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  細(xì)菌感染是傷口愈合和皮膚再生過程中最常遇到的問題，因感染引起的嚴(yán)重炎癥反應(yīng)不僅顯著增加感染相關(guān)的并發(fā)癥，而且明顯降低傷口愈合的質(zhì)量。此外，細(xì)菌感染性慢性傷口治療難度大、療程長、費(fèi)用高，給患者和社會造成巨大的經(jīng)濟(jì)負(fù)擔(dān)。目前，臨床上主要使用抗生素治療感染性傷口。但是，因耐藥性和缺乏合適的皮膚修復(fù)微環(huán)境，抗感染和傷口愈合的治療效果并不理想。因此，如何有效抵御多藥耐藥性細(xì)菌感染并同時促進(jìn)感染性傷口愈合和皮膚再生仍是目前亟需解決的一大難題。針對上述問題，西北工業(yè)大學(xué)張秋禹教授團(tuán)隊將具有優(yōu)異電導(dǎo)率、良好生物相容性和較強(qiáng)抗菌能力的二維（2D）Ti₃C₂T_x MXene引入多功能水凝膠支架（HPEM）用于耐甲氧西林金黃色葡萄球菌（MRSA）感染的傷口愈合研究。

Scheme 1. Scheme showing the fabrication and application of HPEM scaffolds in multidrug-resistant bacteria infected wound healing.

  通過合理的結(jié)構(gòu)設(shè)計制備得到的HPEM支架具有多功能特性，包括自愈合、較高的導(dǎo)電性、組織粘附性、快速止血能力和較強(qiáng)的抗菌性，尤其是對耐多種常用抗生素的MRSA，其抗菌活性高達(dá)99.03%。（Fig. 2和3）。

Figure 2. Multifunctional properties evaluations of scaffolds. (A) Rheological analysis of the HPEM scaffolds at 4℃, 25℃ and 37℃; (B-C) rheological data and rheological recovery rate of HPEM scaffolds under alternating high (1000%) and low shear strain (1%); (D) viscosity of HPEM scaffolds at different shear rate; (E) electronic conductivity of HPEM scaffolds and controls; (F) the normal stress to the adhesive ability of HPEM scaffolds determined by the TA rheometer (*p<0.05, **p<0.01, n=3); (G) the images of the HPEM scaffolds forming; (H) pictures of the self-healing of HPEM scaffolds.

Figure 3. Antibacterial activity and hemostatic ability assay. (A) Bacteria clones and bacterial viability (B) against E. coli, S. aureus, and MRSA treated with different samples; (C) total blood loss and photographs from the damaged livers after 60 s treated with HPEM scaffolds and control (*p < 0.05, **p < 0.01, n=3).

  為了進(jìn)一步驗(yàn)證該HPEM支架的體內(nèi)外生物效應(yīng)，分別進(jìn)行了體外細(xì)胞實(shí)驗(yàn)和動物實(shí)驗(yàn)。細(xì)胞實(shí)驗(yàn)表明：HPEM支架可有效促進(jìn)小鼠成纖維細(xì)胞（L929）增殖，細(xì)胞毒性較低；而且，可促進(jìn)皮膚修復(fù)相關(guān)基因（α-actin、collagen type III和VEGF）的表達(dá)，顯示出了顯著的促進(jìn)皮膚缺損再生的生物學(xué)性能（Fig. 4和S7）。

Figure 4. Cytotoxicity and cell proliferation evaluations of scaffolds. (A) Cell viability of HPEM scaffolds and each composite in L929 cells at different concentrations for 24 h; (B) LIVE/DEAD staining images of L929 cells at 1 d, 3 d and 5 d after treated with HPEM scaffolds and controls (10 μg/mL) (live cells: green, dead cells: red, scale bar: 100 μm, n=3); (C) fluorescence intensity of L929 cells treatment with HPEM scaffolds and controls at 1 d, 3 d and 5 d (*p<0.05, **p<0.01, n=5). Cells without any treatment was used as negative control (NC).

  在動物試驗(yàn)中建立MRSA感染的皮膚全層切除模型，并將該多功能支架填充于缺損部位。研究發(fā)現(xiàn)該支架通過有效的抗炎作用、促進(jìn)細(xì)胞增殖和血管生成過程、刺激肉芽組織形成、膠原蛋白沉積、血管內(nèi)皮分化和血管生成，可顯著促進(jìn)MRSA感染的傷口愈合（愈合率為96.31％）（Fig. 5和6）。

Figure 5. In vivo anti-infection and MRSA-infected wound healing. (A) Representative skin wound images at 0 d, 3 d, 7 d and 14 d, and (B) wound area size of the HPEM scaffolds and controls (*p < 0.05, **P < 0.01); (C) images of MRSA colonies growing on the agar plates derived from the homogenized infected tissues after various treatments at 3 d, 7 d and 14 d; (D) quantitative bacterial colonies densities based on (C); (E) IL-6 (red) immunofluorescence images at 3 d, H&E and Masson’s trichrome staining of wound tissues at 14 d, the black arrows showed the granulation layers in wound beds; Corresponding quantification of (F) fluorescence intensity of IL-6, (G) granulation tissue thickness and (H) collagen content in wound tissues based on (E) (Scale bar =100 μm, n = 6;*p < 0.05 and **p < 0.01).

Figure 6. Immunohistochemistry and immunofluorescence staining of wound healing assay. (A) Immunohistochemistry of Ki67, α-SMA stained (red: α-SMA, blue: nuclei) and CD31 stained (green: CD31, blue: nuclei) images; (B-C) quantitative analysis of α-SMA and CD31 of wound tissues at 7 d, respectively (scale bar = 100 μm; n = 6; *p < 0.05 and **p < 0.01).

  本研究表明多功能Ti₃C₂T_x MXene@聚多巴胺納米片在感染性傷口愈合中的重要作用。此外，具有多功能特性的HPEM支架為MRSA感染的傷口愈合/皮膚再生提供了一種潛在的治療策略。

  以上相關(guān)成果分別發(fā)表在ACS Nano (2021, DOI: 10.1021/acsnano.0c06287)上。論文的第一作者為西北工業(yè)大學(xué)化學(xué)與化工學(xué)院博士后周麗，通訊作者為張秋禹教授。

  論文鏈接：https://doi.org/10.1021/acsnano.0c06287