Tailored extracellular matrix-mimetic coating facilitates reendothelialization and tissue healing of cardiac occluders.

Minimally invasive transcatheter interventional therapy utilizing cardiac occluders represents the primary approach for addressing congenital heart defects and left atrial appendage (LAA) thrombosis. However, incomplete endothelialization and delayed tissue healing after occluder implantation collectively compromise clinical efficacy. In this study, we have customized a recombinant humanized collagen type I (rhCol I) and developed an rhCol I-based extracellular matrix (ECM)-mimetic coating. The innovative coating integrates metal-phenolic networks with anticoagulation and anti-inflammatory functions as a weak cross-linker, combining them with specifically engineered rhCol I that exhibits high cell adhesion activity and elicits a low inflammatory response. The amalgamation, driven by multiple forces, effectively serves to functionalize implantable materials, thereby responding positively to the microenvironment following occluder implantation. Experimental findings substantiate the coating's ability to sustain a prolonged anticoagulant effect, enhance the functionality of endothelial cells and cardiomyocyte, and modulate inflammatory responses by polarizing inflammatory cells into an anti-inflammatory phenotype. Notably, occluder implantation in a canine model confirms that the coating expedites reendothelialization process and promotes tissue healing. Collectively, this tailored ECM-mimetic coating presents a promising surface modification strategy for improving the clinical efficacy of cardiac occluders.

Self-assembled ROS-triggered Bletilla striata polysaccharide-releasing hydrogel dressing for inflammation-regulation and enhanced tissue-healing.

The antimicrobial and pro-healing properties remain critical clinical objectives for skin wound management. However, the escalating problem of antibiotic overuse and the corresponding rise in bacterial resistance necessitates an urgent shift towards an antibiotic-free approach to antibacterial treatment. The quest for antimicrobial efficacy while accelerating wound healing without antibiotic treatment have emerged as innovative strategies in skin wound treatment. Here, a dual-function hydrogel with antimicrobial and enhanced tissue-healing properties was developed by utilizing cyclodextrin, ferrocene, polyethyleneimine (PEI), and Bletilla striata polysaccharide (BSP), through multiple non-covalent interactions, which can intelligently release BSP by recognizing the wound inflammatory microenvironment through the cyclodextrin-ferrocene unit. Moreover, the porosity (65 % - 85 %), Young's modulus (400 KPa - 140 KPa), and DPPH scavenge rate (18 % - 40 %) of the hydrogel are modulated by varying the BSP content. The hydrogel exhibits outstanding antibacterial properties (98.3 % reduction of Escherichia coli observed after exposure to HTFC@BSP-20 for 24 h) and favorable biocompatibility. Furthermore, in a rat full-thickness skin wound model, the dual-function hydrogel significantly accelerates wound healing, increased CD31 expression promotes vascular regeneration, reduced TNF-α express and inhibited the inflammation. This multifunctional ROS responsive hydrogel provides a new perspective for antibiotics-free treatment of skin injuries.

Design and performance of double-layered artificial chordae.

Surgical repair with artificial chordae replacement has emerged as a standard treatment for mitral regurgitation. Expanded polytetrafluoroethylene (ePTFE) sutures are commonly employed as artificial chordae; however, they have certain limitations, such as potential long-term rupture and undesired material/tissue response. This study introduces a novel approach to artificial chordae design, termed the New Artificial Chordae (NAC), which incorporates a double-layered structure. The NAC comprises a multi-strand braided core composed of ultra-high molecular weight polyethylene (UHMWPE) fibers as the inner core, and an outer tube made of hydrophobic porous ePTFE. Compared to traditional ePTFE sutures, NAC exhibits increased flexibility, enhanced tensile strength, longer elongation and improved fatigue resistance. Moreover, NAC exhibits a more hydrophobic surface, which contributes to enhanced hemocompatibility. The study also includes in vivo investigations conducted on animal models to evaluate the biocompatibility and functional efficacy of the artificial chordae. These experiments demonstrate the enhanced durability and biocompatibility of the NAC, characterized by improved mechanical strength, minimal tissue response and reduced thrombus formation. These findings suggest the potential application of NAC as a prosthetic chordae replacement, offering promising prospects to address the limitations associated with current artificial chordae materials and providing novel ideas and approaches for the development of sustainable and biocompatible regenerative biomaterials.

