Incorporating Blood Flow in Nerve Injury and Regeneration Assessment

Abstract

Peripheral nerve injury is a significant public health challenge, with limited treatment options and potential lifelong impact on function. More than just an intrinsic part of nerve anatomy, the vascular network of nerves impact regeneration, including perfusion for metabolic demands, appropriate signaling and growth factors, and structural scaffolding for Schwann cell and axonal migration. However, the established nerve injury classification paradigm proposed by Sydney Sunderland in 1951 is based solely on hierarchical disruption to gross anatomical nerve structures and lacks further information regarding the state of cellular, metabolic, or inflammatory processes that are critical in determining regenerative outcomes. This review covers the anatomical structure of nerve-associated vasculature, and describes the biological processes that makes these vessels critical to successful end-organ reinnervation after severe nerve injuries. We then propose a theoretical framework that incorporates measurements of blood vessel perfusion and inflammation to unify perspectives on all mechanisms of nerve injury.

Keywords: Sunderland injury classification; blood vessel; nerve injury; perfusion; peripheral nerve; regeneration.

Figure 1

Blood supply in peripheral nerves (Reprinted from Lundborg, G: Nerve Injury and Repair, New York, page 43, 1988) (25).

Figure 2

Confocal image (100×) of neuroma-in-continuity formation at the zone of stretch-rupture injury at the hamstring bifurcation, 14 days after injury. Necrotic core (yellow asterisk) is visualized by nuclear disintegration, as hallmarked by blurring of nuclear staining (4′,6-diamidino-2-phenylindole). Necrosis is further demonstrated by large aggregation of CD11b+ cells (orange), a pan-granulocyte marker, which have been associated with clearance of nonviable cells.

Figure 3

Hypoxia-driven macrophage infiltration / the fibrin bridge leads to polarized angiogenesis via VEGF and other growth factor expression, which then guides Schwann cell migration and neurite outgrowth.

Figure 4

In-vivo primary eigenvector RGB component colormaps weighted by fractional anisotropy (FA) for (A) Dfast and (B) Dslow tensors in the sciatic nerve of a rat. Mean diffusivities of 2.2 × 10⁻³ mm²/s and 1.0 × 10⁻³ mm²/s, respectively, indicates blood flow along the longitudinal direction of the nerve.

Figure 5

Schematic representation of three-axis nerve injury severity model. Three prototype injuries are shown, comparing primarily ischemic injury, inflammatory injury, and stretch-rupture injury. All three pathophysiologic process are shown to be interconnected, such as a primary perfusion injury impacts inflammation and both have effect upon microstructural remodeling. The more severe the injury on all three axes, the greater the combined area, and thus spontaneous regeneration is less likely.