Open research questions in Nerve injury and regeneration

What the literature leaves open

• Further research is needed to fully characterise the relationship between circulating BDNF and cognitive impairment severity in pediatric neurodevelopmental disorders. Studies with more robust methodology and larger sample sizes are required to increase the certainty of the evidence.

  Circulating BDNF in pediatric neurodevelopmental disorders: a meta-analysis of case–control differences and cognitive severity · 2026 · DOI

• The relationship between circulating BDNF and cognitive impairment in pediatric neurodevelopmental disorders is not well understood. There is a lack of systematic reviews and meta-analyses on this topic. The evidence on the role of BDNF as a biomarker of cognitive dysfunction is scattered and incomplete.

  Circulating BDNF in pediatric neurodevelopmental disorders: a meta-analysis of case–control differences and cognitive severity · 2026 · DOI

• The study used a limited number of animals, - The study only investigated the effects of anti-LINX in the context of LPS-induced neuroinflammation, - The study did not explore the long-term effects of anti-LINX treatment

  Beyond development: LINX/Islr2 expression and TrkA interaction in the adult nervous system under neuroinflammatory challenge · 2026 · DOI

• Investigate the effects of anti-LINX in other models of neuroinflammation, - Explore the long-term effects of anti-LINX treatment on neuronal function and survival, - Study the role of LINX/TrkA interaction in other neurological disorders

  Beyond development: LINX/Islr2 expression and TrkA interaction in the adult nervous system under neuroinflammatory challenge · 2026 · DOI

• The decision to restrict the database search to only PubMed and CINAHL Plus, - The study did not investigate BDNF's role in mental health conditions, - The study had a limited number of databases

  Brain-Derived Neurotrophic Factor (BDNF) as a Marker of Physical Exercise or Activity Effectiveness in Fatigue, Pain, Depression, and Sleep Disturbances: A Scoping Review · 2025 · DOI

• Further clinical investigations are needed to validate BDNF's potential as a therapeutic target, - Studies should investigate the relationship between BDNF changes and symptom improvements, - Research should explore the effects of different types of exercise on BDNF levels

  Brain-Derived Neurotrophic Factor (BDNF) as a Marker of Physical Exercise or Activity Effectiveness in Fatigue, Pain, Depression, and Sleep Disturbances: A Scoping Review · 2025 · DOI

• The study identifies a gap in the understanding of the mechanisms underlying hippocampal recovery in AN. The study highlights the need to investigate the role of BDNF and cytokines in hippocampal integrity in AN.

  Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index · 2024 · DOI

• investigating the role of Schwann cell plasticity in the pathogenic development of DPN, - exploring the potential of targeting inflammation for therapeutic strategies, - further research on the molecular mechanisms of diabetic neuropathy

  Unveiling the Role of Schwann Cell Plasticity in the Pathogenesis of Diabetic Peripheral Neuropathy · 2024 · DOI

• The precise cellular and molecular mechanisms underlying the pathogenesis of diabetic peripheral neuropathy remain unclear. The role of Schwann cell plasticity in the pathogenic development remains unexplored.

  Unveiling the Role of Schwann Cell Plasticity in the Pathogenesis of Diabetic Peripheral Neuropathy · 2024 · DOI

• This work will motivate allied research disciplines to gain a better understanding and analysis of the current state of the biomolecular mechanisms behind the pathogenesis of DN

  Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy · 2024 · DOI

• The lack of understanding of the distinctive mechanisms underlying diabetic neuropathy. The need for a comprehensive understanding of the biomolecular mechanisms underlying the etiopathogenesis of diabetic neuropathy. The gap in effective treatment and cure for diabetic neuropathy.

  Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy · 2024 · DOI

• Functional recovery after incomplete spinal cord injury depends substantially on the capacity of anatomically spared neurons to remodel their connections, yet the molecular programs underlying this endogenous plasticity remain poorly understood.

  Spared corticospinal neurons activate an endogenous plasticity program after partial CNS injury · 2026 · DOI

• An apoptotic wave sweeps across the Drosophila pupal visual system, but whether neurotrophins participate in forming adult visual circuits remains unknown.

  The neurotrophin DNT-2 via the Toll-2 receptor regulates neuronal survival and morphology during visual system development · 2026 · DOI

• Background: Population aging is significantly altering the clinical conditions of peripheral nerve injury (PNI); however, the age-specific mechanisms that affect nerve regeneration remain unclear.

  Aging and Peripheral Nerve Injuries: Impaired Repair, Inflammaging Impact, and Regeneration Resistance · 2026 · DOI

• While the BDNF/TrkB signalling pathway dysregulation and stem cell therapy are each widely studied in AD, the interplay between those two remains underexplored.

  Modulation of BDNF/TrkB Signalling Pathway in Alzheimer’s Disease: Mechanistic Insights and the Role of Stem Cell Therapy · 2025 · DOI

• Despite its clear physiological role and disease relevance, BDNF's function at the presynaptic terminal, a fundamental unit of neurotransmission, remains poorly understood.

