Bioactive and degradable PEG hydrogels: A multifunctional approach for tissue regeneration and antibacterial protection

Biomaterial-associated infections pose a significant challenge, impairing tissue integration and frequently leading to implant failure and revision surgeries. Upon implantation, host cells and bacteria compete for colonizing the implant, in a process known as the "race for the surface," which is critical for the long-term survival of the implant. However, conventional biomaterials commonly fail to simultaneously promote cellular integration and prevent infections. To address this issue, we developed a protease-degradable PEG hydrogel functionalized with the RGD integrin-binding motif to enhance cell adhesion and the antimicrobial peptide hLf1-11 (LF) to provide antibacterial activity. This hydrogel was crosslinked using a protease-sensitive peptide (VPM), enabling enzymatic degradation, and dynamic adaptation to the cellular microenvironment (PEG-RGDLF). Non-bioactive but degradable (PEG-50) and neither bioactive nor degradable (PEG-0) hydrogels were included as controls. PEG-RGDLF hydrogels showed an adequate internal structure, with well-defined porosity, swelling capacity, and protease-mediated degradation rate. PEG-RGDLF improved the adhesion, spreading, proliferation, and ALP activity of human bone marrow mesenchymal stem cells (hBMSCs) and reduced the viability and adhesion of Gram-positive and Gram-negative bacteria, significantly affecting their morphology. Furthermore, co-culture models were established under two clinically relevant scenarios: "pre-infection" and "post-infection". In both settings, PEG-RGDLF hydrogels supported enhanced cellular responses, with hBMSCs displaying an elongated morphology and improved adhesion. In summary, by integrating cell-instructive and antibacterial properties with a controlled degradation mechanism, this multifunctional hydrogel presents a robust platform for implant-based therapies, actively promoting tissue regeneration while preventing infection, thus addressing the persistent challenge of implant-associated infections in regenerative medicine and clinical applications.