{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:15:43Z","timestamp":1788156943048,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The enthesis is a specialized transitional tissue that enables load transfer between tendon and bone through a graded tendon\u2013fibrocartilage\u2013bone interface. Following injury or surgical repair, regeneration of the native enthesis remains challenging, often resulting in mechanically inferior fibrous scar tissue. Additively manufactured three-dimensional (3D) scaffolds have emerged as a promising strategy to recreate the structural and biological complexity of the tendon\u2013bone interface. This systematic review evaluated the current preclinical evidence on 3D scaffold-based approaches for enthesis regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This systematic review was conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420261388606). PubMed, Embase, and Web of Science were searched from inception to 13 February 2026. Original preclinical studies investigating additively manufactured 3D scaffold-based strategies for tendon\u2013bone interface or enthesis regeneration were included. Data regarding scaffold design, biological augmentation, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      ,\n                      <jats:italic>in vivo<\/jats:italic>\n                      , and biomechanical outcomes were qualitatively synthesized. Methodological quality was assessed using SYRCLE\u2019s Risk of Bias tool.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nine preclinical animal studies published between 2019 and 2025 met the inclusion criteria. Most studies used rabbit rotator cuff repair models. Polymer-based scaffolds, particularly polycaprolactone and poly (lactic-co-glycolic acid), were the most frequently used materials. Advanced architectures included gradient, multiphasic, bioprinted, and coaxial constructs, often combined with mesenchymal stem cells, growth factors, or controlled-release systems. Across studies, scaffold-based strategies consistently promoted enhanced lineage-specific differentiation, fibrocartilage formation, collagen organization, and interface maturation compared with controls. Biomechanical testing demonstrated improved ultimate load, stiffness, tensile strength, or energy absorption in all experimental groups. Constructs combining biomimetic architecture with biological augmentation generally achieved good outcomes, although regenerated interfaces remained inferior to native tissue. Risk-of-bias assessment showed overall unclear methodological quality due to insufficient reporting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Additively manufactured 3D scaffold-based strategies show promise for improving enthesis regeneration in preclinical models. Constructs integrating spatially organized architecture with controlled biological signaling demonstrated the most favorable structural and biomechanical outcomes. However, current evidence is limited to heterogeneous short-term animal studies, and complete restoration of native enthesis structure and function has not yet been achieved.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbioe.2026.1876882","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:40:27Z","timestamp":1788154827000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["3D-printed scaffold-based strategies for enthesis regeneration: a systematic review of the literature"],"prefix":"10.3389","volume":"14","author":[{"given":"Marco","family":"Minelli","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University","place":["Pieve Emanuele\/Milan, Italy"]},{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Bertolino","sequence":"additional","affiliation":[{"name":"Humanitas University","place":["Pieve Emanuele\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Longobardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University","place":["Pieve Emanuele\/Milan, Italy"]},{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Micalizzi","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Potere","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Anzillotti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University","place":["Pieve Emanuele\/Milan, Italy"]},{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Bonanzinga","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University","place":["Pieve Emanuele\/Milan, Italy"]},{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizaveta","family":"Kon","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University","place":["Pieve Emanuele\/Milan, Italy"]},{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Della Rocca","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Oliva","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital","place":["Rozzano\/Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.11138\/mltj\/2014.4.3.333","article-title":"The enthesis: a review of the tendon-to-bone insertion","volume":"4","author":"Apostolakos","year":"2014","journal-title":"Muscles Ligaments Tendons J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"513","DOI":"10.2106\/JBJS.M.00009","article-title":"Augmentation of tendon-to-bone healing","volume":"96","author":"Atesok","year":"2014","journal-title":"J. Bone Jt. Surg. Am."},{"key":"B3","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.actbio.2022.10.058","article-title":"Bioprinted living tissue constructs with layer-specific, growth factor-loaded microspheres for improved enthesis healing of a rotator cuff","volume":"154","author":"Bai","year":"2022","journal-title":"Acta Biomater."},{"key":"B4","doi-asserted-by":"publisher","first-page":"055003","DOI":"10.1088\/2631-7990\/ad5806","article-title":"Coaxial electrohydrodynamic printing of core\u2013shell microfibrous scaffolds with layer-specific growth factors release for enthesis regeneration","volume":"6","author":"Bai","year":"2024","journal-title":"Int. J. Extreme Manuf."