As the population ages and medical standards progress, orthopedic implants play an increasingly critical role. However, implant failure due to bacterial infection remains a significant challenge, with Staphylococci (S. aureus) predominantly accounting for the majority of cases in the microbial spectrum.1 In the current medical landscape, the conventional response to this issue has been the standardized use of antibiotics. However, this approach carries a considerable risk of promoting bacterial resistance, a growing concern in public health.

In response, antimicrobial peptides (AMPs) emerge as a promising alternative due to their favorable attributes: good biocompatibility, a wide antibacterial spectrum, targeted specificity, and low susceptibility to bacterial resistance.2 Nevertheless, as a drawback, AMPs have relatively high costs and great instability during the preparation process. Additionally, their performance can be easily affected by the human body environment due to cleavage by peptidases.

In this work, we have developed the chemical modification of the human host defense peptide KR-12 to improve its stability and enhance its antibacterial activity against gram-positive bacteria. Two established methods, sequence mutation, and dimerization, were employed to increase the stability of the KR12-peptide, with the aim of strengthening its effectiveness in combating bacterial infections.

Following modification, these modified KR-12 derivatives were applied to titanium scaffolds using both non-covalent and covalent immobilization methods. Our findings reveal a rapid release of non-covalently immobilized peptides, with notably higher loading observed on porous or calcium phosphate-coated scaffolds. Moreover, we successfully immobilized the peptides onto the titanium scaffolds using maleimide-click chemistry. Through this covalent chemical method, the peptides bond to the scaffold for an extended period, thereby prolonging their potential antibacterial effect over time.

Crucially, all modified scaffolds demonstrated excellent compatibility with human osteoblasts, underscoring their potential for facilitating osseointegration, an imperative requirement for the long-term success of orthopedic implants.

1) P. Wildeman et al. Clin Orthop Relat Res 2021; 479 (10), 2203. 2) Y.Huan et al. Front Microbiol 2020, 11, 582779. 3) S. Gunasekera et al. Front Microbiol 2020, 11, 168.