A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.

Drug-eluting stent implantation suppresses the excessive proliferation of smooth muscle cells to reduce in-stent restenosis. However, the efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here, we show that a drug-free coating formulation functionalized with tailored recombinant humanized type III collagen exerts one-produces-multi effects in response to injured tissue following stent implantation. We demonstrate that the one-produces-multi coating possesses anticoagulation, anti-inflammatory, and intimal hyperplasia suppression properties. We perform transcriptome analysis to indicate that the drug-free coating favors the endothelialization process and induces the conversion of smooth muscle cells to a contractile phenotype. We find that compared to drug-eluting stents, our drug-free stent reduces in-stent restenosis in rabbit and porcine models and improves vascular neointimal healing in a rabbit model. Collectively, the one-produces-multi drug-free system represents a promising strategy for the next-generation of stents.

Passivation protein-adhesion platform promoting stent reendothelialization using two-electron-assisted oxidation of polyphenols.

Superhydrophilic surfaces play an important role in nature. Inspired by this, scientists have designed various superhydrophilic materials that are widely used in the field of biomaterials, such as PEG molecular brushes and zwitterionic materials. However, superhydrophilic coatings with only anti-fouling properties do not satisfy the requirements for rapid reendothelialization of cardiovascular stent surfaces. Herein, a novel polyphenol superhydrophilic surface with passivated protein-adsorption properties was developed using two-electron oxidation of dopamine and polyphenols. This coating has a multiscale effects: 1) macroscopically: anti-fouling properties of superhydrophilic; 2) microscopically: protein adhesion properties of active groups (quinone-, amino-, hydroxyphenyl groups and aromatic ring). Polyphenols not only enhance the ability of coating to passivate protein-adsorption, but also make the coating have polyphenol-related biological functions. Therefore, the polyphenol and passivated protein-adsorption platform together maintain the stability of the scaffold microenvironment. This, in turn, provides favorable conditions for the growth of endothelial cells on the scaffold surface. In vivo implantation of the coated stents into the abdominal aorta resulted in uniform and dense endothelial cells covering the surface of the neointima. Moreover, new endothelial cells secreted large amounts of functional endothelial nitric oxide synthase like healthy endothelial cells. These results indicate that the polyphenol superhydrophilic coating potentially resists intra-stent restenosis and promotes surface reendothelialization. Hence, polyphenol superhydrophilic coatings with passivated protein-adsorption properties constructed by two-electron-assisted oxidation are a highly effective and versatile surface-modification strategy for implantable cardiovascular devices.

Polyphenol-mediated sandwich-like coating promotes endothelialization and vascular healing.

Drug-eluting stents have become one of the most effective methods to treat cardiovascular diseases. However, this therapeutic strategy may lead to thrombosis, stent restenosis, and intimal hyperplasia and prevent re-endothelialization. In this study, we selected 3-aminophenylboronic acid-modified hyaluronic acid and carboxylate chitosan as polyelectrolyte layers and embedded an epigallocatechin-3-gallate-tanshinone IIA sulfonic sodium (EGCG-TSS) complex to develop a sandwich-like layer-by-layer coating. The introduction of a functional molecular EGCG-TSS complex improved not only the biocompatibility of the coating but also its stability by enriching the interaction between the polyelectrolyte coatings through electrostatic interactions, hydrogen bonding, π-π stacking, and covalent bonding. We further elucidated the effectiveness of sandwich-like coatings in regulating the inflammatory response, smooth muscle cell growth behavior, stent thrombosis and restenosis suppression, and vessel re-endothelialization acceleration via in vivo and in vitro. Conclusively, we demonstrated that sandwich-like coating assisted by an EGCG-TSS complex may be an effective surface modification strategy for cardiovascular therapeutic applications.

Postfunctionalization of biological valve leaflets with a polyphenol network and anticoagulant recombinant humanized type III collagen for improved anticoagulation and endothelialization.

