AbstractEffective antibacterial therapy while accelerating the repair of bone defects is crucial for the treatment of osteomyelitis. Inspired by the protective mechanism of Andrias davidianus, we constructed an antibacterial hydrogel scaffold with excellent rigidity and long-term slow-release activity.

摘要有效的抗菌治疗同时加速骨缺损的修复对于骨髓炎的治疗至关重要。受大鲵保护机制的启发，我们构建了一种抗菌水凝胶支架，具有优异的刚性和长期缓释活性。

While retaining the toughness of the skin secretion of Andrias davidianus (SSAD), the rigidity of the hydrogel material is increased by incorporating hydroxyapatite to meet the demands of bone-defect-filling materials. It also exerted antibacterial effects via the slow-release of vancomycin from local osteomyelitis lesions.

在保持大鲵（SSAD）皮肤分泌物韧性的同时，通过掺入羟基磷灰石来增加水凝胶材料的刚性，以满足骨缺损填充材料的要求。它还通过从局部骨髓炎病变中缓慢释放万古霉素发挥抗菌作用。

Notably, the hydrogel can also carry a high stable recombinant miR-214-3p inhibitor (MSA-anti214). By the delivery of nano vector polyvinylamine, the long-term slow-release of MSA-anti214 is achieved to promote bone repair, making this composite hydrogel a potential SSAD-based osteomyelitis alleviator (SOA).

值得注意的是，水凝胶还可以携带高稳定的重组miR-214-3p抑制剂（MSA-anti214）。通过递送纳米载体聚乙烯胺，实现了MSA-anti214的长期缓释以促进骨修复，使该复合水凝胶成为潜在的基于SSAD的骨髓炎缓解剂（SOA）。

In vitro and vivo results verified that the SOA effectively eliminated Staphylococcus aureus and repaired bone defects, ultimately mitigating the progression of osteomyelitis. This composite hydrogel extends the economic application prospects of A. davidianus and has provided new insights for the treatment of osteomyelitis.

体外和体内结果证实，SOA有效地消除了金黄色葡萄球菌并修复了骨缺损，最终减轻了骨髓炎的进展。这种复合水凝胶扩展了A.davidianus的经济应用前景，并为治疗骨髓炎提供了新的见解。

The study also explored new insights for the bone filling materials of bone defection and other skeletal system diseases..

该研究还为骨缺损和其他骨骼系统疾病的骨填充材料探索了新的见解。。

IntroductionOsteomyelitis is a chronic disease that closely associated with open fractures and joint replacement1,2,3. S. aureus-induced osteomyelitis can lead to prolonged bone pain, osteonecrosis, and even amputation or fatal sepsis4,5. Currently, the typical clinical treatment modalities include thorough debridement and long-term systemic antibiotic therapy.

引言骨髓炎是一种慢性疾病，与开放性骨折和关节置换密切相关1,2,3。S、 金黄色葡萄球菌引起的骨髓炎可导致延长的骨痛，骨坏死，甚至截肢或致命的败血症4,5。目前，典型的临床治疗方式包括彻底清创和长期全身抗生素治疗。

However, traditional long-term antibiotics and the presence of the bone marrow–blood barrier can have severe impacts, such as low local drug concentrations or drug-resistance of bacteria6,7.As a treatment for osteomyelitis, bone-defect-filling materials have attracted the attention of clinicians and scholars owing to their excellent biocompatibility and the local delivery of antibiotics.

然而，传统的长期抗生素和骨髓-血液屏障的存在可能会产生严重的影响，例如局部药物浓度低或细菌耐药性6,7。作为骨髓炎的治疗方法，骨缺损填充材料由于其优异的生物相容性和抗生素的局部递送而引起临床医生和学者的关注。

The reported bone-defect-filling materials mainly include polymethylmethacrylate (PMMA)8, calcium phosphate9, hydroxyapatite (HA)10, collagen implants11, and bioactive glass12. PMMA has excellent mechanical and injectable properties and is the most widely used bone-defect-filling material. For instance, Tan et al.13 synthesized 26% chitosan-loaded PMMA bone cement, which effectively inhibited Staphylococcus on the surface of the bone cement.

报道的骨缺损填充材料主要包括聚甲基丙烯酸甲酯（PMMA）8，磷酸钙9，羟基磷灰石（HA）10，胶原植入物11和生物活性玻璃12。。例如，Tan等[13]合成了26%壳聚糖负载的PMMA骨水泥，可有效抑制骨水泥表面的葡萄球菌。

Nonetheless, owing to the nonbiodegradability, burst effect, and heat production of PMMA, natural polymer-based hydrogels have received increasing attention14.Natural polymer-based hydrogels have emerged as favorable bone-defect-filling materials because of their intrinsic biocompatibility, degradability, and potential slow-release effects15,16,17,18.

