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用于糖尿病傷口治療的水凝膠研究進(jìn)展

2023-03-15 14:43:43馬俊杰劉晨光

馬俊杰 劉晨光

摘 要: 糖尿病傷口是糖尿病的常見并發(fā)癥,具有發(fā)病機(jī)制復(fù)雜、傷口易感染難愈合等特點(diǎn)。為了清除感染、緩解傷口炎癥和防止壞死,多種功能性水凝膠被成功研制并作為傷口敷料用于消除病原體感染,根據(jù)功能不同,水凝膠可分為抗菌水凝膠、抗炎水凝膠及多功能水凝膠。其中,根據(jù)作用原理不同,抗菌水凝膠又包括固有抗菌水凝膠、負(fù)載抗菌劑水凝膠及觸發(fā)式抗菌水凝膠。水凝膠在糖尿病傷口的治療取得了一定的進(jìn)展,但其仍然存在如成本過高、吸水性不足等問題,有待進(jìn)一步完善。該文系統(tǒng)總結(jié)了功能性水凝膠應(yīng)用于糖尿病傷口的研究進(jìn)展,可為糖尿病傷口的臨床治療提供新思路。

關(guān)鍵詞: 糖尿病傷口;傷口敷料;水凝膠;抗菌水凝膠;抗炎水凝膠;多功能水凝膠

中圖分類號(hào): R75

文獻(xiàn)標(biāo)志碼: A

文章編號(hào): 1673-3851 (2023) 11-0795-08

引文格式:馬俊杰,劉晨光.用于糖尿病傷口治療的水凝膠研究進(jìn)展[J]. 浙江理工大學(xué)學(xué)報(bào)(自然科學(xué)),2023,49(6):795-802.

Reference Format: MA? Junjie,LIU? Chenguang. The research progress of hydrogels for diabetic wound treatment[J]. Journal of Zhejiang Sci-Tech University,2023,49(6):795-802.

The research progress of hydrogels for diabetic wound treatment

MA? Junjie,LIU? Chenguang

Abstract:? Diabetic wounds are common complications of diabetes, characterized by complex pathogenesis, susceptibility to infection, and difficulty in healing. To eliminate pathogenic infections, alleviate wound inflammation, and prevent necrosis, various functional hydrogels have been successfully developed as wound dressings. Based on their different functions, hydrogels can be categorized into antibacterial ones, anti-inflammatory ones, and multifunctional ones. Among them, antibacterial hydrogels can be further divided into intrinsic antibacterial ones, drug-loaded antibacterial ones, and triggerable antibacterial ones, depending on their mechanisms of action. While hydrogels have made progress in the treatment of diabetic wounds, there are still some to-be-improved issues such as high cost, and insufficient water absorption. This article systematically summarizes the research progress of functional hydrogels applied to diabetic wounds, aiming to provide new ideas for the clinical treatment of diabetic wounds.

Key words: diabetic wound; wound dressing; hydrogels; antibacterial hydrogel; anti-inflammatory hydrogel; multifunctional hydrogel

0 引 言

糖尿病傷口是指在糖尿病患者身體上出現(xiàn)的難以愈合或緩慢愈合的創(chuàng)傷。糖尿病傷口是糖尿病并發(fā)癥之一,通常由于長期高血糖水平引起的血管、神經(jīng)和免疫系統(tǒng)的損害而導(dǎo)致[1]。糖尿病傷口可能在皮膚上、足部或其他部位產(chǎn)生,嚴(yán)重時(shí)可導(dǎo)致潰爛、感染、壞疽,甚至需要截肢[2]。

糖尿病傷口的形成與多種因素密切相關(guān)。首先,長期高血糖水平可引起糖尿病患者的局部血管損傷,導(dǎo)致血液循環(huán)不良,氧氣和營養(yǎng)物質(zhì)供應(yīng)不足,從而影響傷口的愈合[3]。其次,神經(jīng)損傷會(huì)導(dǎo)致糖尿病患者對(duì)傷口的疼痛和感覺減弱,使其無法及時(shí)發(fā)現(xiàn)和處理傷口,從而增加感染的風(fēng)險(xiǎn)[4-5]。此外,免疫系統(tǒng)功能受損使糖尿病患者更容易受到感染,從而傷口難以愈合[6]。

