey,et al.  Bone morphogenetic protein (BMP) for fracture healing in adults. , 2010, The Cochrane database of systematic reviews.

[37]  A. Papadimitropoulos,et al.  Enhancing the biological performance of synthetic polymeric materials by decoration with engineered, decellularized extracellular matrix. , 2012, Biomaterials.

[38]  Thomas A Einhorn,et al.  Differential Temporal Expression of Members of the Transforming Growth Factor β Superfamily During Murine Fracture Healing , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  R. Rao,et al.  Characterization of human fibroblast-derived extracellular matrix components for human pluripotent stem cell propagation. , 2010, Acta biomaterialia.

[40]  L. Tagliabue,et al.  Risk factors contributing to fracture non-unions. , 2007, Injury.

[41]  M. Menger,et al.  Temporal and spatial vascularization patterns of unions and nonunions: role of vascular endothelial growth factor and bone morphogenetic proteins. , 2012, The Journal of bone and joint surgery. American volume.

[42]  A. Barbero,et al.  Re-engineering development to instruct tissue regeneration. , 2014, Current topics in developmental biology.

[43]  Thomas A Einhorn,et al.  Fracture healing as a post‐natal developmental process: Molecular, spatial, and temporal aspects of its regulation , 2003, Journal of cellular biochemistry.

[44]  Yi Tang,et al.  TGF-β1-induced Migration of Bone Mesenchymal Stem Cells Couples Bone Resorption and Formation , 2009, Nature Medicine.

[45]  Martin Ehrbar,et al.  Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration. , 2012, Advanced drug delivery reviews.

[46]  R. Jilka,et al.  Extracellular Matrix Made by Bone Marrow Cells Facilitates Expansion of Marrow‐Derived Mesenchymal Progenitor Cells and Prevents Their Differentiation Into Osteoblasts , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[47]  R Stalnikowicz-Darvasi,et al.  Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events. A critical analysis. , 1995, Journal of clinical gastroenterology.

[48]  S. Parikh,et al.  Bone graft substitutes: past, present, future. , 2002, Journal of postgraduate medicine.

[49]  H. Ochi,et al.  Effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs. , 2011, American journal of veterinary research.

[50]  Antonios G Mikos,et al.  The influence of an in vitro generated bone-like extracellular matrix on osteoblastic gene expression of marrow stromal cells. , 2008, Biomaterials.

[51]  G. Dai,et al.  Evaluation of multifunctional polysaccharide hydrogels with varying stiffness for bone tissue engineering. , 2013, Tissue engineering. Part A.

[52]  H. Petite,et al.  Strategies for improving the efficacy of bioengineered bone constructs: a perspective , 2011, Osteoporosis International.

[53]  V. Kish,et al.  Expansion on extracellular matrix deposited by human bone marrow stromal cells facilitates stem cell proliferation and tissue-specific lineage potential. , 2011, Tissue engineering. Part A.

[54]  Casey K Chan,et al.  Stem cell homing in musculoskeletal injury. , 2011, Biomaterials.

[55]  A. Schindeler,et al.  The anabolic and catabolic responses in bone repair. , 2007, The Journal of bone and joint surgery. British volume.

[56]  Amir A. Al-Munajjed,et al.  The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs. , 2010, Biomaterials.

[57]  Ivan Martin,et al.  Bioreactor-based roadmap for the translation of tissue engineering strategies into clinical products. , 2009, Trends in biotechnology.

[58]  M. Schaffler,et al.  Osteocyte differentiation is regulated by extracellular matrix stiffness and intercellular separation. , 2013, Journal of the mechanical behavior of biomedical materials.

[59]  P. Layrolle,et al.  Cell therapy for bone repair. , 2014, Orthopaedics & traumatology, surgery & research : OTSR.

[60]  Li Zhang,et al.  Degradation products of extracellular matrix affect cell migration and proliferation. , 2009, Tissue engineering. Part A.

[61]  S. Parikh Bone graft substitutes in modern orthopedics. , 2002, Orthopedics.

[62]  Andrés J. García,et al.  Extracellular matrix-mimetic adhesive biomaterials for bone repair. , 2011, Journal of biomedical materials research. Part A.

[63]  S. Boden Biology of lumbar spine fusion and use of bone graft substitutes: present, future, and next generation. , 2000, Tissue engineering.

[64]  David J Mooney,et al.  New materials for tissue engineering: towards greater control over the biological response. , 2008, Trends in biotechnology.

