Full evidence and analysis

The molecular machinery

After axotomy, Schwann cells dedifferentiate and become the primary source of neurotrophic support. They upregulate NGF and BDNF expression within days. These factors are not simple survival signals—they are directional cues that guide growth cone navigation.

NGF acts through TrkA receptors expressed on sensory axons. When NGF binds TrkA, it triggers PI3K/Akt and MAPK/ERK signaling that promotes both survival and growth cone advance. BDNF signals through TrkB on both motor and sensory neurons, enhancing axon growth velocity and branching. GDNF, acting via the RET receptor with GFRα co-receptors, is particularly critical for motor neuron survival.

The p75NTR receptor adds complexity. It functions as a low-affinity neurotrophin receptor that can mediate either survival or apoptosis depending on context. When co-expressed with Trk receptors, p75NTR enhances neurotrophin binding and signaling through allosteric mechanisms. Without Trk co-expression, p75NTR activation triggers JNK-mediated neuronal death—potentially clearing neurons that fail to reconnect and would become a metabolic burden.

Why clinical trials failed

Multiple trials of systemic NGF or BDNF delivery in the 1990s and 2000s showed limited functional improvement alongside significant side effects. NGF caused severe hyperalgesia. BDNF caused weight loss and motor dysfunction.

These failures were predictable from basic biology. Systemic delivery cannot replicate the spatially restricted gradients that guide axons through complex tissue. NGF activates TrkA on nociceptors throughout the body, not just at the injury site. BDNF crosses the blood-brain barrier and affects central circuits.

The temporal pattern matters too. Schwann cells pulse neurotrophin secretion in response to axonal contact and electrical activity. Sustained high-level exposure causes Trk receptor internalization and degradation—effectively desensitizing neurons to the very signals they need.

The receptor switch phenomenon

As regeneration proceeds, regenerating axons change their receptor expression. Sensory neurons initially express high TrkA levels, then downregulate TrkA and upregulate TrkC as they approach their targets. Motor neurons shift TrkB isoform expression from the full-length kinase-active form to the truncated TrkB.T1 form.

This switching is physiologically appropriate—it reduces growth-promoting signals once connections are re-established. But it means that exogenous neurotrophin delivery late in regeneration may have diminished effects or even interfere with target reinnervation by maintaining growth-promoting states when synapse formation should dominate.

Schwann cell-derived versus target-derived support

During the regeneration phase, Schwann cells in the distal nerve segment provide track-associated guidance cues. Once axons reach their targets, the classic target-derived support model applies—muscle and skin provide trophic support to maintain innervation.

These are functionally distinct phases. Schwann cell-derived factors promote rapid axon elongation. Target-derived factors promote synaptic maturation, receptor clustering, and long-term survival. Disrupting this sequence by providing excess Schwann cell-type signals when targets are already reached may prevent proper synapse formation.

What the evidence suggests

Studies using matrix-bound NGF in nerve conduits show improved sensory regeneration compared to soluble delivery. Gradient-forming delivery systems—where neurotrophin concentration is highest at the distal end of a conduit—produce better directional guidance than uniform concentrations.

GDNF shows particular promise for motor regeneration, which is often the limiting factor in functional recovery. But even here, temporal control matters. Sustained GDNF expression can prevent axons from stopping at appropriate target sites, causing them to overshoot.

Open questions

Can we engineer delivery systems that replicate the dynamic, three-dimensional concentration gradients that living Schwann cells establish? The extracellular matrix in peripheral nerve is a complex mixture of laminin, fibronectin, and proteoglycans that binds neurotrophins with specific affinities. Synthetic matrices may not replicate these binding characteristics.

Also unclear: whether we need to deliver multiple neurotrophins simultaneously or in sequence. Mixed nerves contain both sensory and motor fibers with different receptor profiles. A one-size-fits-all approach is unlikely to work.

Attribution: Research synthesis based on primary literature on neurotrophin biology, peripheral nerve regeneration mechanisms, and clinical trial outcomes.