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This systematic review investigates the biological, molecular and genetic profiles of both (i) non\u2010union tissue and (ii) non\u2013union\u2010related tissues, and the genetic predisposition to fracture non\u2010union. This is crucially important as it could facilitate earlier identification and targeted treatment of high\u2010risk patients, along with improving our understanding on pathophysiology of fracture non\u2010union. Since this is an update on our previous systematic review, we searched the literature indexed in PubMed Medline; Ovid Medline; Embase; Scopus; Google Scholar; and the Cochrane Library using Medical Subject Heading (MeSH) or Title\/Abstract words (non\u2010union(s), non\u2010union(s), human, tissue, bone morphogenic protein(s) (BMPs) and MSCs) from August 2014 (date of our previous publication) to 2 October 2021 for non\u2010union tissue studies, whereas no date restrictions imposed on non\u2013union\u2010related tissue studies. Inclusion criteria of this systematic review are human studies investigating the characteristics and properties of non\u2010union tissue and non\u2013union\u2010related tissues, available in full\u2010text English language. Limitations of this systematic review are exclusion of animal studies, the heterogeneity in the definition of non\u2010union and timing of tissue harvest seen in the included studies, and the search term MSC which may result in the exclusion of studies using historical terms such as \u2018osteoprogenitors\u2019 and \u2018skeletal stem cells\u2019. A total of 24\u00a0studies (non\u2010union tissue: <jats:italic>n<\/jats:italic>\u00a0=\u00a010; non\u2013union\u2010related tissues: <jats:italic>n<\/jats:italic>\u00a0=\u00a014) met the inclusion criteria. Soft tissue interposition, bony sclerosis of fracture ends and complete obliteration of medullary canal are commonest macroscopic appearances of non\u2010unions. Non\u2010union tissue colour and surrounding fluid are two important characteristics that could be used clinically to distinguish between septic and aseptic non\u2010unions. Atrophic non\u2010unions had a predominance of endochondral bone formation and lower cellular density, when compared against hypertrophic non\u2010unions. Vascular tissues were present in both atrophic and hypertrophic non\u2010unions, with no difference in vessel density between the two. Studies have found non\u2010union tissue to contain biologically active MSCs with potential for osteoblastic, chondrogenic and adipogenic differentiation. Proliferative capacity of non\u2010union tissue MSCs was comparable to that of bone marrow MSCs. Rates of cell senescence of non\u2010union tissue remain inconclusive and require further investigation. There was a lower BMP expression in non\u2010union site and absent in the extracellular matrix, with no difference observed between atrophic and hypertrophic non\u2010unions. The reduced BMP\u20107\u00a0gene expression and elevated levels of its inhibitors (Chordin, Noggin and Gremlin) could potentially explain impaired bone healing observed in non\u2010union MSCs. Expression of Dkk\u20101 in osteogenic medium was higher in non\u2010union MSCs. Numerous genetic polymorphisms associated with fracture non\u2010union have been identified, with some involving the BMP and MMP pathways. Further research is required on determining the sensitivity and specificity of molecular and genetic profiling of relevant tissues as a potential screening biomarker for fracture non\u2010unions.<\/jats:p>","DOI":"10.1111\/jcmm.17096","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T07:42:52Z","timestamp":1641368572000},"page":"601-623","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Biological and molecular profile of fracture non\u2010union tissue: A systematic review and an update on current insights"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0905-1432","authenticated-orcid":false,"given":"Michalis","family":"Panteli","sequence":"first","affiliation":[{"name":"Academic Department of Trauma &amp; Orthopaedics School of Medicine University of Leeds Leeds UK"},{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine School of Medicine University of Leeds Leeds UK"},{"name":"Leeds Orthopaedic &amp; Trauma Sciences Leeds General Infirmary University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.H.","family":"Vun","sequence":"additional","affiliation":[{"name":"Academic Department of Trauma &amp; Orthopaedics School of Medicine University of Leeds Leeds UK"},{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine School of Medicine University of Leeds Leeds UK"},{"name":"Leeds Orthopaedic &amp; Trauma Sciences Leeds General Infirmary University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ippokratis","family":"Pountos","sequence":"additional","affiliation":[{"name":"Academic Department of Trauma &amp; Orthopaedics School of Medicine University of Leeds Leeds UK"},{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine School of Medicine University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"J. 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