Almost all commercial bioprosthetic heart valves (BHVs) are crosslinked with glutaraldehyde (GLUT); however, issues such as immune responses, calcification, delayed endothelialization, and especially severe thrombosis threaten the service lifespan of BHVs. Surface modification is expected to impart GLUT-crosslinked BHVs with versatility to optimize service performance. Here, a postfunctionalization strategy was established for GLUT-crosslinked BHVs, which were firstly modified with metal-phenolic networks (MPNs) to shield the exposed calcification site, and then anticoagulant recombinant humanized type III collagen (rhCOLIII) was immobilized to endow them with long-term antithrombogenicity and enhanced endothelialization properties. The postfunctionalization coating exhibited promising mechanical properties and resistance to enzymatic degradation capability resembling that of GLUT-crosslinked porcine pericardium (GLUT-PP). With the introduction of meticulously tailored rhCOLIII, the anti-coagulation and re-endothelialization properties of TA/Fe-rhCOLIII were significantly improved. Furthermore, the mild inflammatory response and reduced calcification were evidenced in TA/Fe-rhCOLIII by subcutaneous implantation. In conclusion, the efficacy of the proposed strategy combining anti-inflammatory MPNs and multifunctional rhCOLIII to improve anticoagulation, reduce the inflammatory response, and ultimately achieve rapid reendothelialization was supported by both ex vivo and in vivo experiments. Altogether, the current findings may provide a simple strategy for enhancing the service function of BHVs after implantation and show great potential in clinical applications.

Polymer Complex Multilayers for Drug Delivery and Medical Devices.

Polymer complex multilayers (PCMs) can be engineered into various structures with tunable properties via layer-by-layer (LBL) assembly driven by noncovalent forces. Due to their ease of preparation, capability of integrating multiple functional components, and excellent substrate compliance, biocompatible PCMs as coating materials or individual entities have attracted extensive attention in biomedical applications. This Spotlight on Applications presents recent progress on PCMs applied for drug delivery and medical devices. We provide several examples to address the importance of using PCM platforms to achieve controlled drug delivery including stimuli-triggered release, sustained release, and spatiotemporal sequential release. The effects of PCM coatings on the bioresponse regulation and performance enhancement of implantable devices are also highlighted. Moreover, the design and fabrication of flexible electrical and optical elements modified with LBL PCMs have been discussed, which demonstrates the great potential to advance emerging wearable devices for disease monitoring and health management.

Drug-Embedded Nanovesicles Assembled from Peptide-Decorated Hyaluronic Acid for Rheumatoid Arthritis Synergistic Therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes endless pain and poor quality of life in patients. Usage of a lubricant combined with anti-inflammatory therapy is considered a reasonable and effective approach for the treatment of RA. Herein, inspired by glycopeptides, a peptide-decorated hyaluronic acid was synthesized, and the grafted Fmoc-phenylalanine-phenylalanine-COOH (FmocFF) peptide self-assembled with ß-sheet conformations could induce the folding of polymer molecular chains to form a vesicle structure in aqueous solution. The hydrophobic anti-inflammatory drug curcumin (Cur) could be embedded in the vesicle walls through π-π interactions with the FmocFF peptide. Furthermore, the inflammation suppression function of the Cur-loaded vesicles both in vitro and in vivo was demonstrated to be an effective treatment for RA therapy. This work proposes new insights into the folding and hierarchical assembly of glycopeptide mimics, providing an efficient approach for constructing intelligent platforms for drug delivery, disease therapy, and diagnostic applications.

An extracellular matrix-mimetic coating with dual bionics for cardiovascular stents.

Anti-inflammation and anti-coagulation are the primary requirements for cardiovascular stents and also the widely accepted trajectory for multi-functional modification. In this work, we proposed an extracellular matrix (ECM)-mimetic coating for cardiovascular stents with the amplified functionalization of recombinant humanized collagen type III (rhCOL III), where the biomimetics were driven by structure mimicry and component/function mimicry. Briefly, the structure-mimic was constructed by the formation of a nanofiber (NF) structure via the polymerization of polysiloxane with a further introduction of amine groups as the nanofibrous layer. The fiber network could function as a three-dimensional reservoir to support the amplified immobilization of rhCoL III. The rhCOL III was tailored for anti-coagulant, anti-inflammatory and endothelialization promotion properties, which endows the ECM-mimetic coating with desired surface functionalities. Stent implantation in the abdominal aorta of rabbits was conducted to validate the in vivo re-endothelialization of the ECM-mimetic coating. The mild inflammatory responses, anti-thrombotic property, promotion of endothelialization and suppression of excessive neointimal hyperplasia confirmed that the ECM-mimetic coating provided a promising approach for the modification of vascular implants.