傷口敷料主要包括水凝膠[7-8]、纖維敷料[9-12]、泡沫敷料[13-14]等。理想的傷口敷料應(yīng)具有以下優(yōu)勢:a)組織相容性良好;b)保濕性好,能保持傷口的濕潤環(huán)境;c)有足夠的物理和機(jī)械強(qiáng)度,保持其完整性;d)具有促細(xì)胞黏附、增殖和分化的功能。水凝膠是一類高度水合的聚合物網(wǎng)絡(luò),具有細(xì)胞友好的水環(huán)境、良好的生物相容性,以及可調(diào)控的機(jī)械性能等優(yōu)勢。在生物材料領(lǐng)域,水凝膠被作為傷口敷料得到廣泛研究與應(yīng)用,包括藥物遞送、傷口敷料、微組織等[15]。目前,基于水凝膠的傷口敷料在糖尿病傷口應(yīng)用中取得了顯著進(jìn)展。相較于傳統(tǒng)敷料,水凝膠的優(yōu)勢在于:a)有益于精準(zhǔn)控制傷口的濕潤度,減少細(xì)菌滋生和感染風(fēng)險(xiǎn);b)由于可控的機(jī)械性能,水凝膠可減少傷口撕裂和疼痛;c)水凝膠的可控降解性使其能根據(jù)傷口的大小或深度調(diào)控吸收和保護(hù)能力,減少頻繁更換敷料對(duì)傷口的損傷,增強(qiáng)傷口實(shí)時(shí)檢測便捷性;d)水凝膠材料易與其他材料或藥物復(fù)合,賦予更多的擴(kuò)展性。盡管如此,水凝膠還是面臨著成本較高、吸水能力不足、不適用于大面積傷口等問題。

本文概述了可用于糖尿病傷口治療的功能性水凝膠的最新研究進(jìn)展。功能性水凝膠可以針對(duì)糖尿病傷口特點(diǎn)促進(jìn)糖尿病傷口愈合。基于不同的功能,水凝膠可分為抗菌水凝膠、抗炎水凝膠及多功能水凝膠。

1 抗菌水凝膠在糖尿病傷口的應(yīng)用研究

糖尿病傷口環(huán)境的性質(zhì)導(dǎo)致傷口感染的幾率很高,這也導(dǎo)致了細(xì)菌感染成為阻礙糖尿病患者傷口愈合的主要因素[16]。除了抗生素之外,目前已開發(fā)出了多種現(xiàn)代抗菌方法,如無機(jī)抗菌納米粒子、抗菌陽離子多肽、光動(dòng)力療法(Photodynamic therapy, PDT)、光熱療法(Photothermal therapy, PTT)等。將這些方法與水凝膠應(yīng)用相結(jié)合,可以顯著提高治療效果。根據(jù)水凝膠發(fā)揮抗菌作用原理不同,抗菌水凝膠可分為三類:a)負(fù)載抗菌劑水凝膠;b)固有抗菌水凝膠;c)觸發(fā)式抗菌水凝膠。

1.1 負(fù)載抗菌劑水凝膠

水凝膠作為廣泛應(yīng)用的藥物載體具有獨(dú)特的優(yōu)點(diǎn),高度吸水性和可調(diào)控的釋放速率使其能夠有效穩(wěn)定藥物,實(shí)現(xiàn)持續(xù)而精確的藥物釋放,從而提高治療效果并減少副作用[17]。并且,水凝膠材料的網(wǎng)格結(jié)構(gòu)和易修飾性使其可攜帶多種不同類型的藥物、生長因子或生物活性物質(zhì)(表1),實(shí)現(xiàn)組合治療或針對(duì)多個(gè)治療目標(biāo)。

從表1可見,抗生素仍然是目前臨床上最常使用的抗菌手段,將抗生素搭載到水凝膠上可以使得抗生素僅在局部發(fā)揮作用,降低抗生素用量,提高生物相容性。根據(jù)報(bào)道,大量抗生素被封裝在水凝膠中以制備成抗菌傷口敷料,包括環(huán)丙沙星[18]、氨芐西林[21]、四環(huán)素[22]等。但是,抗生素的過度使用導(dǎo)致耐藥細(xì)菌數(shù)量增加。

