Antimicrobial peptides for bone tissue engineering: Diversity, effects and applications

Abstract

Bone tissue engineering has been becoming a promising strategy for surgical bone repair, but the risk of infection during trauma repair remains a problematic health concern worldwide, especially for fracture and infection-caused bone defects. Conventional antibiotics fail to effectively prevent or treat bone infections during bone defect repair because of drug-resistance and recurrence, so novel antibacterial agents with limited resistance are highly needed for bone tissue engineering. Antimicrobial peptides (AMPs) characterized by cationic, hydrophobic and amphipathic properties show great promise to be used as next-generation antibiotics which rarely induce resistance and show potent antibacterial efficacy. In this review, four common structures of AMPs (helix-based, sheet-based, coil-based and composite) and related modifications are presented to identify AMPs and design novel analogs. Then, potential effects of AMPs for bone infection during bone repair are explored, including bactericidal activity, anti-biofilm, immunomodulation and regenerative properties. Moreover, we present distinctive applications of AMPs for topical bone repair, which can be either used by delivery system (surface immobilization, nanoparticles and hydrogels) or used in gene therapy. Finally, future prospects and ongoing challenges are discussed.

Keywords: antimicrobial peptides; bone regeneration; delivery system; gene therapy; topical applications.

FIGURE 1

Mechanisms of bone infections and antimicrobial peptide-based strategies for the healing of bone defects susceptible to infections. Created with BioRender.com.

FIGURE 2

Four categories of antimicrobial peptides (helix based, sheet-based, coil-based and composite antimicrobial peptides) and related representative structures and sequences. Reprinted with permission from Di Somma et al. (2020). (Copyright 2020; Biomolecules), Huang et al. (2021). (Copyright 2021; Antibiotics), and Lee et al. (2016). (Copyright 2020; Frontiers in microbiology).

FIGURE 3

Potential effects of antimicrobial peptides for bone tissue engineering, and these effects can be mainly divided into four groups: bactericidal activity, anti-biofilm properties, immunomodulation and regenerative functions. Created with BioRender.com.

FIGURE 4

Bactericidal activity of antimicrobial peptides by targeting cell structures. (A) Antimicrobial peptides target to cell membrane to induce membrane lysis by transmembrane pore models (barrel stave model, toroidal pore model, etc.) and non-membrane pore models (Carpet/detergent-like model, etc.). (B) Antimicrobial peptides target cell wall synthesis and influence cell wall integrity by binding to lipid II, modulating cell wall synthesis related proteins and genes. (C) Antimicrobial peptides target organelles to influence physiological activities of microorganisms, thus exerting bactericidal effects. Created with BioRender.com.

FIGURE 5

Anti-biofilm properties of antimicrobial peptides. Antimicrobial peptides could influence the biofilm cycle by inhibiting aggregation and adhesion as well as restraining the development and maturity. They also promote biofilm aging and dispersion, thus exposing bacteria to antimicrobial peptides to induce bacterial lysis. Besides, some antimicrobial peptides could also promote the matrix degradation of established biofilm. And there are also some antimicrobial peptides could penetrated established biofilm and interact with bacteria to exert bactericidal activity. Created with BioRender.com.

FIGURE 6

Topical strategies to administrate antimicrobial peptides for bone tissue engineering, which include delivery by surface immobilization (direct immobilization, immobilization after modification and indirect immobilization), delivery by nanoparticles, delivery by hydrogels and gene therapies. Created with BioRender.com.