A review of the development of interventional devices for mitral valve repair with the implantation of artificial chords.

Mitral regurgitation (MR) was the most common heart valve disease. Surgical repair with artificial chordal replacement had become one of the standard treatments for mitral regurgitation. Expanded polytetrafluoroethylene (ePTFE) was currently the most commonly used artificial chordae material due to its unique physicochemical and biocompatible properties. Interventional artificial chordal implantation techniques had emerged as an alternative treatment option for physicians and patients in treating mitral regurgitation. Using either a transapical or a transcatheter approach with interventional devices, a chordal replacement could be performed transcatheter in the beating heart without cardiopulmonary bypass, and the acute effect on the resolution of mitral regurgitation could be monitored in real-time by transesophageal echo imaging during the procedure. Despite the in vitro durability of the expanded polytetrafluoroethylene material, artificial chordal rupture occasionally occurred. In this article, we reviewed the development and therapeutic results of interventional devices for chordal implantation and discuss the possible clinical factors responsible for the rupture of the artificial chordal material.

Surface Engineering of Central Venous Catheters via Combination of Antibacterial Endothelium-Mimicking Function and Fibrinolytic Activity for Combating Blood Stream Infection and Thrombosis.

Long-term blood-contacting devices (e.g., central venous catheters, CVCs) still face the highest incidence of blood stream infection and thrombosis in clinical application. To effectively address these complications, this work reports a dual-functional surface engineering strategy for CVCs by organic integration of endothelium-mimicking and fibrinolytic functions. In this proposal, a lysine (Lys)/Cu2+ -incorporated zwitterionic polymer coating (defined as PDA/Lys/Cu-SB) is designed and robustly fabricated onto commercial CVCs using a facile two-step process. Initially, adhesive ene-functionalized dopamine is covalently reacted with Lys and simultaneously coordinated with bactericidal Cu2+ ions, leading to the deposition of a PDA/Lys/Cu coating on CVCs through mussel foot protein inspired surface chemistry. Next, zwitterionic poly(sulfobetaine methacrylate) (pSB) brushes are grafted onto the PDA/Lys/Cu coating to endow lubricant and antifouling properties. In the final PDA/Lys/Cu-SB coating, endothelium-mimicking function is achieved by combining the catalytic generation of nitric oxide from the chelated Cu2+ with antifouling pSB brushes, which led to significant prevention of thrombosis, and bacterial infection in vivo. Furthermore, the immobilized Lys with fibrinolytic activity show remarkably enhanced long-term anti-thrombogenic properties as evidenced in vivo by demonstrating the capability to lyse nascent clots. Therefore, this developed strategy provides a promising solution for long-term blood-contacting devices to combat thrombosis and infection.

Advances in Injectable Hydrogel Strategies for Heart Failure Treatment.

Heart failure (HF) affects 60 million people worldwide and has developed into a global public health problem surpassing cancer and urgently needs to be solved. According to the etiological spectrum, HF due to myocardial infarction (MI) has become the dominant cause of morbidity and mortality. Possible treatments include pharmacology, medical device implantation, and cardiac transplantation, which are limited in their ability to promote long-term functional stabilization of the heart. Injectable hydrogel therapy has emerged as a minimally invasive tissue engineering treatment approach. Hydrogels can provide the necessary mechanical support for the infarcted myocardium and serve as carriers of various drugs, bioactive factors, and cells to improve the cellular microenvironment in the infarcted region and induce myocardial tissue regeneration. Herein, the pathophysiological mechanism of HF is explored and injectable hydrogels as a potential solution for current clinical trials and applications are summarized. Specifically, mechanical support hydrogels, decellularized ECM hydrogels, a variety of biotherapeutic agent-loaded hydrogels and conductive hydrogels for cardiac repair were discussed, and the mechanism of action of these hydrogel-based therapies was emphasized. Finally, the limitations and future prospects of injectable hydrogel therapy for HF post MI were proposed to inspire novel therapeutic strategies.

