AGING; BONE HEALING; CELLULAR MECHANORESPONSE; COMPUTER MODELING; Aging/metabolism; Aging/pathology; Animals; Disease Models, Animal; Female; Femoral Fractures/diagnostic imaging; Femoral Fractures/metabolism; Femoral Fractures/pathology; Mice; X-Ray Microtomography; Fracture Healing; Mechanotransduction, Cellular; Femoral Fractures; Endocrinology, Diabetes and Metabolism; Orthopedics and Sports Medicine
Abstract :
[en] Increasing age is associated with a reduced bone regeneration potential and increased risk of morbidities and mortality. A reduced bone formation response to mechanical loading has been shown with aging, and it remains unknown if the interplay between aging and mechanical stimuli during regeneration is similar to adaptation. We used a combined in vivo/in silico approach to investigate age-related alterations in the mechanical regulation of bone healing and identified the relative impact of altered cellular function on tissue patterns during the regenerative cascade. To modulate the mechanical environment, femoral osteotomies in adult and elderly mice were stabilized using either a rigid or a semirigid external fixator, and the course of healing was evaluated using histomorphometric and micro-CT analyses at 7, 14, and 21 days post-surgery. Computer models were developed to investigate the influence of the local mechanical environment within the callus on tissue formation patterns. The models aimed to identify the key processes at the cellular level that alter the mechanical regulation of healing with aging. Fifteen age-related biological alterations were investigated on two levels (adult and elderly) with a design of experiments setup. We show a reduced response to changes in fixation stability with age, which could be explained by reduced cellular mechanoresponse, simulated as alteration of the ranges of mechanical stimuli driving mesenchymal stem cell differentiation. Cellular mechanoresponse has been so far widely ignored as a therapeutic target in aged patients. Our data hint to mechanotherapeutics as a potential treatment to enhance bone healing in the elderly.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Borgiani, Edoardo ✱; Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany ; Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany
Figge, Christine ✱; Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
Kruck, Bettina; Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
Willie, Bettina M; Research Centre, Shriners Hospital for Children-Canada, Department of Pediatric Surgery, McGill University, Montreal, Canada
Duda, Georg N; Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany ; Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany
Checa, Sara; Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany ; Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany
✱ These authors have contributed equally to this work.
Language :
English
Title :
Age-Related Changes in the Mechanical Regulation of Bone Healing Are Explained by Altered Cellular Mechanoresponse.
This study was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft; WI 3761/4-1, DU298/14-1; CH 1123/4-1). We thank Mario Thiele for help with micro-CT analyses. Authors’ roles: GND, BMW and SC designed the study. BMW, CF and BK conducted the in vivo studies on mice. CF collected histological images, quantified histomorphometry and microCT data and performed statistical analysis. EB conducted in silico studies and performed design of experiments analysis. All the authors performed data interpretation. EB, CF and SC wrote the manuscript with contributions from all the authors.
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