尽管如此，由于PMMA的非生物降解性，爆裂效应和产热，天然聚合物基水凝胶受到越来越多的关注14。天然聚合物基水凝胶由于其固有的生物相容性，降解性和潜在的缓释作用而成为有利的骨缺损填充材料15,16,17,18。

For instance, Yan et al.19 fabricated a functionalized silk fibroin hydrogel that effectively promoted bone defect repair rate. Nilforoushzadeh et al.20 reported that a composite hydrogel of calcium alginate and fibroblast cell-seeded collagen s.

例如，Yan等[19]制造了一种功能化的丝素蛋白水凝胶，可有效促进骨缺损修复率。Nilforoushzadeh等[20]报道，海藻酸钙和成纤维细胞的复合水凝胶接种了胶原蛋白s。

SEM

扫描电镜

SEM (Gemini300; ZEISS, Oberkochen, Germany) was used to characterize the micromorphology of the SSAD/HA hydrogels. The SEM images were captured at a voltage of 3 kV. The pore size was calculated using ImageJ software. The composition of the elements in the SSAD and SSAD/HA hydrogel was analyzed by EDS (EMX; HORIBA, Lyon, France)..

SEM（Gemini300；ZEISS，Oberkochen，Germany）用于表征SSAD/HA水凝胶的微形态。在3 kV的电压下捕获SEM图像。使用ImageJ软件计算孔径。通过EDS（EMX；HORIBA，Lyon，France）分析了SSAD和SSAD/HA水凝胶中元素的组成。。

FTIR: To evaluate changes in the chemical structure, hydrogels with various components were analyzed by FTIR (iS10; Nicolet; Thermo Fisher Scientific, Waltham, MA, USA), with a spectrum range of 400–4,000 cm− 1, resolution of 4 cm− 1 and a signal-to-noise ratio of 50,000:152.

FTIR：为了评估化学结构的变化，通过FTIR（iS10；Nicolet；Thermo Fisher Scientific，Waltham，MA，USA）分析具有各种组分的水凝胶，光谱范围为400-4000 cm-1，分辨率为4 cm-1，信噪比为50000:152。

Rheology

流变学

The rheological properties of different hydrogels were analyzed by a rheometer (MCR92; Anton Paar, Graz, Austria). The appropriate amount of hydrogel was added to the sample table with parallel plates 50 mm apart, a 1 mm gap, and a test temperature of 25 °C. Amplitude scanning was set to a shear strain range of 0.1–10%, and logarithmic take-point52..

通过流变仪（MCR92；Anton Paar，Graz，Austria）分析不同水凝胶的流变性质。将适量的水凝胶添加到样品台中，平行板相距50 mm，间隙1 mm，测试温度25°C。振幅扫描设置为0.1-10%的剪切应变范围，对数取点52。。

Water content

含水量

The water content of the hydrogels was calculated using Eq. (1)52.$$\left( {{{\text{W}}_{\text{w}}} - {{\text{W}}_{\text{d}}}} \right)/{{\text{W}}_{\text{w}}} \times 100\%$$

使用等式（1）52计算水凝胶的含水量。$$$\左（{{{\文本{W}}}u{\文本{W}}}-{\文本{W}}u{\文本{d}}\右）/{\文本{W}}}u{\文本{W}}}\乘以100%$$

(1)

(1)

Ww: hydrogel weight. Wd: freeze-dried hydrogel weight.

Ww：水凝胶重量。Wd：冷冻干燥的水凝胶重量。

Swelling ratio

膨胀率

The swelling ratios were calculated using Eq. (2)53.$$\left( {{{\text{W}}_{\text{N}}} - {{\text{W}}_0}} \right)/{{\text{W}}_0} \times 100\%$$

溶胀率使用等式（2）53计算。$$\左（{{{{\ text{W}}}u{\ text{N}}-{{\ text{W}}u0}\右）/{\ text{W}}u0}\乘以100%$$

(2)

(2)

W0: initial hydrogel weight. WN: water-soaked hydrogel weight.

。WN：水浸泡的水凝胶重量。

Degradation ratio

降解率

The degradation ratio was calculated using Eq. (3)53.$$\left( {{{\text{W}}_{{0}}} - {{\text{W}}_{\text{N}}}} \right)/{{\text{W}}_0} \times 100\%$$

使用等式（3）53计算降解率。$$\左（{{{{\文本{W}}}u{{0}}-{{\文本{W}}u{\文本{N}}}\右）/{\文本{W}}u0}\乘以100%$$

(3)

(3)

W0: initial hydrogel weight. WN: collagenase II treated hydrogel weight.

