Design and Fabrication of Environmentally Responsive Nanoparticles for the Diagnosis and Treatment of Atherosclerosis.

Cardiovascular disease poses a significant threat to human health in today's society. A major contributor to cardiovascular disease is atherosclerosis (AS). The development of plaque in the affected areas involves a complex pathological environment, and the disease progresses rapidly. Nanotechnology, combined with emerging diagnostic and treatment methods, offers the potential for the management of this condition. This paper presents the latest advancements in environment-intelligent responsive controlled-release nanoparticles designed specifically for the pathological environment of AS, which includes characteristics such as low pH, high reactive oxygen species levels, high shear stress, and multienzymes. Additionally, the paper summarizes the applications and features of nanotechnology in interventional therapy for AS, including percutaneous transluminal coronary angioplasty and drug-eluting stents. Furthermore, the application of nanotechnology in the diagnosis of AS shows promising real-time, accurate, and continuous effects. Lastly, the paper explores the future prospects of nanotechnology, highlighting the tremendous potential in the diagnosis and treatment of atherosclerotic diseases, especially with the ongoing development in nano gas, quantum dots, and Metal-Organic Frameworks materials.

Allicin-Loaded Intelligent Hydrogel Coating Improving Vascular Implant Performance.

Coronary atherosclerosis is closely related to inflammation and oxidative stress. Owing to poor biocompatibility, lack of personalized treatment, and late toxic side effects, traditional drug-eluting stent intervention, releasing antiproliferative drugs, can delay endothelial repair and cause late thrombosis. The inflammation caused by atherosclerosis results in an acidic microenvironment and oxidative stress, which can be considered as triggers for precise and intelligent treatment. Here, we used catechol hyaluronic acid (C-HA) and cystamine (Cys) to prepare C-HA-Cys hydrogel coatings by amide reaction. The H2S-releasing donor allicin was loaded in the hydrogel to form an intelligent biomimetic coating. The disulfide bond of Cys made the cross-linked network redox-responsive to the inflammation and oxidative stress in the microenvironment by releasing the drug and H2S intelligently to combat the side effects of stent implantation. This study evaluated the hemocompatibility, anti-inflammatory capacity, vascular wall cytocompatibility, and in vivo histocompatibility of this intelligent hydrogel coating. Furthermore, the effect of H2S released from the coating on atherosclerosis-related signaling pathways such as CD31 and cystathionine γ-lyase (CSE), CD36, and ACAT-1 was investigated. Our results indicate that the C-HA-Cys-Allicin hydrogel coating could be manufactured on the surface of vascular interventional devices to achieve a precise response to the microenvironment of the lesion to release drug, which can attain the purpose of prevention of in-stent restenosis and ensure the effectiveness and safety of the application of interventional devices.

Piranha solution treatment: A facile method for improving the antithrombotic ability and regulating smooth muscle cell growth on blood contact materials.

Blood contact materials require strong anti-fouling capabilities to avoid thrombus formation. Recently, TiO2-based photocatalytic antithrombotic treatment has gained focus. Nevertheless, this method is restricted to titanium materials with photocatalytic abilities. This study offers an alternative solution that can be applied to a broader range of materials: piranha solution treatment. Our findings revealed that the free radicals generated by the treatment effectively altered the surface physicochemical properties of various inorganic materials, enhancing their surface hydrophilicity and oxidizing organic contaminants, thus improving their antithrombotic properties. Additionally, the treatment resulted in contrasting effects on the cellular affinity of SS and TiO2. While it significantly reduced the adhesion and proliferation of SMCs on SS surfaces, it significantly enhanced these on TiO2 surfaces. These observations suggested that the impact of the piranha solution treatment on the cellular affinity of biomaterials was closely tied to the intrinsic properties of the materials. Thus, materials suitable for piranha solution treatment could be selected based on the functional requirements of implantable medical devices. In conclusion, the broad applicability of piranha solution surface modification technology in both blood-contact and bone implant materials highlights its promising prospects.

Photofunctionalized TiO2-TiN micropattern coating with anticoagulant properties and ECs contact-guidance effect.

