Multiomics Comparison of Proline-Rich Peptide-Enhanced Hyaluronic Acid Gels Versus Conventional Regenerative Materials: An Early Wound-Healing Model.

AIMS: To compare the early wound-healing responses to crosslinked hyaluronic acid enriched with two proline-rich peptides (P2, P6) against unmodified hyaluronic acid and the enamel-matrix derivative (EMD) in a porcine gingival-detachment model.

METHODS

In six pigs, defects around premolars were treated with HA, HA + P2, HA + P6 or EMD. After 6 days, the sites were harvested and evaluated using histology, immunohistochemistry, multiplex cytokine assay and untargeted proteomics of the gels, which were examined, informing an integrated multiomics approach analysis.

RESULTS

Both peptide formulations improved the composite histological score compared to HA alone, and HA + P6 matched EMD in suppressing oedema, TNF-α staining and CD80+ macrophages while increasing mannose-receptor labelling. Proteomics revealed that P2 upregulated actin (Q6QAQ1) and histone H2A (F2Z5L5), consistent with active remodelling, whereas EMD reduced trypsin and trypsinogen, indicating a more stabilised wound milieu; HA + P6 showed an intermediate yet favourable profile. IL-6 levels were lower in both peptide groups and EMD than in HA, and all gels proved noncytotoxic, with HA + P6 enhancing cell viability.

CONCLUSION

HA + P6 suppressed TNF-α and trypsin signalling while boosting M2-linked markers and proresolution proteins to the same extent as EMD, whereas plain HA did not. Thus, adding a short proline-rich peptide confers EMD-like early immunomodulation on a fully synthetic HA carrier. These observations, although limited to 6-day soft tissue healing, warrant longer studies in true periodontal regeneration models.