{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:25:03Z","timestamp":1788963903474,"version":"build-2803163510"},"reference-count":202,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Pseudoarthrosis\u2014the failure of normal fracture healing\u2014remains a significant orthopedic challenge affecting approximately 10\u201315% of long bone fractures, and is associated with significant pain, prolonged disability, and repeated surgical interventions. Despite extensive research into the pathophysiological mechanisms of bone healing, diagnostic approaches remain reliant on clinical findings and radiographic evaluations, with little innovation in tools to predict or diagnose non-union. The present review evaluates the current understanding of the genetic and biological basis of pseudoarthrosis and highlights future research directions. Recent studies have highlighted the potential of specific molecules and genetic markers to serve as predictors of unsuccessful fracture healing. Alterations in mesenchymal stromal cell (MSC) function, including diminished osteogenic potential and increased cellular senescence, are central to pseudoarthrosis pathogenesis. Molecular analyses reveal suppressed bone morphogenetic protein (BMP) signaling and elevated levels of its inhibitors, such as Noggin and Gremlin, which impair bone regeneration. Genetic studies have uncovered polymorphisms in BMP, matrix metalloproteinase (MMP), and Wnt signaling pathways, suggesting a genetic predisposition to non-union. Additionally, the biological differences between atrophic and hypertrophic pseudoarthrosis, including variations in vascularity and inflammatory responses, emphasize the need for targeted approaches to management. Emerging biomarkers, such as circulating microRNAs (miRNAs), cytokine profiles, blood-derived MSCs, and other markers (B7-1 and PlGF-1), have the potential to contribute to early detection of at-risk patients and personalized therapeutic approaches. Advancing our understanding of the genetic and biological underpinnings of pseudoarthrosis is essential for the development of innovative diagnostic tools and therapeutic strategies.<\/jats:p>","DOI":"10.3390\/diseases13030075","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T10:15:03Z","timestamp":1740996903000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions"],"prefix":"10.3390","volume":"13","author":[{"given":"Amalia","family":"Kotsifaki","sequence":"first","affiliation":[{"name":"Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Kalouda","sequence":"additional","affiliation":[{"name":"Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sousanna","family":"Maroulaki","sequence":"additional","affiliation":[{"name":"Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Foukas","sequence":"additional","affiliation":[{"name":"Third Department of Orthopaedic Surgery, \u201cKAT\u201d General Hospital of Athens, 2, Nikis Street, 14561 Kifissia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Armakolas","sequence":"additional","affiliation":[{"name":"Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111243","DOI":"10.1016\/j.injury.2023.111243","article-title":"The Burden of Long Bone Fracture and Health System Response in Malawi: A Scoping Review","volume":"55","author":"Abbas","year":"2024","journal-title":"Injury"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.injury.2020.11.029","article-title":"Fracture Nonunion in Long Bones: A Literature Review of Risk Factors and Surgical Management","volume":"52","author":"Nicholson","year":"2021","journal-title":"Injury"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5704\/MOJ.1907.001","article-title":"Fracture Non-Union: A Review of Clinical Challenges and Future Research Needs","volume":"13","author":"Stewart","year":"2019","journal-title":"Malays. Orthop. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bowers, K.M., and Anderson, D.E. (2024). Delayed Union and Nonunion: Current Concepts, Prevention, and Correction: A Review. Bioengineering, 11.","DOI":"10.3390\/bioengineering11060525"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1016\/j.injury.2016.02.022","article-title":"Human Pseudoarthrosis Tissue Contains Cells with Osteogenic Potential","volume":"47","author":"Takahara","year":"2016","journal-title":"Injury"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Perut, F., Roncuzzi, L., G\u00f3mez-Barrena, E., and Baldini, N. (2024). Association between Bone Turnover Markers and Fracture Healing in Long Bone Non-Union: A Systematic Review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13082333"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1080\/1354750X.2021.1985171","article-title":"Predicting Fracture Healing with Blood Biomarkers: The Potential to Assess Patient Risk of Fracture Nonunion","volume":"26","author":"Chitwood","year":"2021","journal-title":"Biomarkers"},{"key":"ref_8","unstructured":"Agrawal, U., and Tiwari, V. (2025). Congenital Tibial Pseudarthrosis. StatPearls, StatPearls Publishing."},{"key":"ref_9","unstructured":"Sheen, J.R., Mabrouk, A., and Garla, V.V. (2025). Fracture Healing Overview. StatPearls, StatPearls Publishing."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s10456-023-09876-7","article-title":"Pathological Angiogenesis: Mechanisms and Therapeutic Strategies","volume":"26","author":"Dudley","year":"2023","journal-title":"Angiogenesis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1089\/wound.2013.0517","article-title":"Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair","volume":"3","author":"Johnson","year":"2014","journal-title":"Adv. Wound Care"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Basile, G., Fozzato, S., Petrucci, Q.A., Gallina, M., Bianco Prevot, L., Accetta, R., and Zaami, S. (2022). Treatment of Femoral Shaft Pseudarthrosis, Case Series and Medico-Legal Implications. J. Clin. Med., 11.","DOI":"10.3390\/jcm11247407"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1186\/s13018-023-04232-3","article-title":"Risk Factors and Healthcare Costs Associated with Long Bone Fracture Non-Union: A Retrospective US Claims Database Analysis","volume":"18","author":"Vanderkarr","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Everts, P.A., Lana, J.F., Onishi, K., Buford, D., Peng, J., Mahmood, A., Fonseca, L.F., van Zundert, A., and Podesta, L. (2023). Angiogenesis and Tissue Repair Depend on Platelet Dosing and Bioformulation Strategies Following Orthobiological Platelet-Rich Plasma Procedures: A Narrative Review. Biomedicines, 11.","DOI":"10.20944\/preprints202306.0745.