Titanium nitride (TiN) and titanium dioxide (TiO2) are two titanium-based coatings commonly used in cardiovascular stent surface engineering. Generally, TiN has good mechanical properties and endothelial cell (ECs) compatibility but poor anticoagulant properties and cannot modulate cell growth orientation and morphology. TiO2 has excellent corrosion resistance and biosafety. Besides, TiO2 has the photocatalytic anticoagulant property, which can migrate to other materials tens of microns away. Based on the above properties, a striped TiO2-TiN micropattern coating was designed and fabricated in this study, and the coating was photofunctionalized by UV irradiation. The obtained photo-functionalized TiO2-TiN micropattern coating showed anticoagulant properties by the migrating effect of the photocatalytic anticoagulant property of TiO2. Besides, the TiO2-TiN micropattern coatings showed ECs compatibility. Furthermore, the growth orientation and cell shape of ECs on TiO2-TiN samples were effectively regulated by the stripe pattern's contact guidance effect, which was particularly evident on the photo-functionalized TiO2-TiN samples. We envision that this photofunctionalized TiO2-TiN striped micropattern coating has significant potential for the surface engineering of vascular stents.

Constructing Mal-Efferocytic Macrophage Model and Its Atherosclerotic Spheroids and Rat Model for Therapeutic Evaluation.

Efferocytosis, responsible for apoptotic cell clearance, is an essential factor against atherosclerosis. It is reported that efferocytosis is severely impaired in fibroatheroma, especially in vulnerable thin cap fibroatheroma. However, there is a shortage of studies on efferocytosis defects in cell and animal models. Here, the impacts of oxidized low density lipoprotein (ox-LDL) and glut 1 inhibitor (STF31) on efferocytosis of macrophages are studied, and an evaluation system is constructed. Through regulating the cell ratios and stimulus, three types of atherosclerotic spheroids are fabricated, and a necrotic core emerges with surrounding apoptotic cells. Rat models present a similar phenomenon in that substantial apoptotic cells are uncleared in time in vulnerable plaque, and the model period is shortened to 7 weeks. Mechanism studies reveal that ox-LDL, through mRNA and miRNA modulation, downregulates efferocytosis receptor (PPARγ/LXRα/MerTK), internalization molecule (SLC29a1), and upregulates the competitive receptor CD300a that inhibits efferocytosis receptor-ligand binding process. The foam cell differentiation has also confirmed that CD36 and Lp-PLA2 levels are significantly elevated, and macrophages present an interesting transition into prothrombic phenotype. Collectively, the atherosclerotic models featured by efferocytosis defect provide a comprehensive platform to evaluate the efficacy of medicine and biomaterials for atherosclerosis treatment.

Ellagic Acid-Cyclodextrin Inclusion Complex-Loaded Thiol-Ene Hydrogel with Antioxidant, Antibacterial, and Anti-inflammatory Properties for Wound Healing.

Hydrogel dressings not only have basic functions such as swelling, water retention, gas permeability, and good biocompatibility but also can be endowed with advanced functions such as antibacterial, antioxidant, adhesion, hemostasis, and anti-inflammation, which make hydrogels have great application potential in clinical trauma. However, the complexity of the wound healing process makes the development of multifunctional wound dressings a great challenge. In this work, based on the thiol-ene photoclickable PEG hydrogel, the inclusion complex of the hydrophobic drug ellagic acid (EA) with mono-(6-mercapto-6-deoxy)-ß-cyclodextrin (SH-ß-CD) participated in the formation of a hydrogel as a crosslinker. The drug EA with antioxidant, antibacterial, and anti-inflammatory activities was introduced into the hydrogel. This strategy increases the loading capacity of the hydrogel for EA and endows the hydrogel with multifunctional properties. Then, dithiothreitol was added to adjust the mechanical stiffness of the hydrogel to meet the requirements of the wound dressing. Our results demonstrated that this wound dressing has excellent cytocompatibility, antioxidant, antibacterial, and anti-inflammatory activities. Furthermore, the results of the infected wound healing model experiment in rats confirmed that the hydrogel has the ability to rapidly shrink the wound area, prevent wound infection, and promote angiogenesis and collagen deposition. All these results suggest that this hydrogel could be a candidate for the treatment of infected wounds and shed new light on the development of multifunctional wound dressings.

