Promoting bone callus formation by taking advantage of the time-dependent fracture gap strain modulation

Abstract

Delayed union and non-union of fractures continue to be a major problem in trauma and orthopedic surgery. These cases are challenging for the surgeon. In addition, these patients suffer from multiple surgeries, pain and disability. Furthermore, these cases are a major burden on healthcare systems. The scientific community widely agrees that the stability of fixation plays a crucial role in determining the outcome of osteosynthesis. The extent of stabilization affects factors like fracture gap strain and fluid flow, which, in turn, influence the regenerative processes positively or negatively. Nonetheless, a growing body of literature suggests that during the fracture healing process, there exists a critical time frame where intervention can stimulate the bone's return to its original form and function. This article provides a summary of existing evidence in the literature regarding the impact of different levels of fixation stability on the strain experienced by newly forming tissues. We will also discuss the timing and nature of this "window of opportunity" and explore how current knowledge is driving the development of new technologies with design enhancements rooted in mechanobiological principles.

Keywords: callus formation; dynamization; fracture healing; secondary bone healing; variable fixation locking screw.

Figure 1

In green, the theoretical strain-temporal “window of opportunity” for fracture healing. On the x-axis the temporal dimension with the, in reality, partially superimposed four phases. Its temporal beginning (X) seems to be “injury-patient tailored (71)” while its extension is limited to the onset of the bone formation phase. On the y-axis the local forming tissue strain. In black, the schematic strain cycles represent the optimal deformation experienced by the newly formed tissue and transmitted to the embedded cells leading to restoration of the bone form and function.

Figure 2

Pictorial representation of a fracture gap fixed with bridge plating. In grey, the proximal and distal bone segments; in blue the locking plate. The bone forming cells are affected by the strain of the surrounding tissue they are attached to. This depends on local gap size, on the loading applied to the affected bone, on the stiffness of the bone-implant construct, on the position with respect to the implant and on the changing mechanical properties of this same local forming tissue. Clinically this results in a substantially higher strain (orange trapezoid) provided to cells far from the plate (in red) and low strain for those close to the plate (in green).

Figure 3

A pictorial representation of the variable fixation concept. On the x-axis, simplified, the fracture healing phases in the window of opportunity. On the y-axis the average local forming tissue strain. The green sigmoid represent the average tissue strain perceived locally by the cells embedded in the callus. The black dots are samples of average strains taken on a continuous curve. After a period of relatively low deformation a moderate and continuous increase in the local tissue strain is achieved during the fibrovascular phase. A moderate increase in the local tissue strain (A) is perceived by the cytoskeleton of the embedded cells and triggers the production of additional extracellular matrix until these same cells return to a quiescent status. The following, moderate, strain increase (B,C) reactivates the same cells to produce additional extracellular matrix. Such increase in average tissue strain shall be limited in order to allow the deposition of mineral. As the callus matures, the increases in its mechanical properties determines a decrease in the average strain perceived by the embedded cells.

Figure 4

The variable fixation locking screw (VFLS®) at the beginning of the implantation (left) and at the end of sleeve resorption (right). The development of this new implantable device has been driven by the latest advancements in our understanding of the strain-temporal window of opportunity. When the degradation process is completed, the sleeve is entirely absorbed, and the load is entirely shifted from the cis to the trans cortex. The increased working length, determines a decrease in construct stiffness and promotes a more uniform and larger stimulation of the forming bone callus (black arrows).

Figure 5

Schematic representation of the effect of a controlled and progressive decrease in construct stability (above) on the average strain perceived by the new forming callus tissue (below) and the respective intent of the design (middle).

Figure 6

On the left, the three groups tested in a biomechanical investigation: a bone substitute construct featuring three standard locking screws in the proximal and distal segment, a construct featuring three VFLS® in the proximal and three standard locking screws in the distal segment and a construct featuring three VFLS® in the proximal and distal segment. Center: the compression test set up. On the right, the chemical method used to dissolve the resorbable material. Such method allowed testing the same samples with intact and without sleeve without loosening the locking mechanism.

Figure 7

On the left, the 3 mm osteotomy fixed with a locking plate and, in this case, variable fixation on the proximal and standard locking screws on the distal segment. On the right the amount of callus volume (ccm) detected at the cis and trans cortices in the groups featuring standard locking technology on both bone segments (A), the group with mixed technologies (B) and the group featuring Variable Fixation on both bone segments (C) These data provide evidence that the dynamization tool was effective in negating the significant cis-trans difference detected when using standard locking technology. Moreover, when the variable fixation stimulation was doubled, it resulted in a notable increase in cis callus volume without causing an excessive rise in trans callus volume.

Figure 8

3d reconstruction of the 3 mm tibia osteotomies stabilized using a locking plate, with variable fixation screws applied to the proximal segment and standard locking screws on the distal segment. In this visual representation, the native cortical bone is depicted in brown, while the callus is shown in grey. It's worth noting the increased volume of callus formation in all proximal bone segments where variable fixation locking screws were used, indicating a response from the periosteum to altered loading conditions (93).