金屬離子如Ag+、Cu2+和Zn2+是眾所周知的抗菌劑,并已普遍應(yīng)用于傷口的治療[48]。Li等[25]將Ca2+和Zn2+搭載到海藻酸鈉水凝膠上,能夠抑制細(xì)菌生長并促進(jìn)傷口愈合。利用無機(jī)金屬制備而成的納米顆粒(Nanoparticles, NPs)合成技術(shù)不斷進(jìn)步,使得將抗菌納米顆粒加入水凝膠中用于傷口愈合稱為可能。在各種金屬NPs中,Ag NPs和ZnO NPs的應(yīng)用范圍最廣。Xie等[32]所研發(fā)出的含有 Ag NPs 的殼聚糖基水凝膠具有更好的機(jī)械性能和抗菌性能。Khorasani等[36]所制備的水凝膠中ZnO NPs表現(xiàn)出廣譜抗菌能力,可改善傷口愈合。

除此之外,一些天然提取物如生物堿、類黃酮、萜類化合物等都被廣泛研究并作為抗菌材料搭載到水凝膠上[17]。Jing 等[42]發(fā)現(xiàn)由絲素蛋白和單寧酸制備的雜化水凝膠可以抑制細(xì)菌活性,并促進(jìn)傷口愈合??咕模ˋntimicrobial peptides, AMPs)也是一類天然產(chǎn)生的蛋白質(zhì)分子,具有廣譜的抗菌活性,可以對(duì)抗多種細(xì)菌、病毒和真菌[49]。天然抗菌肽通常具有較好的生物相容性,減少對(duì)人體的不良影響[46]。Hou等[46]制備的GC/EPL冷凍凝膠由于搭載了乙二醇?xì)ぞ厶牵℅C)和e-聚賴氨酸(EPL)抗菌肽,表現(xiàn)出了優(yōu)異的抗菌功效,可以顯著加快傷口愈合。Lin等[47]將AMP Tet213固定在水凝膠上,對(duì)包括MRSA在內(nèi)的多種細(xì)菌表現(xiàn)出了抗菌活性。

1.2 固有抗菌水凝膠

固有抗菌水凝膠是一類具有天然或固有的抗菌活性的水凝膠材料,其抗菌性能不依賴于外部添加的抗菌劑。固有抗菌水凝膠通過材料本身的特性來實(shí)現(xiàn)對(duì)細(xì)菌的抑制和消除,從而在傷口治療和感染防治中發(fā)揮重要作用,因此固有抗菌水凝膠具有持久抗菌性、長久有效性并降低對(duì)組織的細(xì)胞毒性等優(yōu)點(diǎn)。Chi等[50]利用具有天然抗菌特性的殼聚糖制備的水凝膠微針敷料顯著促進(jìn)傷口愈合,這是由于殼聚糖能與細(xì)菌細(xì)胞壁和細(xì)胞膜上的陰離子基團(tuán)相互作用并破壞生物膜。Chen等[51]利用希夫堿反應(yīng)將氧化魔芋葡甘聚糖(Konjac glucomannan, KGM)和殼聚糖反應(yīng)形成水凝膠,該種水凝膠對(duì)金黃色葡萄球菌(革蘭氏陽性菌)和大腸埃希菌(革蘭氏陰性菌)具有優(yōu)異的抗菌活性,殺滅效率分別為96%和98%。Hoque等[52]利用陽離子殼聚糖衍生物N-(2-羥丙基)-3-三甲基殼聚糖氯化銨(Hydroxypropyltrimethylammonium chloride chitosan, HTCC)和生物黏附聚合物聚葡聚糖醛原位開發(fā)而成的水凝膠可以通過破壞細(xì)菌膜來滅活包括耐甲氧西林金黃色葡萄球菌(Methicillin-resistant Staphylococcus aureus, MRSA)在內(nèi)的細(xì)菌,并且對(duì)傷口愈合也有促進(jìn)作用。

與負(fù)載抗菌劑水凝膠相比,固有抗菌水凝膠不僅避免了細(xì)菌耐藥性,還可減少由于藥物釋放或藥效衰減后更換水凝膠導(dǎo)致的傷口損傷風(fēng)險(xiǎn)[53]。并且固有抗菌水凝膠普遍具備較強(qiáng)的抗菌廣譜性。例如Kito等[54]利用抗菌肽α-聚賴氨酸(Alpha-poly-l-lysine, PLL)制備水凝膠,并發(fā)現(xiàn)其可誘導(dǎo)革蘭氏陰性菌和革蘭氏陽性菌死亡。然而,固有抗菌水凝膠導(dǎo)致細(xì)菌膜破裂裂解的機(jī)制并不完全明確,傷口微環(huán)境(如濕度、pH值、活性因子等)是否改變固有抗菌水凝膠的拓?fù)浣Y(jié)構(gòu)、機(jī)械性能、黏附性能等物理化學(xué)性質(zhì)以調(diào)節(jié)其抗菌效果仍有待研究。

