Improved Blood Compatibility Research Articles

Fabrication of an Antibacterial/Anticoagulant Dual-Functional Surface for Left Ventricular Assist Devices via Mussel-Inspired Polydopamine Chemistry.

Infections and thrombosis remain unsolved problems for implanted cardiovascular devices, such as left ventricular assist devices. Hence, the development of surfaces with improved blood compatibility and antimicrobial properties is imperative to reduce complications after artificial heart implantation. In this work, we report a novel approach to fabricate multifunctional surfaces for left ventricular transplanted ventricular assist devices (LVADs) by immobilizing nitric oxide (NO) generation catalysts and heparin and reducing silver nanoparticles in situ. The general view, structure, and chemical compositions of the pure/modified surfaces were characterized using digital imaging, scanning electron microscope (SEM), atomic force microscope (AFM), water contact angle (WCA), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma (ICP). All of the results demonstrated that the AgNPs and heparin were successfully immobilized on the surface. The Cu ions and NO release experimental results showed that the immobilized copper ions could catalyze the production of NO from S-nitrosothiols within the biological system. Meanwhile, due to the synergistic anticoagulant effect of NO and surface-immobilized heparin, the fabricated modified surfaces exhibited antiplatelet adhesion activities and good hemocompatibility. Finally, the antimicrobial activity of the samples was evaluated by Escherichia coli and Staphylococcus aureus, and cytocompatibility was measured using human umbilical vein endothelial cells (HUVECs). The results demonstrated that silver nanoparticles (AgNPs) immobilized by surface reduction reaction did not cause any significant inhibition of cell proliferation while providing stable and effective antimicrobial properties. We envision that this simple surface modification strategy with bifunctional activities of antimicrobial and anticoagulant will find widespread use in clinically used indwelling left ventricular assist devices.

FeMnCSi alloy for degradable pin implants: Surface and in vitro characterization

Biodegradable metals such iron-based materials, are studied as temporary implants in the orthopedic field due to their adequate mechanical properties, non-toxic degradation products, and the possibility of avoiding a second surgical intervention to remove the device. One strategy to overcome the slow degradation rate of pure Fe is the addition of alloying elements. The aim of this work is to characterize the in vitro behavior of a new FeMnCSi alloy (Fe 26.5Mn 0.5C 1.14Si 0.03P 0.01S), and compare it with the performance of pure iron in simulated body fluid. The alloy performance was characterized in terms of chemical composition, microstructure, hemocompatibility and electrochemical responseIt has been found that FeMnCSi alloy presented a marked and progressive degradation in simulated body fluid after 14 days of immersion, significantly larger than pure Fe. The presence of phosphate-based compounds was confirmed on the surface of the alloy after 1 day of immersion while only after 14 days of immersion was detected on Fe. Additionally, the FeMnCSi alloy demonstrates improved blood compatibility compared to pure iron, indicating its suitability for applications in irrigated areas such as bones.

Hybrid Materials for Vascular Applications: A Preliminary In Vitro Assessment.

The production of biomedical devices able to appropriately interact with the biological environment is still a great challenge. Synthetic materials are often employed, but they fail to replicate the biological and functional properties of native tissues, leading to a variety of adverse effects. Several commercial products are based on chemically treated xenogeneic tissues: their principal drawback is due to weak mechanical stability and low durability. Recently, decellularization has been proposed to bypass the drawbacks of both synthetic and biological materials. Acellular materials can integrate with host tissues avoiding/mitigating any foreign body response, but they often lack sufficient patency and impermeability. The present paper investigates an innovative approach to the realization of hybrid materials that combine decellularized bovine pericardium with polycarbonate urethanes. These hybrid materials benefit from the superior biocompatibility of the biological tissue and the mechanical properties of the synthetic polymers. They were assessed from physicochemical, structural, mechanical, and biological points of view; their ability to promote cell growth was also investigated. The decellularized pericardium and the polymer appeared to well adhere to each other, and the two sides were distinguishable. The maximum elongation of hybrid materials was mainly affected by the pericardium, which allows for lower elongation than the polymer; this latter, in turn, influenced the maximum strength achieved. The results confirmed the promising features of hybrid materials for the production of vascular grafts able to be repopulated by circulating cells, thus, improving blood compatibility.