。WN：胶原酶II处理的水凝胶重量。

PVAm preparationPVAm aqueous solution (molecular weight 1100, concentration 10%) was dialyzed (molecular weight < 10,000) and filtered through a 5 μm pore size syringe. The final solution was freeze-dried to obtain the purified PVAm. Then, the powder was re-dissolved in distilled water for backup use34.Slow-releaseThe prepared hydrogel samples (Rhodamine B: 5 µg/mL, FAM-NC: 100 µM, SSAD/HA: 100 µL) were washed by deionized water for 30 min, then immersed in 200 µL deionized water and placed at 4 °C (Rhodamine B was tested at room temperature) for slow-release.

PVAm制备将PVAm水溶液（分子量1100，浓度10%）透析（分子量<10000）并通过5μm孔径注射器过滤。将最终溶液冷冻干燥以获得纯化的PVAm。然后，将粉末重新溶解在蒸馏水中备用34。缓释将制备的水凝胶样品（罗丹明B:5μg/mL，FAM-NC:100μM，SSAD/HA:100μL）用去离子水洗涤30分钟，然后浸入200μL去离子水中并置于4℃（在室温下测试罗丹明B）以缓释。

After all slow-release solutions were collected at certain intervals (1 d, 2 d, 3 d, 4 d, 7 d, 14 d, 28 d), 200 µL deionized water was added again to continue the slow-release process. The slow-release solution was subsequently collected to measure the fluorescence intensity and assess the slow-release effect of the SSAD/HA hydrogels on small-molecule drugs and nucleic acid drugs.Spread plate methodA standard strain of S.

在以一定间隔（1天，2天，3天，4天，7天，14天，28天）收集所有缓释溶液后，再次加入200μL去离子水以继续缓释过程。随后收集缓释溶液以测量荧光强度并评估SSAD/HA水凝胶对小分子药物和核酸药物的缓释作用。扩散板法S的标准应变。

aureus (ATCC 25923) was selected as the bacterial model for tibial osteomyelitis. S. aureus was cultured as previously described54. In brief, S. aureus preserved in glycerol was added in 3% tryptone soy broth (TSB; Solarbio, Beijing, China) and cultured to the logarithmic growth stage at a constant temperature of 37 ℃ and 100 rpm.

选择金黄色葡萄球菌（ATCC 25923）作为胫骨骨髓炎的细菌模型。S、 如前所述培养金黄色葡萄球菌54。简而言之，将保存在甘油中的金黄色葡萄球菌加入3%胰蛋白胨大豆肉汤（TSB；Solarbio，Beijing，China）中，并在37℃和100 rpm的恒温下培养至对数生长阶段。

The absorbance at 600 nm was adjusted to 0.36 using TSB, and the concentration of S. aureus was 5.4 × 107 colony-forming units (CFUs) mL− 1. The prepared S. aureus bacterial solution was mixed with different hydrogels for 1 h. The samples were diluted 1,000-fold with TSB and evenly coated onto a soybean agar plate.

使用TSB将600 nm处的吸光度调节至0.36，金黄色葡萄球菌的浓度为5.4×107菌落形成单位（CFU）mL-1。将制备的金黄色葡萄球菌细菌溶液与不同的水凝胶混合1小时。将样品用TSB稀释1000倍，并均匀涂布在大豆琼脂平板上。

Then, the CFUs were counted after incubation for 12 h.Cell culture and cytotoxicity assayhMSCs were cultured in Dulbecco’s Modified Eagle Medium, High Glucos.

然后，孵育12小时后计数CFU。细胞培养和细胞毒性测定hMSCs在Dulbecco改良的Eagle培养基High Glucos中培养。

Data availability

数据可用性

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

。

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Download referencesAcknowledgementsThis work was supported by the National Natural Science Foundation of China (82272436, 32000924), Sichuan Science and Technology Program (23NSFSC6012), Medical Science and Technology Project of the Health Planning Committee of Sichuan (21PJ101), Doctor Foundation of North Sichuan Medical College (CBY19-QD01), “Take the Lead” Program of Affiliated Hospital of North Sichuan Medical College (2022JB007), Clinical Research Program of Affiliated Hospital of North Sichuan Medical College (2021LC008), Sichuan Science and Technology Innovation Seed Project (MZGC20230044), and Sichuan Science and Technology Program (2022NSFSC1554).Author informationAuthor notesChong Yin, Meng Deng and Jinshu Yu contributed equally to this work.Authors and AffiliationsDepartment of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of ChinaChong Yin, Meng Deng, Jinshu Yu, Yonghao Chen, Yi Huang, Yuwen Ma, Xiaolan Guo & Bin GuoSchool of Laboratory Medicine, Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, People’s Republic of ChinaChong Yin, Meng Deng, Jinshu Yu, Yonghao Chen, Yi Huang, Yuwen Ma, Xiaolan Guo & Bin GuoDepartment of Rehabilitation Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of ChinaKaiyuan ZhengKey Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, 710072, Shaanxi, People’s Republic of ChinaXudong Deng & Ye TianDepartment of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of ChinaBeilei ZengAuthorsChong YinView author publicationsYou can also search for this author .

