Reversible dougong structured receptor–ligand recognition for building dynamic extracellular matrix mimics

Dynamic biomaterials excel at recapitulating the reversible interlocking and remoldable structure of the extracellular matrix (ECM), particularly in manipulating cell behaviors and adapting to tissue morphogenesis. While strategies based on dynamic chemistries have been extensively studied for ECM-mimicking dynamic biomaterials, biocompatible molecular means with biogenicity are still rare. Here, we report a nature-derived strategy for fabrication of dynamic biointerface as well as a three-dimensional (3D) hydrogel structure based on reversible receptor–ligand interaction between the glycopeptide antibiotic vancomycin and dipeptide d-Ala-d-Ala. We demonstrate the reversible regulation of multiple cell types with the dynamic biointerface and successfully implement the dynamic hydrogel as a functional antibacterial 3D scaffold to treat tissue repair. In view of the biogenicity and high applicability, this nature-derived reversible molecular strategy will bring opportunities for malleable biomaterial design with great potential in biomedicine.

More than 2,500 y ago, the Chinese built their nail- and glue-less architectures (e.g., from Beijing''s Forbidden City to Sichuan Province''s Bao''en Temple) with a “dougong” structure, which is part of the network of wooden supports essential to the timber frame structure of the building. A typical dougong consists of a flat block of wood (dou), the top of which is fixed with an interlocking set of curved bows (gong), without the aid of nails or glue, to provide mechanical support to hold the three-dimensional (3D) network structure. Intriguingly, the microstructure of extracellular matrix (ECM) also demonstrates such reversible interlocking structure, which supports the integrity of tissues and organs. In natural ECM, the dougong structure occurs at the cell–ECM interfaces accompanied by a constant remodeling of the ECM network, giving rise to specific cell signaling, intracellular cascades, and subsequently, all relevant cell behaviors (1–3). Biomaterial designs based on the reversible interactions mimicking the cell–ECM interfaces are believed to boast distinct advantages, including the capability to modulate cell–biomaterial interactions, adapt to the development of cellular processes (1, 4–6), and facilitate the morphogenesis of tissues and organs (7, 8). Although the dynamic design of biomaterials is relatively complicated and challenging, this field attracts significant attention in building dynamic ECM mimics for regenerative medicine (1, 9–11).To faithfully reproduce the dynamics of ECM in artificial matrices, various strategies, including congenitally reversible noncovalent interactions (e.g., hydrogen bonds, coordinate bonds, hydrophobic forces, π–π interactions, van der Waals forces, and electrostatic effects) and dynamic covalent bonds (e.g., reversible boronic esters and benzoic–imine bonds and photosensitive nitrophenyl and azobenzene groups), have been exploited. Currently, biomaterial interfaces with dynamically functionalized bioligands are mainly designed through reversible covalent phenylboronic esters or benzoic–imine bonds (12–16), deformable azobenzene bonds (17), DNA and peptide molecular assemblies (18, 19), cyclodextrins/cucurbiturils-based macrocycle host–guest supermolecules (20–22), metal–ligand coordination (23, 24), and other multiple noncovalent interactions (25–29). They can elicit controllable and reversible cell behaviors (e.g., adhesion, migration, differentiation, and apoptosis) on the biomaterial interfaces (1, 4, 8). Unfortunately, these dynamic ECM-mimicking strategies carry critical problems (13). First, most dynamic strategies are based on nonbiogenic chemical molecules, which are usually nonbiocompatible and probably harmful. Second, the dynamics of these strategies commonly rely on the nonbiological stimuli (e.g., ultraviolet [UV] light or toxic chemicals), which are potentially invasive to cells. Third, current studies on mimicking dynamic ECM are usually limited to either reversible bioligand presentation or remoldable network fabrication; few works focus on both. In this context, the exploration of biocompatible molecular means for recapitulation of both dynamic bioactivity and dynamic structure in ECM is highly anticipated.Here, we present a nature-derived reversible strategy inspired by the receptor–ligand molecular recognition for design of dynamic ECM-mimicking biomaterial. The receptor–ligand molecular recognition relies on multi-noncovalent interaction between two or more molecules with exquisite complementarity in their chemical groups and geometries (30). With this in mind, we focus our attention on a typical simple yet elegant receptor–ligand system (i.e., the glycopeptide antibiotic vancomycin [Van] and the dipeptide d-Ala-d-Ala [AA]). Produced by a bacterial species named Amycolatopsis orientalis, Van exhibits strong bactericidal effect by inhibiting cell wall biosynthesis via the specific binding (K_d = 1.6 μM) (31) toward the terminal AA dipeptide of the bacterial cell wall precursors (Fig. 1A). As a proof of concept, we employ the reversible Van–AA interaction for building both a reversible dynamic biointerface and a 3D hydrogel network (Fig. 1 B and C). Due to the specific but reversible AA–Van molecular recognition, the dynamic biointerface demonstrates excellent reversibility in binding to cell-adhesive tripeptide arginylglycylaspartic acid (RGD) and modulating adhesion of multiple cells, demonstrating our strategy’s general applicability. In addition, the 3D hydrogel network based on the reversible AA–Van molecular recognition demonstrates self-recovery and injectability. The inherently antibacterial activity of the Van–AA hydrogel well equips the 3D hydrogel network for treating infected open skin wounds; the hydrogel could adapt to the shape of wound sites, resist self-fragmentation, and inhibit proliferation of pathogenic bacteria while continuously supporting wound healing. We believe that the specific but reversible Van–AA molecular recognition would be a strategy for dynamic biomaterial fabrication, and the easy-handling merit, ECM-like remoldability, and inherently antibacterial activity involved in this dynamic system will bring insights to biomaterial scaffold design in tissue engineering and regenerative medicine.Open in a separate windowFig. 1.Schematics showing the mechanism of dynamic biointerface and 3D ECM mimics based on a reversible dougong-structured natural receptor–ligand recognition. (A) The Van–AA molecular recognition on bacterial cell wall in nature. (B) Schematic illustration of the dynamic biointerface based on the reversible Van–AA interaction. Reversible bioligand presentation and controllable cell behaviors could be readily realized through the Van–AA interaction. (C) Schematic illustration of the dynamic hydrogels with remoldable network structure and its application in tissue repair.     