Graphene Oxide Chemical Refining Screening to Improve Blood Compatibility of Graphene-Based Nanomaterials

Graphene oxide (GO) nanoparticles, due to their favorable water solubility, compared to graphene (GA), are a hot research topic in biomedical and pharmaceutical research. However, GO clinical translation may be complicated by its high surface/volume ratio enhancing the interaction with human blood components. In fact, GO’s bi-dimensional nature and strong negative charge may lead to severe biological effects, such as thrombogenicity and immune cell activation. This study explores the impact of further GO surface chemical modulation on major adverse effects: blood plasma coagulation and hemolysis. To this aim, we refined GO nanoparticles by fine-tuned reduction chemistry, esterification and introduction of negative or positive charges. With this approach, we were able to mitigate plasma coagulation and hemolysis at variable degrees and to identify GO derivatives with improved biocompatibility. This opens the door to the progress of graphene-based nanotheranostic applications.

Characterization and Performance Evaluation of Magnesium Chloride-Enriched Polyurethane Nanofiber Patches for Wound Dressings.

Wound patches are essential for wound healing, yet developing patches with enhanced mechanical and biological properties remains challenging. This study aimed to enhance the mechanical and biological properties of polyurethane (PU) by incorporating magnesium chloride (MgCl2) into the patch. The composite patch was fabricated using the electrospinning technique, producing nanofibers from a mixture of PU and MgCl2 solutions. The electrospun PU/MgCl2 was then evaluated for various physico-chemical characteristics and biological properties to determine its suitability for wound healing applications. Tensile strength testing showed that the mechanical properties of the composite patch (10.98 ± 0.18) were significantly improved compared to pristine PU (6.66 ± 0.44). Field scanning electron microscopy (FESEM) revealed that the electrospun nanofiber patch had a smooth, randomly oriented non-woven structure (PU - 830 ± 145 nm and PU/MgCl2 - 508 ± 151 nm). Fourier infrared spectroscopy (FTIR) confirmed magnesium chloride's presence in the polyurethane matrix via strong hydrogen bond formation. Blood compatibility studies using coagulation assays, including activated partial thromboplastin time (APTT), prothrombin time (PT), and hemolysis assays, demonstrated improved blood compatibility of the composite patch (APTT - 174 ± 0.5 s, PT - 91 ± 0.8s, and Hemolytic percentage - 1.78%) compared to pristine PU (APTT - 152 ± 1.2s, PT - 73 ± 1.7s, and Hemolytic percentage - 2.55%). Antimicrobial testing showed an enhanced zone of inhibition (Staphylococcus aureus - 21.5 ± 0.5 mm and Escherichia coli - 27.5 ± 2.5 mm) compared to the control, while cell viability assays confirmed the non-cytotoxic nature of the developed patches on fibroblast cells. The study concludes that adding MgCl2 to PU significantly improves the mechanical, biological, and biocompatibility properties of the patch. This composite patch shows potential for future wound healing applications, with further studies needed to validate its efficacy in-vivo.

Hydrogen sulfide releasing and carboxybetaine modified vascular graft with enhanced anticoagulant, anticalcification, and pro-endothelialization properties

In the cardiovascular system, hydrogen sulfide(H2S) gasotransmitter regulates physiological processes involved in vasorelaxation, cardioprotection, anti-inflammation, and anti-oxidation. In this study, H2S releasing and carboxybetaine modified vascular graft with enhanced anticoagulant, anticalcification, and pro-endothelialization properties was designed and fabricated to meet the demand for small-diameter vascular grafts. Initially, a keratin-based bio-macromolecular donor of H2S was synthesized and then coelectrospun with polycaprolactone(PCL) to afford nanofibrous mats. Next, zwitterionic carboxybetaine was immobilized through dopamine self-polymerization to prolong the release of H2S, improve blood compatibility, and reduce calcification effectively. The biocomposite mats performed cell selectivity by promoting the adhesion and migration of HUVECs while inhibiting the proliferation of HUASMCs. Furthermore, the mats showed an excellent ability to resist oxidative stress. The results of the 3D perfusion culture proved that the grafts could promote endothelium formation under shear force. In vivo implantation results suggested that these grafts were capable of facilitating rapid endothelialization and reducing calcification.

