Neural electrodes are capable of recording or modulating neural activities [1], [2], and have important applications in the field of neurorestoration, brain-computer monitoring, and treatment for neurodegenerative diseases [3], [4], [5]. However, neural electrode implantation faces the challenge of electrode failure due to immune response [6], [7], which involves multiple cells [8], [9]. Astrocytes are the main cells in the central nervous system involved in tissue inflammation and scar formation, which subsequently lead to electrode failure [10], [11]. In the healthy brain, astrocytes play multiple roles including regulating energy metabolism, homeostatic balance, transmission of neural signals, and neurovascular coupling [12], [13]. However, when electrode implantation triggers disruption of the blood-brain barrier, microglia and macrophages are successively activated and create an inflammatory environment, resulting in the inflammatory activation of astrocytes [14], [15]. Activated reactive astrocytes exhibit abnormal proliferation, upregulation of glial fibrillary acidic protein (GFAP), cellular hypertrophy, and release of inflammatory cytokines to exacerbate inflammation [10], [16]. Eventually, inflammatory activated astrocytes wrap around the electrode interface and form a glial scar after apoptosis, leading to electrode failure. In addition, long-term inflammatory activation of astrocytes has been reported to exacerbate neurodegenerative diseases [13], [17], [18]. Therefore, how to inhibit the inflammatory activation of astrocytes after implantation is a concern in the field of neural electrode applications.

Modulating the interfacial microenvironment at the electrode interface to enhance its anti-inflammatory properties is a strategy to alleviate the neuroinflammation [19], [20]. The composition and structure of the extracellular matrix (ECM) have significant anti-inflammatory properties [21], [22], [23], and hence ECM-based biomimetic materials can be an appropriate chosen for electrode interface modification. Oakes et al. [24] modified a penetrating nerve microelectrode with an astrocyte-derived ECM coating, which significantly inhibited the activation of macrophages and the appearance of reactive astrocytes after implantation. Ceyssens et al. [25] coated tissue decellularized ECM around the implanted electrodes and demonstrated that it helped to reduce damage and inhibit inflammatory activation. Similarly, our previous studies have also shown that cell-derived ECM had significant anti-inflammatory properties and can reduce inflammatory factor secretion by immune cells on the electrode interface [26]. Furthermore, many studies have shown that the use of electrode coatings composed of an individual ECM protein component (collagen, laminin, fibronectin, etc.) also had the effect of reducing astrocyte reactive activation, inhibiting inflammation and promoting neuron regeneration [27], [28], [29].

The electrical microenvironment can also modulate cell behaviors, which has been studied quite extensively in other fields such as bone tissue and muscle tissue [30], [31], [32]. Considering the function of neural electrodes, especially for stimulating electrodes, it is also a feasible idea to inhibit neuroinflammation through regulating the electrical microenvironment at the interface by exogenous electrical stimulation. Therefore, in recent years, the study of influencing the inflammatory activation of astrocytes by electrical stimulation has begun to attract attention. Xu et al. [33] modulated the activation of astrocytes by electrical stimulation of mouse spinal nerves, which resulted in the inhibition of nociceptive perception. It was demonstrated that astrocytes could be influenced by their surrounding electrical microenvironment. Campos et al. [34], on the other hand, reported that high-frequency electrical stimulation could inhibit the inflammatory activation of astrocytes and reduce their secretion of inflammatory factors in the Parkinson's disease. Moreover, the results by two-photon microscopy showed that the modulation of the inflammatory state of astrocytes by electrical stimulation was related to calcium ions and that the stimulation effect was dependent on the electrical stimulation parameters [35].

If both ECM biochemical cues and an appropriate electrical microenvironment can be provided simultaneously at the interface, it would be expected to maximize the inhibition of astrocyte inflammatory activation. However, changing the electrical microenvironment by electrical stimulation requires good electrical properties, while it is well known that ECM-associated protein components have extremely poor electrical properties [36], [37]. These proteins cannot enhance or even will hinder the electrical performance of neural electrodes [38], deactivating their recording or stimulation functions. Therefore, it is an urgent need to enhance the electrical properties of ECM-based proteins. Moreover, the mechanisms by which the electrical microenvironment affects astrocytes still await further investigation.

In this work, composite films based on collagen and polypyrrole were prepared and used to modify indium tin oxide (ITO) electrodes. Among them, collagen, as the main component of ECM [39], [40], provided good biocompatibility and anti-inflammatory properties for the interface [41], [42]. Polypyrrole, as a commonly used electroactive material and conductive polymer [43], [44], was used to improve the electrochemical properties and electrical stimulation effect [45], [46], [47]. Taking collagen films and polypyrrole films as control groups, on the basis of characterizing the materialistic and electrochemical properties, the effects of the composite films on the inflammatory marker expression and the inflammatory factor secretion in astrocytes under electrical stimulation were investigated. In addition, the potential mechanism of the electrical microenvironment on modulating astrocyte inflammatory activation was further revealed.