Journey into Bone Models: A Review

Bone is a complex tissue with a variety of functions, such as providing mechanical stability for locomotion, protection of the inner organs, mineral homeostasis and haematopoiesis. To fulfil these diverse roles in the human body, bone consists of a multitude of different cells and an extracellular matrix that is mechanically stable, yet flexible at the same time. Unlike most tissues, bone is under constant renewal facilitated by a coordinated interaction of bone-forming and bone-resorbing cells. It is thus challenging to recreate bone in its complexity in vitro and most current models rather focus on certain aspects of bone biology that are of relevance for the research question addressed. In addition, animal models are still regarded as the gold-standard in the context of bone biology and pathology, especially for the development of novel treatment strategies. However, species-specific differences impede the translation of findings from animal models to humans. The current review summarizes and discusses the latest developments in bone tissue engineering and organoid culture including suitable cell sources, extracellular matrices and microfluidic bioreactor systems. With available technology in mind, a best possible bone model will be hypothesized. Furthermore, the future need and application of such a complex model will be discussed.

[1]  Vamsi Krishna Balla,et al.  Porous tantalum structures for bone implants: fabrication, mechanical and in vitro biological properties. , 2010, Acta biomaterialia.

[2]  L. B. Solomon,et al.  Isolation of osteocytes from human trabecular bone. , 2015, Bone.

[3]  D. Kohane,et al.  HYDROGELS IN DRUG DELIVERY: PROGRESS AND CHALLENGES , 2008 .

[4]  Alexander G Robling,et al.  Biomechanical and molecular regulation of bone remodeling. , 2006, Annual review of biomedical engineering.

[5]  Yang Sun,et al.  Release and bioactivity of bone morphogenetic protein-2 are affected by scaffold binding techniques in vitro and in vivo. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[6]  M. Zilliox,et al.  Efficient assembly of rat hepatocyte spheroids for tissue engineering applications , 1996, Biotechnology and bioengineering.

[7]  K. Aoki,et al.  Physico-Chemical, In Vitro, and In Vivo Evaluation of a 3D Unidirectional Porous Hydroxyapatite Scaffold for Bone Regeneration , 2017, Materials.

[8]  Murat Guvendiren,et al.  Recent Advances in Bioink Design for 3D Bioprinting of Tissues and Organs , 2017, Front. Bioeng. Biotechnol..

[9]  Woo Y Lee,et al.  Ex vivo replication of phenotypic functions of osteocytes through biomimetic 3D bone tissue construction. , 2018, Bone.

[10]  Peng Zhang,et al.  Porous composite scaffold incorporating osteogenic phytomolecule icariin for promoting skeletal regeneration in challenging osteonecrotic bone in rabbits. , 2018, Biomaterials.

[11]  Jiake Xu,et al.  Natural bone collagen scaffold combined with autologous enriched bone marrow cells for induction of osteogenesis in an ovine spinal fusion model. , 2009, Tissue engineering. Part A.

[12]  Uwe Marx,et al.  Bone marrow-on-a-chip: Long-term culture of human hematopoietic stem cells in a 3D microfluidic environment , 2017 .

[13]  Seeram Ramakrishna,et al.  Three-dimensional bioprinting for bone tissue regeneration , 2017 .

[14]  M. Gümüşderelioğlu,et al.  A bioprintable form of chitosan hydrogel for bone tissue engineering , 2017, Biofabrication.

[15]  E. Mackie,et al.  Endochondral ossification: how cartilage is converted into bone in the developing skeleton. , 2008, The international journal of biochemistry & cell biology.

[16]  M. Capulli,et al.  Osteoblast and osteocyte: games without frontiers. , 2014, Archives of biochemistry and biophysics.

[17]  B. Hashemi,et al.  Co-existence effect of tricalcium phosphate and bioactive glass on biological and biodegradation characteristic of Poly L-Lactic Acid (PLLA) in trinary composite scaffold form. , 2017, Bio-medical materials and engineering.

[18]  Shreyasee Amin,et al.  Skeletal health in long‐duration astronauts: Nature, assessment, and management recommendations from the NASA bone summit , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  Jing Lim,et al.  Review: development of clinically relevant scaffolds for vascularised bone tissue engineering. , 2013, Biotechnology advances.

[20]  Yunqing Kang,et al.  Engineering Vascularized Bone Grafts by Integrating a Biomimetic Periosteum and β-TCP Scaffold , 2014, ACS applied materials & interfaces.

[21]  M. Lewandowska-Szumieł,et al.  How calcite and modified hydroxyapatite influence physicochemical properties and cytocompatibility of alpha-TCP based bone cements , 2017, Journal of Materials Science: Materials in Medicine.

[22]  G. Finkenzeller,et al.  Evaluation of adenoviral vascular endothelial growth factor-activated chitosan/hydroxyapatite scaffold for engineering vascularized bone tissue using human osteoblasts: In vitro and in vivo studies , 2014, Journal of biomaterials applications.

[23]  M. K. Knothe Tate,et al.  The osteocyte. , 2004, The international journal of biochemistry & cell biology.

[24]  Yongwon Choi,et al.  Osteoimmunology: interactions of the bone and immune system. , 2008, Endocrine reviews.

[25]  Š. Polák,et al.  iPS cell technologies and their prospect for bone regeneration and disease modeling: A mini review , 2017, Journal of advanced research.