Controlled and customizable baculovirus NOS3 gene delivery using PVA-based hydrogel systems.

Nitric oxide synthase 3 (NOS3) eluting polyvinyl alcohol-based hydrogels have a large potential in medical applications and device coatings. NOS3 promotes nitric oxide and nitrate production and can effectively be delivered using insect cell viruses, termed baculoviruses. Nitric oxide is known for regulating cell proliferation, promoting blood vessel vasodilation, and inhibiting bacterial growth. The polyvinyl alcohol (PVA)-based hydrogels investigated here sustained baculovirus elution from five to 25 days, depending on the hydrogel composition. The quantity of viable baculovirus loaded significantly declined with each freeze-thaw from one to four (15.3 ± 2.9% vs. 0.9 ± 0.5%, respectively). The addition of gelatin to the hydrogels protected baculovirus viability during the freeze-thaw cycles, resulting in a loading capacity of 94.6 ± 1.2% with sustained elution over 23 days. Adding chitosan, PEG-8000, and gelatin to the hydrogels altered the properties of the hydrogel, including swelling, blood coagulation, and antimicrobial effects, beneficial for different therapeutic applications. Passive absorption of the baculovirus into PVA hydrogels exhibited the highest baculovirus loading (96.4 ± 0.6%) with elution over 25 days. The baculovirus-eluting hydrogels were hemocompatible and non-cytotoxic, with no cell proliferation or viability reduction after incubation. This PVA delivery system provides a method for high loading and sustained release of baculoviruses, sustaining nitric oxide gene delivery. This proof of concept has clinical applications as a medical device or stent coating by delivering therapeutic genes, improving blood compatibility, preventing thrombosis, and preventing infection.

Improving the Performance of Poly(caprolactone)-Cellulose Acetate-Tannic Acid Tubular Scaffolds by Mussel-Inspired Coating.

Small-diameter artificial blood vessels are increasingly being used in clinical practice. However, these vessels are prone to thrombus, and it is necessary to improve blood compatibility. Surface coating is one of the commonly used methods in this regard. Inspired by the biomimicry of mussels, the use of deposition technology to obtain coating coverage on the surface of fibers has significantly piqued the interest of researchers recently. In this study, tubular scaffolds consisting of a composite of poly(caprolactone), cellulose acetate, and tannic acid (TA) were electrospun, and then the scaffolds were treated with different Fe(III) solutions (iron(III) chloride hexahydrate (FeCl3'6H2O)) to obtain four tubular scaffolds: F0, F5, F15, and F45. According to scanning electron microscopy (SEM) and field emission-SEM results, TA/Fe(III) complex is coated on the fiber of the scaffold after post-treatment; the fiber surface morphology changes with different Fe(III) concentrations. This provides designability to the performance of tubular scaffolds. The tensile strength of the F5 tubular scaffold (3.33 MPa) is higher than that of F45 (3.14 MPa), while the strain (83.9%) of the F45 tubular stent was 2.26 times that of the F5 (37.2%). In addition, cytotoxicity and antithrombotic performance were evaluated. The test results show that surface TA/Fe(III) coating treatment can affect the cytotoxicity and anticoagulation performance of the scaffold surface. The biomimetic TA/Fe(III) coating of mussels used in this study improves the performance of artificial blood vessels.

