Biodegradable, electroconductive self-healing hydrogel based on polydopamine-coated polyurethane nano-crosslinker for...

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons, causing motor and neurological impairments. Current treatments offer only temporary symptom relief without halting progression. Herein, a fully biodegradable, electroconductive self-healing hydrogel (CPUD gel) is developed, incorporating electroconductive polydopamine-coated polyurethane nanoparticles (PUD) as crosslinker. The core-shell PUD nanoparticles have a highly uniform size of ∼36 nm with a polydopamine shell of ∼4.8 nm thick on polyurethane core, revealed by small angle X-ray scattering, and own a conductivity of ∼0.82 mS/cm. As nano-crosslinker, the PUD can react with chitosan to form the dynamic CPUD hydrogel with shear modulus (∼280 Pa) and conductivity (∼4.34 mS/cm), mimicking brain tissue properties. In vitro, CPUD gel supports neural stem cell (NSC) proliferation (∼565 %) and differentiation, with elevated neuronal marker expression at 14 days, while exhibiting strong antioxidative and anti-inflammatory effects, rescuing ∼88 % inflamed NSCs. A therapeutic strategy combining injectable CPUD gel with acupuncture in a PD rat model, aiming to activate the innate regenerative mechanisms of body through mobilized endogenous stem cells, is further established. Using this approach, this hydrogel significantly elevates serum TGF-β1/SDF-1 levels, promotes dopaminergic neuron regeneration (>80 %), modulates neuroinflammation through M1-to M2-microglia transition (∼12.6-fold M2/M1 ratio), and improves motor function (from 8 % to 37 % forelimb contacts) in 14 days. Particularly, the electrophysiological spike rate is recovered from 66 to 19 spikes/s, close to the healthy rate 15 spikes/s. The synergistic immunomodulation and neuroprotection highlight the potential of CPUD gel as an advanced therapeutic tool for PD.