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Future directions At least five important questions regarding local IGF-I/IGF-IR signaling warrant future investigation: 1) What are the local sources of IGF-I controlling chondorcyte, osteoblast and osteoclast functions

Upon severe peripheral nerve injuries, drastic disturbance in both physical barriers and physiological/immune homeostasis happens in the injured nerve microenvironment characterized by excessive inflammation, dysregulated metabolism, abnormal vascularization, and disrupted transduction of electric signals, etc., while such imbalanced neuronal microenvironment has dramatic negative effects on the regeneration and functional recovery of injured nerves [62]