P44: Toward 3D-Printed Microfluidic Artificial Lungs with Complex, Biomimetic Geometries

Purpose: Current hollow-fiber oxygenators used in Extracorporeal Membrane Oxygenation have suboptimal gas exchange performance and hemocompatibility. Microfluidic artificial lungs (µALs) promise smaller feature sizes, improving gas exchange efficiency, and biomimetic flow paths, improving blood compatibility. For the first time, we leverage the geometric freedom of 3D-printing technology to demonstrate µALs with truly 3D, biomimetic branching capillaries and gas-side designs to increase gas exchange surface area. Methods: Two µAL designs were generated in Solidworks and printed on an Asiga MAX X27 UV printer. The first was a “simple branching” µAL (Fig 1A) with quadfurcating, biomimetic branching for blood distribution. The second was a “hatched” µAL (Fig 1B) employing a gas phase with strategically placed supports to maximize gas exchange surface area while maintaining structural stability. These changes are only to the gas, and so the blood-phase is unchanged. Dyed water was used to visualize internal structures (Fig 1D). Geometric analysis and proven models were used to calculate theoretical shear rate and rated flow. Computational Fluid Dynamics (CFD) was used to visualize flow (Fig 1E,F). Experimental pressure drop vs water flow rates were measured (Fig 2). Results: Through geometric analysis (Table 1), branching distribution technique provides more uniform shear stress (0.95-1.34 dyn/cm2) compared to a non-branching “open-plenum” control (0.09-1.27 dyn/cm2). The hatched µAL has a 3.18 mL/min rated flow, 1.7x greater than the 1.84 mL/min rated flow of the non-hatched branching µAL. As a result of the higher rated flow, it also has higher theoretical shear of 1.64-2.31 dyn/cm2 (at rated flow) despite identical blood-side geometry. The branching lung demonstrated a pressure drop up to 12 mmHg at flows up to 5 mL/min (Fig 2). These are significantly larger than analytically predicted values (extrapolated 7 mmHg vs 0.233 mmHg at 3.2 mL/min), prompting investigation into resolution of internal capillaries and effects of surface roughness on pressure drop. Conclusion: We have demonstrated the first 3D-printed branching biomimetic µAL formed from a gas permeable material, with gas-side geometries to improve gas exchange efficiency. These geometries are expected to translate to greater blood flows enabling creation of future animal and human-scale µALs. Table 1. Theoretical calculations. All uALs have 256 8.5mm long 216x324 µm blood and gas channels, with 54 µm-thick membranes. They differ in their effective gas exchange area, and blood distribution method, resulting in differing rated flows, shears, and pressure drops. The Branching uAL employs a branching distribution, resulting in a much tighter shear stress range. The GasHatch uAL employs both a branching distribution, and a blood-gas geometric-synchronization, with 100% rather than 58% of the gas-exchange capillary face being used for gas exchange. Values for a theoretical “control” lung (not fabricated; contains an open plenum/ non-branching distribution region) are displayed for comparison. Flow velocity and shear stresses are calculated separately for capillary and distribution areas.Figure 1. Blood flows are indicated using red arrows, and gas flows are indicated using blue arrows. (A) Design of simple (non-hatched) branched μAL. (B) Close-up of the hatched μAL capillaries and gas channels, showing how gas-side supports are only in regions not adjacent to capillaries and therefore not reducing gas exchange surface area. (C) Hatched μAL with the gas phase filled with blue dye for visualization. (D) Non-hatched branching μAL with blood phase filled with blue dye, and gas phase filled with red dye. (E) CFD visualization of flow velocities in the branching blood distribution network; (F) CFD analysis of pressure drop in the biomimetic blood distribution channels.Figure 2. Pressure drop of branching µALs (water; n=3)

Bioinspired PLCL/Elastin Nanofibrous Vascular Tissue Engineering Scaffold Enhances Endothelial Cells and Inhibits Smooth Muscle Cells.