Effects of Coupled-/soluble-Copper, Generating from Copper-doped Titanium Dioxide Nanotubes on Cell Response.

BACKGROUND: Endothelialization in vitro is a very common method for surface modification of cardiovascular materials. However, mature endothelial cells are not suitable because of the difficulty in obtaining and immunogenicity. METHODS: In this patent work, we determined the appropriate amount of copper by constructing a copper- loaded titanium dioxide nanotube array that can catalyze the release of nitric oxide, compared the effects of coupled-/soluble-copper on stem cells, and then induced stem cells to differentiate into endothelial cells. RESULTS: The results showed that it had a strong promotion effect on the differentiation of stem cells into endothelial cells, which might be used for endothelialization in vitro. CONCLUSION: SEM and EDS results prove that a high content of copper ions are indeed doped onto the surface of nanotubes with small amounts of Cu release. The release of NO confirms that the release of several samples within a period of time is within the physiological concentration.

Multi-functional plant flavonoids regulate pathological microenvironments for vascular stent surface engineering.

In-stent restenosis (ISR) and late thrombosis, usually caused by excessive smooth muscle cell (SMC) proliferation and delayed endothelial layer repair, respectively, are the main risks for the failure of vascular stent implantation. For years, modification of stents with biomolecules that could selectively inhibit SMC proliferation and support endothelial cell (EC) growth had drawn extensive attention. However, the modulatory effect of these biomolecules faces the impact of oxidative stress, inflammation, and hyperlipidemia of the pathological vascular microenvironment, which is caused by the stent implantation injury and atherosclerosis lesions. Here, we modified stents with a natural and multi-functional flavonoid, baicalin (BCL), using poly-dopamine (PDA) coating technology to combat the harmful impact of the pathological microenvironment. Stent with an appropriate BCL immobilization density (approximately 2.03 µg/cm2) successfully supported ECs growth while inhibited SMC proliferation. Furthermore, baicalin-modified surfaces regulated the oxidative stress, inflammation, and high-lipid of the pathological microenvironment to inhibit endothelial dysfunction and the oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cells formation. In vivo results showed that baicalin-modified stents exhibited significant anti-ISR, anti-inflammatory, and endothelialization-promoting functions. Our study suggests that the multi-functional baicalin with pathological microenvironment-regulation (PMR) effect has potential use in the surface engineering of cardiovascular devices. STATEMENT OF SIGNIFICANCE: Empowering vascular stents with selective modulation of smooth muscle cells and endothelial cells by surface technology has become an important research direction for stent surface engineering. However, stent coatings that can furthermodulate the pathological microenvironment of blood vessels have been rarely reported. In this study, we constructed a multifunctional coating based on a flavonoid, baicalin, which can selectively modulate vascular wall cells and improve the pathological microenvironment. This study may provide a reference for developing advanced vascular stents.

Dual-catalytic CuTPP/TiO2 nanoparticles for surface catalysis engineering of cardiovascular materials.

Endowing materials with catalytic activities analogous to those of the natural endothelium to thus enhance their biological performance has become an option for constructing advanced blood-contact materials. The electron transfer between Cu2+ and Cu+ in the porphyrin center can catalyze the reaction of GSH and GSNO to generate NO, and this electron transfer can also catalyze the decomposition of ROS. Based on this, we created a dual-catalytic surface possessing NO-generating and ROS-scavenging activities to better mimic the versatile catalytic abilities of the endothelium. Copper tetraphenylporphyrin/titanium dioxide nanoparticles (CuTPP/TiO2-NPs) exhibiting excellent NO-generating and ROS-scavenging activities were synthesized and immobilized on the material surface to form a dual-catalytic film (CuTPP/TiO2-film) with the help of the catechol chemistry technique. Unlike most single catalytic surfaces, the dual-catalytic CuTPP/TiO2-film effectively regulated the microenvironment surrounding the implanted device by releasing NO signaling molecules and scavenging harmful ROS. This dual-catalytic film exhibited excellent biosafety and biocompatibility with anti-thrombosis, vascular wall cells (ECs and SMCs) modulation, and anti-inflammatory properties. We envision that this dual-catalytic endothelial bionic strategy may provide a promising solution to the clinical problems plaguing blood-contact devices and provide a novel basis for the further development of surface catalytic-engineered biomaterials.