[26]  J. Collins,et al.  Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro , 2014, Nature Methods.

[27]  S. Nukavarapu,et al.  Design, fabrication and in vitro evaluation of a novel polymer‐hydrogel hybrid scaffold for bone tissue engineering , 2014, Journal of tissue engineering and regenerative medicine.

[28]  L. Kunz-Schughart,et al.  Multicellular tumor spheroids: an underestimated tool is catching up again. , 2010, Journal of biotechnology.

[29]  Takashi Nakamura,et al.  Fully functional bioengineered tooth replacement as an organ replacement therapy , 2009, Proceedings of the National Academy of Sciences.

[30]  Antonios G. Mikos,et al.  Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Elena García-Gareta,et al.  Osteoinduction of bone grafting materials for bone repair and regeneration. , 2015, Bone.

[32]  M. Matsusaki,et al.  In vitro reproduction of endochondral ossification using a 3D mesenchymal stem cell construct. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[33]  F. Guillemot,et al.  Laser-assisted bioprinting for creating on-demand patterns of human osteoprogenitor cells and nano-hydroxyapatite , 2011, Biofabrication.

[34]  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.

[35]  P Zioupos,et al.  Mechanical properties and the hierarchical structure of bone. , 1998, Medical engineering & physics.

[36]  David B. Jones,et al.  Development of a mechanical testing and loading system for trabecular bone studies for long term culture. , 2003, European cells & materials.

[37]  Ali Khademhosseini,et al.  Chip-Based Comparison of the Osteogenesis of Human Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem Cells under Mechanical Stimulation , 2012, PloS one.

[38]  S. Cartmell,et al.  Development of magnetic particle techniques for long-term culture of bone cells with intermittent mechanical activation. , 2002, IEEE transactions on nanobioscience.

[39]  Linda G Griffith,et al.  Engineering principles of clinical cell-based tissue engineering. , 2004, The Journal of bone and joint surgery. American volume.

[40]  M. H. Fernandes,et al.  Reciprocal induction of human dermal microvascular endothelial cells and human mesenchymal stem cells: time‐dependent profile in a co‐culture system , 2012, Cell proliferation.

[41]  Zhengguo Wang,et al.  The effects of spheroid formation of adipose-derived stem cells in a microgravity bioreactor on stemness properties and therapeutic potential. , 2015, Biomaterials.

[42]  Fabien Guillemot,et al.  In situ printing of mesenchymal stromal cells, by laser-assisted bioprinting, for in vivo bone regeneration applications , 2017, Scientific Reports.

[43]  B. Clarke,et al.  Normal bone anatomy and physiology. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[44]  C. Haasper,et al.  Influence of perfusion and cyclic compression on proliferation and differentiation of bone marrow stromal cells in 3-dimensional culture. , 2008, Journal of biomechanics.

[45]  R. G. Richards,et al.  In search of an osteoblast cell model for in vitro research. , 2012, European cells & materials.

[46]  B. Hallgrímsson,et al.  Comparison of Microcomputed Tomographic and Microradiographic Measurements of Cortical Bone Porosity , 2004, Calcified Tissue International.

[47]  Arnold I Caplan,et al.  The MSC: an injury drugstore. , 2011, Cell stem cell.

[48]  Dong-Woo Cho,et al.  3D printing technology to control BMP-2 and VEGF delivery spatially and temporally to promote large-volume bone regeneration. , 2015, Journal of materials chemistry. B.

[49]  Matthias W Laschke,et al.  Life is 3D: Boosting Spheroid Function for Tissue Engineering. , 2017, Trends in biotechnology.

[50]  S. Ljunghall,et al.  Three isolation techniques for primary culture of human osteoblast-like cells: a comparison. , 1999, Acta orthopaedica Scandinavica.

[51]  M. Kassem,et al.  The Human Umbilical Cord Blood: A Potential Source for Osteoblast Progenitor Cells , 2003, Calcified Tissue International.

[52]  Wei Li,et al.  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. , 2014, Journal of biomedical materials research. Part A.

[53]  L. Lanyon,et al.  Mechanical Strain and Bone Cell Function: A Review , 2002, Osteoporosis International.

[54]  Bin Wu,et al.  Polydopamine-assisted BMP-2-derived peptides immobilization on biomimetic copolymer scaffold for enhanced bone induction in vitro and in vivo. , 2016, Colloids and surfaces. B, Biointerfaces.

[55]  R T Turner,et al.  Invited review: what do we know about the effects of spaceflight on bone? , 2000, Journal of applied physiology.

[56]  P. Manson,et al.  The effect of incorporating RGD adhesive peptide in polyethylene glycol diacrylate hydrogel on osteogenesis of bone marrow stromal cells. , 2005, Biomaterials.

[57]  Thierry Balaguer,et al.  Human Primary Osteocyte Differentiation in a 3D Culture System , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[58]  D. Mooney,et al.  Hydrogels for tissue engineering. , 2001, Chemical Reviews.

[59]  J. Yun,et al.  Development of Porous Beads to Provide Regulated BMP-2 Stimulation for Varying Durations: In Vitro and In Vivo Studies for Bone Regeneration. , 2016, Biomacromolecules.

[60]  T. Webster,et al.  A review of fibrin and fibrin composites for bone tissue engineering , 2017, International journal of nanomedicine.

[61]  S. Pacelli,et al.  Controlling Adult Stem Cell Behavior Using Nanodiamond-Reinforced Hydrogel: Implication in Bone Regeneration Therapy , 2017, Scientific Reports.