In vascular tissue engineering, a scaffold that can enhance the proliferation of endothelial cells (ECs) while inhibiting the synthetic differentiation of smooth muscle cells (SMCs) is crucial to prevent thrombus and restenosis after graft implantation. However, it is always challenging to incorporate both properties simultaneously in a vascular tissue engineering scaffold. In this study, a novel composite material was developed by combining a synthetic biopolymer of poly(l-lactide-co-caprolactone) (PLCL) and a natural biopolymer of elastin through electrospinning. Cross-linking of the PLCL/elastin composite fibers using EDC/NHS was performed to stabilize the elastin component. The incorporation of elastin into PLCL was found to enhance the hydrophilicity and biocompatibility of the resulting PLCL/elastin composite fibers, as well as the mechanical properties. Additionally, as a natural component of the extracellular matrix, elastin displayed antithrombotic properties reducing platelet adhesion and improving blood compatibility. Results of cell culture experiments with human umbilical vein ECs (HUVECs) and human umbilical artery SMCs (HUASMCs) showed that the composite fiber membrane had high cell viability, promoting the proliferation and adhesion of HUVECs and inducing a contractile phenotype in HUASMCs. These results indicate that the PLCL/elastin composite material has great potential for use in vascular graft applications due to its favorable properties and rapid endothelialization and contractile phenotypes of cells.

Preparation and properties of cellulose acetate graft copolymer‐coated adsorbent resin for hemoperfusion device

AbstractIn this paper, acrylic acid (AA) and sodium styrene sulfonate (SSS) were grafted onto the surface of cellulose acetate (CA) by free radical polymerization to obtain a heparin unit‐containing graft copolymer CA‐g‐P(AA/SSS). It was used to coat the adsorbent resin for disposable hemoperfusion devices to improve blood compatibility. The adsorption capacity of the modified CA‐coated adsorbent resin to creatinine, Vitamin B12, bilirubin, and imidacloprid was tested. The results showed that the modified CA‐coated adsorbent resin had a good adsorption effect on small and medium‐sized molecules. The hemolysis and coagulation tests showed that the CA‐g‐P(AA/SSS) coating could greatly improve the blood compatibility of the adsorbent resin. The hemolysis rate was 1.6%, which met the requirement of international standards for the hemolysis rate of blood contact equipment less than 5%. The coagulation index was higher than 1.55, which was comparable to the heparin‐preflashed HA130 currently in use. In addition, the CA‐g‐P(AA/SSS)‐coated adsorbent resin has good biocompatibility, no pyrogenic reaction, low vitro cytotoxicity, and no acute systemic toxicity. The resin has a good application prospect in uremia, hyperbilirubinemia, and rapid treatment of pesticide poisoning.

Improved Hemocompatibility on Superhemophobic Micro-Nano-Structured Titanium Surfaces.

Blood-contacting titanium-based implants such as endovascular stents and heart valve casings are prone to blood clotting due to improper interactions at the surface level. In complement, the current clinical demand for cardiovascular implants is at a new apex. Hence, there is a crucial necessity to fabricate an implant with optimal mechanical properties and improved blood compatibility, while simultaneously interacting differentially with cells and other microbial agents. The present study intends to develop a superhydrophobic implant surface with the novel micro-nano topography, developed using a facile thermochemical process. The surface topography, apparent contact angle, and crystal structure are characterized on different surfaces. The hemo/blood compatibility on different surfaces is assessed by evaluating hemolysis, fibrinogen adsorption, cell adhesion and identification, thrombin generation, complement activation, and whole blood clotting kinetics. The results indicate that the super-hemo/hydrophobic micro-nano titanium surface improved hemocompatibility by significantly reducing fibrinogen adsorption, platelet adhesion, and leukocyte adhesion. Thus, the developed surface has high potential to be used as an implant. Further studies are directed towards analyzing the mechanisms causing the improved hemocompatibility of micro/nano surface features under dynamic in vitro and in vivo conditions.

Tannic Acid-Assisted Immobilization of Copper(II), Carboxybetaine, and Argatroban on Poly(ethylene terephthalate) Mats for Synergistic Improvement of Blood Compatibility and Endothelialization.

