BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design
Abstract Aims The BioBone consortium aims to validate circulating CD8 + TEMRA cells as a prognostic biomarker for predicting impaired fracture healing outcomes in a prospective, blinded, multicenter clinical study. The primary performance parameters are the pre-operative identification of at least 3...
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2025-06-01
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| Series: | Journal of Orthopaedic Surgery and Research |
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| Online Access: | https://doi.org/10.1186/s13018-025-05987-7 |
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| author | Simon Reinke Anja Maria Bauer Michael Dahne Georg Duda Denis Gümbel Christian Kleber Georg Matziolis Sven Märdian Georg Osterhoff Carsten Perka Michael J. Raschke Sebastian Rohe Klaus-Dieter Schaser Philipp Schwabe Frederik Maximilian Schäfer Richard Stange Maik Stiehler Ulrich Stöckle Hans-Dieter Volk Stefan Weber Sven Geißler the BioBone Author Consortium |
| author_facet | Simon Reinke Anja Maria Bauer Michael Dahne Georg Duda Denis Gümbel Christian Kleber Georg Matziolis Sven Märdian Georg Osterhoff Carsten Perka Michael J. Raschke Sebastian Rohe Klaus-Dieter Schaser Philipp Schwabe Frederik Maximilian Schäfer Richard Stange Maik Stiehler Ulrich Stöckle Hans-Dieter Volk Stefan Weber Sven Geißler the BioBone Author Consortium |
| author_sort | Simon Reinke |
| collection | DOAJ |
| description | Abstract Aims The BioBone consortium aims to validate circulating CD8 + TEMRA cells as a prognostic biomarker for predicting impaired fracture healing outcomes in a prospective, blinded, multicenter clinical study. The primary performance parameters are the pre-operative identification of at least 30% of patients who ultimately experience impaired healing at the first clinical endpoint, with a specificity greater than 90% to minimize the false-positive rate. Methods BioBone is a prospective, blinded, multicenter biomarker validation study designed to assess the prognostic value of circulating CD8 + TEMRA cells in fracture healing. A total of 640 patients aged 18 to 80 years with fractures of the humeral diaphysis, radial and/or ulnar diaphysis, femoral neck, trochanteric femur, femoral diaphysis, distal femur, proximal tibia, tibial diaphysis and distal tibia will be enrolled. The study is powered to validate the target assay performance and accounting for 6–7 potential confounders at an expected incidence of 10% impaired healing. Biomarker levels will be measured pre- and post-operatively using flow cytometry (FC) and patients will be monitored for one year. The primary endpoint is fracture healing status at 17–19 weeks (normal healing or delayed healing), while the secondary endpoint evaluates healing at nine months (delayed healing or pseudarthrosis). Fracture consolidation will be assessed through radiographs or computed tomography (CT) scans in conjunction with clinical assessments such as range of motion and weight-bearing capacity. Key outcome measures include radiographic analysis (RUST/RUSH scores), functional and patient-reported outcomes (e.g. weight bearing ability, range of motion, and the SF-36 questionnaire), as well as socioeconomic parameters (e.g. work capacity, rehabilitation needs, mobility). The predictive performance (sensitivity, specificity, NPV, PPV) of the biomarker will be determined in a prospective, double-blinded analysis, where CD8 + TEMRA blood levels are measured prior to surgical treatment and healing status at clinical endpoints is assessed by independent observers. Additional immunological examination and in vitro analysis of blood and fracture hematoma samples will further investigate the mechanism of action of CD8 + TEMRA cells in impaired human bone regeneration. Conclusion The BioBone study will validate the suitability of CD8 + TEMRA cells as a prognostic marker for impaired fracture healing and their integration into routine clinical practice. The results could have a global impact by incorporating immune-based prognostic tools into clinical workflows, paving the way for precision medicine approaches in trauma care. The BioBone study is funded by the German Federal Ministry of Education and Research (BMBF). |
| format | Article |
| id | doaj-art-97d19c7aa5ed425eaef2fcc0235044eb |
| institution | OA Journals |
| issn | 1749-799X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Journal of Orthopaedic Surgery and Research |
| spelling | doaj-art-97d19c7aa5ed425eaef2fcc0235044eb2025-08-20T02:37:33ZengBMCJournal of Orthopaedic Surgery and Research1749-799X2025-06-0120111010.1186/s13018-025-05987-7BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study designSimon Reinke0Anja Maria Bauer1Michael Dahne2Georg Duda3Denis Gümbel4Christian Kleber5Georg Matziolis6Sven Märdian7Georg Osterhoff8Carsten Perka9Michael J. Raschke10Sebastian Rohe11Klaus-Dieter Schaser12Philipp Schwabe13Frederik Maximilian Schäfer14Richard Stange15Maik Stiehler16Ulrich Stöckle17Hans-Dieter Volk18Stefan Weber19Sven Geißler20the BioBone Author Consortium21Berlin Institute of Health Center for Regenerative Therapies, Charité – Universitätsmedizin BerlinDepartment for Trauma and Orthopaedic Surgery, Vivantes-Hospital SpandauCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Center for Musculoskeletal SurgeryBerlin Institute of Health at Charité – Universitätsmedizin Berlin, Julius Wolff InstituteTrauma Surgery and Orthopedics Clinic, BG Hospital Unfallkrankenhaus BerlinDepartment for Orthopaedics, Trauma and Plastic Surgery, Leipzig University HospitalOrthopaedics University Hospital Jena, Campus Eisenberg, Friedrich-Schiller-University JenaClinic of