Experimental studies of bone mechanoadaptation: bridging in vitro and in vivo studies with multiscale systems

Abstract

Despite advancements in technology and science over the last century, the mechanisms underlying Wolff's law—bone structure adaptation in response to physical stimuli—remain poorly understood, limiting the ability to effectively treat and prevent skeletal diseases. A challenge to overcome in the study of the underlying mechanisms of this principle is the multiscale nature of mechanoadaptation. While there exist in silico systems that are capable of studying across these scales, experimental studies are typically limited to interpretation at a single dimension or time point. For instance, studies of single-cell responses to defined physical stimuli offer only a limited prediction of the whole bone response, while overlapping pathways or compensatory mechanisms complicate the ability to isolate critical targets in a whole animal model. Thus, there exists a need to develop experimental systems capable of bridging traditional experimental approaches and informing existing multiscale theoretical models. The purpose of this article is to review the process of mechanoadaptation and inherent challenges in studying its underlying mechanisms, discuss the limitations of traditional experimental systems in capturing the many facets of this process and highlight three multiscale experimental systems which bridge traditional approaches and cover relatively understudied time and length scales in bone adaptation.

Effect of capsaicin-sensitive sensory neurons on bone architecture and mechanical properties in the rat hindlimb suspension model

“…It has been reported that HLS results in large reduction in bone formation and cancellous bone loss in both sexes, and the mechanisms are similar in both sexes [25] . Mechanical strain [26] and fluid shear stress [27] are the two most commonly accepted mechanisms for coupling the loading with bone formation changes. The current theory about the mechanisms of bone reaction to mechanical stimulus considers that mechanical strain to the cell membrane activates stretch-sensitive ion channels and other membrane-associated proteins such as integrins, which are involved in various cellular processes and structures [28] .…”

Ex Vivo Organ Cultures as Models to Study Bone Biology

“…Protocols and examples for the establishment of ex vivo bone organ cultures to study bone mechanobiology can be found in refs 47 to 49. (47)(48)(49) In summary, the studies described here demonstrate that ex vivo bone organ cultures are a cost-and time-effective approach to perform mechanistic studies, to evaluate the consequences of genetic deletions, to predict the effects of therapeutic interventions in bone, and to study mechanobiology in a controlled environment that reflects the cellular diversity and molecular complexity of the bone niche.…”

“…Finally, ex vivo bone organ cultures have been useful to investigate the bone effects of mechanical stimulation because of their ability to maintain the 3D distribution and canalicular network of osteocytes, the main mechanosensor cells in bone. Protocols and examples for the establishment of ex vivo bone organ cultures to study bone mechanobiology can be found in refs 47 to 49 …”

Implantable Sensors for Regenerative Medicine

“…Other approaches to overcome limitations in longitudinal in vivo measurement techniques while maintaining some aspects of in vivo complexity include top-down ex vivo models such as explant cultures, as well as bottom-up organ-on-achip in vitro systems [30,31]. These experimental platforms are especially valuable to precisely study cellular and molecular mechanisms of healing while approximating physiological conditions.…”