1.3 觸發(fā)式抗菌水凝膠

觸發(fā)式抗菌水凝膠是一種智能型水凝膠,它能夠在受到特定刺激時(shí)釋放抗菌物質(zhì),并有效抑制細(xì)菌的生長和擴(kuò)散。觸發(fā)式抗菌水凝膠具有較高的選擇性及廣譜抗菌活性。觸發(fā)式抗菌水凝膠的刺激類型主要包括光照、溫度、pH值、化學(xué)物質(zhì)、生物分子等。鑒于修復(fù)急性期的pH值較低,研究者們開發(fā)出了一些在酸性pH值下增強(qiáng)釋放的水凝膠。例如,在酸性條件下通過降低單寧酸與金屬離子之間的配位來制備單寧酸釋放的抗菌抗炎水凝膠[55]。

光照作為觸發(fā)式抗菌水凝膠主要的觸發(fā)方式,包括PTT和PDT兩種。PTT是一種通過近紅外(700~1100 nm)輻射光熱劑產(chǎn)生傷口局部高溫的熱療抗菌手段。Liu等[56]將沒食子酸修飾的銀(GA-Ag)納米顆粒嵌入水凝膠的網(wǎng)絡(luò)結(jié)構(gòu)中,作為光熱劑的GA-Ag納米顆粒在808 nm的近紅外輻射幫助下賦予水凝膠快速有效的抗菌活性。Zhao等[57]所開發(fā)水凝膠通過兒茶酚-Fe3+發(fā)揮協(xié)同作用,使水凝膠具有良好的光熱滅菌活性。

與PTT不同,PDT主要依靠輻照光敏劑后ROS的產(chǎn)生。根據(jù)光敏劑的不同,所產(chǎn)生的ROS包括單線態(tài)氧、羥基自由基等,它們具有強(qiáng)氧化活性,從而對(duì)細(xì)胞造成氧化損傷。Mao等[58]開發(fā)的Ag/Ag@AgCl水凝膠暴露于模擬可見光后,增強(qiáng)了ZnO的光催化和抗菌活性,95 min內(nèi)殺死95.98%的大腸埃希菌和49.20%的金黃色葡萄球菌。

2 抗炎水凝膠在糖尿病傷口的應(yīng)用研究

糖尿病傷口組織在炎癥期的初始階段產(chǎn)生各種促炎細(xì)胞因子和趨化因子,導(dǎo)致中性粒細(xì)胞和巨噬細(xì)胞在受傷部位浸潤。中度炎癥有助于去除壞死組織,殺死局部細(xì)菌并促進(jìn)傷口愈合。然而,過度的炎癥浸潤會(huì)干擾正常的愈合事件,如膠原蛋白沉積、血管生成和肉芽組織形成。因此,必須將傷口中的炎癥精確調(diào)節(jié)到適合促進(jìn)傷口愈合并且避免阻礙傷口愈合的水平??寡姿z通常從以下兩種途徑對(duì)炎癥進(jìn)行改善:a)促進(jìn)巨噬細(xì)胞由M1(促炎型)向M2(抗炎型)轉(zhuǎn)化;b)促進(jìn)螯合趨化因子,清除活性氧。