[65]  Ivan Martin,et al.  Manufacturing Challenges in Regenerative Medicine , 2014, Science Translational Medicine.

[66]  Huipin Yuan,et al.  BIOMATERIALS : CURRENT KNOWLEDGE OF PROPERTIES , EXPERIMENTAL MODELS AND BIOLOGICAL MECHANISMS , 2011 .

[67]  B. Hallgrímsson,et al.  Stem Cell–Derived Endochondral Cartilage Stimulates Bone Healing by Tissue Transformation , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[68]  R. Cancedda,et al.  The recruitment of two consecutive and different waves of host stem/progenitor cells during the development of tissue-engineered bone in a murine model. , 2010, Biomaterials.

[69]  E. Munting,et al.  Effect of sterilization on osteoinduction. Comparison of five methods in demineralized rat bone. , 1988, Acta orthopaedica Scandinavica.

[70]  J. Jansen,et al.  Analysis of the osteoinductive capacity and angiogenicity of an in vitro generated extracellular matrix. , 2009, Journal of biomedical materials research. Part A.

[71]  V. Sikavitsas,et al.  Effect of bone extracellular matrix synthesized in vitro on the osteoblastic differentiation of marrow stromal cells. , 2005, Biomaterials.

[72]  Cato T. Laurencin,et al.  Bone-Graft Substitutes: Facts, Fictions, and Applications , 2001, The Journal of bone and joint surgery. American volume.

[73]  MartinIvan Engineered tissues as customized organ germs. , 2014 .

[74]  M. Urist,et al.  Intertransverse process lumbar arthrodesis with autogenous bone graft. , 1981, Clinical orthopaedics and related research.

[75]  Charles A. Rockwood,et al.  Rockwood and Green's Fractures in Adults , 1991 .

[76]  Yoshinobu Watanabe,et al.  Bone regeneration in a massive rat femur defect through endochondral ossification achieved with chondrogenically differentiated MSCs in a degradable scaffold. , 2014, Biomaterials.

[77]  D. Hu,et al.  Action of IL‐1β during fracture healing , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[78]  M. Urist,et al.  The bone induction principle. , 1967, Clinical orthopaedics and related research.

[79]  S. Tsai,et al.  Influence of topography of nanofibrils of three-dimensional collagen gel beads on the phenotype, proliferation, and maturation of osteoblasts. , 2009, Journal of biomedical materials research. Part A.

[80]  G. Zimmermann,et al.  Allograft bone matrix versus synthetic bone graft substitutes. , 2011, Injury.

[81]  Matthew J Dalby,et al.  Biomimetic microtopography to enhance osteogenesis in vitro. , 2011, Acta biomaterialia.

[82]  T A Einhorn,et al.  The cell and molecular biology of fracture healing. , 1998, Clinical orthopaedics and related research.

[83]  Ricardo Londono,et al.  Consequences of ineffective decellularization of biologic scaffolds on the host response. , 2012, Biomaterials.

[84]  I. Martin,et al.  Perspective on the Evolution of Cell-Based Bone Tissue Engineering Strategies , 2012, European Surgical Research.

[85]  Stephen F Badylak,et al.  The extracellular matrix as a scaffold for tissue reconstruction. , 2002, Seminars in cell & developmental biology.

[86]  Jian Ling,et al.  Reconstitution of marrow-derived extracellular matrix ex vivo: a robust culture system for expanding large-scale highly functional human mesenchymal stem cells. , 2010, Stem cells and development.

[87]  A. Allori,et al.  Biological basis of bone formation, remodeling, and repair-part II: extracellular matrix. , 2008, Tissue engineering. Part B, Reviews.

[88]  M. Wendel,et al.  Cell-derived matrix enhances osteogenic properties of hydroxyapatite. , 2011, Tissue engineering. Part A.

[89]  Gerhard Schmidmaier,et al.  What should be the characteristics of the ideal bone graft substitute? Combining scaffolds with growth factors and/or stem cells. , 2011, Injury.

[90]  Benjamin G. Keselowsky,et al.  Integrin binding specificity regulates biomaterial surface chemistry effects on cell differentiation , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[91]  D. Graves,et al.  Molecular Mechanisms Controlling Bone Formation during Fracture Healing and Distraction Osteogenesis , 2008, Journal of dental research.

[92]  Thomas A Einhorn,et al.  The biology of fracture healing. , 2011, Injury.