Engineered bacillus subtilis enhances bone regeneration via immunoregulation and anti-Infection

Abstract

Chronic osteomyelitis caused by implant infections is a common complication following orthopedic surgery. Preventing bacterial infection and simultaneously improving bone regeneration are the key for osteomyelitis. Current treatments include systemic antibiotics and multiple surgical interventions, but the strategies available for treatment are limited. In this study, a multifunctional engineered Bacillus subtilis ( B. sub ) hydrogel with sulfasalazine (SSZ) is developed to treat methicillin-resistant Staphylococcus aureus (MRSA) infection and anti-inflammatory and promote bone regeneration. B. sub in alginate hydrogels protects B. sub from being cleared by the host immune system while allowing the release of its bioactive substances, including antibacterial peptides and anti-inflammatory agents such as SSZ. The results show that the engineered probiotic hydrogels exhibit excellent antibacterial efficacy against MRSA (97 %) and prevent the development of bacterial resistance. The antibacterial effect is primarily mediated through the secretion of bioactive peptides by B. sub , which not only inhibit MRSA growth but also reduce the likelihood of resistance development. Meanwhile, the probiotic hydrogel has a greater ability to induce M2 polarization of macrophages and promote angiogenesis, resulting in enhanced osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs) and thus enhancing bone regeneration. This engineered probiotic hydrogel offers a promising strategy by simultaneously combating bacterial infection and enhancing osteogenic differentiation for chronic osteomyelitis. An engineered probiotic hydrogel was developed to achieve sustained treatment of osteomyelitis. The live engineered probiotic hydrogel exhibits multifunctional bioactivities, including anti-bacterial, pro-osteogenesis, pro-angiogenesis effects, and immunoregulation effects. Our study on the live probiotic hydrogel offers promising prospects for the treatment of localized chronic osteomyelitis. • Probiotic bacillus subtilis , combined with Sulfasalazine in a hydrogel, offers a new approach to treating osteomyelitis by inhibiting MRSA growth and promoting bone regeneration. • Sulfasalazine reduces inflammation by converting harmful M1 macrophages into M2 macrophages, improving the bone's immune microenvironment. • The hydrogel-encapsulated biohybrid enables minimally invasive treatment, ensuring sustained therapeutic effects and preventing drug resistance.

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