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Various complications can result in different forms of impaired bone healing including nonunion, critical\u2010size defects, or stress fractures. While a nonunion may occur due to impaired biological signaling and\/or mechanical instability, a critical\u2010size defect exhibits extensive bone loss that will not spontaneously heal. Comparatively, a stress fracture occurs from repetitive forces and results in a non\u2010healing crack or break in the bone. Clinical standards of treatment vary between these bone defects due to their pathological differences. The use of appropriate animal models for modeling healing defects is critical to improve current treatment methods and develop novel rescue therapies. This review provides an overview of these clinical bone healing impairments and current animal models available to study the defects in vivo. The techniques used to create these models are compared, along with the outcomes, to clarify limitations and future objectives. Finally, rescue techniques focused on tissue engineering and cell\u2010based therapies currently applied in animal models are specifically discussed to analyze their ability to initiate healing at the defect site, providing information regarding potential future therapies. In summary, this review focuses on the current animal models of nonunion, critical\u2010size defects, and stress fractures, as well as interventions that have been tested in vivo to provide an overview of the clinical potential and future directions for improving bone healing.<\/jats:p>","DOI":"10.1002\/jor.25277","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T10:03:27Z","timestamp":1643018607000},"page":"767-778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Animal models of impaired long bone healing and tissue engineering\u2010 and cell\u2010based in vivo interventions"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-5537","authenticated-orcid":false,"given":"Katherine R.","family":"Hixon","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University  St. Louis Missouri USA"},{"name":"Thayer School of Engineering Thayer School of Engineering, Dartmouth College  Hanover New Hampshire USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna N.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-989-5_2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005393"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3791\/58122"},{"key":"e_1_2_10_5_1","volume-title":"Fracture Healing Overview, in StatPearls","author":"Sheen JR"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.20870"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2009.0187"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-0266(02)00072-4"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3109\/17453679308993640"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.050806"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.22181"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03124-z"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-0266(02)00209-7"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1783"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v026a01"},{"issue":"2","key":"e_1_2_10_16_1","first-page":"101","article-title":"Bone healing in 2016","volume":"13","author":"Buza JA","year":"2016","journal-title":"Clin Cases Miner Bone Metab"},{"key":"e_1_2_10_17_1","volume-title":"StatPearls","author":"Thomas JD","year":"2021"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.orthres.2004.03.008"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/17453674.2017.1321351"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOT.0000000000001173"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2016.2775"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/708574"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.injury.2017.04.020"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.injury.2005.10.008","article-title":"Classification of non\u2010union","volume":"36","author":"Megas P","year":"2005","journal-title":"Injury"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.1100030401"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620X.94B7.27370"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.5312\/wjo.v8.i6.471"},{"key":"e_1_2_10_28_1","unstructured":"PelserP.Management of septic non\u2010unions. 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