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s10456-022-09832-x","article-title":"The Vascularization Paradox of Non-Union Formation","volume":"25","author":"Menger","year":"2022","journal-title":"Angiogenesis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/jcmm.17096","article-title":"Biological and Molecular Profile of Fracture Non-Union Tissue: A Systematic Review and an Update on Current Insights","volume":"26","author":"Panteli","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Aluganti Narasimhulu, C., and Singla, D.K. (2020). The Role of Bone Morphogenetic Protein 7 (BMP-7) in Inflammation in Heart Diseases. Cells, 9.","DOI":"10.3390\/cells9020280"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Proia, P., Rossi, C., Alioto, A., Amato, A., Polizzotto, C., Pagliaro, A., Kuli\u015b, S., and Baldassano, S. (2023). MiRNAs Expression Modulates Osteogenesis in Response to Exercise and Nutrition. Genes, 14.","DOI":"10.20944\/preprints202308.0220.v1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bravo V\u00e1zquez, L.A., Moreno Becerril, M.Y., Mora Hern\u00e1ndez, E.O., de Le\u00f3n Carmona, G.G., Aguirre Padilla, M.E., Chakraborty, S., Bandyopadhyay, A., and Paul, S. (2021). The Emerging Role of MicroRNAs in Bone Diseases and Their Therapeutic Potential. Molecules, 27.","DOI":"10.3390\/molecules27010211"},{"key":"ref_20","first-page":"e3631","article-title":"Radiographic Rate and Clinical Impact of Pseudarthrosis in Spine Radiosurgery for Metastatic Spinal Disease","volume":"10","author":"Zhang","year":"2018","journal-title":"Cureus"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00223-022-01020-9","article-title":"New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1)","volume":"112","author":"Dincel","year":"2023","journal-title":"Calcif. Tissue Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/jcmm.12532","article-title":"Biological and Molecular Profile of Fracture Non-Union Tissue: Current Insights","volume":"19","author":"Panteli","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s00068-018-0906-y","article-title":"Autologous Cell-Based Therapy for Treatment of Large Bone Defects: From Bench to Bedside","volume":"44","author":"Verboket","year":"2018","journal-title":"Eur. J. Trauma Emerg. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nasadiuk, K., Kolanowski, T., Kowalewski, C., Wozniak, K., Oldak, T., and Rozwadowska, N. (2025). Harnessing Mesenchymal Stromal Cells for Advanced Wound Healing: A Comprehensive Review of Mechanisms and Applications. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26010199"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bone.2016.06.013","article-title":"The Roles of Vascular Endothelial Growth Factor in Bone Repair and Regeneration","volume":"91","author":"Hu","year":"2016","journal-title":"Bone"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1007\/s13555-023-00952-w","article-title":"Hypoxia-Inducible Factor-1\u03b1 (HIF-1\u03b1) as a Biomarker for Changes in Microcirculation in Individuals with Systemic Sclerosis","volume":"13","author":"Maciejewska","year":"2023","journal-title":"Dermatol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/j.injury.2013.09.009","article-title":"Fracture Non-Union: Can Biomarkers Predict Outcome?","volume":"44","author":"Pountos","year":"2013","journal-title":"Injury"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1530\/EOR-21-0137","article-title":"Risk Factors for Nonunion Following Surgically Managed, Traumatic, Diaphyseal Fractures: A Systematic Review and Meta-Analysis","volume":"7","author":"Jensen","year":"2022","journal-title":"EFORT Open Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s10456-017-9541-1","article-title":"The Role of Vasculature in Bone Development, Regeneration and Proper Systemic Functioning","volume":"20","author":"Filipowska","year":"2017","journal-title":"Angiogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shineh, G., Patel, K., Mobaraki, M., and Tayebi, L. (2023). Functional Approaches in Promoting Vascularization and Angiogenesis in Bone Critical-Sized Defects via Delivery of Cells, Growth Factors, Drugs, and Particles. J. Funct. Biomater., 14.","DOI":"10.3390\/jfb14020099"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rajabi, M., and Mousa, S.A. (2017). The Role of Angiogenesis in Cancer Treatment. Biomedicines, 5.","DOI":"10.3390\/biomedicines5020034"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Goncharov, E.N., Koval, O.A., Nikolaevich Bezuglov, E., Engelgard, M., Igorevich, E.I., Velentinovich Kotenko, K., Encarnacion Ramirez, M.D.J., and Montemurro, N. (2024). Comparative Analysis of Stromal Vascular Fraction and Alternative Mechanisms in Bone Fracture Stimulation to Bridge the Gap between Nature and Technological Advancement: A Systematic Review. Biomedicines, 12.","DOI":"10.3390\/biomedicines12020342"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1089\/wound.2012.0420","article-title":"Mesenchymal Stem Cells in Bone Regeneration","volume":"2","author":"Knight","year":"2013","journal-title":"Adv. Wound Care"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Arellano, M.Y.G., VanHeest, M., Emmadi, S., Abdul-Hafez, A., Ibrahim, S.A., Thiruvenkataramani, R.P., Teleb, R.S., Omar, H., Kesaraju, T., and Mohamed, T. (2024). Role of Mesenchymal Stem\/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging. Bioengineering, 11.","DOI":"10.3390\/bioengineering11060524"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40001-023-01604-7","article-title":"Modulation of Fracture Healing by Senescence-Associated Secretory Phenotype (SASP): A Narrative Review of the Current Literature","volume":"29","author":"Zhao","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.reth.2023.08.005","article-title":"Mesenchymal Stem Cells Derived from the Fibrotic Tissue of Atrophic Nonunion or the Bone Marrow of Iliac Crest: A Donor-Matched Comparison","volume":"24","author":"Shen","year":"2023","journal-title":"Regen. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Halloran, D., Durbano, H.W., and Nohe, A. (2020). Bone Morphogenetic Protein-2 in Development and Bone Homeostasis. J. Dev. Biol., 8.","DOI":"10.3390\/jdb8030019"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"618","DOI":"10.2174\/1574888X14666190628103528","article-title":"Application of Cytokines of the Bone Morphogenetic Protein (BMP) Family in Spinal Fusion\u2014Effects on the Bone, Intervertebral Disc and Mesenchymal Stromal Cells","volume":"14","author":"May","year":"2019","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/jid.2013.419","article-title":"Bone Morphogenetic Protein Signalling Suppresses Wound-Induced Skin Repair by Inhibiting Keratinocyte Proliferation and Migration","volume":"134","author":"Lewis","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_40","first-page":"e66619","article-title":"Bone Morphogenetic Proteins: A Promising Approach for Enhancing Fracture Healing","volume":"16","author":"Nair","year":"2024","journal-title":"Cureus"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41422-023-00918-9","article-title":"The Roles and Regulatory Mechanisms of TGF-\u03b2 and BMP Signaling in Bone and Cartilage Development, Homeostasis and Disease","volume":"34","author":"Wu","year":"2024","journal-title":"Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Morikawa, M., Derynck, R., and Miyazono, K. (2016). TGF-\u03b2 and the TGF-\u03b2 Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb. Perspect. Biol., 8.","DOI":"10.1101\/cshperspect.a021873"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"MacFarlane, E.G., Haupt, J., Dietz, H.C., and Shore, E.M. (2017). TGF-\u03b2 Family Signaling in Connective Tissue and Skeletal Diseases. Cold Spring Harb. Perspect. Biol., 9.","DOI":"10.1101\/cshperspect.a022269"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Baba, A.B., Rah, B., Bhat, G.R., Mushtaq, I., Parveen, S., Hassan, R., Hameed Zargar, M., and Afroze, D. (2022). Transforming Growth Factor-Beta (TGF-\u03b2) Signaling in Cancer-A Betrayal Within. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.791272"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41413-024-00342-8","article-title":"Wnt\/\u03b2-Catenin Signaling Components and Mechanisms in Bone Formation, Homeostasis, and Disease","volume":"12","author":"Hu","year":"2024","journal-title":"Bone Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16009","DOI":"10.1038\/boneres.2016.9","article-title":"TGF-\u03b2 and BMP Signaling in Osteoblast, Skeletal Development, and Bone Formation, Homeostasis and Disease","volume":"4","author":"Wu","year":"2016","journal-title":"Bone Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13287-024-03761-w","article-title":"TGF-\u03b2 Signaling Regulates Differentiation of MSCs in Bone Metabolism: Disputes among Viewpoints","volume":"15","author":"Wei","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1042\/BCJ20160254","article-title":"Structure of Gremlin-1 and Analysis of Its Interaction with BMP-2","volume":"473","author":"Wang","year":"2016","journal-title":"Biochem. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00427-024-00714-4","article-title":"Highly Conserved and Extremely Evolvable: BMP Signalling in Secondary Axis Patterning of Cnidaria and Bilateria","volume":"234","author":"Knabl","year":"2024","journal-title":"Dev. Genes. Evol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1530\/JME-18-0198","article-title":"Gremlin, Noggin, Chordin and Follistatin Differentially Modulate BMP Induced Suppression of Androgen Secretion by Bovine Ovarian Theca Cells","volume":"62","author":"Glister","year":"2019","journal-title":"J. Mol. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41392-021-00762-6","article-title":"Wnt\/\u03b2-Catenin Signalling: Function, Biological Mechanisms, and Therapeutic Opportunities","volume":"7","author":"Liu","year":"2022","journal-title":"Sig Transduct. Target. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.2106\/JBJS.22.01092","article-title":"Dual Inhibition of the Wnt Inhibitors DKK1 and Sclerostin Promotes Fracture Healing and Increases the Density and Strength of Uninjured Bone: An Experimental Study in Nonhuman Primates","volume":"105","author":"Florio","year":"2023","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Starlinger, J., Santol, J., Kaiser, G., and Sarahrudi, K. (2024). Close Negative Correlation of Local and Circulating Dickkopf-1 and Sclerostin Levels during Human Fracture Healing. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-55756-5"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1210\/er.2011-1060","article-title":"Sclerostin and Dickkopf-1 as Therapeutic Targets in Bone Diseases","volume":"33","author":"Ke","year":"2012","journal-title":"Endocr. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s10020-024-00838-3","article-title":"Dickkopf-1 (DKK1) Blockade Mitigates Osteogenesis Imperfecta (OI) Related Bone Disease","volume":"30","author":"Ko","year":"2024","journal-title":"Mol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Breinbauer, R., M\u00e4ling, M., Ehnert, S., Blumenstock, G., Schwarz, T., Jazewitsch, J., Erne, F., Reumann, M.K., Rollmann, M.F., and Braun, B.J. (2024). B7-1 and PlGF-1 Are Two Possible New Biomarkers to Identify Fracture-Associated Trauma Patients at Higher Risk of Developing Complications: A Cohort Study. BMC Musculoskelet. Disord., 25.","DOI":"10.1186\/s12891-024-07789-0"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Cabral-Pacheco, G.A., Garza-Veloz, I., Castruita-De la Rosa, C., Ramirez-Acu\u00f1a, J.M., Perez-Romero, B.A., Guerrero-Rodriguez, J.F., Martinez-Avila, N., and Martinez-Fierro, M.L. (2020). The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249739"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13287-016-0393-1","article-title":"Effects of Matrix Metalloproteinases on the Fate of Mesenchymal Stem Cells","volume":"7","author":"Almalki","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13619-023-00181-8","article-title":"BMP Signaling in Cancer Stemness and Differentiation","volume":"12","author":"Zhou","year":"2023","journal-title":"Cell Regen."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.bone.2015.05.026","article-title":"Non-Coding RNAs: Epigenetic Regulators of Bone Development and Homeostasis","volume":"81","author":"Hassan","year":"2015","journal-title":"Bone"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.omtn.2020.07.017","article-title":"Small and Long Non-Coding RNAs as Functional Regulators of Bone Homeostasis, Acting Alone or Cooperatively","volume":"21","author":"Sikora","year":"2020","journal-title":"Mol. Ther.\u2014Nucleic Acids"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jot.2022.07.002","article-title":"Specific microRNAs Are Associated with Fracture Healing Phases, Patient Age and Multi-Trauma","volume":"37","author":"Groven","year":"2022","journal-title":"J. Orthop. Translat"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"111410","DOI":"10.1016\/j.injury.2024.111410","article-title":"MicroRNAs in Osteoblast Differentiation and Fracture Healing: From Pathogenesis to Therapeutic Implication","volume":"55","author":"Yao","year":"2024","journal-title":"Injury"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/imr.13249","article-title":"Biomarkers of Immune Checkpoint Inhibitor Response and Toxicity: Challenges and Opportunities","volume":"318","author":"Goodman","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_65","first-page":"e176802","article-title":"Spatial Transcriptomics Implicates Impaired BMP Signaling in NF1 Fracture Pseudarthrosis in Murine and Patient Tissues","volume":"9","author":"Rios","year":"2024","journal-title":"JCI Insight"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kaspiris, A., Savvidou, O.D., Vasiliadis, E.S., Hadjimichael, A.C., Melissaridou, D., Iliopoulou-Kosmadaki, S., Iliopoulos, I.D., Papadimitriou, E., and Chronopoulos, E. (2022). Current Aspects on the Pathophysiology of Bone Metabolic Defects during Progression of Scoliosis in Neurofibromatosis Type 1. J. Clin. Med., 11.","DOI":"10.3390\/jcm11020444"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/s13023-019-1196-0","article-title":"Identification and Characterization of NF1 and Non-NF1 Congenital Pseudarthrosis of the Tibia Based on Germline NF1 Variants: Genetic and Clinical Analysis of 75 Patients","volume":"14","author":"Zhu","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Saul, D., Menger, M.M., Ehnert, S., N\u00fcssler, A.K., Histing, T., and Laschke, M.W. (2023). Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions\u2014Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors. Bioengineering, 10.","DOI":"10.3390\/bioengineering10010085"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4","DOI":"10.21037\/sci-2022-038","article-title":"The Role of Macrophages in Fracture Healing: A Narrative Review of the Recent Updates and Therapeutic Perspectives","volume":"10","author":"Frade","year":"2023","journal-title":"Stem Cell Investig."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Sun, Y., Li, J., Xie, X., Gu, F., Sui, Z., Zhang, K., and Yu, T. (2021). Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.778078"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1002\/jor.25564","article-title":"Reduced Angiogenesis and Delayed Endochondral Ossification in CD163\u2212\/\u2212 Mice Highlights a Role of M2 Macrophages during Bone Fracture Repair","volume":"41","author":"Ren","year":"2023","journal-title":"J. Orthop. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/bonekey.2013.34","article-title":"CXCL12\/CXCR4 Signaling and Other Recruitment and Homing Pathways in Fracture Repair","volume":"2","author":"Yellowley","year":"2013","journal-title":"Bonekey Rep."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Schulze, F., Lang, A., Schoon, J., Wassilew, G.I., and Reichert, J. (2023). Scaffold Guided Bone Regeneration for the Treatment of Large Segmental Defects in Long Bones. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020325"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1097\/SHK.0000000000001950","article-title":"Trauma-Derived Extracellular Vesicles Are Sufficient to Induce Endothelial Dysfunction and Coagulopathy","volume":"58","author":"Zeineddin","year":"2022","journal-title":"Shock"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Zieba, J.T., Chen, Y.-T., Lee, B.H., and Bae, Y. (2020). Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis. Biomolecules, 10.","DOI":"10.3390\/biom10020332"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-024-00689-6","article-title":"Cell Signaling and Transcriptional Regulation of Osteoblast Lineage Commitment, Differentiation, Bone Formation, and Homeostasis","volume":"10","author":"Zhu","year":"2024","journal-title":"Cell Discov."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9919361","DOI":"10.1155\/2021\/9919361","article-title":"An In Vitro and In Vivo Comparison of Osteogenic Differentiation of Human Mesenchymal Stromal\/Stem Cells","volume":"2021","author":"Mollentze","year":"2021","journal-title":"Stem Cells Int."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.2741\/2296","article-title":"Signaling and Transcriptional Regulation in Osteoblast Commitment and Differentiation","volume":"12","author":"Huang","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1055\/s-0041-1732334","article-title":"Bone Healing and Inflammation: Principles of Fracture and Repair","volume":"35","author":"ElHawary","year":"2021","journal-title":"Semin. Plast. Surg."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Diban, F., Lodovico, S.D., Fermo, P.D., D\u2019Ercole, S., D\u2019Arcangelo, S., Giulio, M.D., and Cellini, L. (2023). Biofilms in Chronic Wound Infections: Innovative Antimicrobial Approaches Using the In Vitro Lubbock Chronic Wound Biofilm Model. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021004"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Vestby, L.K., Gr\u00f8nseth, T., Simm, R., and Nesse, L.L. (2020). Bacterial Biofilm and Its Role in the Pathogenesis of Disease. Antibiotics, 9.","DOI":"10.3390\/antibiotics9020059"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Tjempakasari, A., Suroto, H., and Santoso, D. (2021). Mesenchymal Stem Cell Senescence and Osteogenesis. Medicina, 58.","DOI":"10.3390\/medicina58010061"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Reible, B., Schmidmaier, G., Moghaddam, A., and Westhauser, F. (2018). Insulin-Like Growth Factor-1 as a Possible Alternative to Bone Morphogenetic Protein-7 to Induce Osteogenic Differentiation of Human Mesenchymal Stem Cells in Vitro. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061674"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.52711\/0974-360X.2022.00291","article-title":"The Roles of Insulin Growth Factors-1 (IGF-1) in Bone Graft to Increase Osteogenesis","volume":"15","author":"Prahasanti","year":"2022","journal-title":"Res. J. Pharm. Technol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"101157","DOI":"10.1016\/j.bonr.2021.101157","article-title":"A Pilot Study of Circulating Levels of TGF-\u03921 and TGF-\u03922 as Biomarkers of Bone Healing in Patients with Non-Hypertrophic Pseudoarthrosis of Long Bones","volume":"16","author":"Chaverri","year":"2021","journal-title":"Bone Rep."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Jim\u00e9nez-Ortega, R.F., Ortega-Mel\u00e9ndez, A.I., Pati\u00f1o, N., Rivera-Paredez, B., Hidalgo-Bravo, A., and Vel\u00e1zquez-Cruz, R. (2024). The Involvement of microRNAs in Bone Remodeling Signaling Pathways and Their Role in the Development of Osteoporosis. Biology, 13.","DOI":"10.3390\/biology13070505"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Krzyszczyk, P., Schloss, R., Palmer, A., and Berthiaume, F. (2018). The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-Wound Healing Phenotypes. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.00419"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"El-Jawhari, J.J., Kleftouris, G., El-Sherbiny, Y., Saleeb, H., West, R.M., Jones, E., and Giannoudis, P.V. (2019). Defective Proliferation and Osteogenic Potential with Altered Immunoregulatory Phenotype of Native Bone Marrow-Multipotential Stromal Cells in Atrophic Fracture Non-Union. