Polylactide Degradation Activates Immune Cells by Metabolic Reprogramming

Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet method...

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Published inbioRxiv
Main Authors Maduka, Chima V, Alhaj, Mohammed, Ural, Evran, Habeeb, Michael O, Kuhnert, Maxwell M, Smith, Kylie, Makela, Ashley V, Pope, Hunter, Chen, Shoue, Hix, Jeremy M, Mallet, Christiane L, Seock-Jin Chung, Maxwell Hakun, Tundo, Anthony, Zinn, Kurt R, Hankenson, Kurt D, Goodman, Stuart B, Narayan, Ramani, Contag, Christopher H
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 23.09.2022
Subjects
Acidity
Biocompatibility
Bioenergetics
Biomaterials
Biopolymers
Cell activation
Cytokines
Degradation products
Drug delivery
Fibrosis
Immunological tolerance
Immunomodulation
Inflammation
Lactic acid
Metabolism
Microenvironments
Nanotechnology
Patent applications
Polylactic acid
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Summary:Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet methods to neutralize the pH have not significantly reduced adverse responses. Using a bioenergetic model, we observed delayed cellular changes that were not apparent in the short-term. Amorphous and semi-crystalline PLA degradation products, including monomeric L-lactic acid, mechanistically remodel metabolism in cells leading to a reactive immune microenvironment characterized by elevated proinflammatory cytokines. Selective inhibition of metabolic reprogramming and altered bioenergetics both reduce these undesirable high cytokine levels and stimulate anti-inflammatory signals. Our results present a new biocompatibility paradigm by identifying metabolism as a target for immunomodulation to increase tolerance to biomaterials, ensuring safe clinical application of PLA-based implants for soft- and hard-tissue regeneration, and advancing nanomedicine and drug delivery. Competing Interest Statement C.V.M and C.H.C are inventors on a pending patent application filed by Michigan State University on metabolic reprogramming to biodegradable polymers.
DOI:10.1101/2022.09.22.509105