Moving a segment of the shinbone, as in the Ilizarov method, accelerated wound healing on rats’ backs: the effect depended on sensory nerve fibers, and supplying their peptide CGRP largely restored healing
Moving a segment of the shinbone, as in the Ilizarov method, accelerated wound healing on rats’ backs: the effect depended on sensory nerve fibers, and supplying their peptide CGRP largely restored healing
Surgeons have long observed that chronic wounds near a bone being lengthened by the Ilizarov method often heal unusually quickly. Orthopedic researchers at Zhejiang University tested the role of nerves in rats, creating fresh wounds on their backs, far from the surgical site. The paper was published on October 25 in Advanced Science.
In 1951, surgeon Gavriil Ilizarov developed an external fixation device that attaches to a bone. After the bone is cut, its ends are moved apart in tiny increments, allowing new bone to grow in the gap. In China, surgeons use a related procedure to treat severe foot ulcers in people with diabetes: they move a segment of the dense outer layer of the shinbone. In a 2023 clinical study, the authors concluded that surgery on one leg effectively treated ulcers on both feet.
Earlier studies attributed faster healing to blood vessel growth and systemic immune activation. The authors of the new paper proposed that sensory nerves provide the missing link. Their hypothesis draws on a 2024 study in Nature: in mice, sensory nerves grow into wounds and release the peptide CGRP, which shifts wound immune cells from inflammation toward tissue repair. Blocking CGRP is the basis of the first drugs developed specifically to prevent migraine.
The researchers fitted rats with an external fixation device on the lower leg and moved a bone segment by a quarter of a millimeter each day during the first week, then moved it back. They created wounds on the rats’ backs to exclude the effects of local tissue stretching and blood flow. Controls included rats fitted with the same device without bone movement and rats that had no lower-leg surgery. Wounds healed at the same rate in both control groups, indicating that bone movement itself accelerated healing. By day 14, wounds in rats that underwent bone movement had closed almost completely, reaching about 99% closure compared with 88–90% in controls.
By day three, nerve fibers, most of them containing CGRP, were growing into the wounds of these rats, and CGRP levels had risen to more than five times those in control rats. At the same time, among the macrophages that clear damaged tissue debris, the proportion involved in tissue repair increased while the inflammatory proportion decreased. Neutrophils, the first cells to arrive at a wound, also cleared more quickly.
To test whether nerves were necessary, the researchers treated some rats with capsaicin, the compound responsible for the heat of chili peppers, which destroys pain- and heat-sensing nerve fibers throughout the body. In these rats, wounds reached approximately 72% closure by day 14, compared with 88% in untreated rats. Wound closure was the same with and without bone movement, and macrophages remained inflammatory.
These nerve fibers release several substances, so the researchers tested the role of CGRP separately. A locally administered CGRP receptor blocker reduced the acceleration of healing. In rats whose nerve fibers had been destroyed and whose bone segment was moved, CGRP injections around the wound edges largely restored healing. In cell culture, rat sensory neurons alone shifted macrophages toward a tissue-repair phenotype, and the blocker almost completely prevented this shift.
The authors suggest that mechanical loading of bone may regulate repair in distant tissues. They propose three possible routes for the signal from the lower leg to the back: along nerves through the spinal cord, through the blood, or via bone marrow cells. They offer two reasons for attributing CGRP release in the wound to local nerve fibers: CGRP-containing fibers grew within the wound itself, and CGRP disappears from the blood within minutes, making sustained delivery of CGRP through the blood from the lower leg less likely. They suggest peptides that mimic CGRP and local delivery of nerve-derived peptides as possible treatments that could avoid surgery.