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-53927-3"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.injury.2014.09.006","article-title":"Femoral and Tibial Blood Supply: A Trigger for Non-Union?","volume":"45","author":"Santolini","year":"2014","journal-title":"Injury"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.injury.2011.03.035","article-title":"Angiogenesis in Bone Regeneration","volume":"42","author":"Hankenson","year":"2011","journal-title":"Injury"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bone.2014.09.017","article-title":"Bringing New Life to Damaged Bone: The Importance of Angiogenesis in Bone Repair and Regeneration","volume":"70","author":"Stegen","year":"2015","journal-title":"Bone"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1302\/0301-620X.98B7.36061","article-title":"A Unified Theory of Bone Healing and Nonunion: BHN Theory","volume":"98-B","author":"Elliott","year":"2016","journal-title":"Bone Jt. J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1016\/j.injury.2015.08.009","article-title":"Surgical Management of Infected Non-Unions: An Update","volume":"46","author":"Kanakaris","year":"2015","journal-title":"Injury"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Miclau, K.R., Brazina, S.A., Bahney, C.S., Hankenson, K.D., Hunt, T.K., Marcucio, R.S., and Miclau, T. (2017). Stimulating Fracture Healing in Ischemic Environments: Does Oxygen Direct Stem Cell Fate during Fracture Healing?. Front. Cell Dev. Biol., 5.","DOI":"10.3389\/fcell.2017.00045"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/j.1524-475X.2005.00078.x","article-title":"Hyperoxia and Angiogenesis","volume":"13","author":"Hopf","year":"2005","journal-title":"Wound Repair Regen."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"311","DOI":"10.4248\/BR201304002","article-title":"Skeletal Blood Flow in Bone Repair and Maintenance","volume":"1","author":"Tomlinson","year":"2013","journal-title":"Bone Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"S82","DOI":"10.1097\/00003086-199810001-00010","article-title":"Angiogenesis in Fracture Repair","volume":"355S","author":"Glowacki","year":"1998","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"13601","DOI":"10.1038\/ncomms13601","article-title":"Blood Flow Controls Bone Vascular Function and Osteogenesis","volume":"7","author":"Ramasamy","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ocl.2004.03.002","article-title":"Vascular Anatomy and Microcirculation of Skeletal Zones Vulnerable to Osteonecrosis: Vascularization of the Femoral Head","volume":"35","author":"Johnson","year":"2004","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"xiii","DOI":"10.1016\/S0030-5898(04)00036-7","article-title":"Osteonecrosis of the Human Skeleton","volume":"35","author":"Soucacos","year":"2004","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s11914-018-0432-1","article-title":"Clinical and Research Approaches to Treat Non-Union Fracture","volume":"16","author":"Schlundt","year":"2018","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Carlier, A., Geris, L., Bentley, K., Carmeliet, G., Carmeliet, P., and Van Oosterwyck, H. (2012). MOSAIC: A Multiscale Model of Osteogenesis and Sprouting Angiogenesis with Lateral Inhibition of Endothelial Cells. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002724"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/ncb2103","article-title":"Endothelial Cells Dynamically Compete for the Tip Cell Position during Angiogenic Sprouting","volume":"12","author":"Jakobsson","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2011.08.039","article-title":"Basic and Therapeutic Aspects of Angiogenesis","volume":"146","author":"Potente","year":"2011","journal-title":"Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1210\/endo.143.4.8719","article-title":"Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A","volume":"143","author":"Deckers","year":"2002","journal-title":"Endocrinology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3109\/03008208909023898","article-title":"Effects of Acidic and Basic Fibroblast Growth Factors on Osteoblastic Cells","volume":"20","author":"Rodan","year":"1989","journal-title":"Connect. Tissue Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0736-0266(02)00159-6","article-title":"Effects of Locally Applied Vascular Endothelial Growth Factor (VEGF) and VEGF-inhibitor to the Rabbit Tibia during Distraction Osteogenesis","volume":"21","author":"Eckardt","year":"2003","journal-title":"J. Orthop. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2147\/JIR.S110621","article-title":"The Treatment of Nonunions with Application of BMP-7 Increases the Expression Pattern for Angiogenic and Inflammable Cytokines: A Matched Pair Analysis","volume":"9","author":"Haubruck","year":"2016","journal-title":"J. Inflamm. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1016\/S0020-1383(13)70012-3","article-title":"Genetic Predisposition to Non-Union: Evidence Today","volume":"44","author":"Dimitriou","year":"2013","journal-title":"Injury"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Dimitriou, R., Carr, I.M., West, R.M., Markham, A.F., and Giannoudis, P.V. (2011). Genetic Predisposition to Fracture Non-Union: A Case Control Study of a Preliminary Single Nucleotide Polymorphisms Analysis of the BMP Pathway. BMC Musculoskelet. Disord., 12.","DOI":"10.1186\/1471-2474-12-44"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1002\/jor.22455","article-title":"Polymorphisms in BMP4 and FGFR1 Genes Are Associated with Fracture Non-Union","volume":"31","author":"Duarte","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Huang, W., Zhang, K., Zhu, Y., Wang, Z., Li, Z., and Zhang, J. (2018). Genetic Polymorphisms of NOS2 and Predisposition to Fracture Non-Union: A Case Control Study Based on Han Chinese Population. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193673"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.2106\/JBJS.M.00453","article-title":"Single Nucleotide Polymorphisms in Osteogenic Genes in Atrophic Delayed Fracture-Healing: A Preliminary Investigation","volume":"96","author":"Sathyendra","year":"2014","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1002\/jor.21443","article-title":"Are Polymorphisms of Molecules Involved in Bone Healing Correlated to Aseptic Femoral and Tibial Shaft Non-Unions?","volume":"29","author":"Zeckey","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"144766","DOI":"10.1016\/j.gene.2020.144766","article-title":"Genetic Determinants of Fracture Non-Union: A Systematic Review from the Literature","volume":"751","author":"Yan","year":"2020","journal-title":"Gene"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s00402-010-1171-7","article-title":"Genetic Factors Responsible for Long Bone Fractures Non-Union","volume":"131","author":"Olszewski","year":"2011","journal-title":"Arch. Orthop. Trauma Surg."},{"key":"ref_117","first-page":"754872","article-title":"Study of Cysteine-Rich Protein 61 Genetic Polymorphism in Predisposition to Fracture Nonunion: A Case Control","volume":"2015","author":"Ali","year":"2015","journal-title":"Genet. Res. Int."