2.1 用于促進(jìn)巨噬細(xì)胞由M1向M2轉(zhuǎn)化的抗炎水凝膠

早期炎癥型(M1)巨噬細(xì)胞積累和過度炎癥是糖尿病傷口中常見的問題,這會(huì)導(dǎo)致糖尿病傷口修復(fù)受到阻滯。因此,具有免疫調(diào)節(jié)能力的水凝膠在糖尿病傷口愈合的臨床實(shí)踐中具有很大的前景[59]。Saleh等[60] 研發(fā)的負(fù)載有miR-223 5p模擬物(miR-223*)的水凝膠,其中miR-223*可控制傷口愈合過程中的巨噬細(xì)胞向抗炎(M2)表型極化,這改善了傷口愈合過程中的過度炎癥反應(yīng)。Yang等[61]制備的透明質(zhì)酸基水凝膠,其中引入的芍藥苷(paeoniflorin)能顯著促進(jìn)巨噬細(xì)胞從M1到 M2的極化,這一結(jié)果伴隨著炎癥、血管生成、再上皮化和膠原沉積的改善。此外,近年來無添加劑的水凝膠逐漸成為熱點(diǎn),科研人員通過修飾水凝膠材料或調(diào)控水凝膠的機(jī)械性能、拓?fù)浣Y(jié)構(gòu)等調(diào)控水凝膠的生物功能。Qian等[62]開發(fā)了一種具有內(nèi)在免疫調(diào)節(jié)特性的新型甘草酸(Glycyrrhizic acid, GA)雜化水凝膠,該水凝膠可以調(diào)節(jié)炎癥微環(huán)境中的巨噬細(xì)胞反應(yīng),并避免使用任何添加劑,以促進(jìn)糖尿病傷口的快速愈合。

2.2 可用于螯合趨化因子,清除活性氧的抗炎水凝膠

傷口中過多的活性氧(Reactive oxygen species, ROS)和趨化因子都會(huì)導(dǎo)致炎癥細(xì)胞的過度浸潤,炎癥反應(yīng)加深。Zhang等[63]研發(fā)的雜化水凝膠具有高吸水性(聚丙烯酸)和抗氧化特性(聚酯酰胺),使其能夠吸收滲出物并與之相互作用,從而清除ROS。葡聚糖具有出色的保水能力,可作為ROS的溫和清除劑,并減少血小板過度活化[64]。Qiu等[65]利用羧基甜菜堿葡聚糖和磺基甜菜堿葡聚糖構(gòu)建了基于兩性離子葡聚糖的水凝膠,該水凝膠具有出色的抗氧化能力,并且相比于商業(yè)化傷口敷料具有更好的促進(jìn)傷口愈合能力。Lohmann等[66]定制了一種基于肝素衍生物的模塊化水凝膠,有效螯合炎癥趨化因子IL-8、巨噬細(xì)胞炎癥蛋白-1和單核細(xì)胞化學(xué)引誘蛋白-1,抑制了人單核細(xì)胞和中性粒細(xì)胞的遷移。

3 多功能水凝膠在糖尿病傷口的應(yīng)用研究

糖尿病傷口的愈合過程復(fù)雜多變,因此在不同階段有不同需求。例如,在炎癥階段需要抗氧化功能;在組織重塑階段需要促進(jìn)細(xì)胞增殖和分化;在整個(gè)傷口愈合階段,需要提供一定濃度的氧氣[67]。目前,市面上一種名為Mepilex(莫爾博爾)的多功能水凝膠,具有滲出液吸收和防止傷口感染的功能,適用于糖尿病多種傷口類型。

Li等[68]設(shè)計(jì)了一種由鳥苷、2-甲?;脚鹚岷透方M成的鳥苷四聯(lián)體水凝膠能有效清除金黃色葡萄球菌及銅綠假單胞菌,并且降低傷口周圍葡萄糖濃度,從而結(jié)合抗菌和緩解傷口微環(huán)境功能,顯著促進(jìn)糖尿病傷口愈合。Yin等[69]開發(fā)了一種基于鎂有機(jī)框架的多功能微針貼片,可實(shí)現(xiàn)糖尿病患者的透皮給藥和聯(lián)合治療,該凝膠通過釋放Mg和沒食子酸可以誘導(dǎo)細(xì)胞遷移,清除活性氧,促進(jìn)膠原沉積,并促進(jìn)血管生成。Zhou等[70]研發(fā)了一種抗三明治結(jié)構(gòu)光電子水凝膠,可以有效清除MRSA,促進(jìn)新生血管生成,以及降低炎癥反應(yīng)。Yang等[71]開發(fā)了一種基于單寧酸(Tannic acid, TA)的水凝膠創(chuàng)可貼,該水凝膠具有優(yōu)異的耐濕黏附性和器官止血性,優(yōu)異的抗炎、抗菌和抗氧化性能,并且可有效促進(jìn)糖尿病小鼠皮膚切口和缺損的恢復(fù)。Di Luca等[72]利用明膠-姜黃素偶聯(lián)物和聚乙二醇二甲基丙烯酸酯進(jìn)行聚合所得到的水凝膠具有抗氧化能力,并且有效抑制MRSA的增殖。Chen等[73]開發(fā)了一種由乙二醇?xì)ぞ厶呛托滦涂缮锝到庀7蚧宦?lián)劑雙官能團(tuán)聚氨酯制備一種多功能冷凍凝膠生物材料,具有抗菌活性和生物降解性,可以有效促進(jìn)慢性糖尿病傷口愈合。