  Brain-derived neurotrophic factor scales presynaptic calcium transients to modulate excitatory neurotransmission · 2024 · DOI

• Despite new developments in nanotechnology in the treatment of PD, in-depth exploration of their biological effects, in particular, the specific mechanisms of inflammation inhibition are lacking.

  Functional Monomers Equipped Microgel System for Managing Parkinson's Disease by Intervening Chemokine Axis‐mediated Nerve Cell Communications · 2024 · DOI

• However, an effective method to inhibit muscle atrophy following PNI remains elusive.

  Sea Cucumber-Inspired Microneedle Nerve Guidance Conduit for Synergistically Inhibiting Muscle Atrophy and Promoting Nerve Regeneration · 2024 · DOI

• Chirality is a fundamental factor controlling cell fate, and its potential role in regulation of SC reprogramming has long been ignored and remains poorly understood.

  Chiral Hydrogel Nerve Conduit Boosts Peripheral Nerve Regeneration via Regulation of Schwann Cell Reprogramming · 2024 · DOI

• However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-β (Aβ) and tau burden remains to be elucidated.

  Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults · 2024 · DOI

• Together, these results suggest that targeting p75 NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration.

  p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial · 2024 · DOI

• While these conduits show surgical potential, their clinical use is currently limited to the repair of minor injuries, as their ability to reinnervate limiting gap lesions is still unsatisfactory.

  Combining external physical stimuli and nanostructured materials for upregulating pro-regenerative cellular pathways in peripheral nerve repair · 2024 · DOI

• This topic has been critically underexplored due to the research silos between studies of the brain and studies of peripheral nerves and an overemphasis on the brain in neuroscience as a field of study.

  One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes · 2024 · DOI

• This evidence supports the claim that the two arms of the nervous system are critically linked and that previously understudied conditions of central neurodegeneration or peripheral neurodegeneration may actually be manifesting across the entire nervous system at the same time, through shared genetic and cellular mechanisms.

  One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes · 2024 · DOI

• How the initial type of tissue injury influences early damage signaling and regenerative growth of sensory axons remains unclear.

  Damage-induced basal epithelial cell migration modulates the spatial organization of redox signaling and sensory neuron regeneration · 2024 · DOI

Most-cited papers in Nerve injury and regeneration

• FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy · Injury · 2011 · 663 citations
• Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential · Translational Neurodegeneration · 2022 · 508 citations
• BDNF as a biomarker for successful treatment of mood disorders: A systematic & quantitative meta-analysis · Journal of Affective Disorders · 2014 · 450 citations
• Peripheral Nerve Injury Treatments and Advances: One Health Perspective · International Journal of Molecular Sciences · 2022 · 355 citations
• Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects · Archives of General Psychiatry · 2010 · 317 citations
• Central nervous system regeneration · Cell · 2022 · 307 citations
• Association of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism With Reduced Hippocampal Volumes in Major Depression · Archives of General Psychiatry · 2007 · 293 citations
• Oxidative Stress and Programmed Cell Death in Diabetic Neuropathy · Annals of the New York Academy of Sciences · 2002 · 248 citations
• Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration · Acta Pharmacologica Sinica · 2020 · 216 citations
• Artificial nerve tubes and their application for repair of peripheral nerve injury: an update of current concepts · Injury · 2008 · 188 citations

Most recent work

• Neonatal Spinal-Cord-Like Scaffold with Hierarchical Structural and Neurogenetic Microenvironments for Spinal Cord Injury Repair · ACS Nano · 2026
• Multimodal electroconductive PLGA-based scaffold orchestrates neuroprotection and regeneration following severe spinal cord injury · Journal of Nanobiotechnology · 2026
• CAR Treg therapies for neurodegenerative diseases · iScience · 2026
• Aging and Peripheral Nerve Injuries: Impaired Repair, Inflammaging Impact, and Regeneration Resistance · Biomedicines · 2026
• Aligned piezoelectric fibrous scaffolds for prevention of traumatic neuroma formation · Frontiers in Bioengineering and Biotechnology · 2026
• Integrating 3D bioprinting and neural stem cell therapy for central nervous system repair: implications for regenerative neurosurgery · Frontiers in Bioengineering and Biotechnology · 2026
• PTEN Deletion Robustly Boosts BRAF-Driven Intraspinal Sensory Axon Regeneration · bioRxiv · 2026
• A Dural Extracellular Matrix Hydrogel with Neural Stem Cells Improves Recovery from Traumatic Brain Injury in Mice · ACS Biomaterials Science & Engineering · 2026
• Multimodal synapse analysis reveals limitations in transplanted neuron integration mediated by TREM2 · bioRxiv · 2026
• Plasticity in thoracic paravertebral sympathetic postganglionic neurons after high spinal cord transection · The Journal of Neuroscience · 2026

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