[62]  A. Mikos,et al.  Modulation of marrow stromal osteoblast adhesion on biomimetic oligo[poly(ethylene glycol) fumarate] hydrogels modified with Arg-Gly-Asp peptides and a poly(ethyleneglycol) spacer. , 2002, Journal of biomedical materials research.

[63]  Warren L. Grayson,et al.  Engineering bone tissue from human embryonic stem cells , 2012, Proceedings of the National Academy of Sciences.

[64]  K. Mustafa,et al.  Endothelial cells influence the osteogenic potential of bone marrow stromal cells , 2009, Biomedical engineering online.

[65]  Anita H. Undale,et al.  Characterization of circulating osteoblast lineage cells in humans. , 2007, Bone.

[66]  George M. Cater,et al.  Engineering liver tissue spheroids with inverted colloidal crystal scaffolds. , 2009, Biomaterials.

[67]  Ivan Martin,et al.  Three‐Dimensional Perfusion Culture of Human Adipose Tissue‐Derived Endothelial and Osteoblastic Progenitors Generates Osteogenic Constructs with Intrinsic Vascularization Capacity , 2007, Stem cells.

[68]  K. Ng,et al.  Cell lines and primary cell cultures in the study of bone cell biology , 2004, Molecular and Cellular Endocrinology.

[69]  R. Bacabac,et al.  UvA-DARE ( Digital Academic Repository ) Mechanical loading and how it affects bone cells : the role of the osteocyte cytoskeleton in maintaining our skeleton , 2017 .

[70]  Michael J Yaszemski,et al.  Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering. , 2008, Biomaterials.

[71]  X. Li,et al.  Human adipose stem cells maintain proliferative, synthetic and multipotential properties when suspension cultured as self-assembling spheroids , 2012, Biofabrication.

[72]  R. G. Richards,et al.  A phenotypic comparison of osteoblast cell lines versus human primary osteoblasts for biomaterials testing. , 2014, Journal of biomedical materials research. Part A.

[73]  G. Duda,et al.  Influence of particulate and dissociated metal-on-metal hip endoprosthesis wear on mesenchymal stromal cells in vivo and in vitro. , 2016, Biomaterials.

[74]  P. Frenette,et al.  Making sense of hematopoietic stem cell niches. , 2015, Blood.

[75]  J. Gerlach,et al.  Long‐term three‐dimensional perfusion culture of human adult bone marrow mononuclear cells in bioreactors , 2015, Biotechnology and bioengineering.

[76]  Xuebin B. Yang,et al.  Fabrication and in vitro evaluation of a sponge-like bioactive-glass/gelatin composite scaffold for bone tissue engineering. , 2013, Materials science & engineering. C, Materials for biological applications.

[77]  Mitsugu Todo,et al.  In vitro bone formation by mesenchymal stem cells with 3D collagen/β-TCP composite scaffold , 2013, 2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[78]  A. Mehdipour,et al.  Optimization of nanofibrous silk fibroin scaffold as a delivery system for bone marrow adherent cells: in vitro and in vivo studies , 2015, Biotechnology and applied biochemistry.

[79]  J. Feijen,et al.  Validation of human periodontal ligament-derived cells as a reliable source for cytotherapeutic use. , 2010, Journal of clinical periodontology.

[80]  G. Vacun,et al.  A perfusion bioreactor system efficiently generates cell‐loaded bone substitute materials for addressing critical size bone defects , 2015, Biotechnology journal.

[81]  Yongsung Kim,et al.  Effect of serum-derived albumin scaffold and canine adipose tissue-derived mesenchymal stem cells on osteogenesis in canine segmental bone defect model , 2015, Journal of veterinary science.

[82]  D. Cho,et al.  Bioprinting of a mechanically enhanced three-dimensional dual cell-laden construct for osteochondral tissue engineering using a multi-head tissue/organ building system , 2012 .

[83]  G. Finkenzeller,et al.  Effects of endothelial cells on proliferation and survival of human mesenchymal stem cells and primary osteoblasts , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[84]  Yukun Zhang,et al.  In vitro osteogenesis of human adipose-derived stem cells by coculture with human umbilical vein endothelial cells. , 2011, Biochemical and biophysical research communications.

[85]  H. Höhling,et al.  Aspects of collagen mineralization in hard tissue formation. , 2005, International review of cytology.

[86]  Martin Fussenegger,et al.  Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. , 2003, Biotechnology and bioengineering.

[87]  P. Cavanagh,et al.  Exercise and pharmacological countermeasures for bone loss during long-duration space flight. , 2005, Gravitational and space biology bulletin : publication of the American Society for Gravitational and Space Biology.

[88]  Aysel Koç,et al.  Evaluation of a biomimetic poly(ε-caprolactone)/β-tricalcium phosphate multispiral scaffold for bone tissue engineering: in vitro and in vivo studies. , 2014, Biointerphases.

[89]  B Vamsi Krishna,et al.  Processing and biocompatibility evaluation of laser processed porous titanium. , 2007, Acta biomaterialia.

[90]  Mark A. Skylar-Scott,et al.  Three-dimensional bioprinting of thick vascularized tissues , 2016, Proceedings of the National Academy of Sciences.

[91]  A. Knight Animal experiments scrutinised: systematic reviews demonstrate poor human clinical and toxicological utility. , 2007, ALTEX.