A fully degradable transcatheter ventricular septal defect occluder: Towards rapid occlusion and post-regeneration absorption.

Degradable heart occluders are a promising replacement for currently clinically used non-degradable ones without concerns about the complications caused by the persistent residue of a foreign implant. However, the inherent mechanical properties of degradable occluders are poor and decline with material degradation, leading to a preference for a long degradation period upon designing a degradable heart occluder. This configuration can lower the risk of occluder dislodgement but reduce the benefits of degradable implants over their non-degradable counterparts due to a longer retention of foreign materials in the human body. Here, we fabricated a fully degradable ventricular septum defect (VSD) occluder consisting of polydioxanone (PDO) fiber and poly-L-lactic acid (PLLA) membrane featuring an auto-locking function. The degradable occluder showed an excellent shape recovery effect after transcatheter delivery and anchored securely to a heart defect as evidenced by in vitro and in vivo experiments. The degradable occluder could warrant robust fixation ability during the first 3-months of implantation within which tissue reconstruction was accomplished and be completely absorbed within 12 months. Benefitting from these merits, the degradable occluder displayed desired occlusion and no complications after being implanted in the VSD sites of canines during a 24-months follow-up. Compared with traditional non-degradable occluders, our degradable occluder could provide a potentially superior approach for rapidly repairing the congenital VSD without interfering with the normal development and physiological function of the heart.

Hemocompatibility Multi-in-One Hydrogel Coating with ROS-Triggered Inflammation Suppression and Anti-Infection Properties for Blood-Contacting Device.

In traditional blood-contacting medical devices, infection and thrombosis are easily formed on the surface of the materials. In addition, inflammation is also a clinical complication that cannot be ignored. More importantly, there is a mutually promoting relationship between the inflammatory response and the infection as well as thrombosis. In this work, we propose a self-adaptive anti-inflammatory coating strategy combined with anti-infection and anticoagulant capacity, which was accomplished based on nano-Ag particles and dexamethasone (Dex)-loaded hydrogel coating. The coating loaded with nano-Ag endows it with good bactericidal performance, including Gram-positive and Gram-negative bacteria. As an anti-inflammatory drug, Dex was grafted onto hydrogel coating by a reactive oxygen species (ROS)-cleavable thioketal (TK) bond and released upon the trigger of an inflammatory environment, blocking further inflammatory cascade, providing self-adaptive anti-inflammatory properties, and avoiding side effects of the drug. It was demonstrated that the coating worked as a precise strategy to resist coagulation, infection, and inflammation, provided a new perspective for designing clinical complication-conformable coatings, and had great application prospects on blood-contacting medical devices.

Development of Innovative Biomaterials and Devices for the Treatment of Cardiovascular Diseases.

Cardiovascular diseases have become the leading cause of death worldwide. The increasing burden of cardiovascular diseases has become a major public health problem and how to carry out efficient and reliable treatment of cardiovascular diseases has become an urgent global problem to be solved. Recently, implantable biomaterials and devices, especially minimally invasive interventional ones, such as vascular stents, artificial heart valves, bioprosthetic cardiac occluders, artificial graft cardiac patches, atrial shunts, and injectable hydrogels against heart failure, have become the most effective means in the treatment of cardiovascular diseases. Herein, an overview of the challenges and research frontier of innovative biomaterials and devices for the treatment of cardiovascular diseases is provided, and their future development directions are discussed.

Yes-associated protein contributes to magnesium alloy-derivedinflammation in endothelial cells.

