Nerve Injury-on-a-Chip Uncovers Extracellular Matrix and Mitochondrial Roles in Axonal Regeneration

Area of Science:

• Biomaterials Science
• Neuroscience
• Regenerative Medicine

Background:

• Peripheral nerve regeneration is hindered by limited functional recovery and a lack of physiologically relevant in vitro models.
• Evaluating biomaterials and mitochondria-targeted therapies for nerve repair requires dynamic, quantitative analysis systems.

Purpose of the Study:

• To develop and validate a nerve injury-on-a-chip (NI-Chip) platform for real-time, quantitative assessment of axonal regeneration dynamics.
• To investigate the influence of extracellular matrix composition and mitochondrial transport on nerve regeneration.
• To explore the potential of sustained drug delivery via nanofibers for enhancing peripheral nerve repair.

Main Methods:

• Integration of dorsal root ganglion explants, aligned nanofibers, and microfluidics in a controlled axotomy model.
• Real-time, quantitative analysis of axonal regeneration velocity and mitochondrial dynamics.
• Pharmacological modulation of mitochondrial transport using compound M1 and assessment of sustained delivery via M1-loaded nanofibers.

Main Results:

• Extracellular matrix composition significantly affects axonal regeneration velocity; laminin promoted faster growth than fibronectin.
• Mitochondrial transport enhancement using compound M1 dose-dependently improved axonal regeneration by increasing mitochondrial motility, particularly retrograde transport.
• M1 treatment efficacy was maintained in older neurons, indicating mitochondrial dynamics as an age-independent therapeutic target.
• Localized and sustained delivery of M1 via nanofibers further enhanced axonal regrowth.

Conclusions:

• The NI-Chip provides a versatile platform for dissecting the interplay between biomaterials, mitochondrial dynamics, and axonal regeneration.
• Mitochondrial dynamics represent a promising, age-independent target for enhancing peripheral nerve repair.
• This platform facilitates the design and optimization of biomaterials and therapeutic strategies for clinical translation in peripheral nerve repair.