Exosome-Loaded Pro-efferocytic Vascular Stent with Lp-PLA2-Triggered Release for Preventing In-Stent Restenosis.

The efferocytosis defect is regarded as a pivotal event of atherosclerosis. The failure to clear apoptotic cells in atherosclerotic plaques under vascular stents causes a failure to resolve the inflammation underneath. However, efferocytosis repair is still confined to nonstenting therapeutics. Here, we identified a pro-efferocytotic agent and accordingly developed a bioresponsive pro-efferocytotic vascular stent aimed for poststenting healing. Exosomes derived from mesenchymal stem cells were found to be able to regulate efferocytosis via SLC2a1, STAT3/RAC1, and CD300a pathways and modulate foam cell formation processes through a CD36-mediated pathway. Pro-efferocytotic exosomes were encapsulated into liposome-based multivesicular chambers and grafted onto vascular stents. The multivesicular vesicles were able to release exosomes under the Lp-PLA2 environment. Compared to bare metal stents, exosome-stents in the presence of Lp-PLA2 enhanced the ratio of apoptotic cell clearance and reduced the neointimal thickness in the mal-efferocytotic rat model. Overall, we identified a pro-efferocytic agent─exosomes that are able to regulate target cells via multiple signaling pathways and are good candidates to serve complex pathological environments, and this bioresponsive pro-efferocytotic vascular stent is an attractive approach for prevention of poststenting complications.

Catechol-chitosan/polyacrylamide hydrogel wound dressing for regulating local inflammation.

Chronic wounds and the accompanying inflammation are ongoing challenges in clinical treatment. They are usually accompanied by low pH and high oxidative stress environments, limiting cell growth and proliferation. Ordinary medical gauze has limited therapeutic effects on chronic wounds, and there is active research to develop new wound dressings. The chitosan hydrogel could be widely used in biomedical science with great biocompatibility, but the low mechanical properties limit its development. This work uses polyacrylamide to prepare double-network (DN) hydrogels based on bioadhesive catechol-chitosan hydrogels. Cystamine and N, N'-Bis(acryloyl)cystamine, which can be cross-linking agents with disulfide bonds to prepare redox-responsive DN hydrogels and pH-responsive nanoparticles (NPs) prepared by acetalized cyclodextrin (ACD) are used to intelligently release drugs against chronic inflammation microenvironments. The addition of catechol groups and ACD-NPs loaded with the Resolvin E1 (RvE1), promotes cell adhesion and regulates the inflammatory response at the wound site. The preparation of the DN hydrogel in this study can be used to treat and regulate the inflammatory microenvironment of chronic wounds accurately. It provides new ideas for using inflammation resolving factor loaded in DN hydrogel of good biocompatibility with enhanced mechanical properties to intelligent regulate the wound inflammation and promote the wound repaired.

WITHDRAWN: Specialized Pro-resolving Lipid Mediators: Endogenous Regulation of Vascular Inflammation and Remodeling

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Enhanced Hemocompatibility of Silver Nanoparticles Using the Photocatalytic Properties of Titanium Dioxide.

Silver nanoparticles (AgNPs) are widely used because of their excellent antimicrobial properties. However, the poor hemocompatibility limits the application of AgNPs in blood contact materials. General approaches to improve the hemocompatibility of AgNPs-containing surfaces are to construct barrier layers or co-immobilize anticoagulant biomolecules. But such modification strategies are often cumbersome to prepare and have limited applications. Therefore, this study proposes a simple UV-photo-functionalization strategy to improve the hemocompatibility of AgNPs. We loaded AgNPs onto titanium dioxide (TiO2) nanoparticles to form a composite nanoparticles (Ag@TiO2NPs). Then, UV treatment was performed to the Ag@TiO2NPs, utilizing the diffusible photo-induced anticoagulant properties of TiO2 nanoparticles to enhance the hemocompatibility of AgNPs. After being deposited onto the PU surface, the photo-functionalized Ag@TiO2NPs coating showed excellent antibacterial properties against both Gram-positive/Gram-negative bacteria. Besides, In vitro and ex-vivo experiments demonstrated that the photo-functionalized Ag@TiO2NPs coating had desirable hemocompatibility. This modification strategy can provide a new solution idea to improve the hemocompatibility of metal nanoparticles.