Due to thrombosis and intimal hyperplasia, small-diameter vascular grafts have poor long-term patency. A combination strategy based on nitric oxide (NO) and anticoagulants has the potential to address those issues. In this study, poly(ethylene terephthalate) (PET) mats were prepared by electrospinning and coated with tannic acid (TA)/copper ion complexes. The chelated copper ions endowed the mats with sustained NO generation by catalytic decomposition of endogenous S-nitrosothiol. Subsequently, zwitterionic carboxybetaine acrylate (CBA) and argatroban (AG) were immobilized on the mats. The introduced AG and CBA had synergistic effects on the improvement of blood compatibility, resulting in reduced platelet adhesion and prolonged blood clotting time. The biocomposite mats selectively promoted the proliferation and migration of human umbilical vein endothelial cells while inhibiting the proliferation and migration of human umbilical arterial smooth muscle cells under physiological conditions. In addition, the prepared mats exhibited antibacterial activity against Escherichia coli and Staphylococcus aureus. Collectively, the prepared mats hold great promise as artificial small-diameter vascular grafts.

One-step PDA coating strategy on pure Zn for blood-contacting engineering

The mechanical performance degradation caused by pitting corrosion and the insufficient biocompatibility induced with ion release inhibit the application of Zn as the new biodegradable metallic materials for blood-contacting intervention therapy. This work successfully coats a uniform polydopamine (PDA) layer on pure Zn via a one-step deposition process without introducing heavy metal elements or detrimental additives. Enhanced corrosion resistance and uniform corrosion have been performed on PDA coated Zn with corrosion products and pits reduced significantly than pure Zn during in vitro degradation. Thrombosis could be prohibited by anticoagulation performance with prothrombin time and activated partial thromboplastin time prolonged after co-incubation, and an almost 40% decrease of platelets adhesion, indicating the improved blood compatibility of coated Zn. Additionally, the poly (lactic-co-glycolic acid) (PLGA) is filmed on PDA coated Zn to realize a smooth double-coated structure with superior mechanical performance under stress loading to stably serve the multifunctional application, such as drug loading. Our strategy not only represents a facile and biological friendly method for Zn surface modification but also puts forward new ideas on preparing PDA-based coatings on active biodegradable alloys, which are beneficial for better blood-contacting engineering.

BIO16: Toward a Blood-Compatible, 3D Printing Resin For Microfluidic Artificial Organs

Purpose: Thrombogenic events are a limitation of artificial lung technologies for device longevity and patient safety. Currently, hollow fiber lungs and microfluidic artificial lungs (µALs) rely on surface modifications to improve hemocompatibility. Our goal to 3D print µALs inspired the development of a blood-compatible 3D printing resin to streamline fabrication of devices and remove the need for surface coatings. We aim to improve the blood compatibility of 3D-printed µALs via the inclusion of hydrophilic molecules directly into a high-resolution, polydimethylsiloxane 3D-printing resin formula. Methods: Hydrophilic molecules, dimethylsiloxane-[60-70% ethylene oxide] block copolymer (PEG-PDMS) and 2-Methacryloyloxyethyl phosphorylcholine (MPC) were directly integrated into our high-resolution 3D printing resin. Following resin work and printing characterization, thin films were made on the Asiga MAX X27 UV printer for subsequent testing. Wettability of the cured resin was determined with contact angle measurements over time. Blood compatibility was measured by exposing cured films to whole ovine blood, then running fluorescent assays and imaging for clot formation. Results: Incorporation of hydrophilic molecules induced a surface change from hydrophobic to hydrophilic when cured resin is exposed to water (Fig 1a). Printed surfaces containing hydrophilic additives reduced blood protein and cell adhesion after exposure to whole blood, as illustrated by reduced fluorescence intensity of FITC Fibrinogen and Membrite cell membrane stains (Fig 1b). Conclusion: The inclusion of hydrophilic molecules in the resin reduces the formation of blood clots thereby improving blood compatibility and potentially removing the need for subsequent surface modifications of printed parts. Fig. 1. (A) Contact angle measurements of commercially available PDMS, Sylgard 184, high-resolution resin alone referred to as “baseline resin”, the baseline resin with 1%MPC, and the baseline resin with 2%PEG (B) Protein (FITC Fibrinogen) and cell adhesion (Membrite) to cured films of resins (n=3 each) with and without hydrophilic additives. Images of representative films after testing with freshly drawn sheep blood are shown for (C) Sylgard 184, (D) Baseline resin, (E) 1% MPC, and (F) 2% PEG. The addition of hydrophilic molecules PEG and MPC to the resin decrease protein and cell adhesion compared to both the baseline resin and Sylgard 184.

