Toll-like receptor mediated responses to adsorbed damage-associated molecular patterns on biomaterial surfaces
Bibliographic record
Abstract
The foreign body reaction is a chronic inflammatory response to an implanted biomaterial that ultimately leads to fibrous encapsulation of the implant. It is widely accepted that the host response to implanted biomaterials is largely dependent on the species and conformations of proteins adsorbed onto the material surface, due to the adsorbate’s role in mediating cellular interactions with the implanted material. While the cellular response to adsorbed serum-derived proteins has been studied extensively, the presence of endogenous, matrix- and cell-derived mediators of inflammation within the adsorbed protein layer and their impact on cell-material interactions is not well understood. Damage-associated molecular patterns (DAMPs) are endogenous ligands released by stressed or damaged tissues to stimulate sterile inflammatory responses via Toll-like receptors (TLRs) and other pattern recognition receptors. The work in this thesis explored the contribution of cellular damage molecules in cell lysate and TLR signalling in macrophage responses to a range of non-resorbable polymers, including insulin infusion cannulas. \nThe in vitro data showed that adsorbed DAMPs on polymeric surfaces, both alone and in the presence of blood proteins, strongly induced NF-B/AP-1 transcription factor activity and pro-inflammatory cytokine secretion in reporter macrophages, compared to serum- and plasma-adsorbed surfaces. Lysate-dependent NF-B/AP-1 activation and cytokine production was strongly attenuated by TLR2 neutralizing antibodies. Work with primary bone marrow-derived macrophages confirmed the similar contribution of TLR2- and MyD88-dependent signalling in pro-inflammatory, anti-inflammatory, and angiogenic cytokine gene expression and production in response to model cannula surfaces with adsorbed DAMPs and plasma. Trends in the results from short term cannula implants in wildtype (WT) and TLR-knockout mice demonstrated that, while WT mice had an increase in inflammation over the 7 days, TLR2-/- and MyD88-/- mice had a decreasing trend. Furthermore, TLR2-/- and MyD88-/- mice had similar inflammatory cell layer thicknesses after 7 days, which were thinner than in WT mice. The results of the work presented here demonstrate that TLR2- and MyD88-dependent signalling are promising targets to modulate the acute inflammatory response, and merit further investigation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.096 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".