Design and Optimization of the Circulatory Cell-Driven Drug Delivery Platform.

Achievement of high targeting efficiency for a drug delivery system remains a challenge of tumor diagnoses and nonsurgery therapies. Although nanoparticle-based drug delivery systems have made great progress in extending circulation time, improving durability, and controlling drug release, the targeting efficiency remains low. And the development is limited to reducing side effects since overall survival rates are mostly unchanged. Therefore, great efforts have been made to explore cell-driven drug delivery systems in the tumor area. Cells, particularly those in the blood circulatory system, meet most of the demands that the nanoparticle-based delivery systems do not. These cells possess extended circulation times and innate chemomigration ability and can activate an immune response that exerts therapeutic effects. However, new challenges have emerged, such as payloads, cell function change, cargo leakage, and in situ release. Generally, employing cells from the blood circulatory system as cargo carriers has achieved great benefits and paved the way for tumor diagnosis and therapy. This review specifically covers (a) the properties of red blood cells, monocytes, macrophages, neutrophils, natural killer cells, T lymphocytes, and mesenchymal stem cells; (b) the loading strategies to balance cargo amounts and cell function balance; (c) the cascade strategies to improve cell-driven targeting delivery efficiency; and (d) the features and applications of cell membranes, artificial cells, and extracellular vesicles in cancer treatment.

Cell-friendly photo-functionalized TiO2 nano-micro-honeycombs for selectively preventing bacteria and platelet adhesion.

Titanium dioxide (TiO2) is a widely used biomaterial. It is a great challenge to confer antibacterial and antithrombotic properties to TiO2 while maintaining its cell affinity. Here, we developed a new strategy to achieve the above goal by comprehensively controlling the chemical cues and geometrical cues of the surface of TiO2. Using colloidal etching technology and UV irradiation treatment, we obtained the photofunctionalized nano-micro-honeycomb structured TiO2. The honeycomb structured increased the photocatalytic activity of TiO2, which endowed TiO2 with photo-induced superhydrophilicity to inhibit bacterial adhesion. The high photocatalytic activity also induced the strong photocatalytic oxidation of TiO2 surface organic adsorbates to suppress fibrinogen and platelet attachment. In addition, owing to the micropore trapping-isolation effect on the bacteria and the nano-frames' contact guidance effect on the growth and spreading of platelet pseudopods, the honeycomb structure also shows a considerable inhibiting effect on bacterial and platelet adhesion. Therefore, due to the controlled chemical and geometrical cues' synergistic effect, the photo-functionalized TiO2 honeycomb structure shows excellent bacterial-adhesion resistance and antithrombotic properties. More importantly, the photo-functionalized TiO2 honeycomb did not inhibit the adhesion and growth of endothelial cells (ECs) after culturing for 3 d, indicating a good cell affinity that the traditional antifouling surfaces do not possess.

Comparison of in Vascular Bioreactors and In Vivo Models of Degradation and Cellular Response of Mg-Zn-Mn Stents.

Traditional in vitro evaluation criteria of magnesium (Mg)-based stents cannot reflect the degradation process in vivo, due to the interdependence and interference between biodegradable properties and bioenvironment. The current direct and indirect evaluation approaches of in vitro biocompatibility do not have a hydrodynamic environment and vascular biological structure existing in vivo. Herein, we designed a vascular bioreactor to provide an ex vivo culture environment for vessels, which reveals the degradation behavior of Mg-Zn-Mn stent and the effect of its degradation on cells. We reported that rabbit carotid arteries could maintain native morphology and viability in the bioreactor under the best condition within a flow rate of 5.4 mL min-1 and a culture time of one week. With this culture condition, Mg-Zn-Mn stents were implanted into the arteries in the bioreactors and compared with in vivo rabbit models. The arteries maintained cell survival in the bioreactor, but the cell attachment was absent on the stent struts, associated with a fast degradation. Conversely, the stents achieved a rapid and complete endothelialization in vivo for two weeks. This study could provide a correlation and difference of the degradation behavior and cellular response to the degradation of Mg-based stent between ex vivo and in vivo approaches.

