Mouse Digit Tip Regeneration Is Mechanical Load Dependent

Abstract

Amputation of the mouse digit tip results in blastema‐mediated regeneration. In this model, new bone regenerates de novo to lengthen the amputated stump bone, resulting in a functional replacement of the terminal phalangeal element along with associated non‐skeletal tissues. Physiological examples of bone repair, such as distraction osteogenesis and fracture repair, are well known to require mechanical loading. However, the role of mechanical loading during mammalian digit tip regeneration is unknown. In this study, we demonstrate that reducing mechanical loading inhibits blastema formation by attenuating bone resorption and wound closure, resulting in the complete inhibition of digit regeneration. Mechanical unloading effects on wound healing and regeneration are completely reversible when mechanical loading is restored. Mechanical unloading after blastema formation results in a reduced rate of de novo bone formation, demonstrating mechanical load dependence of the bone regenerative response. Moreover, enhancing the wound‐healing response of mechanically unloaded digits with the cyanoacrylate tissue adhesive Dermabond improves wound closure and partially rescues digit tip regeneration. Taken together, these results demonstrate that mammalian digit tip regeneration is mechanical load‐dependent. Given that human fingertip regeneration shares many characteristics with the mouse digit tip, these results identify mechanical load as a previously unappreciated requirement for de novo bone regeneration in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).

Microcomputed tomography staging of bone histolysis in the regenerating mouse digit

“…In addition, anatomical staging of the bone stump is a method to identify the timing of wound closure. Thus, while micro CT analysis has long been utilised to investigate P3 bone regeneration, 11,13–17,22–26,30–34 the current study demonstrates that visualising the bone via micro CT staging also provides a means to infer the state of the radiolucent soft tissue (e.g. cell proliferation and wound closure).…”

Home-Based Rehabilitation Following Subtalar Dislocation: A Case Report

“…Lasanianos et al recommend rehabilitation should commence as early as three weeks following diagnosis [ 2 - 4 ]. In addition, a recent study by Dolan et al demonstrated that mechanical loading is a critical factor in facilitating soft tissue and bone regeneration which provides additional support for an early rehabilitation approach [ 9 ]. Thus, we hypothesize that a shorter immobilization period of less than four weeks following dislocation could have resulted in a higher functional score.…”

Neural dependency in wound healing and regeneration

“…Interestingly, the bone and nail matrices of denervated digits gave rise to an increased number of dividing cells and total cells per clone compared to innervated digits, 55 suggesting that peripheral nerves may regulate blastemal cell proliferation, which is consistent with findings in nonmammalian limb regeneration models. More recently, the Muneoka group observed that denervation disrupts digit stump wound healing and transiently impairs bone regeneration 90 . However, they determined that the effect on bone regeneration is not due to the lack of nerves but rather the accompanying reduction in mechanical loading of the limb, an off‐target effect of the sciatic nerve transection 90 .…”

“…More recently, the Muneoka group observed that denervation disrupts digit stump wound healing and transiently impairs bone regeneration 90 . However, they determined that the effect on bone regeneration is not due to the lack of nerves but rather the accompanying reduction in mechanical loading of the limb, an off‐target effect of the sciatic nerve transection 90 . Supporting the hypothesis that digit regeneration is nerve‐independent, it has also been reported that regenerates from both the regeneration‐capable distal digit 91 and the non‐regenerating proximal digit stump 92 have a reduced nerve presence compared to the original digits.…”

“…Future work investigating the roles of nerves would benefit from the implementation of newly developed tools. For example, determining a method in mammalian models to impair nerve function without limb mechanical disruption would limit off‐target effects such as mechanical load and help to isolate the role of nerve‐dependent mechanisms alone 90 . Advances in scRNA‐seq technologies have opened this technique for analysis of the regenerating blastema.…”