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e2406069","DOI":"10.1002\/smll.202406069","article-title":"Electrohydrodynamic-printed dual-triphase microfibrous scaffolds reshaping the lipidomic profile for enthesis healing in a rat rotator cuff repair model","volume":"21","author":"Bai","year":"2025","journal-title":"Small"},{"key":"B6","doi-asserted-by":"publisher","first-page":"100547","DOI":"10.1016\/j.cobme.2024.100547","article-title":"Achieving tendon enthesis regeneration across length scales","volume":"31","author":"Bousso","year":"2024","journal-title":"Curr. Opin. Biomed. Eng."},{"key":"B7","doi-asserted-by":"publisher","first-page":"26559","DOI":"10.1021\/acsami.9b03595","article-title":"Understanding the stiff-to-compliant transition of the meniscal attachments by spatial correlation of composition, structure, and mechanics","volume":"11","author":"Boys","year":"2019","journal-title":"ACS Appl. Mater Interfaces"},{"key":"B8","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.ijbiomac.2019.07.041","article-title":"The application of BMP-12-overexpressing mesenchymal stem cells loaded 3D-printed PLGA scaffolds in rabbit rotator cuff repair","volume":"138","author":"Chen","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"963689720973647","DOI":"10.1177\/0963689720973647","article-title":"The 3D-Printed PLGA scaffolds loaded with bone marrow-derived mesenchymal stem cells augment the healing of rotator cuff repair in the rabbits","volume":"29","author":"Chen","year":"2020","journal-title":"Cell Transpl."},{"key":"B10","doi-asserted-by":"publisher","first-page":"102571","DOI":"10.1016\/j.mtbio.2025.102571","article-title":"Strong living scaffolds for load-bearing musculoskeletal tissue regeneration","volume":"35","author":"Chen","year":"2025","journal-title":"Mater Today Bio"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e109","DOI":"10.2106\/JBJS.18.00200","article-title":"Enthesis repair: challenges and opportunities for effective tendon-to-bone healing","volume":"100","author":"Derwin","year":"2018","journal-title":"J. Bone Jt. Surg. Am."},{"key":"B12","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.actbio.2017.01.037","article-title":"Micro-mechanical properties of the tendon-to-bone attachment","volume":"56","author":"Deymier","year":"2017","journal-title":"Acta Biomater."},{"key":"B13","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.jobcr.2019.10.003","article-title":"Polycaprolactone as biomaterial for bone scaffolds: review of literature","volume":"10","author":"Dwivedi","year":"2020","journal-title":"J. Oral Biol. Craniofac Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"20210421","DOI":"10.1098\/rsif.2021.0421","article-title":"Enthesis strength, toughness and stiffness: an image-based model comparing tendon insertions with varying bony attachment geometries","volume":"18","author":"Golman","year":"2021","journal-title":"J. R. Soc. Interface"},{"key":"B15","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.actbio.2019.07.014","article-title":"Bio-instructive materials for musculoskeletal regeneration","volume":"96","author":"Gonzalez-Fernandez","year":"2019","journal-title":"Acta Biomater."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.3390\/nano13121847","article-title":"Bioactive nanostructured scaffold-based approach for tendon and ligament tissue engineering","volume":"13","author":"Govindaraju","year":"2023","journal-title":"Nanomater. (Basel)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1177\/1941738118803616","article-title":"Trends in incidence of ACL reconstruction and concomitant procedures among commercially insured individuals in the United States, 2002-2014","volume":"10","author":"Herzog","year":"2018","journal-title":"Sports Health"},{"key":"B18","doi-asserted-by":"publisher","first-page":"124120","DOI":"10.1016\/j.biomaterials.2026.124120","article-title":"Regeneration of the gradient structure at the tendon-bone interface: biomimetic design strategies of biomaterials and translational challenges","volume":"331","author":"Huang","year":"2026","journal-title":"Biomaterials"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1056\/NEJMcp1909797","article-title":"Degenerative rotator-cuff disorders","volume":"391","author":"Jain","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"33800","DOI":"10.1038\/srep33800","article-title":"Histomorphometric and ultrastructural analysis of the tendon-bone interface after rotator cuff repair in a rat model","volume":"6","author":"Kanazawa","year":"2016","journal-title":"Sci. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.semcdb.2021.07.015","article-title":"Growth and mechanobiology of the tendon-bone enthesis","volume":"123","author":"Killian","year":"2022","journal-title":"Semin. Cell Dev. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.bioactmat.2024.10.002","article-title":"3D bioprinted multi-layered cell constructs with gradient core-shell interface for tendon-to-bone tissue regeneration","volume":"43","author":"Kim","year":"2024","journal-title":"Bioact. Mater"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2491","DOI":"10.1016\/j.bioactmat.2021.01.022","article-title":"Biomimetic strategies for tendon\/ligament-to-bone interface regeneration","volume":"6","author":"Lei","year":"2021","journal-title":"Bioact. Mater"},{"key":"B24","doi-asserted-by":"publisher","first-page":"rbac091","DOI":"10.1093\/rb\/rbac091","article-title":"Scaffold-based tissue engineering strategies for soft-hard interface regeneration","volume":"10","author":"Li","year":"2022","journal-title":"Regen. Biomater."