{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:11:54Z","timestamp":1779343914926,"version":"3.51.4"},"reference-count":133,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>The functional and structural reconstruction of the tendon-bone interface (TBI) is a major challenge in orthopedics and sports medicine. Under the influence of chronic degenerative pathologies such as aging, diabetes, and rheumatoid arthritis, the cascading collapse of the local immune-metabolic network disrupts the regenerative microenvironment of the tissue, making the clinical translation of traditional inert physical scaffolds extremely difficult. This review systematically summarizes the latest paradigm shifts in \u201cbone immunoengineering\u201d aimed at overcoming the complex challenges of TBI regeneration. We first decode the core regulatory networks that control interface heterogeneity remodeling, thoroughly analyzing the spatiotemporal polarization dynamics of macrophages, the double-edged effects of the Piezo1-YAP mechanotransduction axis, and the \u201cneuro-immune-skeletal\u201d ternary communication mechanism. Based on this pathological framework, we comprehensively overview next-generation intelligent biophysical and chemical intervention strategies for actively reprogramming extreme microenvironments. These strategies include piezoelectric nanohydrogels for electromechanical-metabolic coupling, Janus asymmetric microfluidic interfaces for multi-ion spatiotemporal rectification, and precise spatial delivery platforms for targeted clearance of senescent cells and engineered exosomes. Furthermore, to overcome the translational barriers between underlying mechanisms and clinical applications, we focus on the cross-scale evolution of preclinical evaluation systems, elaborating on the core value of three-dimensional tendon-bone organoids, microfluidic organ-on-chip systems, and high-resolution spatial transcriptomics. Finally, this review envisions advanced microphysiological systems characterized by closed-loop dynamic adaptive biomaterials, spatiotemporal matching of degradation kinetics, and deep integration with artificial intelligence (AI), highlighting their broad prospects in driving the next-generation of personalized, precise regenerative medicine in orthopedics.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1844904","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:43:24Z","timestamp":1779342204000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunoengineering in the field of tendon and bone regeneration: immunomodulatory biomaterials, delivery platforms, and preclinical models for chronic diseases"],"prefix":"10.3389","volume":"14","author":[{"given":"Wanxue","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Sports Medicine, the Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine, the Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junmiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, Public Health College, Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dexi","family":"Cui","sequence":"additional","affiliation":[{"name":"Knee Preservation Center, the Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinge","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine, the Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Knee Preservation Center, the Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Sheng","sequence":"additional","affiliation":[{"name":"Huangshi Love & Health Hospital Affiliated of Hubei Polytechnic University","place":["Huangshi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusen","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine, the Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1038\/s12276-025-01480-7","article-title":"Hallmarks of cellular senescence: biology, mechanisms, regulations","volume":"57","author":"Ajoolabady","year":"2025","journal-title":"Exp. 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