Ångstrom-scale silver particle-infused hydrogels eliminate orthopedic implant infections and support fracture healing
Orthopedic implant-associated infections pose a significant clinical challenge, often requiring surgical intervention along with systemic antibiotic treatments. To address this issue, we developed a novel approach using Ångstrom-scale silver particles (AgÅPs) with broad-spectrum antibacterial properties. Specifically, we formulated a polyethylene glycol hydrogel infused with AgÅPs (Gel-AgÅPs) designed for treating fracture fixation infections. This novel hydrogel formulation is injectable, ensuring precise adherence to both the exposed tissue and fracture surfaces, thereby allowing the direct targeted action of AgÅPs at the infection site. The Gel-AgÅPs significantly reduced the infection caused by Escherichia coli (a model pathogen of orthopedic implant infection) in a murine femoral fracture model. Moreover, the Gel-AgÅPs-treated infected fractures healed completely within 6 weeks, exhibiting bone formation and mechanical strength comparable to those of uninfected fractures. Further analysis revealed a significant downregulation of local inflammatory response as evidenced by a lower expression of inflammatory markers in Gel-AgÅPs-treated fractures compared to untreated infected controls. Furthermore, Gel-AgÅPs exhibited a unique ability to inhibit osteoclast differentiation, a critical factor in infection-induced bone degradation, without impacting osteoblast activity. In conclusion, Gel-AgÅPs exerted a dual therapeutic effect by eradicating bacterial infection and mitigating inflammation-induced osteoclast activity, thereby expediting infected fracture healing. This innovative approach is a promising therapeutic alternative to conventional antibiotic treatments, potentially transforming the treatment landscape for orthopedic implant-associated infections.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
- Depypere, M.; Morgenstern, M.; Kuehl, R.; Senneville, E.; Moriarty, T. F.; Obremskey, W. T.; Zimmerli, W.; Trampuz, A.; Lagrou, K.; Metsemakers, W. J. Pathogenesis and management of fracture-related infection. Clin Microbiol Infect. 2020, 26, 572-578. doi: 10.1016/j.cmi.2019.08.00
- Darouiche, R. O. Treatment of infections associated with surgical implants. N Engl J Med. 2004, 350, 1422-1429. doi: 10.1056/NEJMra035415
- Moriarty, T. F.; Metsemakers, W. J.; Morgenstern, M.; Hofstee, M. I.; Vallejo, D. A.; Cassat, J. E.; Wildemann, B.; Depypere, M.; Schwarz, E. M.; Geoff Richards, R. Fracture-related infection. Nat Rev Dis Primers. 2022, 8, 67. doi: 10.1038/s41572-022-00396-0
- Campoccia, D.; Montanaro, L.; Arciola, C. R. The significance of infection related to orthopedic devices and issues of antibiotic resistance. Biomaterials. 2006, 27, 2331-2339. doi: 10.1016/j.biomaterials.2005.11.044
- Arciola, C. R.; Campoccia, D.; Montanaro, L. Implant infections: Adhesion, biofilm formation and immune evasion. Nat Rev Microbiol. 2018, 16, 397-409. doi: 10.1038/s41579-018-0019-y
- Metsemakers, W. J.; Morgenstern, M.; Senneville, E.; Borens, O.; Govaert, G. A. M.; Onsea, J.; Depypere, M.; Geoff Richards, R.; Trampuz, A.; Verhofstad, M. H. J.; Kates, S. J.; Raschke, M.; McNally, M. A.; Obremskey, W. T.; Fracture-Related Infection (FRI) Group. General treatment principles for fracture-related infection: Recommendations from an international expert group. Arch Orthop Trauma Surg. 2020, 140, 1013-1027. doi: 10.1007/s00402-019-03287-4
- Iliaens, J.; Onsea, J.; Hoekstra, H.; Nijs, S.; Peetermans, W. E.; Metsemakers, W. J. Fracture-related infection in long bone fractures: A comprehensive analysis of the economic impact and influence on quality of life. Injury. 2021, 52, 3344-3349. doi: 10.1016/j.injury.2021.08.023
- Holmes, A. H.; Moore, L. S.; Sundsfjord, A.; Steinbakk, M.; Regmi, S.; Karkey, A.; Guerin, P. J.; Piddock, L. J. V. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet. 2016, 387, 176-187. doi: 10.1016/S0140-6736(15)00473-0