},{"key":"B25","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1146\/annurev-bioeng-071910-124656","article-title":"Functional attachment of soft tissues to bone: development, healing, and tissue engineering","volume":"15","author":"Lu","year":"2013","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"B26","doi-asserted-by":"publisher","first-page":"763","DOI":"10.18063\/ijb.763","article-title":"Multimaterial and multiscale scaffold for engineering enthesis organ","volume":"9","author":"Micalizzi","year":"2023","journal-title":"Int. J. Bioprint"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1021\/acsbiomaterials.4c02340","article-title":"3D-Printed PCL scaffolds loaded with bFGF and BMSCs enhance tendon-bone healing in rat rotator cuff tears by immunomodulation and osteogenesis promotion","volume":"11","author":"Ni","year":"2025","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.3390\/cells11111752","article-title":"Enthesis healing is dependent on scaffold interphase morphology\u2014results from a rodent patellar model","volume":"11","author":"Peniche Silva","year":"2022","journal-title":"Cells"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1002\/jor.23810","article-title":"Integrating soft and hard tissues via interface tissue engineering","volume":"36","author":"Patel","year":"2018","journal-title":"J. Orthop. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.ijpharm.2018.01.006","article-title":"Growth factor delivery strategies for rotator cuff repair and regeneration","volume":"544","author":"Prabhath","year":"2018","journal-title":"Int. J. Pharm."},{"key":"B31","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1038\/nmat4863","article-title":"The microstructure and micromechanics of the tendon-bone insertion","volume":"16","author":"Rossetti","year":"2017","journal-title":"Nat. Mater"},{"key":"B32","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.addr.2014.11.018","article-title":"Spatial regulation of controlled bioactive factor delivery for bone tissue engineering","volume":"84","author":"Samorezov","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"645544","DOI":"10.3389\/fbioe.2021.645544","article-title":"Tissue engineering for the insertions of tendons and ligaments: an overview of electrospun biomaterials and structures","volume":"9","author":"Sensini","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1111\/joa.70043","article-title":"Functional anatomy of entheses and enthesis organs: a celebration of professor mike Benjamin's contribution to enthesis biology","volume":"248","author":"Shaw","year":"2026","journal-title":"J. Anat."},{"key":"B35","doi-asserted-by":"publisher","first-page":"105","DOI":"10.2147\/ORR.S501260","article-title":"Artificial single-layer, multi-layer, and gradient scaffolds for enhancing the healing of tendon-to-bone interfaces: a mini-review","volume":"17","author":"Song","year":"2025","journal-title":"Orthop. Res. Rev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1016\/j.jbiomech.2005.05.021","article-title":"Collagen fiber orientation at the tendon to bone insertion and its influence on stress concentrations","volume":"39","author":"Thomopoulos","year":"2006","journal-title":"J. Biomech."},{"key":"B37","doi-asserted-by":"publisher","first-page":"16534","DOI":"10.1038\/s41598-021-95917-4","article-title":"Local anisotropy in mineralized fibrocartilage and subchondral bone beneath the tendon-bone interface","volume":"11","author":"Tits","year":"2021","journal-title":"Sci. Rep."},{"key":"B38","first-page":"161","article-title":"Biological aspects of rotator cuff healing","volume":"1","author":"Wildemann","year":"2012","journal-title":"Muscles Ligaments Tendons J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"132","DOI":"10.3390\/bioengineering7040132","article-title":"Mineralization of biomaterials for bone tissue engineering","volume":"7","author":"Wu","year":"2020","journal-title":"Bioeng. (Basel)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1629816","DOI":"10.3389\/fbioe.2025.1629816","article-title":"Recent advances in gradient biomimetic scaffolds for tendon-bone interface regeneration","volume":"13","author":"Xie","year":"2025","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"28964","DOI":"10.1021\/acsami.3c03793","article-title":"Three-dimensional bioprinting of a structure-composition-and mechanics-graded biomimetic scaffold coated with specific decellularized extracellular matrix to improve the tendon-to-bone healing","volume":"15","author":"Zhang","year":"2023","journal-title":"ACS Appl. Mater Interfaces"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e1707306","DOI":"10.1002\/adma.201707306","article-title":"Design and fabrication of a hierarchically structured scaffold for tendon-to-bone repair","volume":"30","author":"Zhu","year":"2018","journal-title":"Adv. Mater"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e2002269","DOI":"10.1002\/adhm.202002269","article-title":"Augmenting tendon-to-bone repair with functionally graded scaffolds","volume":"10","author":"Zhu","year":"2021","journal-title":"Adv. Healthc. Mater"},{"key":"B44","doi-asserted-by":"publisher","first-page":"101549","DOI":"10.1016\/j.mtbio.2025.101549","article-title":"Sustained slow-release TGF-\u03b23 in a three-dimensional-printed titanium microporous scaffold composite system promotes ligament-to-bone healing","volume":"31","author":"Zhu","year":"2025","journal-title":"Mater Today Bio"}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2026.1876882\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:40:28Z","timestamp":1788154828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2026.1876882\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":44,"alternative-id":["10.3389\/fbioe.2026.1876882"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2026.1876882","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"article-number":"1876882"}}