Profs. Huang Nan and Yang Zhilu at the Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering and their associates recently published a paper entitled "Bioclickable and mussel adhesive peptide mimics for engineering vascular stent surfaces” in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) with Southwest Jiaotong University as the authors’ first affiliation. Founded in 1914, PNAS is one of the four top journals (Nature, Science, Cell and PNAS) as well as the world’s most-cited and comprehensive multidisciplinary scientific journals.

Since Haeshin Lee and other scientists first reported the multi-functional polydopamine coating of mussel-inspired surface chemistry in 2007, the “material-independent” chemical surface modification strategy based on catechol has exerted significant influence in almost all scientific and engineering fields including those of biomedical science, energy storage, environmental science, etc. However, in the surface functionalization of biomedical materials, such strategy is usually applied by means of biomolecules group, i.e., amino- or thiol- one, and catechol group reaction, i.e., Michael reaction or Schiff base, which often gives rise to defects such as reduced biomolecular activities, incomplete surface reaction, random molecular orientation, low controllability of molecule modification, etc.

Figure 1. The molecular structure of the mussel-inspired and bioclickable peptide mimic and its application on surface modification of vascular stent

Recently, based on molecule structure and adhesion of mussel foot proteins, Profs. Huang Nan and Yang Zhilu from Southwest Jiaotong University in collaboration with Prof. Pan Guoqing at Jiangsu University and Prof. Zhao Xin at Hong Kong Polytechnic University designed and synthesized a peptide mimic with catechol groups and azide groups through the successful combination of mussel-inspired molecular adhesion with the specific molecule modification. The research results were applied to surface modification of vascular stent to solve the important clinical problems of in-stent restenosis and late stent thrombosis during long-term implantation of vascular stents (Figure 1).

With the mussel molecular adhesion (covalent/non-covalent synergistic effect), this advanced mussel-inspired peptide mimic can stably adhere to the vascular stent through the coordination of catechol/metal, resulting in bioclickable azide surfaces. Compared with traditional polydopamine coating, azide surface can prevent the reduction of biological activities and disordered molecular orientation in the secondary biological modification process of polydopamine surface coating with the integration of modified bioactive ligand modified by dibenzo cyclooctyne group (DBCO) through specific bioorthogonal reaction. Moreover, the specificity and thoroughness of click chemistry contribute to the controllability and co-modification on multi-molecule in the application of the method.

Figure 2. The bifunctional vascular stent constructed with the bioclickable mussel peptide is characterized by rapid reendothelialization and long-term inhibition of smooth muscle cell proliferation and in-stent restenosis.

To demonstrate the advantage of the advanced mussel-inspired surface functionalization strategy in improving reendothelialization and inhibition of smooth muscle cell proliferation and in-stent restenosis, the authors presented in the paper the concept of two vasoactive moieties, i.e. the targeted endothelial progenitor cell (EPC) and the auto-generating nitric-oxide (NO) coating (figure 1). The authors obtained the surface-engineered stents with significant anticoagulant, inhibition of smooth muscle cell migration/proliferation, improvement of EPC adhesion and directional into endothelial cells by means of coupling the different components of EPC-targeting peptide (TPS) and NO-generating organoselenium (SeCA) onto the grafted stent surface via mussels molecular adhesion of biomimetic peptides and bioorthogonal click reaction, and through the adjustment of the feeding ratios to optimize two vasoactive moieties.

Vivo studies further manifested that the bifunctional stent optimized with bioclickable mussel-insipired peptide can effectively and rapidly promote endothelialization of the stent surface (week 1). Under long-term implantation (weeks 4-12), vascular stents with two vasoactive moieties significantly inhibited smooth muscle cell proliferation and in-stent restenosis (Figure 2). The results of this study provide theoretical support and guidance for the multi-function surface design of vascular implant devices. In terms of application,  the effective combination of the specific molecular modification of bioorthogonal click chemistry with the universality of mussel-inspired molecular adhesion paves the way for the considerable reduction of/solution to clinical complications such as in-stent restenosis and late thrombosis through rapid reendothelialization.