下载参考文献致谢这项工作得到了国家自然科学基金（822724363200924），四川省科学技术计划（23NSFSC6012），四川省卫生计划委员会医学科技项目（21PJ101），川北医学院博士基金（CBY19-QD01），川北医学院附属医院“带头”项目（2022JB007），川北医学院附属医院临床研究项目（2021LC008），四川省科技创新种子项目（MZGC0230044）和四川省科技计划（2022NSFSC1554）的支持。作者信息作者注：尹，孟登和余金淑对这项工作做出了同样的贡献。作者和所属单位川北医学院附属医院临床实验室，南充，637000，中华人民共和国张茵，孟登，余金淑，陈永浩，黄毅，马玉文，郭小兰和郭斌川北医学院转化医学研究中心，南充，637000，中华人民共和国张茵，孟登，余金淑，陈永浩，黄毅，马玉文，郭小兰和郭斌川北医学院附属医院康复医学科，南充，637000 7000，中华人民共和国西北工业大学生命科学学院空间生物科学与生物技术开元正重点实验室，西安710072，陕西徐东邓和叶天川北医学院附属医院肿瘤科，南充，637000，中华人民共和国北磊曾国通YinView作者出版物您也可以搜索这位作者。

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PubMed Google ScholarContributionsConceptualization, C.Y. and M.D.; Data curation, C.Y., M.D. and J. Y.; Formal analysis, C.Y. and M.D.; Funding acquisition, C.Y. and B.G.; Investigation, C.Y., M.D., J.Y., Y.C., K.Z., Y.H. and Y.M.; Methodology, C.Y., M.D., Y.T. and B.Z.; Project administration, C.Y.

PubMed谷歌学术贡献概念化，C.Y.和M.D。；数据管理，C.Y.，M.D.和J.Y。；形式分析，C.Y.和M.D。；资金收购，C.Y.和B.G。；调查，C.Y.，M.D.，J.Y.，Y.C.，K.Z.，Y.H.和Y.M。；方法论，C.Y.，M.D.，Y.T.和B.Z。；项目管理，C.Y。

and M.D.; Resources, C.Y., X.D., X.G. and B.G.; Supervision, C.Y., M.D., X.D., X.G. and B.G.; Validation, C.Y. and M.D.; Visualization, C.Y. and M.D.; Writing–original draft, C.Y., M.D., Y.C. and B.G.; Writing–review & editing, C.Y., M.D., Y.C. and B.G.Corresponding authorsCorrespondence to.

和医学博士。；资源，C.Y.，X.D.，X.G.和B.G。；监督，C.Y.，M.D.，X.D.，X.G.和B.G。；验证，C.Y.和M.D。；可视化，C.Y.和M.D。；写作-原稿，C.Y.，M.D.，Y.C.和B.G。；写作-评论与编辑，C.Y.，M.D.，Y.C.和B.G.通讯作者通讯。

Xiaolan Guo or Bin Guo.Ethics declarations

郭小兰或郭斌。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

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Ethics declarations

道德宣言

The study was conducted according to the ARRIVE guidelines, and approved by the Ethics Committee of North Sichuan Medical College (protocol code 2023078 and date 2023Y 09 M 05D of approval). We confirm that all methods were performed in accordance with the relevant guidelines and regulations.

。我们确认所有方法均按照相关指南和法规进行。

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Reprints and permissionsAbout this articleCite this articleYin, C., Deng, M., Yu, J. et al. An Andrias davidianus derived composite hydrogel with enhanced antibacterial and bone repair properties for osteomyelitis treatment.

转载和许可本文引用本文Yin，C.，Deng，M.，Yu，J。等人。一种Andrias davidianus衍生的复合水凝胶，具有增强的抗菌和骨修复特性，可用于骨髓炎治疗。

Sci Rep 14, 24626 (2024). https://doi.org/10.1038/s41598-024-75997-8Download citationReceived: 02 May 2024Accepted: 09 October 2024Published: 19 October 2024DOI: https://doi.org/10.1038/s41598-024-75997-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1424626（2024）。https://doi.org/10.1038/s41598-024-75997-8Download引文接收日期：2024年5月2日接受日期：2024年10月9日发布日期：2024年10月19日OI：https://doi.org/10.1038/s41598-024-75997-8Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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Keywords

关键词

Andrias davidianus

安德里亚斯·戴维迪亚努斯

OsteomyelitisNatural polymer-based hydrogelsNucleic acid drugsBone-defect-filling materials

骨髓炎基于天然聚合物的水凝胶核酸药物骨缺损填充材料