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/jbm4.10063","article-title":"Genomewide Association Study of Fracture Nonunion Using Electronic Health Records","volume":"3","author":"McCoy","year":"2019","journal-title":"JBMR Plus"},{"key":"ref_119","first-page":"569","article-title":"Genetic Influence of Fracture Nonunion (FNU): A Systematic Review","volume":"16","author":"AlTabash","year":"2023","journal-title":"Pharmacogenom. Pers. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.injury.2011.10.031","article-title":"Differential Gene Expression Analysis in Fracture Callus of Patients with Regular and Failed Bone Healing","volume":"43","author":"Zimmermann","year":"2012","journal-title":"Injury"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/jbmr.219","article-title":"Genetic Profiling and Individualized Prognosis of Fracture","volume":"26","author":"Tran","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Xiao, D., Fang, L., Liu, Z., He, Y., Ying, J., Qin, H., Lu, A., Shi, M., Li, T., and Zhang, B. (2024). DNA Methylation\u2013Mediated Rbpjk Suppression Protects against Fracture Nonunion Caused by Systemic Inflammation. J. Clin. Investig., 134.","DOI":"10.1172\/JCI168558"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1080\/17453674.2017.1321351","article-title":"The Risk of Non-Union per Fracture: Current Myths and Revised Figures from a Population of over 4 Million Adults","volume":"88","author":"Mills","year":"2017","journal-title":"Acta Orthop."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/j.injury.2013.08.003","article-title":"Fracture Non-Union: Who Is at Risk?","volume":"44","author":"Copuroglu","year":"2013","journal-title":"Injury"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1097\/00007632-200112010-00018","article-title":"Smoking as a Predictor of Negative Outcome in Lumbar Spinal Fusion","volume":"26","author":"Andersen","year":"2001","journal-title":"Spine"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s00264-013-1809-5","article-title":"Smoking as a Predictor of Negative Outcome in Diaphyseal Fracture Healing","volume":"37","author":"Hernigou","year":"2013","journal-title":"Int. Orthop."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/j.1530-0277.2002.tb02568.x","article-title":"Fracture Healing and Bone Mass in Rats Fed on Liquid Diet Containing Ethanol","volume":"26","author":"Elmali","year":"2002","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e162775","DOI":"10.1001\/jamasurg.2016.2775","article-title":"Epidemiology of Fracture Nonunion in 18 Human Bones","volume":"151","author":"Zura","year":"2016","journal-title":"JAMA Surg."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1302\/2058-5241.5.190037","article-title":"Nonunion\u2014Consensus from the 4th Annual Meeting of the Danish Orthopaedic Trauma Society","volume":"5","author":"Schmal","year":"2020","journal-title":"EFORT Open Rev."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.2217\/bmm-2017-0180","article-title":"Toward the Clinical Use of Circulating Biomarkers Predictive of Bone Union","volume":"11","author":"Chaverri","year":"2017","journal-title":"Biomark. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1097\/00003086-198611000-00016","article-title":"The Treatment of Noninfected Pseudarthrosis of the Femur and Tibia with Locked Intramedullary Nailing","volume":"212","author":"Kempf","year":"1986","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"3674045","DOI":"10.1155\/2017\/3674045","article-title":"Changes of Bone Turnover Markers in Long Bone Nonunions Treated with a Regenerative Approach","volume":"2017","author":"Granchi","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s00068-017-0879-2","article-title":"Prognostic Potential of Markers of Bone Turnover in Delayed-Healing Tibial Diaphyseal Fractures","volume":"45","author":"Kumar","year":"2019","journal-title":"Eur. J. Trauma Emerg. Surg."},{"key":"ref_134","first-page":"2263","article-title":"Different Kinetics of Bone Markers in Normal and Delayed Fracture Healing of Long Bones","volume":"48","author":"Herrmann","year":"2002","journal-title":"Clin. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s10195-009-0047-5","article-title":"Increased Serum OPG in Atrophic Nonunion Shaft Fractures","volume":"10","author":"Marchelli","year":"2009","journal-title":"J. Orthop. Traumatol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.jcyt.2019.06.002","article-title":"Biomarkers of Bone Healing Induced by a Regenerative Approach Based on Expanded Bone Marrow\u2013Derived Mesenchymal Stromal Cells","volume":"21","author":"Granchi","year":"2019","journal-title":"Cytotherapy"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.injury.2010.11.017","article-title":"TRACP 5b and CTX as Osteological Markers of Delayed Fracture Healing","volume":"42","author":"Moghaddam","year":"2011","journal-title":"Injury"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Burska, A.N., Giannoudis, P.V., Tan, B.H., Ilas, D., Jones, E., and Ponchel, F. (2020). Dynamics of Early Signalling Events during Fracture Healing and Potential Serum Biomarkers of Fracture Non-Union in Humans. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020492"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Liu, C., Liu, Y., Yu, Y., Zhao, Y., Zhang, D., and Yu, A. (2022). Identification of Up-Regulated ANXA3 Resulting in Fracture Non-Union in Patients With T2DM. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.890941"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1016\/j.injury.2014.04.003","article-title":"Biological Perspectives of Delayed Fracture Healing","volume":"45","author":"Hankenson","year":"2014","journal-title":"Injury"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.bone.2005.02.011","article-title":"TGF-Beta1 as a Marker of Delayed Fracture Healing","volume":"36","author":"Zimmermann","year":"2005","journal-title":"Bone"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/jbmr.3871","article-title":"High-Dose TGF-\u03921 Impairs Mesenchymal Stem Cell-Mediated Bone Regeneration via Bmp2 Inhibition","volume":"35","author":"Xu","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/jor.22219","article-title":"Serum Levels of Fibroblast Growth Factor 2 in Children with Orthopedic Diseases: Potential Role in Predicting Bone Healing","volume":"31","author":"Granchi","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1002\/jor.20857","article-title":"FGF23 Is a Putative Marker for Bone Healing and Regeneration","volume":"27","author":"Goebel","year":"2009","journal-title":"J. Orthop. Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.niox.2009.02.006","article-title":"The Effects of Shockwave on Bone Healing and Systemic Concentrations of Nitric Oxide (NO), TGF-Beta1, VEGF and BMP-2 in Long Bone Non-Unions","volume":"20","author":"Wang","year":"2009","journal-title":"Nitric Oxide"},{"key":"ref_146","first-page":"2519","article-title":"MiR-133a Inhibits Fracture Healing via Targeting RUNX2\/BMP2","volume":"22","author":"Peng","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"e18522","DOI":"10.1111\/jcmm.18522","article-title":"Identification and Validation of miR-29b-3p and LIN7A as Important Diagnostic Markers for Bone Non-Union by WGCNA","volume":"28","author":"Jian","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e21653","DOI":"10.1097\/MD.0000000000021653","article-title":"Experimental Study of Expression Profile and Specific Role of Human microRNAs in Regulating Atrophic Bone Nonunion","volume":"99","author":"Wei","year":"2020","journal-title":"Medicine"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"e1161","DOI":"10.1002\/ctm2.1161","article-title":"Prognostic and Therapeutic Potential of microRNAs for Fracture Healing Processes and Non-Union Fractures: A Systematic Review","volume":"13","author":"Breulmann","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1302\/0301-620X.97B8.34966","article-title":"Profiling microRNA Expression in Fracture Nonunions: Potential Role of microRNAs in Nonunion Formation Studied in a Rat Model","volume":"97-B","author":"Waki","year":"2015","journal-title":"Bone Jt. J."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1111\/j.1445-2197.2007.04175.x","article-title":"Bone Morphogenetic Proteins in Clinical Applications","volume":"77","author":"Gautschi","year":"2007","journal-title":"ANZ J. Surg."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.injury.2004.11.039","article-title":"Surgical Treatment of Non-Unions: A Case for Internal Fixation","volume":"37","author":"Olson","year":"2006","journal-title":"Injury"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ocl.2006.10.006","article-title":"Long Bone Reconstruction with Vascularized Bone Grafts","volume":"38","author":"Pederson","year":"2007","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"S75","DOI":"10.1016\/j.injury.2007.02.012","article-title":"Autologous Iliac Crest Bone Graft: Should It Still Be the Gold Standard for Treating Nonunions?","volume":"38","author":"Sen","year":"2007","journal-title":"Injury"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0030-5898(20)31513-3","article-title":"Treatment of Tibial Malunions and Nonunions with Reamed Intramedullary Nails","volume":"21","author":"Mayo","year":"1990","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1302\/0301-620X.97B9.35626","article-title":"Life- and Limb-Threatening Infections Following the Use of an External Fixator","volume":"97-B","author":"Jauregui","year":"2015","journal-title":"Bone Jt. J."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1007\/s00264-010-1189-z","article-title":"Reamer-Irrigator-Aspirator Indications and Clinical Results: A Systematic Review","volume":"35","author":"Cox","year":"2011","journal-title":"Int. Orthop. (SICOT)"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1302\/0301-620X.98B4.34870","article-title":"Exchange Nailing for Nonunion of Diaphyseal Fractures of the Tibia: Our Results and an Analysis of the Risk Factors for Failure","volume":"98-B","author":"Tsang","year":"2016","journal-title":"Bone Jt. J."},{"key":"ref_159","first-page":"437","article-title":"The Effect of Low-Intensity Pulsed Ultrasound Therapy on Time to Fracture Healing: A Meta-Analysis","volume":"166","author":"Busse","year":"2002","journal-title":"CMAJ"},{"key":"ref_160","first-page":"e34","article-title":"Electrical Stimulation in Bone Healing: Critical Analysis by Evaluating Levels of Evidence","volume":"11","author":"Griffin","year":"2011","journal-title":"Eplasty"},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Schofer, M.D., Block, J.E., Aigner, J., and Schmelz, A. (2010). Improved Healing Response in Delayed Unions of the Tibia with Low-Intensity Pulsed Ultrasound: Results of a Randomized Sham-Controlled Trial. BMC Musculoskelet. Disord., 11.","DOI":"10.1186\/1471-2474-11-229"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1017\/S1462399410001493","article-title":"Gene Therapy for Bone Healing","volume":"12","author":"Evans","year":"2010","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Dimitriou, R., Jones, E., McGonagle, D., and Giannoudis, P.V. (2011). Bone Regeneration: Current Concepts and Future Directions. BMC Med., 9.","DOI":"10.1186\/1741-7015-9-66"},{"key":"ref_164","first-page":"450","article-title":"Treatment of Rabbit Femoral Defect by Firearm With BMP-4 Gene Combined With TGF-\u03921","volume":"66","author":"Li","year":"2009","journal-title":"J. Trauma Inj. Infect. Crit. Care"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"0035","DOI":"10.34133\/bmef.0035","article-title":"Intracellular Protein Delivery: Approaches, Challenges, and Clinical Applications","volume":"5","author":"Chan","year":"2024","journal-title":"BME Front."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/path.1896","article-title":"Viral Gene Therapy Strategies: From Basic Science to Clinical Application","volume":"208","author":"Young","year":"2006","journal-title":"J. Pathol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1136\/mp.53.4.173","article-title":"Retroviral Vectors","volume":"53","author":"Kurian","year":"2000","journal-title":"Mol. Pathol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"430","DOI":"10.2174\/156652308786848012","article-title":"Non-Integrating Lentiviral Vectors","volume":"8","author":"Sarkis","year":"2008","journal-title":"Curr. Gene Ther."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12033-007-0021-5","article-title":"Adenoviral Vectors for Gene Therapy","volume":"36","author":"Douglas","year":"2007","journal-title":"Mol. Biotechnol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/nrg1577","article-title":"Towards Safe, Non-Viral Therapeutic Gene Expression in Humans","volume":"6","author":"Glover","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"96","DOI":"10.22203\/eCM.v018a09","article-title":"Use of Genetically Modified Muscle and Fat Grafts to Repair Defects in Bone and Cartilage","volume":"18","author":"Evans","year":"2009","journal-title":"Eur. Cells Mater."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00264-009-0892-0","article-title":"Efficacy of Minimally Invasive Techniques for Enhancement of Fracture Healing: Evidence Today","volume":"34","author":"Pountos","year":"2010","journal-title":"Int. Orthop. (SICOT)"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.abb.2008.03.024","article-title":"Bridging the Regeneration Gap: Stem Cells, Biomaterials and Clinical Translation in Bone Tissue Engineering","volume":"473","author":"Dawson","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.3892\/ijo.2014.2385","article-title":"Paracrine Effects of Stem Cells in Wound Healing and Cancer Progression","volume":"44","author":"Dittmer","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Brown, M.G., Brady, D.J., Healy, K.M., Henry, K.A., Ogunsola, A.S., and Ma, X. (2024). Stem Cells and Acellular Preparations in Bone Regeneration\/Fracture Healing: Current Therapies and Future Directions. Cells, 13.","DOI":"10.3390\/cells13121045"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"e12712","DOI":"10.1111\/cpr.12712","article-title":"Immune Modulation by Mesenchymal Stem Cells","volume":"53","author":"Jiang","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1302\/2046-3758.57.2000587","article-title":"Mesenchymal Stem Cell Implantation in Atrophic Nonunion of the Long Bones: A Translational Study","volume":"5","author":"Ismail","year":"2016","journal-title":"Bone Jt. Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1186\/s13287-024-03968-x","article-title":"Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells: Whether They Can Become New Stars of Cell Therapy","volume":"15","author":"Wu","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1177\/154405910708601213","article-title":"Healing Cranial Defects with AdRunx2-Transduced Marrow Stromal Cells","volume":"86","author":"Zhao","year":"2007","journal-title":"J. Dent. Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.injury.2005.07.019","article-title":"Current Concepts of Molecular Aspects of Bone Healing","volume":"36","author":"Dimitriou","year":"2005","journal-title":"Injury"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1111\/jcpe.13546","article-title":"Differences in Platelet-rich Plasma Composition Influence Bone Healing","volume":"48","author":"Rodan","year":"2021","journal-title":"J. Clin. Periodontol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/aps.2009.15","article-title":"Composite Glycidyl Methacrylated Dextran (Dex-GMA)\/Gelatin Nanoparticles for Localized Protein Delivery","volume":"30","author":"Chen","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_183","first-page":"19","article-title":"The Genetic Profile of Bone Repair","volume":"10","author":"Dimitriou","year":"2013","journal-title":"Clin. Cases Miner. Bone Metab."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1152\/japplphysiol.00839.2010","article-title":"Production of VEGF Receptor 1 and 2 mRNA and Protein during Endochondral Bone Repair Is Differential and Healing Phase Specific","volume":"109","author":"Reumann","year":"2010","journal-title":"J. Appl. Physiol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41584-019-0173-2","article-title":"GWAS Cracks Fracture Risk","volume":"15","author":"Trenkmann","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_186","first-page":"254","article-title":"\u201cGenetic Scissors\u201d CRISPR\/Cas9 Genome Editing Cutting-Edge Biocarrier Technology for Bone and Cartilage Repair","volume":"22","author":"Li","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_187","first-page":"284","article-title":"3D Bioprinting Methods and Techniques: Applications on Artificial Blood Vessel Fabrication","volume":"35","author":"Papaioannou","year":"2019","journal-title":"Acta Cardiol. Sin."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrrheum.2014.164","article-title":"Fracture Healing: Mechanisms and Interventions","volume":"11","author":"Einhorn","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1749-799X-9-18","article-title":"Bone Regenerative Medicine: Classic Options, Novel Strategies, and Future Directions","volume":"9","author":"Oryan","year":"2014","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.2147\/IJN.S209431","article-title":"Advancements and Frontiers in Nano-Based 3D and 4D Scaffolds for Bone and Cartilage Tissue Engineering","volume":"14","author":"Qasim","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_191","doi-asserted-by":"crossref","unstructured":"Tafat, W., Budka, M., McDonald, D., and Wainwright, T.W. (2024). Artificial Intelligence in Orthopaedic Surgery: A Comprehensive Review of Current Innovations and Future Directions. Comput. Struct. Biotechnol. Rep., 1.","DOI":"10.1016\/j.csbr.2024.100006"},{"key":"ref_192","doi-asserted-by":"crossref","unstructured":"Liu, H., Chen, H., Han, Q., Sun, B., Liu, Y., Zhang, A., Fan, D., Xia, P., and Wang, J. (2023). Recent Advancement in Vascularized Tissue-Engineered Bone Based on Materials Design and Modification. Mater. Today Bio, 23.","DOI":"10.1016\/j.mtbio.2023.100858"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"110049","DOI":"10.1016\/j.matdes.2021.110049","article-title":"Collagen-Based Biomaterials for Bone Tissue Engineering","volume":"210","author":"Li","year":"2021","journal-title":"Mater. Des."},{"key":"ref_194","doi-asserted-by":"crossref","unstructured":"Yu, H., Wang, Y., Wang, D., Yi, Y., Liu, Z., Wu, M., Wu, Y., and Zhang, Q. (2022). Landscape of the Epigenetic Regulation in Wound Healing. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.949498"},{"key":"ref_195","doi-asserted-by":"crossref","unstructured":"Ball, J.R., Shelby, T., Hernandez, F., Mayfield, C.K., and Lieberman, J.R. (2023). Delivery of Growth Factors to Enhance Bone Repair. Bioengineering, 10.","DOI":"10.3390\/bioengineering10111252"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13018-022-03041-4","article-title":"Methods for Bone Quality Assessment in Human Bone Tissue: A Systematic Review","volume":"17","author":"Wang","year":"2022","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"2495848","DOI":"10.1155\/2018\/2495848","article-title":"Advances in Regenerative Medicine and Tissue Engineering: Innovation and Transformation of Medicine","volume":"2018","author":"Dzobo","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Mousaei Ghasroldasht, M., Seok, J., Park, H.-S., Liakath Ali, F.B., and Al-Hendy, A. (2022). Stem Cell Therapy: From Idea to Clinical Practice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052850"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"101656","DOI":"10.1016\/j.bonr.2023.101656","article-title":"Mesenchymal Stromal Cells for Bone Trauma, Defects, and Disease: Considerations for Manufacturing, Clinical Translation, and Effective Treatments","volume":"18","author":"Jimenez","year":"2023","journal-title":"Bone Rep."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"09636897231183530","DOI":"10.1177\/09636897231183530","article-title":"Stem Cells and Their Derivatives: An Implication for the Regeneration of Nonunion Fractures","volume":"32","author":"Smolinska","year":"2023","journal-title":"Cell Transplant."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.addr.2018.09.010","article-title":"Therapeutic Strategies for Enhancing Angiogenesis in Wound Healing","volume":"146","author":"Veith","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_202","doi-asserted-by":"crossref","unstructured":"Zhou, J., Ning, E., Lu, L., Zhang, H., Yang, X., and Hao, Y. (2024). Effectiveness of Low-Intensity Pulsed Ultrasound on Osteoarthritis: Molecular Mechanism and Tissue Engineering. Front. 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