Role of the Neurologic System in Fracture Healing: An Extensive Review

Abstract

Purpose of review: Despite advances in orthopedics, there remains a need for therapeutics to hasten fracture healing. However, little focus is given to the role the nervous system plays in regulating fracture healing. This paucity of information has led to an incomplete understanding of fracture healing and has limited the development of fracture therapies that integrate the importance of the nervous system. This review seeks to illuminate the integral roles that the nervous system plays in fracture healing.

Recent findings: Preclinical studies explored several methodologies for ablating peripheral nerves to demonstrate ablation-induced deficits in fracture healing. Conversely, activation of peripheral nerves via the use of dorsal root ganglion electrical stimulation enhanced fracture healing via calcitonin gene related peptide (CGRP). Investigations into TLR-4, TrkB agonists, and nerve growth factor (NGF) expression provide valuable insights into molecular pathways influencing bone mesenchymal stem cells and fracture repair. Finally, there is continued research into the connections between pain and fracture healing with findings suggesting that anti-NGF may be able to block pain without affecting healing. This review underscores the critical roles of the central nervous system (CNS), peripheral nervous system (PNS), and autonomic nervous system (ANS) in fracture healing, emphasizing their influence on bone cells, neuropeptide release, and endochondral ossification. The use of TBI models contributes to understanding neural regulation, though the complex influence of TBI on fracture healing requires further exploration. The review concludes by addressing the neural connection to fracture pain. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Keywords: AI; Artificial intelligence; Autonomic nervous system; ChatGPT; Fracture and Chronic Pain; Fracture and Neural Regulation; Fracture and Neuropeptides; Fracture and Traumatic Brain Injury; Fracture healing; Neural regulation; Neuropeptides; Pain management in fractures.

Fig. 1

Neurotrophic and neuropeptide impact on fracture healing. This figure summarizes the roles of neurotransmitters and neurotrophic factors in bone repair, illustrating their diverse effects on healing pathways. CGRP, SP, NPY, and VIP are represented on the left, detailing their contributions to reduced healing time and enhanced bone formation and osteogenesis. The central image depicts a bone cross-section with sensory, autonomic, and hematopoietic-derived factor release, signifying the localized effects of these factors. To the right, BDNF, NGF, and EGF are linked with cellular processes essential for bone repair, such as cell adhesion, nerve regeneration, and osteoblast differentiation. The negative influences of NE on bone formation and bone marrow stem cell (BMSC) trafficking are also noted, demonstrating the complex regulatory mechanisms of neurotransmitters in fracture healing. Created with BioRender.com

Fig. 2

Nervous system regulation of fracture healing. This diagram delineates the influence of different components of the nervous system on fracture healing. The central nervous system (CNS) is represented at the top, with the effects of traumatic brain injury (TBI) on healing shown through varying degrees of impact. The sensory nervous system (SNS) is illustrated on the left with peptidergic or non-peptidergic nociceptive sensory fibers and their effect on fracture healing. The autonomic nervous system (ANS), divided into local sympathetic and systemic nerves, is mapped out on the right, indicating their respective roles in bone repair. Symbols and color gradients provide visual cues to their contributory or detrimental effects, with “ +  + ” denoting a positive influence and “—” a negative one on fracture healing. Created with BioRender.com