[92]  P. Robey Cell sources for bone regeneration: the good, the bad, and the ugly (but promising). , 2011, Tissue engineering. Part B, Reviews.

[93]  Richard A. Lasher,et al.  Design and characterization of a modified T‐flask bioreactor for continuous monitoring of engineered tissue stiffness , 2010, Biotechnology progress (Print).

[94]  M. Jäger,et al.  Bone marrow concentrate: a novel strategy for bone defect treatment. , 2009, Current stem cell research & therapy.

[95]  A. Kamali,et al.  Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence? , 2017, Cells Tissues Organs.

[96]  M. Oelgeschläger,et al.  Defining the optimal animal model for translational research using gene set enrichment analysis , 2016, EMBO molecular medicine.

[97]  S. Shi,et al.  Skeletal site-specific characterization of orofacial and iliac crest human bone marrow stromal cells in same individuals. , 2006, Bone.

[98]  S. Kang,et al.  Bone Regeneration of Hydroxyapatite/Alumina Bilayered Scaffold with 3 mm Passage-Like Medullary Canal in Canine Tibia Model , 2015, BioMed research international.

[99]  A. Keramane,et al.  Principles and Design of a Novel Magnetic Force Mechanical Conditioning Bioreactor for Tissue Engineering, Stem Cell Conditioning, and Dynamic In Vitro Screening , 2006, IEEE Transactions on NanoBioscience.

[100]  Noo Li Jeon,et al.  Microfluidic vascularized bone tissue model with hydroxyapatite-incorporated extracellular matrix. , 2015, Lab on a chip.

[101]  J. K. Leach,et al.  Bioreactor culture duration of engineered constructs influences bone formation by mesenchymal stem cells. , 2017, Biomaterials.

[102]  Mei Wei,et al.  Development of a novel alginate-polyvinyl alcohol-hydroxyapatite hydrogel for 3D bioprinting bone tissue engineered scaffolds. , 2017, Journal of biomedical materials research. Part A.

[103]  Changsheng Liu,et al.  Biomimetic porous scaffolds for bone tissue engineering , 2014 .

[104]  A. Bandyopadhyay,et al.  Bone tissue engineering using 3D printing , 2013 .

[105]  O. Wichterle,et al.  Hydrophilic Gels for Biological Use , 1960, Nature.

[106]  G. Duda,et al.  Osteogenic Predifferentiation of Human Bone Marrow-Derived Stem Cells by Short-Term Mechanical Stimulation , 2011, The open orthopaedics journal.

[107]  C. Colnot Cell sources for bone tissue engineering: insights from basic science. , 2011, Tissue engineering. Part B, Reviews.

[108]  Changsheng Liu,et al.  Segmental bone regeneration using rhBMP-2-loaded collagen/chitosan microspheres composite scaffold in a rabbit model , 2012, Biomedical materials.

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

[110]  G. Duda,et al.  Multi-elemental nanoparticle exposure after tantalum component failure in hip arthroplasty: In-depth analysis of a single case. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[111]  Georg N Duda,et al.  Qualifying stem cell sources: how to overcome potential pitfalls in regenerative medicine? , 2016, Journal of tissue engineering and regenerative medicine.

[112]  J. Adjaye,et al.  Human Stromal (Mesenchymal) Stem Cells from Bone Marrow, Adipose Tissue and Skin Exhibit Differences in Molecular Phenotype and Differentiation Potential , 2012, Stem Cell Reviews and Reports.

[113]  Hermann Eichler,et al.  Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, or Adipose Tissue , 2006, Stem cells.

[114]  P. Robey,et al.  Species Differences in Growth Requirements for Bone Marrow Stromal Fibroblast Colony Formation In Vitro , 1996, Calcified Tissue International.

[115]  D. Beebe,et al.  The present and future role of microfluidics in biomedical research , 2014, Nature.

[116]  Rimantas Kodzius,et al.  Organ-on-Chip Technology: Current State and Future Developments , 2017, Genes.

[117]  K. Nguyen,et al.  A review of materials, fabrication methods, and strategies used to enhance bone regeneration in engineered bone tissues. , 2008, Journal of biomedical materials research. Part B, Applied biomaterials.

[118]  P. Kostenuik,et al.  Fracture healing physiology and the quest for therapies for delayed healing and nonunion , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[119]  H. Frost Bone's mechanostat: a 2003 update. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[120]  A. Görg,et al.  Expansion and differentiation of human primary osteoblasts in two- and three-dimensional culture , 2013, Biotechnic & histochemistry : official publication of the Biological Stain Commission.

[121]  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.

[122]  C. Rorabeck,et al.  The operation of the century: total hip replacement , 2007, The Lancet.

[123]  J. Gerlach,et al.  Effect of Calcium-Infiltrated Hydroxyapatite Scaffolds on the Hematopoietic Fate of Human Umbilical Vein Endothelial Cells , 2017, Journal of Vascular Research.

[124]  Y. Ikada,et al.  Controlled release of growth factors based on biodegradation of gelatin hydrogel , 2001, Journal of biomaterials science. Polymer edition.

[125]  J. Morgan,et al.  Advances in the formation, use and understanding of multi-cellular spheroids , 2012, Expert opinion on biological therapy.

[126]  G. Korbutt,et al.  Expansion of mesenchymal stem cells from human pancreatic ductal epithelium , 2006, Laboratory Investigation.

