Mechanotransduction and fracture repair

Abstract

Fracture-healing is regulated in part by mechanical factors. Study of the processes by which the mechanical environment of a fracture modulates healing can yield new strategies for the treatment of bone injuries. This article focuses on several key unanswered questions in the study of mechanotransduction and fracture repair. These questions concern identifying the mechanical stimuli that promote bone-healing, defining the mechanisms that are involved in this process, and examining the potential for cross-talk between investigations of mechanotransduction in bone-healing and in healing of other mesenchymally derived tissues. Several approaches to obtain accurate estimates of the mechanical stimuli present within a fracture callus are proposed, and our current understanding of the mechanotransduction processes involved in bone-healing is reviewed. Further study of mechanotransduction mechanisms is needed in order to identify those that are most critical and active during the various phases of fracture repair. A better understanding of the effect of mechanical factors on bone-healing will also benefit the study of healing, regeneration, and engineering of other skeletal tissues.

Fig. 1

Creation of a finite element model of a rat fracture callus from micro-computed tomography (μCT) image data. A: Semiautomated image segmentation is performed to define the boundaries of the cortex and callus in each image. B: The resulting finite element mesh. C: An estimate of the distribution of maximum principal strain on a longitudinal section of the callus using the finite element mesh shown in Fig. 1, B. Displacements were applied to the left end of the cortical bone to create an 11° bending angle. D: An estimate of the distribution of maximum principal strain on a longitudinal section of a callus of idealized geometry. Displacements were applied in the same manner as in Fig. 1, C. In addition, the μCT-derived and idealized geometry meshes have identical gap size, cortical thickness, and medullary canal diameter, as well as comparable maximum callus diameters. The same tissue material properties and comparable element sizes were used in both analyses. Results are only shown in the callus tissues and not in the cortex or medullary canal.

Fig. 2

Elastic modulus of callus tissues obtained via nanoindentation. Indentations were performed on 200-μm-thick, longitudinal sections of a rat callus using a 50-μm conospherical tip. Sections were made with a sliding microtome, and no embedding, dehydration, or polishing was performed. Four indents were performed in each of two areas, one consisting of partially mineralized bone and one consisting of granulation tissue. For mature cortical bone, four indents were performed on a transverse cross section of a rat femoral diaphysis. The indentation protocol used a trapezoidal load function consisting of a 2-sec loading ramp to a specified peak force (9000, 300, 20 μN for cortical bone, partially mineralized bone, and granulation tissue, respectively), a hold period (15 sec, 15 sec, and 5 sec for cortical bone, partially mineralized bone, and granulation tissue, respectively), and a 2-sec unloading ramp to zero force. The indentation modulus was calculated using the method of Oliver and Pharr. Shown in the graph is the mean indentation modulus for each tissue type; error bars indicate 1 standard deviation.

Fig. 3

Bending stimulation of a full-thickness, transverse osteotomy gap. Three-dimensional reconstructions of serial histological sections of (A) a specimen following two weeks of bending stimulation and (B) a time-matched control that underwent continuous fixation with a four-pin external fixator. The mechanical stimulation induces formation of large amounts of cartilage within the gap and flaring outward toward the callus periphery in wedge-shaped configurations. Small amounts of fibrocartilage are found at the callus periphery, and bone formation is restricted to regions along the periosteal surface. No osseous bridging is observed. The control specimen exhibits bone formation within and surrounding the gap as well as a small amount of cartilage within the gap.