Magnesium alloy (Mg alloy) has attracted massive attention in the potential applications of cardiovascular stents because of its good biocompatibility and degradability. However, whether and how the Mg alloy induces inflammation in endothelial cells remains unclear. In the present work, we investigated the activation of Yes-associated protein (YAP) upon Mg alloy stimuli and unveiled the transcriptional function in Mg alloy-induced inflammation. Quantitative RT-PCR, western blotting and immunofluorescence staining showed that Mg alloy inhibited the Hippo pathway to facilitate nuclear shuttling and activation of YAP in human coronary artery endothelial cells (HCAECs). Chromatin immunoprecipitation followed sequencing was carried out to explore the transcriptional function of YAP in Mg alloy-derived inflammation. This led to the observation that nuclear YAP further bonded to the promoter region of inflammation transcription factors and co-transcription factors. This binding event activated their transcription and modified mRNA methylation of inflammation-related genes through regulating the expression of N6-methyladenosine modulators (METTL3, METTL14, FTO and WTAP). This then promoted inflammation-related gene expression and aggravated inflammation in HCAECs. In YAP deficiency cells, Mg alloy-induced inflammation was reduced. Collectively, our data suggest that YAP contributes to the Mg alloy-derived inflammation in HCAECs and may provide a potential therapeutic target that alleviates inflammation after Mg alloy stent implantation.

Ag-Incorporated Polydopamine/Tannic Acid Coating on Titanium With Enhanced Cytocompatible and Antibacterial Properties.

Titanium (Ti) and its alloys are the most commonly used materials for bone implants. However, implant failure often happens due to bacterial infection. Developing antibacterial coatings on Ti implants is an effective strategy. Dopamine and tannic acid were cross-linked to form coating on Ti through Michael addition and Schiff base reaction. In addition, the Ag ions were grafted on the coating by the redox reaction of phenolic hydroxyl groups. Thus, an Ag-incorporated polydopamine/tannic acid coating was prepared on Ti substrate. SEM, EDS, water contact angle, FTIR, and XRD results demonstrated that the coating was formed on Ti successfully. The antibacterial activity of the coating against Gram-negative E. coli was examined, and the cytotoxicity of the coating was investigated by mouse fibroblast cells. The improvement of hydrophilicity, good cytocompatibility, and antibacterial effectiveness indicates that the coating has potential to surface modification of Ti implants.

A Polyphenol-Network-Mediated Coating Modulates Inflammation and Vascular Healing on Vascular Stents.

Localized drug delivery from drug-eluting stents (DESs) to target sites provides therapeutic efficacy with minimal systemic toxicity. However, DESs failure may cause thrombosis, delay arterial healing, and impede re-endothelialization. Bivalirudin (BVLD) and nitric oxide (NO) promote arterial healing. Nevertheless, it is difficult to combine hydrophilic signal molecules with hydrophobic antiproliferative drugs while maintaining their bioactivity. Here, we fabricated a micro- to nanoscale network assembly consisting of copper ion and epigallocatechin gallate (EGCG) via π-π interactions, metal coordination, and oxidative polymerization. The network incorporated rapamycin and immobilized BVLD by the thiol-ene "click" reaction and provided sustained rapamycin and NO release. Unlike rapamycin-eluting stents, those coated with the EGCG-Cu-rapamycin-BVLD complex favored competitive endothelial cell (EC) growth over that of smooth muscle cells, exhibited long-term antithrombotic efficacy, and attenuated the negative impact of rapamycin on the EC. In vivo stent implantation demonstrated that the coating promoted endothelial regeneration and hindered restenosis. Therefore, the polyphenol-network-mediated surface chemistry can be an effective strategy for the engineering of multifunctional surfaces.

A thrombin-triggered self-regulating anticoagulant strategy combined with anti-inflammatory capacity for blood-contacting implants.

Interrelated coagulation and inflammation are impediments to endothelialization, a prerequisite for the long-term function of cardiovascular materials. Here, we proposed a self-regulating anticoagulant coating strategy combined with anti-inflammatory capacity, which consisted of thrombin-responsive nanogels with anticoagulant and anti-inflammatory components. As an anticoagulant, rivaroxaban was encapsulated in nanogels cross-linked by thrombin-cleavable peptide and released upon the trigger of environmental thrombin, blocking the further coagulation cascade. The superoxide dismutase mimetic Tempol imparted the antioxidant property. Polyphenol epigallocatechin gallate (EGCG), in addition to its anti-inflammatory function in synergy with Tempol, also acted as a weak cross-linker to stabilize the coating. The effectiveness and versatility of this coating were validated using two typical cardiovascular devices as models, biological valves and vascular stents. It was demonstrated that the coating worked as a precise strategy to resist coagulation and inflammation, escorted reendothelialization on the cardiovascular devices, and provided a new perspective for designing endothelium-like functional coatings.