Foreign body reaction mimicking local recurrence from polyactide adhesion barrier film after laparoscopic colorectal cancer surgery

ACS Biomater. Sci. Eng.

et al. 2023

Repeating l- and d-chiral configurations determine polylactide (PLA) stereochemistry, which affects its thermal and physicochemical properties, including degradation profiles. Clinically, degradation of implanted PLA biomaterials promotes prolonged inflammation and excessive fibrosis, but the role of PLA stereochemistry is unclear. Additionally, although PLA of varied stereochemistries causes differential immune responses in vivo, this observation has yet to be effectively modeled in vitro. A bioenergetic model was applied to study immune cellular responses to PLA containing >99% l-lactide (PLLA), >99% d-lactide (PDLA), and a 50/50 melt-blend of PLLA and PDLA (stereocomplex PLA). Stereocomplex PLA breakdown products increased IL-1β, TNF-α, and IL-6 protein levels but not MCP-1. Expression of these proinflammatory cytokines is mechanistically driven by increases in glycolysis in primary macrophages. In contrast, PLLA and PDLA degradation products selectively increase MCP-1 protein expression. Although both oxidative phosphorylation and glycolysis are increased with PDLA, only oxidative phosphorylation is increased with PLLA. For each biomaterial, glycolytic inhibition reduces proinflammatory cytokines and markedly increases anti-inflammatory (IL-10) protein levels; differential metabolic changes in fibroblasts were observed. These findings provide mechanistic explanations for the diverse immune responses to PLA of different stereochemistries and underscore the pivotal role of immunometabolism in the biocompatibility of biomaterials applied in medicine.

Section: Discussionsupporting

confidence: 84%

Stereochemistry Determines Immune Cellular Responses to Polylactide Implants

ACS Biomater. Sci. Eng.

et al. 2023

“…We showed enhanced radiolabeled glucose (fluorodeoxyglucose; FDG) uptake in the PLA microenvironment which was abrogated by inhibiting glycolysis 6 . In agreement, persistent foreign body (sterile inflammatory) reactions to PLA devices employed after human surgeries manifest elevated FDG uptake, which could be mistaken for cancer recurrence 43,44 . By comparing glycolytic inhibition to neutralization strategies, we showed that the former was more effective in reducing CD86 (proinflammatory) expression in the amorphous PLA microenvironment, without affecting CD11b or F4/80 (macrophage recruitment) levels, supporting our in-vitro model 6 .…”

Section: Discussionmentioning

confidence: 84%

Stereochemistry Determines Immune Cellular Responses to Polylactide Implants

et al. 2022

Preprint

Repeating L- and D-chiral configurations determine polylactide (PLA) stereochemistry which affects its thermal and physicochemical properties, including degradation profiles. Clinically, degradation of implanted PLA biomaterials promotes prolonged inflammation and excessive fibrosis, but the role of PLA stereochemistry is unclear. Additionally, although PLA of varied stereochemistries cause differential immune responses in-vivo, this observation has yet to be effectively modeled in-vitro. A bioenergetic model was applied to study immune cellular responses to PLA containing > 99% L-lactide (PLLA), > 99% D-lactide (PDLA) and a 50/50 melt-blend of PLLA and PDLA (stereocomplex PLA). Stereocomplex PLA breakdown products increased IL-1b, TNF-a and IL-6 protein levels but not MCP-1. Expression of these proinflammatory cytokines is mechanistically driven by increases in glycolysis in primary macrophages. In contrast, PLLA and PDLA degradation products selectively increase MCP-1 protein expression. Whereas both oxidative phosphorylation and glycolysis are increased with PDLA, only oxidative phosphorylation is increased with PLLA. For each biomaterial, glycolytic inhibition reduces proinflammatory cytokines and markedly increases anti-inflammatory (IL-10) protein levels; differential metabolic changes in fibroblasts were observed. These findings provide mechanistic explanations for the diverse immune responses to PLA of different stereochemistries, and underscore the pivotal role of immunometabolism on the biocompatibility of biomaterials applied in medicine.

“…We observed increased glycolytic dependence in the PLA inflammatory microenvironment using sterile amorphous PLA, which was abrogated by 2DG, one of the glycolytic inhibitors applied in our in-vitro studies. Unsurprisingly, after surgical resection of colorectal and cervical tumors in human patients, chronic, sterile inflammation from PLA-based adhesion barriers elevate FDG uptake, falsely mimicking cancer recurrence 63,64 .…”

Section: Discussionmentioning

confidence: 99%

Polylactide Degradation Activates Immune Cells by Metabolic Reprogramming

et al. 2022

Preprint

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.