Foreign body responses in mouse central nervous system mimic natural wound responses and alter biomaterial functions

Timothy M OʼShea,Michael V Sofroniew,Yan Ao,Alexander L Wollenberg,Timothy J Deming,Jae H Kim

doi:10.1038/s41467-020-19906-3

Timothy M OʼShea, Michael V Sofroniew + Show 4 more

Open Access

https://doi.org/10.1038/s41467-020-19906-3

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Journal: Nature Communications	Publication Date: Dec 1, 2020
Citations: 40	License type: open-access

Affiliation: University of California, Los Angeles

Abstract

Biomaterials hold promise for therapeutic applications in the central nervous system (CNS). Little is known about molecular factors that determine CNS foreign body responses (FBRs) in vivo, or about how such responses influence biomaterial function. Here, we probed these factors in mice using a platform of injectable hydrogels readily modified to present interfaces with different physiochemical properties to host cells. We found that biomaterial FBRs mimic specialized multicellular CNS wound responses not present in peripheral tissues, which serve to isolate damaged neural tissue and restore barrier functions. We show that the nature and intensity of CNS FBRs are determined by definable properties that significantly influence hydrogel functions, including resorption and molecular delivery when injected into healthy brain or stroke injuries. Cationic interfaces elicit stromal cell infiltration, peripherally derived inflammation, neural damage and amyloid production. Nonionic and anionic formulations show minimal levels of these responses, which contributes to superior bioactive molecular delivery. Our results identify specific molecular mechanisms that drive FBRs in the CNS and have important implications for developing effective biomaterials for CNS applications.

Highlights

Biomaterials hold promise for therapeutic applications in the central nervous system (CNS)
The caudate putamen (CP) site is accessible, allows for consistent and reproducible hydrogel injections that are well tolerated by the mice, and is composed of neural tissue with neuronal cell bodies, myelinated axon bundles and a diversity of neuroglial making it an advantageous location for standardized CNS foreign body responses (FBRs) assessments[25]
Hydrogel FBRs and wound responses were characterized with immunohistochemistry (IHC) for CD13 to identify non-neural cells including stromal and peripheral myeloid lineage cells recruited as part of the sterile inflammatory response to tissue damage[28]

Summary

Results

Hydrogel-evoked FBRs vary and mimic CNS wound responses. We first compared cellular profiles of mild or severe CNS wound responses with FBRs of two structurally similar, synthetic, diblock copolypeptide hydrogels (DCH) that present either strongly cationic (DCHK) or nonionic (DCHMO) interfaces to host cells (Fig. 1a). At 6 weeks, Aβ levels had reduced markedly and were evident only within the persistent nonneural tissue lesions for DCHK and L-NIO stroke (Fig. 5d) These finds show that the inflammatory and fibrotic FBRs evoked by cationic hydrogels were driven by narrow but measurable zones of host neural tissue damage occurring along hydrogel-host interfaces soon after injection and that this was essentially absent with the nonionic DCHMO. Around L-NIO stroke lesions and cationic DCHK, serum proteins remained significantly elevated in neural tissue at 6 weeks (Fig. 6e, f, Supplementary Fig. 12a–c) These findings show that astrocytes rapidly form limitans borders around hydrogels in a manner similar to borders formed around ischemic or traumatic tissue damage, or that exist along meningeal non-neural stromal tissue around healthy CNS.

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Discussion

Methods