局部皮瓣修复面部软组织缺损疗效观察

目的 探讨局部皮瓣在面部软组织缺损修复中的应用效果。方法 给予2017年11月至2019年12月襄城县人民医院收治的50例面部软组织缺损患者行局部皮瓣修复治疗,观察术后皮瓣成活情况、切口愈合时间、瘢痕增生情况以及患者满意度。结果 50例患者均顺利完成局部皮瓣修复手术,术后均未出现皮瓣血运不良、创面血肿、切口感染等并发症,皮瓣成活率为100%;切口均一期愈合,愈合时间为(7.28±0.51) d;术后6个月愈后皮肤瘢痕色泽评分为(0.68±0.62)分、血管分布评分为(0.74±0.64)分、厚度评分为(0.80±0.65)分、柔软度评分为(0.98±0.66)分;术后1年患者对修复效果非常满意17例、满意28例、不满意5例,总满意度为90%。结论 采用局部皮瓣修复面部软组织缺损,术后皮瓣成活率较高,美容修复效果较好,患者较为满意。     

复合骨碎补总黄酮的丝素蛋白/壳聚糖支架在兔关节软骨损伤中的应用研究

目的 以丝素蛋白/壳聚糖支架为载体将骨碎补总黄酮应用于兔软骨损伤局部,观察修复效果,为临床提供实验数据。方法 制备丝素蛋白/壳聚糖支架、骨碎补总黄酮缓释微球与负载骨碎补总黄酮缓释微球的丝素蛋白/壳聚糖支架,扫描电子显微镜下观察支架形貌,同时检测该支架的体外缓释能力。24只新西兰大白兔随机分3组,利用电钻在股骨滑车部位构建直径3.5 mm、深1.5 mm的软骨损伤模型,空白组软骨缺损处不植入任何材料,对照组植入单纯的丝素蛋白/壳聚糖支架,实验组植入负载骨碎补总黄酮缓释微球的丝素蛋白/壳聚糖支架,术后12周、24周行标本大体与组织学观察,RT-PCR检测修复组织Sox-9、II型胶原与聚集蛋白聚糖mRNA的表达量,Western blot检测软骨缺损部位II型胶原蛋白表达,分析软骨修复效果。结果 丝素蛋白/壳聚糖支架具有良好的三维孔隙结构,孔洞之间相互联通;制备的载药微球表面较光滑,为较规则的圆球形;载药微球均匀分散于丝素蛋白/壳聚糖支架基质中。丝素蛋白/壳聚糖支架可在体外持续稳定地释放骨碎补总黄酮,实验组软骨损伤修复效果优于对照组,对应的ICRS评分与Wakitani组织学评分高于对照组...     