- Jiang, N.; Wu, H. T.; Lin, Q. R.; Hu, Y. J.; Yu, B. Health care costs of post-traumatic osteomyelitis in China: Current situation and influencing factors. J Surg Res. 2020, 247, 356-363. doi: 10.1016/j.jss.2019.10.008
- Pelgrift, R. Y.; Friedman, A. J. Nanotechnology as a therapeutic tool to combat microbial resistance. Adv Drug Deliv Rev. 2013, 65, 1803-1815. doi: 10.1016/j.addr.2013.07.011
- Wu, Z.; Chan, B.; Low, J.; Chu, J. J. H.; Hey, H. W. D.; Tay, A. Microbial resistance to nanotechnologies: An important but understudied consideration using antimicrobial nanotechnologies in orthopaedic implants. Bioact Mater. 2022, 16, 249-270. doi: 10.1016/j.bioactmat.2022.02.014
- Brennan, S. A.; Ní, F. C.; Devitt, B. M.; O’Mahony, F. J.; Brabazon, D.; Walsh, A. Silver nanoparticles and their orthopaedic applications. Bone Joint J. 2015, 97-b, 582-589. doi: 10.1302/0301-620X.97B5.33336
- Xu, L.; Wang, Y. Y.; Huang, J.; Chen, C.Y.; Wang, Z. X.; Xie, H. Silver nanoparticles: Synthesis, medical applications and biosafety. Theranostics. 2020, 10, 8996-9031. doi: 10.7150/thno.45413
- Wang, Z. X.; Chen, C. Y.; Wang, Y.; Li, F. X. Z.; Huang, J.; Luo, Z. W.; Rao, S. S.; Tan, S. Y.; Liu, Y. W.; Yin, H.; Wang, Y. Y.; He, Z. H.; Xia, K.; Wu, B.; Hu, H. K.; Luo, M. J.;… &. Xie, H. Angstrom-scale silver particles as a promising agent for low-toxicity broad-spectrum potent anticancer therapy. Adv Funct Mater. 2019, 29, 1808556. doi: 10.1002/adfm.201808556
- Chen, C. Y.; Yin, H.; Chen, X.; Chen, T. H.; Liu, H. M.; Rao, S. S.; Tan, Y. J.; Qian, Y. X.; Liu, Y. W.; Hu, X. K.; Luo, M. J.; Wang, Z. X.; Liu, Z. Z.; Cao, J.; He, Z. H. Ångstrom-scale silver particle-embedded carbomer gel promotes wound healing by inhibiting bacterial colonization and inflammation. Sci Adv. 2020, 6, eaba0942. doi: 10.1126/sciadv.aba0942
- Yin, H.; Zhou, M.; Chen, X.; Wan, T. F.; Jin, L.; Rao, S. S.; Tan, Y. J.; Duan, R. J.; Zhang, Y.; Wang, Z. X.; Wang, Y. Y.; He, Z. H. Fructose-coated Ångstrom silver prevents sepsis by killing bacteria and attenuating bacterial toxin-induced injuries. Theranostics. 2021, 11, 8152-8171. doi: 10.7150/thno.55334
- Gong, J. S.; Zhu, G. Q.; Zhang, Y.; Chen, B.; Liu, Y. W.; Li, H. M.; He, Z. H.; Zou, J. T.; Qian, Y. X.; Zhu, S.; Hu, X. Y.; Rao, S. S.; Cao, J.; Xie, H.; Wang, Z. X.; Du, W. Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells. Mater Today Bio. 2023, 23, 100854. doi: 10.1016/j.mtbio.2023.100854
- Deng, Y. Q.; Wang, Z. X.; Liu, X.; Wang, Y. Y.; Chen, Q.; Li, Z. L.; Bai Song Zheng 5, Zheng, B. S.; Ye, Q.; Gong, J. S.; Gong, J. S.; Zhu, G. Q.; Cao, T. S.; Cao, T. S. Ångstrom-scale silver particles potently combat SARS-CoV-2 infection by suppressing the ACE2 expression and inflammatory responses. J Mater Chem B. 2022, 10, 5454-5464. doi: 10.1039/d2tb00336h
- Kuang, X.; Wang, Z.; Luo, Z.; He, Z.; Liang, L.; Gao, Q.; Li, Y.; Xia, K.; Xie, Z.; Chang, R.; Wang, Y.; Liu, Y.; Zhao, S.; Su, J.; Wang, Y.; Situ, W.;…. &. Liu, H. Ag nanoparticles enhance immune checkpoint blockade efficacy by promoting of immune surveillance in melanoma. J Colloid Interface Sci. 2022, 616, 189-200. doi: 10.1016/j.jcis.2022.02.050
- Yu, J. J.; Chen, F.; Wang, X. C.; Dong, N. G.; Lu, C. F.; Yang, G. C.; Chen, Z. Synthesis and characterization of MMP degradable and maleimide cross-linked PEG hydrogels for tissue engineering scaffolds. Polym Degrad Stabil. 2016, 133, 312-320. doi: 10.1016/j.polymdegradstab.2016.09.008
- Zhao, Y.; Wang, D. D.; Qian, T. W.; Zhang, J. M.; Li, Z. H.; Gong, Q. Y.; Ren, X.; Zhao, Y. Biomimetic nanozyme-decorated hydrogels with H (2) O(2)-activated oxygenation for modulating immune microenvironment in diabetic wound. ACS Nano. 2023, 17, 16854-16869. doi: 10.1021/acsnano.3c03761