Trauma, Hand and Reconstructive Surgery, University of RostockDepartment for Orthopaedics, Trauma and Plastic Surgery, Leipzig University HospitalCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Center for Musculoskeletal SurgeryDepartment of Trauma, Hand and Reconstructive Surgery, University Hospital MünsterOrthopaedics University Hospital Jena, Campus Eisenberg, Friedrich-Schiller-University JenaUniversitätsCentrum Für OrthopädieUnfall- Und Plastische Chirurgie (OUPC), Universitätsklinikum Carl Gustav Carus an Der Technischen UniversitätDepartment for Trauma and Orthopaedic Surgery, Vivantes-Hospital SpandauDepartment of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu BerlinDepartment of Regenerative Musculoskeletal Medicine, Institute for Musculoskeletal Medicine (IMM), University Hospital MünsterUniversitätsCentrum Für OrthopädieUnfall- Und Plastische Chirurgie (OUPC), Universitätsklinikum Carl Gustav Carus an Der Technischen UniversitätCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Center for Musculoskeletal SurgeryCharité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Institute of Medical ImmunologyDepartment of Plastic and Hand Surgery, Burn Centre, BG Klinikum Bergmannstrost HalleBerlin Institute of Health Center for Regenerative Therapies, Charité – Universitätsmedizin BerlinBeckman Coulter Life SciencesAbstract Aims The BioBone consortium aims to validate circulating CD8 + TEMRA cells as a prognostic biomarker for predicting impaired fracture healing outcomes in a prospective, blinded, multicenter clinical study. The primary performance parameters are the pre-operative identification of at least 30% of patients who ultimately experience impaired healing at the first clinical endpoint, with a specificity greater than 90% to minimize the false-positive rate. Methods BioBone is a prospective, blinded, multicenter biomarker validation study designed to assess the prognostic value of circulating CD8 + TEMRA cells in fracture healing. A total of 640 patients aged 18 to 80 years with fractures of the humeral diaphysis, radial and/or ulnar diaphysis, femoral neck, trochanteric femur, femoral diaphysis, distal femur, proximal tibia, tibial diaphysis and distal tibia will be enrolled. The study is powered to validate the target assay performance and accounting for 6–7 potential confounders at an expected incidence of 10% impaired healing. Biomarker levels will be measured pre- and post-operatively using flow cytometry (FC) and patients will be monitored for one year. The primary endpoint is fracture healing status at 17–19 weeks (normal healing or delayed healing), while the secondary endpoint evaluates healing at nine months (delayed healing or pseudarthrosis). Fracture consolidation will be assessed through radiographs or computed tomography (CT) scans in conjunction with clinical assessments such as range of motion and weight-bearing capacity. Key outcome measures include radiographic analysis (RUST/RUSH scores), functional and patient-reported outcomes (e.g. weight bearing ability, range of motion, and the SF-36 questionnaire), as well as socioeconomic parameters (e.g. work capacity, rehabilitation needs, mobility). The predictive performance (sensitivity, specificity, NPV, PPV) of the biomarker will be determined in a prospective, double-blinded analysis, where CD8 + TEMRA blood levels are measured prior to surgical treatment and healing status at clinical endpoints is assessed by independent observers. Additional immunological examination and in vitro analysis of blood and fracture hematoma samples will further investigate the mechanism of action of CD8 + TEMRA cells in impaired human bone regeneration. Conclusion The BioBone study will validate the suitability of CD8 + TEMRA cells as a prognostic marker for impaired fracture healing and their integration into routine clinical practice. The results could have a global impact by incorporating immune-based prognostic tools into clinical workflows, paving the way for precision medicine approaches in trauma care. The BioBone study is funded by the German Federal Ministry of Education and Research (BMBF).https://doi.org/10.1186/s13018-025-05987-7Long bone fractureImpaired healingCD8 + TEMRAPrognostic biomarker |
| spellingShingle | Simon Reinke Anja Maria Bauer Michael Dahne Georg Duda Denis Gümbel Christian Kleber Georg Matziolis Sven Märdian Georg Osterhoff Carsten Perka Michael J. Raschke Sebastian Rohe Klaus-Dieter Schaser Philipp Schwabe Frederik Maximilian Schäfer Richard Stange Maik Stiehler Ulrich Stöckle Hans-Dieter Volk Stefan Weber Sven Geißler the BioBone Author Consortium BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design Journal of Orthopaedic Surgery and Research Long bone fracture Impaired healing CD8 + TEMRA Prognostic biomarker |
| title | BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design |
| title_full | BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design |
| title_fullStr | BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design |
| title_full_unstemmed | BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design |
| title_short | BioBone – A prospective, blinded, multicenter validation study of the CD8 + terminal differentiated effector memory cells (CD8 + TEMRA cells) as prognostic biomarker for disturbed fracture healing – study design |
| title_sort | biobone a prospective blinded multicenter validation study of the cd8 terminal differentiated effector memory cells cd8 temra cells as prognostic biomarker for disturbed fracture healing study design |
| topic | Long bone fracture Impaired healing CD8 + TEMRA Prognostic biomarker |
| url | https://doi.org/10.1186/s13018-025-05987-7 |
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