免疫检查点抑制剂对耐药结直肠癌的研究现状

错配修复缺陷(dMMR)/微卫星高频不稳定(MSI-H)结直肠癌因其致癌机制引起程序性细胞死亡蛋白1(PD-1)/程序性细胞死亡配体1(PD-L1)上调,对5-氟尿嘧啶(5-FU)等为基础的化疗方案产生肿瘤免疫性抵抗,出现耐药性.本文从以下几方面进行综述:dMMR/MSI-H结直肠癌耐药的特点和PD-1/PD-L1抑制...     

同期腹腔镜手术治疗病态性肥胖合并腹壁疝7例疗效分析

目的 探讨病态性肥胖合并腹壁疝病人行同期腹腔镜胃袖状切除术(LSG)和腹壁疝修补术的临床疗效.方法 回顾性分析2018年1月至2020年7月中国科学技术大学附属第一医院疝与减重代谢外科中心和芜湖市南陵县医院普外科收治的同期行LSG+腹壁疝修补术的7例病态性肥胖合并腹壁疝病人的临床资料,BMI为38.2(33.5～42....     

覆膜支架治疗37例Stanford B型胸主动脉夹层的疗效分析

目的:分析覆膜支架腔内修复治疗Stanford B型胸主动脉夹层的临床疗效。方法:对2015年1月至2016年12月收治的37例因Stanford B型胸主动脉夹层行覆膜支架腔内修复术患者的病历资料进行回顾性分析,其中男性29例,女性8例。术前诊断依据临床表现及CT血管造影(CTA),术中造影再次评估病变部位及解剖位置,切开股动脉,行覆膜内支架置入,封堵原发破口,手术成功后再次造影检查。结果:37例患者共置入支架37枚,全部获得成功。术中造影见少量内漏4例,3例经支架近端球囊扩张后内漏消失,1例无需特殊处理。患者临床症状均明显改善,降主动脉及腹主动脉真腔明显扩大。结论:采用覆膜支架腔内修复术治疗Stanford B型胸主动脉夹层安全、创伤小、恢复快,临床效果显著。     

Influence of experience on procedure steps,safety, and functional results in edge to edge mitral valve repair—a single center study

Objectives: We sought to determine the effects of experience on the Mitraclip^® procedure steps as well as procedure safety and functional results. Background: MR has proven deleterious in heart failure. Mitraclip^® therapy evolved an important option in patients with severely reduced left ventricular function (LVEF). Methods: Between 2011 and 2016, 126 consecutive patients were grouped in three groups and investigated in a prospective observational study. We evaluated the duration of procedural steps, safety endpoints, and functional results. Results: The median logistic EuroScore was 32% (7–40%). Ninety‐five percent of patients were in NYHA‐stage ≥III and 51% had a LVEF <30%. Groups were homogeneous as to their baseline NYHA status and right heart catheterization data. Echocardiography data are comparable, albeit with a decreasing effective regurgitant orifice area (0.44 ± 0.21 group I vs. 0.34 ± 0.22 group III, P = 0.02). Frailty was less frequent and baseline 6 min walking test results improved from group I to group III. Duration of a first clip placement decreased from 106 ± 50 to 50 ± 21 min (P < 0.001). Total procedure time decreased from 221 ± 70 to 144 ± 68 (P < 0.001). The number of clips implanted increased from 66 to 79 (P = 0.02). MitraClip^® implantation was effective in either group but the combined safety endpoint was reached less frequent in group III (P = 0.01). There was no difference in MACCE rate, 30 day‐ or intrahospital‐mortality between groups. Conclusion: Safety and duration of procedure steps improved substantially with experience. MR reduction was sustained from the beginning without further improvement. Patient selection is a key factor for success. © 2016 Wiley Periodicals, Inc.