4 結(jié)論與展望

與正常傷口愈合相比,糖尿病引起的傷口愈合過程更為復(fù)雜,自我條件環(huán)境更為不利,長期暴露在外界環(huán)境中會(huì)大大增加感染的幾率。同時(shí),慢性期持續(xù)的炎癥環(huán)境和高血糖造成的血管屏障,大大延緩了傷口的愈合。而在過去的幾十年中,水凝膠已成為最具競爭力的傷口敷料候選材料,并且在傷口敷料的應(yīng)用中呈逐年增加的趨勢。本文綜述了水凝膠在糖尿病傷口愈合過程中的作用,展示了水凝膠在糖尿病傷口中的應(yīng)用潛力。

近年來糖尿病傷口水凝膠正朝抗菌、抗炎和多功能化的方向發(fā)展,不同負(fù)載型和非負(fù)載型水凝膠的抗菌、抗炎機(jī)制不斷被揭示與深化。傳統(tǒng)抗生素引起的細(xì)菌耐藥問題飽受詬病,因而如今的水凝膠逐步發(fā)生從抗生素遞送到其他抗菌物質(zhì)遞送的轉(zhuǎn)變,如金屬和金屬納米顆粒、陽離子、抗菌肽、天然產(chǎn)物中的抗菌成分遞送。水凝膠也出現(xiàn)了抗菌策略的轉(zhuǎn)變,如光熱、光動(dòng)力抗菌和多功能協(xié)同抗菌策略等。

同時(shí),水凝膠在抗炎、調(diào)控傷口免疫微環(huán)境、促血管化等方向也不斷被研究。但傷口的炎癥水平是動(dòng)態(tài)的,巨噬細(xì)胞的表型根據(jù)傷口微環(huán)境而變化,目前的敷料缺乏精確調(diào)節(jié)巨噬細(xì)胞表型以達(dá)到可預(yù)測的理想結(jié)果的能力。傷口修復(fù)過程通常是復(fù)雜、動(dòng)態(tài)的,例如,在傷口愈合的炎癥噬菌體期間控制炎癥很重要,但在傷口修復(fù)的其他時(shí)期則沒有必要。此外,傷口敷料中裝載的細(xì)胞、細(xì)胞因子和功能成分通常僅在特定時(shí)間需要,而在其他時(shí)間,它們甚至可能發(fā)揮相反的效果。因此,響應(yīng)型材料和炎癥響應(yīng)激活的水凝膠可能成為突破傷口環(huán)境動(dòng)態(tài)調(diào)控的研究新思路。得益于近年來許多復(fù)合多功能水凝膠的出現(xiàn),針對(duì)復(fù)雜傷口修復(fù)的多功能水凝膠具有極大的發(fā)展?jié)摿ΑMㄟ^將抗炎、抗菌、傷口微環(huán)境調(diào)控功能與內(nèi)源或外源響應(yīng)功能結(jié)合,未來水凝膠在糖尿病傷口治療的發(fā)展方向包括智能化和個(gè)性化治療、創(chuàng)新的藥物載體、生物材料整合、納米技術(shù)的應(yīng)用、個(gè)體化醫(yī)療和更多的臨床研究驗(yàn)證。這些發(fā)展方向旨在提高治療效果、減輕患者痛苦,并為糖尿病患者的傷口管理提供更先進(jìn)的解決方案。

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(責(zé)任編輯:張會(huì)?。?/p>

收稿日期: 2023-08-22網(wǎng)絡(luò)出版日期:2023-10-08

基金項(xiàng)目: 國家自然科學(xué)基金項(xiàng)目(32201092)

作者簡介: 馬俊杰(1998— ),男,安徽池州人,碩士研究生,主要從事生物化學(xué)與分子生物學(xué)方面的研究。

通信作者: 劉晨光,E-mail:cgliu@zstu.edu.cn

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