Extracellular matrix and nitric oxide based functional coatings for vascular stents

• Intravascular stents face perpetuating shortcomings, including thrombogenecity, poor re-endothelialization, and in-stent restenosis. • Extracellular matrix-based coatings improve stent performance by regulating vascular cell types and improving hemocompatibility. • Nitric oxide-based coatings regulate vascular homeostasis by promoting re-endothelialization and diminishing thrombogenecity. • Such bio-inspired coatings can also be extended to other medical devices, such as artificial blood vessels and blood-contacting materials. Cardiovascular diseases cause huge morbidity and mortality worldwide. Recently, vascular stents have been most frequently used to treat cardiovascular diseases thanks to their effectiveness at dilating blood vessels and maintaining the circulation of blood. However, stent expansion leads to endothelium injury posing thrombogenic and in-stent restenosis (ISR). In addition, the bioinertness and an acute lack of endothelium-like function on the surface of implanted vascular stents compromise their performance. Functional coatings of vascular stents to mimic endothelium- and extracellular matrix (ECM)-like functions could prevent thrombosis, inhibit the overgrowth of smooth muscle cells (SMCs), and promote the rapid restoration of native endothelium, hence effectively suppressing stent-related complications. Noticeably, ECM-based coatings including a multitude of bioactive molecular, such as growth factors, heparin, hyaluronic acid (HA)and so on, have been proven to play important effects on regulating ECs/SMCs behavior and improving blood compatibility of stents. Additionally, nitric oxide (NO), which is fundamental to the endothelium-mediated anti-thrombogenesity, anti-intimal hyperplasia and anti-inflammation, has been leveraged to improve vascular stent functions. Therefore, this review will highlight different strategies and biological role of ECM and NO based functional coatings on vascular stent. Lastly, some potential important factors for stents development are suggested as well.

PDMS-Zwitterionic Hybrid for Facile, Antifouling Microfluidic Device Fabrication.

Poly(dimethylsiloxane) (PDMS) has been used in a wide range of biomedical devices and medical research due to its biostability, cytocompatibility, gas permeability, and optical properties. Yet, some properties of PDMS create critical limitations, particularly fouling through protein and cell adhesion. In this study, a diallyl-terminated sulfobetaine (SB-diallyl) molecule was synthesized and then directly mixed with a commercial PDMS base (Sylgard 184) and curing agent to produce a zwitterionic group-bearing PDMS (PDMS-SB) hybrid that does not require a complex or an additional surface modification process for the desired end product. In vitro examination of antifouling behavior following exposure to fresh ovine blood showed a significant reduction in platelet deposition for the PDMS-SB hybrid surface compared to that of a PDMS control (p < 0.05, n = 5). The manufacturability via soft lithography using the synthesized polymers was found to be comparable to that for unmodified PDMS. Bonding via O2 plasma treatment was confirmed, and the strength was measured and again found to be comparable to the control. PDMS-SB microfluidic devices were successfully fabricated and showed improved blood compatibility that could reduce channel occlusion due to clot formation relative to PDMS control devices. Further, gas (CO2) transfer through a PDMS-SB hybrid membrane was also tested with a proof-of-concept microchannel device and shown to be comparable to that through the PDMS control.