[127]  G. Balian,et al.  Use of a bioactive scaffold for the repair of bone defects in a novel reproducible vertebral body defect model. , 2010, Bone.

[128]  W. Richter,et al.  Adipose-derived stromal cells for osteoarticular repair: trophic function versus stem cell activity , 2014, Expert Reviews in Molecular Medicine.

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

[130]  S. Rumiński,et al.  Contribution of endothelial cells to human bone-derived cells expansion in coculture. , 2013, Tissue engineering. Part A.

[131]  R. Rao,et al.  Cell-based approaches to the engineering of vascularized bone tissue. , 2013, Cytotherapy.

[132]  PhD Hideki Yoshikawa MD,et al.  Bone tissue engineering with porous hydroxyapatite ceramics , 2005, Journal of Artificial Organs.

[133]  Tiina Laitala-Leinonen,et al.  Osteoclast lineage and function. , 2008, Archives of biochemistry and biophysics.

[134]  A. E. El Haj,et al.  Dynamic 3D culture: models of chondrogenesis and endochondral ossification. , 2015, Birth defects research. Part C, Embryo today : reviews.

[135]  B. Clarke,et al.  Osteoporosis prevention, screening, and treatment: a review. , 2014, Journal of women's health.

[136]  N. Fisk,et al.  Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. , 2001, Blood.

[137]  V. Guarino,et al.  Bioactivity and bone healing properties of biomimetic porous composite scaffold: in vitro and in vivo studies. , 2015, Journal of biomedical materials research. Part A.

[138]  S. Bertoldi,et al.  Polyurethane foam/nano hydroxyapatite composite as a suitable scaffold for bone tissue regeneration. , 2018, Materials science & engineering. C, Materials for biological applications.

[139]  N Selvamurugan,et al.  Nanohydroxyapatite-reinforced chitosan composite hydrogel for bone tissue repair in vitro and in vivo , 2015, Journal of Nanobiotechnology.

[140]  N. Bai,et al.  Porous stable poly(lactic acid)/ethyl cellulose/hydroxyapatite composite scaffolds prepared by a combined method for bone regeneration. , 2018, Carbohydrate polymers.

[141]  A. Oryan,et al.  Effectiveness of tissue engineered based platelet gel embedded chitosan scaffold on experimentally induced critical sized segmental bone defect model in rat. , 2017, Injury.

[142]  N. Kawazoe,et al.  Cultured cell-derived extracellular matrix scaffolds for tissue engineering. , 2011, Biomaterials.

[143]  C. Shuai,et al.  Improvement in degradability of 58s glass scaffolds by ZnO and β-TCP modification , 2016, Bioengineered.

[144]  K. Shinomiya,et al.  Bone Defect Regeneration by a Combination of a β-Tricalcium Phosphate Scaffold and Bone Marrow Stromal Cells in a Non-Human Primate Model , 2016, The open biomedical engineering journal.

[145]  C. Persson,et al.  Osteoinduction by Foamed and 3D-Printed Calcium Phosphate Scaffolds: Effect of Nanostructure and Pore Architecture. , 2017, ACS applied materials & interfaces.

[146]  M. Rohrer,et al.  Clinical evaluation alveolar ridge preservation with a beta-tricalcium phosphate socket graft. , 2009, Compendium of continuing education in dentistry.

[147]  Liang Dong,et al.  3D- Printed Poly(ε-caprolactone) Scaffold Integrated with Cell-laden Chitosan Hydrogels for Bone Tissue Engineering , 2017, Scientific Reports.

[148]  S. Kang,et al.  Bone-Healing Capacity of PCL/PLGA/Duck Beak Scaffold in Critical Bone Defects in a Rabbit Model , 2016, BioMed research international.

[149]  B. Guillotin,et al.  Interaction between human umbilical vein endothelial cells and human osteoprogenitors triggers pleiotropic effect that may support osteoblastic function. , 2008, Bone.

[150]  Mukesh Doble,et al.  Design of biocomposite materials for bone tissue regeneration. , 2015, Materials science & engineering. C, Materials for biological applications.

[151]  S. Morrison,et al.  The bone marrow niche for haematopoietic stem cells , 2014, Nature.

[152]  R. Reis,et al.  Evaluation of a starch‐based double layer scaffold for bone regeneration in a rat model , 2014, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[153]  Y. Tabata,et al.  Initial bone regeneration around fenestrated implants in Beagle dogs using basic fibroblast growth factor-gelatin hydrogel complex with varying biodegradation rates. , 2009, Journal of prosthodontic research.

[154]  Simone Bersini,et al.  Human in vitro 3D co-culture model to engineer vascularized bone-mimicking tissues combining computational tools and statistical experimental approach. , 2016, Biomaterials.

[155]  Jinchao Zhang,et al.  Innovative biodegradable poly(L-lactide)/collagen/hydroxyapatite composite fibrous scaffolds promote osteoblastic proliferation and differentiation , 2017, International journal of nanomedicine.

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

[157]  I. Banerjee,et al.  Alginate Bead Based Hexagonal Close Packed 3D Implant for Bone Tissue Engineering. , 2016, ACS applied materials & interfaces.

[158]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[159]  S. Lehmann,et al.  Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials. , 2008, Experimental cell research.

[160]  Christian Bergmann,et al.  3D printing of bone substitute implants using calcium phosphate and bioactive glasses , 2010 .