In vitro performance of 3D printed PCL-ß-TCP degradable spinal fusion cage.

Spinal fusion cages are commonly used to treat spinal diseases caused by degenerative changes, deformities, and trauma. At present, most of the main clinical spinal fusion cage products are non-degradable and still cause some undesirable side effects, such as the stress shielding phenomenon, interference with postoperative medical imaging, and obvious foreign body sensation in patients. Degradable spinal fusion cages have promising potential with extensive perspectives. The purpose of this study was to fabricate a degradable spinal fusion cage from both polycaprolactone (PCL) and high-proportion beta-tricalcium phosphate (ß-TCP), using the highly personalised, accurate, and rapid fused deposition modelling 3 D printing technology. PCL and ß-TCP were mixed in three different ratios (60:40, 55:45, and 50:50). Both in vitro degradation and cell experiments proved that all cages with the different PCL:ß-TCP ratios met the mechanical properties of human cancellous bone while maintaining their structural integrity. The biological activity of the cages improved with higher amounts of the ß-TCP content. This study also showed that a spinal fusion cage with high ß-TCP content and suitable mechanical properties can be manufactured using extruding rods and appropriate models, providing a new solution for the design of degradable spinal fusion cages.

Intelligent H2S release coating for regulating vascular remodeling.

Coronary atherosclerotic lesions exhibit a low-pH chronic inflammatory response. Due to insufficient drug release control, drug-eluting stent intervention can lead to delayed endothelialization, advanced thrombosis, and unprecise treatment. In this study, hyaluronic acid and chitosan were used to prepare pH-responsive self-assembling films. The hydrogen sulfide (H2S) releasing aspirin derivative ACS14 was used as drug in the film. The film regulates the release of the drug adjusted to the microenvironment of the lesion, and the drug balances the vascular function by releasing the regulating gas H2S, which comparably to NO promotes the self-healing capacity of blood vessels. Drug releasing profiles of the films at different pH, and other biological effects on blood vessels were evaluated through blood compatibility, cellular, and implantation experiments. This novel method of self-assembled films which H2S in an amount, which is adjusted to the condition of the lesion provides a new concept for the treatment of cardiovascular diseases.

Photo-functionalized TiO2 nanotubes decorated with multifunctional Ag nanoparticles for enhanced vascular biocompatibility.

Titanium dioxide (TiO2) has a long history of application in blood contact materials, but it often suffers from insufficient anticoagulant properties. Recently, we have revealed the photocatalytic effect of TiO2 also induces anticoagulant properties. However, for long-term vascular implant devices such as vascular stents, besides anticoagulation, also anti-inflammatory, anti-hyperplastic properties, and the ability to support endothelial repair, are desired. To meet these requirements, here, we immobilized silver nanoparticles (AgNPs) on the surface of TiO2 nanotubes (TiO2-NTs) to obtain a composite material with enhanced photo-induced anticoagulant property and improvement of the other requested properties. The photo-functionalized TiO2-NTs showed protein-fouling resistance, causing the anticoagulant property and the ability to suppress cell adhesion. The immobilized AgNPs increased the photocatalytic activity of TiO2-NTs to enhances its photo-induced anticoagulant property. The AgNP density was optimized to endow the TiO2-NTs with anti-inflammatory property, a strong inhibitory effect on smooth muscle cells (SMCs), and low toxicity to endothelial cells (ECs). The in vivo test indicated that the photofunctionalized composite material achieved outstanding biocompatibility in vasculature via the synergy of photo-functionalized TiO2-NTs and the multifunctional AgNPs, and therefore has enormous potential in the field of cardiovascular implant devices. Our research could be a useful reference for further designing of multifunctional TiO2 materials with high vascular biocompatibility.