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A smart hydrogel for on-demand delivery of antibiotics and efficient eradication of biofilms

可按需释放抗生素并高效清除生物被膜的智能水 凝胶

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Abstract

Biofilm-associated infections are difficult to treat in the clinics because the bacteria embedded in biofilm are ten to thousand times more resistant to traditional antibiotics than planktonic ones. Here, a smart hydrogel comprised of aminoglycoside antibiotics, pectinase, and oxidized dextran was developed to treat local biofilm-associated infections. The primary amines on aminoglycosides and pectinase were reacted with aldehyde groups on oxidized dextran via a pH-sensitive Schiff base linkage to form the hydrogel. Upon bacterial infection, the increased acidity triggers the release of both pectinase and aminoglycoside antibiotics. The released pectinase efficiently degrades extracellular polysaccharides surrounding the bacteria in biofilm, and thus greatly sensitizes the bacteria to aminoglycosides. The smart hydrogel efficiently eradicated biofilms and killed the embedded bacteria both n tvitro and in vivo. This study provides a promising strategy for the treatment of biofilm-associated infections.

摘要

生物被膜相关感染在临床上的治疗难度极大, 这是由于被包 裹在被膜中的细菌对传统抗生素的抵抗力是浮游细菌的数十至数 千倍. 本文研究开发了一种由氨基糖苷类抗生素、果胶酶以及氧 化葡聚糖组成的智能水凝胶, 用于治疗与生物被膜相关的局部感 染. 氨基糖苷和果胶酶结构中的伯胺可与氧化葡聚糖的醛基形成 对pH敏感的希夫碱键, 从而形成凝胶. 当发生感染时, 局部增强的 酸性会触发果胶酶和氨基糖苷类抗生素的释放, 所释放出的果胶 酶可有效降解生物被膜中包裹在细菌周围的多糖, 从而提高细菌 对氨基糖苷类药物的敏感度. 该智能水凝胶可有效消除生物膜, 并 能在体内有效杀灭被膜中的细菌. 该研究为生物被膜相关感染的 治疗提供了一种具有良好潜力的策略.

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Acknowledgements

This work was supported by the National Key R&D Program of China, Synthetic Biology Research (2019YFA0904500), the National Natural Science Foundation of China (21725402 and 51672191), and the Natural Science Foundation of Shanghai (19ZR1415600). The authors acknowledge the ECNU Multifunctional Platform for Innovation (011) for the animal experiments.

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Authors and Affiliations

  1. Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Jingjing Hu  (胡婧婧), Qianyu Hu  (胡倩瑜) & Yiyun Cheng  (程义云)

  2. Department of Orthopetics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China

    Chenglin Zhang  (张成林), Lei Zhou  (周磊) & Dianwen Song  (宋滇文)

  3. Department of Orthopaedics, Fengxian Hospital Affiliated to Anhui University of Science and Technology, Shanghai, 201499, China

    Yanlong Kong  (孔彦龙) & Yadong Zhang  (张亚东)

  4. Department of Orthopaedics, Fengxian Hospital Affiliated to Southern Medical University, Shanghai, 201499, China

    Yadong Zhang  (张亚东)

Authors
  1. Jingjing Hu  (胡婧婧)
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  2. Chenglin Zhang  (张成林)
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  3. Lei Zhou  (周磊)
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  4. Qianyu Hu  (胡倩瑜)
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  5. Yanlong Kong  (孔彦龙)
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  6. Dianwen Song  (宋滇文)
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  7. Yiyun Cheng  (程义云)
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  8. Yadong Zhang  (张亚东)
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Contributions

Hu J prepared and evaluated the in vitro antibacterial properties of the hydrogels; Hu J, Zhang C, Zhou L and Kong Y performed the in vivo experiments; Hu Q contributed to the physicochemical characterization of the hydrogel; Song D, Zhang Y and Cheng Y designed and supervised the study and wrote the manuscript. All the authors contributed to the general discussion.

Corresponding authors

Correspondence to Dianwen Song  (宋滇文), Yiyun Cheng  (程义云) or Yadong Zhang  (张亚东).

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Conflict of interest

The authors declare that they have no conflict of interest.

Jingjing Hu is an associate professor of biomaterials at the School of Life Science, East China Normal University. She received her PhD degree from the University of Science and Technology of China. Her research interests mainly focus on the design of antibacterial materials and smart hydrogels.

Dianwen Song is a full professor and chief physician at the Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University. He received his MD and PhD degrees from the Second Military Medical University. His research interests focus on the development of tissue-engineered bone and mechanism of bone metastasis in malignancies.

Yiyun Cheng is a full professor of biomedical engineering at the School of Life Sciences, East China Normal University. He received his PhD degree from the University of Science and Technology of China and was a postdoctoral fellow at Washington University in St. Louis, MO. His research interests focus on the rational design of polymers for the delivery of biomacromolecules.

Yadong Zhang is a chief physician and professor at the Department of Orthopaedics, Fengxian Hospital affiliated to Southern Medical University. He received his PhD from Shanghai Jiao Tong University. He is expert in the treatment of spinal diseases. His research interests focus on the design of smart hydrogels and nanomedicines for bone repair and the treatment of bacterial infection.

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Hu, J., Zhang, C., Zhou, L. et al. A smart hydrogel for on-demand delivery of antibiotics and efficient eradication of biofilms. Sci. China Mater. 64, 1035–1046 (2021). https://doi.org/10.1007/s40843-020-1480-3

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