A 3D in vitro model of the device-tissue interface: functional and structural symptoms of innate neuroinflammation are mitigated by antioxidant ceria nanoparticles

Abstract

Objective: The recording instability of neural implants due to neuroinflammation at the device-tissue interface is a primary roadblock to broad adoption of brain-machine interfaces. While a multiphasic immune response, marked by glial scaring, oxidative stress (OS), and neurodegeneration, is well-characterized, the independent contributions of systemic and local “innate” immune responses are not well-understood. We aimed to understand and mitigate the isolated the innate neuroinflammatory response to devices. Approach: Three-dimensional primary neural cultures provide a unique environment for studying the drivers of neuroinflammation by decoupling the innate and systemic immune systems, while conserving an endogenous extracellular matrix and structural and functional network complexity. We created a three-dimensional in vitro model of the DTI by seeding primary cortical cells around microwires. Live imaging of both dye and AAV-mediated functional, structural, and lipid peroxidation fluorescence was employed to characterize the neuroinflammatory response. Main Results: Live imaging of microtissues over time revealed independent innate neuroinflammation, marked by increased OS, decreased neuronal density, and increased functional connectivity. We demonstrated the use of this model for therapeutic screening by directly applying drugs to neural tissue, bypassing low bioavailability through the in vivo blood brain barrier. As there is growing interest in long-acting antioxidant therapies, we tested efficacy of “perpetual” antioxidant ceria nanoparticles, which reduced OS, increased neuronal density, and protected functional connectivity. Significance: Our 3D in vitro model of the device-tissue interface exhibited symptoms of OS-mediated innate neuroinflammation, indicating a significant local immune response to devices. The dysregulation of functional connectivity of microcircuits surround implants suggests the presence of an observer effect, in which the process of recording neural activity may fundamentally change the neural signal. Finally, the demonstration of antioxidant ceria nanoparticle treatment exhibited substantial promise as a neuroprotective and anti-inflammatory treatment strategy.

A xenogeneic extracellular matrix-based 3D printing scaffold modified by ceria nanoparticles for craniomaxillofacial hard tissue regeneration via osteo-immunomodulation

“…Nanoparticles have shown great prospects in regenerative medicine, because they can better work in the intricate microenvironment and interact with cells benefited from their unique nano scale and high specific surface area [29,31,32]. Commercial inorganic nanoparticles have advantages due to their cheapness and chemical stability such as silver, magnesium, manganese, cerium etc [12,28,[33][34][35]. Among them, silver nanoparticles are commonly used as an efficient antibacterial agent [33].…”

“…Manganese has been reported to catalyze hydrogen peroxide and affect the inflammation microenvironment [12]. Recently, ceria nanoparticles (CNPs) have attracted attention for their great promise at protecting tissues from oxidative stress and affecting macrophages polarization [34][35][36]. CNPs have also been applied on the modification of the bone tissue engineering scaffolds, and it turned out that CNPs modification promoted the osteogenesis via immunomodulation [37,38].…”

Increasing the antioxidant capacity of ceria nanoparticles with catechol-grafted poly(ethylene glycol)

“…5–7 Such perpetual antioxidants have many interesting applications especially in medicine where they can act as anti-inflammatory agents, as well as therapeutics for retinal disease and neurodegeneration. 8–12…”

“…[5][6][7] Such perpetual antioxidants have many interesting applications especially in medicine where they can act as anti-inflammatory agents, as well as therapeutics for retinal disease and neurodegeneration. [8][9][10][11][12] Increasing the antioxidant performance of nanoparticle ceria requires schemes that tilt the balance of cerium redox states towards the more reduced cerium(III) character. 13 To date, materials strategies for achieving this goal have primarily leveraged dimension control, 14 but factors such as particle purity, 15 shape, 16 and polymer architecture can also influence antioxidant performance.…”