- Cyphert, E. L.; Zhang, N.; Learn, G. D.; Hernandez, C. J.; von Recum, H. A. Recent advances in the evaluation of antimicrobial materials for resolution of orthopedic implant-associated infections in vivo. ACS Infect Dis. 2021, 7, 3125-3160. doi: 10.1021/acsinfecdis.1c00465
- Rampersad, S. N. Multiple applications of Alamar Blue as an indicator of metabolic function and cellular health in cell viability bioassays. Sensors (Basel). 2012, 12, 12347-12360. doi: 10.3390/s120912347
- Li, P.; Gao, Z.; Tan, Z.; Xiao, J.; Wei, L.; Chen, Y. New developments in anti-biofilm intervention towards effective management of orthopedic device related infections (ODRI’s). Biofouling. 2021, 37, 1-35. doi: 10.1080/08927014.2020.1869725
- Sharma, S.; Mohler, J.; Mahajan, S. D.; Schwartz, S. A.; Bruggemann, L.; Aalinkeel, R. Microbial biofilm: A review on formation, infection, antibiotic resistance, control measures, and innovative treatment. Microorganisms. 2023, 11, 1614. doi: 10.3390/microorganisms11061614
- Metsemakers, W. J.; Morgenstern, M.; McNally, M. A.; Moriarty, T. F.; McFadyen, I.; Scarborough, M.; Athanasou, N. A.; Ochsner, P. E.; Kuehl, R.; Raschke, M.; Borens, O.; Xie, Z.; Velkes, S.; Hungerer, S.; Kates, S. L. Fracture-related infection: A consensus on definition from an international expert group. Injury. 2018, 49, 505-510. doi: 10.1016/j.injury.2017.08.040
- Ambrosi, T. H.; Marecic, O.; McArdle, A.; Sinha, R.; Gulati, G. S., Tong, X.; Wang, Y.; Steininger, H. M.; Hoover, M. Y.; Koepke, L. S.; Murphy, M. P.; Sokol, S.,….&. Chan, C. K. F. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature. 2021, 597, 256-262. doi: 10.1038/s41586-021-03795-7
- Steinmetz, S.; Wernly, D.; Moerenhout, K.; Trampuz, A.; Borens, O. Infection after fracture fixation. EFORT Open Rev. 2019, 4, 468-475. doi: 10.1302/2058-5241.4.180093
- Medzhitov, R. The spectrum of inflammatory responses. Science. 2021, 374, 1070-1075. doi: 10.1126/science.abi5200
- Claes, L.; Recknagel, S.; Ignatius, A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012, 8, 133-143. doi: 10.1038/nrrheum.2012.1
- Masters, E. A.; Ricciardi, B. F.; Bentley, K. L. M.; Moriarty, T. F.; Schwarz, E. M.; Muthukrishnan, G. Skeletal infections: Microbial pathogenesis, immunity and clinical management. Nat Rev Microbiol. 2022, 20, 385-400. doi: 10.1038/s41579-022-00686-0
- Yang, Y.; Li M.; Zhou, B.; Jiang, X.; Zhang, D.; Luo, H. Graphene oxide/gallium nanoderivative as a multifunctional modulator of osteoblastogenesis and osteoclastogenesis for the synergistic therapy of implant-related bone infection. Bioact Mater. 2023, 25, 594-614. doi: 10.1016/j.bioactmat.2022.07.015
- Ma, L.; Cheng, Y.; Feng, X.; Zhang, X.; Lei, J.; Wang, H.;.; Xu, Y.; Tong, B.; Zhu, D.; Wu, D.; Zhou, X.; Liang, H.; Zhao, K.; Wang, K.; Tan, L.; Zhao, Y.; Yang, C. A Janus-ROS healing system promoting infectious bone regeneration via sono-epigenetic modulation. Adv Mater. 2024, 36, e2307846. doi: 10.1002/adma.202307846
- Takayanagi, H. Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007, 7,292-304. doi: 10.1038/nri2062
- Wang, Z. X.; Lin, X.; Cao, J.; Liu, Y. W.; Luo, Z. W.; Rao, S. S.; Wang, Q.; Wang, Y. Y.; Chen, C. Y.; Zhu, G. Q.; Li, F. X. Z.; Tan, Y. J.; Hu, Y.; Yin, H.; Li, Y. Y.;…. &. Xie, H. Young osteocyte-derived extracellular vesicles facilitate osteogenesis by transferring tropomyosin-1. J Nanobiotechnology. 2024, 22, 208. doi: 10.1186/s12951-024-02367-x
- Tang, Y.; Wu, X. W.; Lei, W. Q., Pang, L. J.; Wan, C.; Shi, Z., Zhao, L.; Nagy, T. R.; Peng, X.; Hu, J.; Feng, X.; Hul, W. V.; Wan, M.; Cao, X. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med. 2009, 15, 757-765. doi: 10.1038/nm.1979
- Xian, L. L.; Wu, X. W.;Pang, L. J.; Lou, M.; Rosen, C. J.; Qiu, T.; Crane, J.; Frassica, F.; Zhang, L.; Pablo Rodriguez, J.; Jia, X.; Yakar, S.; Xuan, S.; Efstratiadis, A.; Wan, M.; Cao, X. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med. 2012, 18, 1095-1101. doi: 10.1038/nm.2793