Electrospun nanofiber scaffolds loaded with copper oxide for repairing traumatic brain injury through restoring copper homeostasis and regulating pyroptosis pathway.

Background: Traumatic brain injury (TBI) is one of the leading causes of injury and disability worldwide. Pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Copper ions play an important role in anti-inflammation and anti-oxidative stress. There is a more active copper metabolism in neurons after injury, and that neurons may require more copper ions and downstream copper-based enzymes to maintain normal physiological functions. Given these understandings of the roles of pyroptosis and copper ions in TBI pathology, this study aims to elucidate the interplay between copper ions and pyroptosis following TBI, with the goal of identifying novel therapeutic targets for TBI management. Methods: We developed an electrostatic spinning scaffold loaded with copper oxide (CuO@PCL/gelatiin, CuO@PG) to achieve small-dose local administration and avoid toxic side effects. The membranes underwent preparation and characterization through various techniques including Fourier transform infrared spectroscopy, measurement of water contact angle, antibacterial experiment, scanning electron microscopy, and assessment of in vitro release of copper. In addition, we used a controlled cortical impact to establish a TBI model in mice to examine the effect of CuO@PG on TBI-induced pyroptosis and the ability of the membranes to heal brain injury. Results: CuO@PG inhibited TBI-induced neuronal pyroptosis. CuO@PG can inhibit the expression of the pyroptosis-related proteins. Moreover, CuO@PG also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of CuO@PG was further confirmed by wire-grip test, open field test, Morris water maze test. Lastly, the beneficial results were significantly inhibited by the use of the copper chelator tetrathiomolybdate. Conclusions: In this study, we successfully constructed electrostatically spun scaffolds loaded with copper oxide to achieve slow, continuous and low-dose copper supply to the local brain, which provides a new theoretical basis for the imbalance of copper homeostasis in the brain after TBI.