Microenvironment-activatable cascaded responsive carbonized polymer dots as a theranostic platform for precise rapamycin delivery to potentiate the synergy of chemotherapy and γδ T cells-mediated immunotherapy against tumor

The combination of chemotherapy and immunotherapy (also known as chemo/immunotherapy) promoted by nanomedicine has the potential to enhance the therapeutic effect in more patient populations. However, it is still affected by the inactivation of immune cells induced by traditional chemotherapy, which greatly impairs the synergistic effect of chemotherapy/immunotherapy substantially. Moreover, once tumor cells lose their MHC expression, the current popular CD8+ T cell-based immunotherapy may fail consequently. Herein, rapamycin, as mTOR signaling inhibitor associated with serious side effect once systemically administered, was incorporated into shell-core theranostic nanoplatform to augment synergy of chemotherapy and γδ T cell-mediated MHC-unrestricted immunotherapy against tumor without toxicity on γδ T cells. This nano-platform assembled from a cleavable shell and a carbonized polymer dot core can achieve accurate delivery of rapamycin with traceable imaging and cascade response. Such cascaded responsiveness has endowed it with improved blood compatibility, effective tumor accumulation, microenvironment-selective endocytosis, and hierarchical drug release facilitated by microenvironment-triggered programmable properties (size shrinkage, charge conversion and degradability) transition responding to blood-tissue-cells multi-level biological barriers. In vitro and in vivo experiments have shown that the nanoplatform not only promotes tumor chemotherapy by down-regulating mTOR signals, but also enhances γδ T cell-mediated immunotherapy by promoting the NKG2D pathway in a microenvironment-selective manner. In addition, the TCR-δ knockout mouse model was used to verify the synergy of chemical/immunotherapy promoted by the nanoplatform. In addition to multifunctional integrated therapeutic and diagnostic strategies, we also provide a paradigm to enhance the synergistic effect of chemotherapy/immunotherapy, and broaden the horizons of immunotherapy through γδ T cell-mediated replacement therapy assisted by nano-drugs.

Synthesis of sialic acid conjugates of the clinical near-infrared dye as next-generation theranostics for cancer phototherapy.

Cancer is a multifaceted global health problem that requires continuous action to develop next-generation cancer theranostics. Inspired by the emerging use of indocyanine green (ICG), the only clinically approved near-infrared (NIR) dye for cancer phototherapy, here we synthesized two ICG conjugate theranostics by coupling ICG to sialic acid (Sia) through the C2 and C9 positions of Sia, respectively, referred to as Sia-C2-ICG and Sia-C9-ICG. Encouragingly, Sia-C2/C9-ICGs show superior in vitro properties, including enhanced stability, reduced non-specific binding to serum proteins, and improved blood compatibility, highlighting the benefits of Sia coupling. Notably, in vivo NIR imaging shows that Sia-C9-ICG significantly promotes tumor targeting and effectively prolongs the circulation time in the body, while Sia-C2-ICG is superior to ICG but inferior to Sia-C9-ICG in targeting tumors. Furthermore, Sia-C9-ICG combined with NIR laser irradiation can lead to excellent photothermal and photodynamic therapies for cancer cells, resulting in superior solid tumor ablation. To our knowledge, this is the first report of Sia-NIR conjugates achieving significant tumor reduction in vivo. Together, these advances render Sia-C9-ICG an attractive lead as next-generation cancer theranostics that can be translated clinically to treat human patients.

A hydrophobic antifouling surface coating on bioprosthetic heart valves for enhanced antithrombogenicity.

Thrombosis is an important factor that causes the failure of artificial biological valves in addition to calcification and immune rejection. A hydrophobic antifouling surface can improve blood compatibility by reducing the absorption of protein. In this study, porcine pericardium was cross-linked with glycidyl methacrylate, and carbon-carbon double bonds were introduced. Then, fluoride monomer was added so that the pericardial surface would become hydrophobic and antifouling. Fluoride modification changed the hydrophilicity of the pericardium surface, and the surface water contact angle increased from 84° to 143°. Compared with unmodified pericardium, the adsorption of bovine serum albumin and fibrinogen decreased by 93.1% and 85%, respectively, and the anti-thrombogenicity was greatly enhanced.