[161]  Bing Chen,et al.  3D bioprinting of BMSC-laden methacrylamide gelatin scaffolds with CBD-BMP2-collagen microfibers , 2015, Biofabrication.

[162]  Mandi J. Lopez,et al.  Collagen and Hydroxyapatite Scaffolds Activate Distinct Osteogenesis Signaling Pathways in Adult Adipose-Derived Multipotent Stromal Cells , 2017, Tissue engineering. Part C, Methods.

[163]  Promita Bhattacharjee,et al.  Effect of different mineralization processes on in vitro and in vivo bone regeneration and osteoblast-macrophage cross-talk in co-culture system using dual growth factor mediated non-mulberry silk fibroin grafted poly (Є-caprolactone) nanofibrous scaffold. , 2017, Colloids and surfaces. B, Biointerfaces.

[164]  Han-Tsung Liao,et al.  Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells. , 2014, World journal of stem cells.

[165]  X. Sherry Liu,et al.  Engineering anatomically shaped human bone grafts , 2009, Proceedings of the National Academy of Sciences.

[166]  M. Gümüşderelioğlu,et al.  RGD-bearing peptide-amphiphile-hydroxyapatite nanocomposite bone scaffold: an in vitro study , 2013, Biomedical materials.

[167]  G. de Haan,et al.  Hematopoietic stem cell expansion: challenges and opportunities , 2012, Annals of the New York Academy of Sciences.

[168]  N. Puig,et al.  MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry , 2016, Cell Communication and Signaling.

[169]  Maik Stiehler,et al.  Bioreactor systems for bone tissue engineering. , 2011, Tissue engineering. Part B, Reviews.

[170]  D. Wendt,et al.  Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing , 2015, Front. Bioeng. Biotechnol..

[171]  I. Kerkis,et al.  Mesenchymal progenitor cells from canine fetal tissues: yolk sac, liver, and bone marrow. , 2011, Tissue engineering. Part A.

[172]  Fergal J O'Brien,et al.  The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering. , 2010, Biomaterials.

[173]  Yun Lu,et al.  Segmental bone regeneration using an rhBMP-2-loaded gelatin/nanohydroxyapatite/fibrin scaffold in a rabbit model. , 2009, Biomaterials.

[174]  Elizabeth Blaber,et al.  Bioastronautics: the influence of microgravity on astronaut health. , 2010, Astrobiology.

[175]  Amit Bandyopadhyay,et al.  Recent advances in bone tissue engineering scaffolds. , 2012, Trends in biotechnology.

[176]  Marco N Helder,et al.  The use of poly(L-lactide-co-caprolactone) as a scaffold for adipose stem cells in bone tissue engineering: application in a spinal fusion model. , 2011, Macromolecular bioscience.

[177]  Xin Zhang,et al.  One-step articular cartilage repair: combination of in situ bone marrow stem cells with cell-free poly(L-lactic-co-glycolic acid) scaffold in a rabbit model. , 2012, Orthopedics.

[178]  F. Jakob,et al.  Deformation strain is the main physical driver for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation , 2018, Journal of tissue engineering and regenerative medicine.

[179]  Donald E Ingber,et al.  Modeling Hematopoiesis and Responses to Radiation Countermeasures in a Bone Marrow-on-a-Chip. , 2016, Tissue engineering. Part C, Methods.

[180]  G. Duda,et al.  The impact of substrate stiffness and mechanical loading on fibroblast-induced scaffold remodeling. , 2012, Tissue engineering. Part A.

[181]  Zhongze Gu,et al.  Organ-on-a-Chip Systems: Microengineering to Biomimic Living Systems. , 2016, Small.

[182]  A. Mikos,et al.  Review: Hydrogels for cell immobilization , 2000, Biotechnology and bioengineering.

[183]  Ping Chen,et al.  Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. , 2008, Stem cells and development.

[184]  N. Selvamurugan,et al.  Proliferation and differentiation of mesenchymal stem cells on scaffolds containing chitosan, calcium polyphosphate and pigeonite for bone tissue engineering , 2018, Cell proliferation.

[185]  Z. Ivanovic,et al.  Concise Review: The Role of Oxygen in Hematopoietic Stem Cell Physiology , 2015, Journal of cellular physiology.

[186]  K. Dai,et al.  3D printed scaffolds of calcium silicate-doped β-TCP synergize with co-cultured endothelial and stromal cells to promote vascularization and bone formation , 2017, Scientific Reports.

[187]  G. Duda,et al.  BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway , 2012, BMC Biology.

[188]  F. Miller,et al.  Isolation and Characterization of Multipotent Skin‐Derived Precursors from Human Skin , 2005, Stem cells.

[189]  J D Andrade,et al.  Water and hydrogels. , 1973, Journal of biomedical materials research.

[190]  J. Hilborn,et al.  Bone morphogenetic protein-2 delivered by hyaluronan-based hydrogel induces massive bone formation and healing of cranial defects in minipigs. , 2010, Plastic and reconstructive surgery.

[191]  G. Duda,et al.  Functional Comparison of Chronological and In Vitro Aging: Differential Role of the Cytoskeleton and Mitochondria in Mesenchymal Stromal Cells , 2012, PloS one.

[192]  Xiongfei Zheng,et al.  BMSCs-laden gelatin/sodium alginate/carboxymethyl chitosan hydrogel for 3D bioprinting , 2016 .