The related research achievements, recorded in the paper “Bioclickable and mussel adhesive peptide mimics for engineering vascular stent surfaces”, were published in the international top journal PNAS (DOI: 10.1073/pnas.2003732117). Prof. Yang Zhilu of Southwest Jiaotong University and Prof. Zhao Xin at Hong Kong Polytechnic University are the first authors of the paper, Huang Nan and Pan Guoqing are the corresponding authors, and the Key Laboratory of Advanced Technologies of Materials, Ministry of Education, Southwest Jiaotong University/ the School of Materials Science and Engineering of Southwest Jiaotong University are the authors’ first affiliation. The research was supported by the National Key Research and Development Program and the National Natural Science Foundation of China, etc.

Paper link: https://www.pnas.org/content/early/2020/06/25/2003732117

In recent years, Profs. Huang Nan and Yang Zhilu developed “revolutionary cardiovascular stent with in situ regeneration of atherosclerosis (AS) diseased blood vessels” to solve the problems such as “in-stent restenosis” , “late thrombosis”, etc. that have long plagued the clinical application of vascular stents. In this field, they has published over 40 papers (average IF > 7) in international top journals, such as PNAS, Research (the first one in the Science Partner Journal (SPJ) program since its foundation in 1880, 2 papers), Biomaterials (IF: 10.273, 9 papers) and Chemistry of Materials (IF: 10.159), and obtained more than 20 invention patents including 1 in the United States. The independent intellectual property right “biodegradable stent coating with functions of lesion cure and vascular tissue repair” has been successfully transferred (transfer fee: RMB 15 million).

About Prof. Yang Zhilu:

Yang Zhilu, research fellow and doctoral supervisor at Southwest Jiaotong University, was the winner of “Outstanding Youth Fund of Sichuan Province”, the reserve candidate of “Academic and Technical Pioneers of Sichuan Province”, and the “Yang Hua Scholar” of Southwest Jiaotong University. He presently acts as chief editor of Smart Materials in Medicine, editor of Engineered Regeneration, and guest editor of Bioactive Materials and Medical Gas Research, all of which are KeAi international journals. He currently focuses on studies of the pathologic mechanism of atherosclerosis plaque in coronary arteries, nano-targeted drugs for the treatment of coronary/peripheral artery disease, drug balloons and vascular stents with functions of lesion cure and vascular tissue repair. Up to date, he has published over 40 SCI papers as the first/corresponding author in top journals, such as PNAS, Research (2 papers), Chemistry of Materials, Biomaterials (9 papers), including 10 papers with IF greater than 10 and 7 papers with IF between 8-10. He has delivered lectures and been invited to deliver lectures at over 10 international/national conferences. He has obtained 14 invention patents including 1 in the United States. His independent intellectual property right “biodegradable stent coating with functions of lesion cure and vascular tissue repair” has been successfully transferred (transfer fee: RMB 15 million).

About Prof. Huang Nan:

Huang Nan, professor and doctoral supervisor at Southwest Jiaotong University, was included in “the New Century National Hundred, Thousand and Ten Thousand Talent Project” and granted the government special allowance of the State Council. He is one of the earliest scholars specializing in cardiovascular biomaterials research in China and participated in the strategic planning for the development of cardiovascular biomaterials in China. He acts as the Fellow of the International Union of Societies for Biomaterials Science and Engineering (IUSBSE), Chairman of the International Committee of the International Symposium on Surfaces and Interfaces of Biomaterials (ISSIB). He has successively presided over projects supported by the “973 Program” , “863 Program”, Key Programs and General Programs of National Natural Science Foundation of China with the total amount of project funds exceeding RMB 30 million yuan. He has developed a series of advanced technologies for surface modification of cardiovascular materials with independent intellectual property rights and key technologies for cardiovascular implant intervention devices. The vascular stents he developed with intellectual property rights has been proved to be superior to the existing products at home and abroad (more than 200,000 clinical applications at present). He has obtained more than 80 patents, won 3 Provincial and Ministerial Science and Technology Advancement Awards, published nearly 300 SCI papers which have been cited for more than 10,000 times. He also has delivered lectures or has been invited to deliver lectures at over 40 international/national conferences.