Our lab is dedicated to the development of various biomaterials and minimally invasive medical devices for cardiovascular disease treatment, such as bioresorbable cardiac occluder and bioresorbable vascular stent. For more details about our lab, please visit our Cardiovascular Materials and Devices Innovation Research Team website (https://www.x-mol.com/groups/wang_yunbing). In the case of vascular stents, we target and focus on the development of functional coatings with anticoagulant, anti-inflammatory and rapid endothelialization behaviors in response to the complex microenvironment surrounding the cardiovascular stent implant (Wang, Y. et al. Advanced Materials. 34, 2201971 (2022); Wang, Y. Engineering. 7, 1707-1709 (2021); Yang, L. et al. Biomaterials. 276, 121055 (2021); Zhou, Z. et al. Matter. 5, 1-18 (2022); Wang, Y. et al. Science advances. 8, eabm3378 (2022)).

Cardiovascular stent implantation has become the most effective surgical treatment for coronary artery disease, which is the number one leading cause of mortality worldwide. Commercial drug-eluting stent (DES) implantation has been successful in inhibiting the excessive proliferation of smooth muscle cells (SMCs) and thus neointimal hyperplasia. However, anti-hyperplasia drugs can also slow down the re-endothelization process, delay vascular healing, and increase the risk of late/very late thrombosis and in-stent restenosis (ISR). Recognizing this limitation, we sought to develop drug-free stents that can both avoid late thrombus formation and promote vascular neointimal healing without the use of anti-hyperplasia drugs, as an alternative to the DES.

Stent implantation procedures often damage the endothelial layer, which can trigger several pathological reactions, such as thrombosis, acute inflammation, and hyperplasia. These reactions can lead to the failure of cardiovascular implant devices. To address this issue, many surface modification strategies have been developed, but they often involve introducing multiple components, which can make the system complex and inconvenient. Despite rapid progress that has been made towards the surface modification of cardiovascular stents, there are still scarce data on drug-free coating formulation for single component possessing multiple functions. To overcome this challenge, we meticulously tailored recombinant humanized collagen type III (rhCol III), which can perform multiple functional behaviors in response to the complex microenvironment surrounding the cardiovascular stent implants. Different from traditional natural-derived collagen, the customized rhCol III possessed enhanced cell adhesion activity and anticoagulant properties, which were attributed to the retention of highly adhesive fragments (Gly-Glu-Arg (GER) and Gly-Glu-Lys (GEK)) of humanized collagen type III and bypassed the hydroxyproline (O) sequence that might induce platelet adhesion and activation. Additionally, rhCol III presented good water solubility and low inflammatory response. Overall, the development of rhCol III-coated stents was an exciting journey for our team.

Our preliminary results were promising, providing an efficient and continuous coverage of tailored rhCol III on the surface of the substrates in a simple approach denoted as (rhCol III/PDA-PEI)_n. This offers a basis for an in-depth spotlight to investigate the application of rhCol III in cardiovascular materials. The blood compatibility assays confirmed the excellent anti-thrombosis capacity of our drug-free rhCol III-based coating, which was very exciting. Moreover, our rhCol III-based coating inhibit the overgrowth of SMCs while promoting adhesion and proliferation of endothelial cells (ECs), implying the potential for ideal restoration of the endothelium. The above positive results encouraged us towards further investigation.

Then we moved towards further figuring out the reason of the single component rhCol III drug-free coating in facilitating the selective adhesion of ECs through transcriptome analysis. It was very exciting to observe that our drug-free coating favored ECs adhesion and proliferation through activation of EC-related signaling pathway, and inhibited the growth of SMCs by inducing the conversion to a contractile phenotype. The above results imply that our coating possesses the capability of maintaining the blood vessel patency rate and promoting neointimal healing. Next, we turned our attention to the host response evaluation by subcutaneous implantation assays in male Sprague-Dawley rats. The in vivo anti-inflammatory results substantiated that the (rhCol III/PDA-PEI)_n coatings could effectively reduce the in vivo inflammatory response of PLA substrates, displaying good tissue compatibility.

Finally, we used rabbit and porcine models to further evaluate whether our developed (rhCol III/PDA-PEI)_n coating could effectively promote in-situ endothelialization while inhibiting intimal hyperplasia. We found that in the rabbit model the (rhCol III/PDA-PEI)₂ coating reduced the inflammatory response by facilitating M2 macrophage polarization, accelerating the endothelialization process, and inhibiting the transition of SMCs from a synthetic to a secretory phenotype, thereby reducing restenosis and facilitating long-term stent patency. Surprisingly, in the porcine animal model, the neointima formed on the surface of the drug-free ((rhCol III/PDA-PEI)₂) stents was thinner than that formed on the commercially available rapamycin-eluting (RAPA) stents from the perspective of the entire segment of stented arteries, which further increased the clinical interest in developing drug-free stents.

We are excited to have developed (rhCol III/PDA-PEI)_n coatings, which aims to accomplish the ideal vascular neointimal healing by a “one produces multi” drug-free formulation against drug-eluting coating. We believe it holds great potential for translation from the laboratory to industrial applications and opens an avenue for surface modification of cardiovascular implantable devices including but not restricted to vascular stents. Given the stability, multifunctionality and easy fabrication procedures, we believe that the one-produces-multi drug-free system represents a promising strategy for the next-generation of stents.

Haoshuang Wu ^{1, 5}, Li Yang ^{1, 5}, Yunbing Wang ^1,4*
National Engineering Research Center for Biomaterials and College of Biomedical Engineering, Sichuan University, Chengdu 610065, China.
Nat. Commun. 2024, 15, 735.
DOI: 10.1038/s41467-024-44902-2
More details in Nature Communications via https://www.nature.com/articles/s41467-024-44902-2