[193]  D. Seliktar,et al.  A novel poly(ethylene glycol)-fibrinogen hydrogel for tibial segmental defect repair in a rat model. , 2007, Journal of biomedical materials research. Part A.

[194]  James J. Yoo,et al.  A 3D bioprinting system to produce human-scale tissue constructs with structural integrity , 2016, Nature Biotechnology.

[195]  D. Hutmacher,et al.  Scaffold–cell bone engineering in a validated preclinical animal model: precursors vs differentiated cell source , 2017, Journal of tissue engineering and regenerative medicine.

[196]  K. Scheffler,et al.  A 3D in vitro bone organ model using human progenitor cells. , 2011, European cells & materials.

[197]  G. Duda,et al.  Simulation of cell differentiation in fracture healing: mechanically loaded composite scaffolds in a novel bioreactor system. , 2006, Tissue engineering.

[198]  H. Thielecke,et al.  A scaffold-free in vitro model for osteogenesis of human mesenchymal stem cells. , 2011, Tissue & cell.

[199]  Tomoko Ito,et al.  Controlled Release of Simvastatin from Biomimetic β-TCP Drug Delivery System , 2013, PloS one.

[200]  Fangxiu Yuan,et al.  Dynamic perfusion bioreactor system for 3D culture of rat bone marrow mesenchymal stem cells on nanohydroxyapatite/polyamide 66 scaffold in vitro. , 2013, Journal of biomedical materials research. Part B, Applied biomaterials.

[201]  J. K. Leach,et al.  Alginate hydrogels containing cell‐interactive beads for bone formation , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[202]  K. Moharamzadeh,et al.  Characterization of Multilayered Tissue-Engineered Human Alveolar Bone and Gingival Mucosa. , 2017, Tissue engineering. Part C, Methods.

[203]  G. Dickson,et al.  Fabrication and repair of cartilage defects with a novel acellular cartilage matrix scaffold. , 2010, Tissue engineering. Part C, Methods.

[204]  Ben D. MacArthur,et al.  Mesenchymal and haematopoietic stem cells form a unique bone marrow niche , 2010, Nature.

[205]  Andrew Knight,et al.  Systematic Reviews of Animal Experiments Demonstrate Poor Human Clinical and Toxicological Utility , 2007, Alternatives to laboratory animals : ATLA.

[206]  M. Longaker,et al.  Stem Cells in Bone Regeneration , 2016, Stem Cell Reviews and Reports.

[207]  S. Goldenberg,et al.  Dissimilar Differentiation of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, and Adipose Tissue , 2008, Experimental biology and medicine.

[208]  Mandi J. Lopez,et al.  In Vitro Mesenchymal Trilineage Differentiation and Extracellular Matrix Production by Adipose and Bone Marrow Derived Adult Equine Multipotent Stromal Cells on a Collagen Scaffold , 2013, Stem Cell Reviews and Reports.

[209]  S. Popoff,et al.  Bone cell biology: the regulation of development, structure, and function in the skeleton. , 1988, The American journal of anatomy.

[210]  G. Ginalska,et al.  In vitro evaluation of the risk of inflammatory response after chitosan/HA and chitosan/β-1,3-glucan/HA bone scaffold implantation. , 2016, Materials science & engineering. C, Materials for biological applications.

[211]  Yang Du,et al.  Synthesis of and in vitro and in vivo evaluation of a novel TGF-β1-SF-CS three-dimensional scaffold for bone tissue engineering , 2016, International journal of molecular medicine.

[212]  T. Albrektsson,et al.  Osteoinduction, osteoconduction and osseointegration , 2001, European Spine Journal.

[213]  R. Borojevic,et al.  Osteoblasts and Bone Marrow Mesenchymal Stromal Cells Control Hematopoietic Stem Cell Migration and Proliferation in 3D In Vitro Model , 2010, PloS one.

[214]  Uwe Marx,et al.  ‘Human-on-a-chip’ Developments: A Translational Cutting-edge Alternative to Systemic Safety Assessment and Efficiency Evaluation of Substances in Laboratory Animals and Man? , 2012, Alternatives to laboratory animals : ATLA.

[215]  T. Laurent,et al.  Functions of hyaluronan. , 1995, Annals of the rheumatic diseases.

[216]  S. Samavedi,et al.  Calcium phosphate ceramics in bone tissue engineering: a review of properties and their influence on cell behavior. , 2013, Acta biomaterialia.

[217]  Yasuhiko Tabata,et al.  Synergistic effects of the dual release of stromal cell-derived factor-1 and bone morphogenetic protein-2 from hydrogels on bone regeneration. , 2011, Biomaterials.

[218]  K. Kim,et al.  Differentiation Potential of Mesenchymal Stem Cells Is Related to Their Intrinsic Mechanical Properties , 2017, International neurourology journal.

[219]  B. Hall,et al.  Buried alive: How osteoblasts become osteocytes , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[220]  D. Wendt,et al.  Oscillating perfusion of cell suspensions through three‐dimensional scaffolds enhances cell seeding efficiency and uniformity , 2003, Biotechnology and bioengineering.

[221]  Jean D Sibonga,et al.  Evaluating Bone Loss in ISS Astronauts. , 2015, Aerospace medicine and human performance.

[222]  Mehdi Ebrahimi,et al.  Biphasic calcium phosphates bioceramics (HA/TCP): Concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research. , 2017, Materials science & engineering. C, Materials for biological applications.

[223]  Paiyz E. Mikael,et al.  Functionalized Carbon Nanotube Composite Scaffolds for Bone Tissue Engineering: Prospects and Progress , 2011 .

[224]  D. Ingber,et al.  Microfluidic organs-on-chips , 2014, Nature Biotechnology.

[225]  Keekyoung Kim,et al.  3D bioprinting for engineering complex tissues. , 2016, Biotechnology advances.

[226]  Yu Du,et al.  Differential regulation of stiffness, topography, and dimension of substrates in rat mesenchymal stem cells. , 2013, Biomaterials.

[227]  Navrag B. Singh,et al.  Terminally Differentiated CD8+ T Cells Negatively Affect Bone Regeneration in Humans , 2013, Science Translational Medicine.

[228]  T. Guda,et al.  A Novel Secretome Biotherapeutic Influences Regeneration in Critical Size Bone Defects , 2017, The Journal of craniofacial surgery.

[229]  Ivan Martin,et al.  Three‐Dimensional Perfusion Culture of Human Bone Marrow Cells and Generation of Osteoinductive Grafts , 2005, Stem cells.

[230]  A. Lode,et al.  Optimization of culture conditions for osteogenically‐induced mesenchymal stem cells in β‐tricalcium phosphate ceramics with large interconnected channels , 2011, Journal of tissue engineering and regenerative medicine.

[231]  H. Murata,et al.  Candidates Cell Sources to Regenerate Alveolar Bone from Oral Tissue , 2012, International journal of dentistry.

[232]  K. Shakesheff,et al.  Controlled release of BMP‐2 from a sintered polymer scaffold enhances bone repair in a mouse calvarial defect model , 2014, Journal of tissue engineering and regenerative medicine.

[233]  A. Friedenstein,et al.  THE DEVELOPMENT OF FIBROBLAST COLONIES IN MONOLAYER CULTURES OF GUINEA‐PIG BONE MARROW AND SPLEEN CELLS , 1970, Cell and tissue kinetics.

[234]  J. Vallée,et al.  Amino-polyvinyl alcohol coated superparamagnetic iron oxide nanoparticles are suitable for monitoring of human mesenchymal stromal cells in vivo. , 2014, Small.

[235]  M. Costache,et al.  In vitro cytocompatibility evaluation of chitosan/graphene oxide 3D scaffold composites designed for bone tissue engineering. , 2014, Bio-medical materials and engineering.

[236]  J. Hilborn,et al.  Bone reservoir: Injectable hyaluronic acid hydrogel for minimal invasive bone augmentation. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[237]  Ji-Hoon Bae,et al.  Combination therapy with BMP-2 and BMSCs enhances bone healing efficacy of PCL scaffold fabricated using the 3D plotting system in a large segmental defect model , 2012, Biotechnology Letters.

[238]  L. Malaval,et al.  Validation of an in vitro 3D bone culture model with perfused and mechanically stressed ceramic scaffold. , 2015, European cells & materials.

[239]  PeiYan Ni,et al.  Injectable and thermo-sensitive PEG-PCL-PEG copolymer/collagen/n-HA hydrogel composite for guided bone regeneration. , 2012, Biomaterials.

[240]  Hojae Bae,et al.  Organ-On-A-Chip: Development and Clinical Prospects Toward Toxicity Assessment with an Emphasis on Bone Marrow , 2015, Drug Safety.

[241]  Teiji Wada,et al.  RANKL-RANK signaling in osteoclastogenesis and bone disease. , 2006, Trends in molecular medicine.

[242]  S. Tuck,et al.  The cell biology of bone metabolism , 2008, Journal of Clinical Pathology.

[243]  K. Furukawa,et al.  Development of bioactive porous α-TCP/HAp beads for bone tissue engineering. , 2013, Journal of biomedical materials research. Part A.

[244]  L. Bonewald,et al.  Establishment of an Osteoid Preosteocyte‐like Cell MLO‐A5 That Spontaneously Mineralizes in Culture , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[245]  Zunpeng Liu,et al.  Combination of Controlled Release Platelet-Rich Plasma Alginate Beads and Bone Morphogenetic Protein-2 Genetically Modified Mesenchymal Stem Cells for Bone Regeneration. , 2016, Journal of periodontology.

[246]  Dietmar W Hutmacher,et al.  Scaffold-based bone engineering by using genetically modified cells. , 2005, Gene.

[247]  L. Bačáková,et al.  Evaluation of the potential of chitosan/β-1,3-glucan/hydroxyapatite material as a scaffold for living bone graft production in vitro by comparison of ADSC and BMDSC behaviour on its surface , 2017, Biomedical materials.

[248]  Sang Hoon Lee,et al.  Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells. , 2007, Biomaterials.

[249]  K. Na,et al.  Bone morphogenic protein-2 (BMP-2) loaded nanoparticles mixed with human mesenchymal stem cell in fibrin hydrogel for bone tissue engineering. , 2009, Journal of bioscience and bioengineering.

[250]  Marta A. Walasek,et al.  HEMATOPOIETIC STEM CELLS VIII , 2012 .

[251]  De-xin Wang,et al.  Enhancing the bioactivity of Poly(lactic-co-glycolic acid) scaffold with a nano-hydroxyapatite coating for the treatment of segmental bone defect in a rabbit model , 2013, International journal of nanomedicine.