Enhancing thromboresistance of neurovascular nickel-titanium devices with responsive heparin hydrogel coatings.

BACKGROUND: Neurointerventional devices, particularly laser-cut thin-strut stents made of self-expanding nickel-titanium alloy, are increasingly utilized for endovascular applications in intracranial arteries and dural venous sinuses. Preventing thrombosis and stroke necessitates systemic anticoagulant and antiplatelet therapies with the risk of bleeding complications. Antithrombotic coatings present a promising solution. METHODS: In this study, we investigated the potential of hydrogels composed of four-armed poly(ethylene glycol) (starPEG) and heparin, with or without coagulation-responsive heparin release, as coatings for neurovascular devices to mitigate blood clot formation. We evaluated the feasibility and efficacy of these coatings on neurovascular devices through in vitro Chandler-Loop assays and implantation experiments in the supra-aortic arteries of rabbits. RESULTS: Stable and coagulation-responsive starPEG-heparin hydrogel coatings exhibited antithrombotic efficacy in vitro, although with a slightly reduced thromboprotection observed in vivo. Furthermore, the hydrogel coatings demonstrated robustness against shear forces encountered during deployment and elicited only marginal humoral and cellular inflammatory responses compared with the reference standards. CONCLUSION: Heparin hydrogel coatings offer promising benefits for enhancing the hemocompatibility of neurointerventional devices made of self-expanding nickel-titanium alloy. The variance in performance between in vitro and in vivo settings may be attributed to differences in low- and high-shear blood flow conditions inherent to these models. These models may represent the differences in venous and arterial systems. Further optimization is warranted to tailor the hydrogel coatings for improved efficacy in arterial applications.

Precision Culture Scaling to Establish High-Throughput Vasculogenesis Models.

Hydrogel-based 3D cell cultures can recapitulate (patho)physiological phenomena ex vivo. However, due to their complex multifactorial regulation, adapting these tissue and disease models for high-throughput screening workflows remains challenging. In this study, a new precision culture scaling (PCS-X) methodology combines statistical techniques (design of experiment and multiple linear regression) with automated, parallelized experiments and analyses to customize hydrogel-based vasculogenesis cultures using human umbilical vein endothelial cells and retinal microvascular endothelial cells. Variations of cell density, growth factor supplementation, and media composition are systematically explored to induce vasculogenesis in endothelial mono- and cocultures with mesenchymal stromal cells or retinal microvascular pericytes in 384-well plate formats. The developed cultures are shown to respond to vasculogenesis inhibitors in a compound- and dose-dependent manner, demonstrating the scope and power of PCS-X in creating parallelized tissue and disease models for drug discovery and individualized therapies.

Adsorbed polymer conjugates to adaptively inhibit blood coagulation activation by medical membranes.

Adaptive drug release can combat coagulation and inflammation activation at the blood-material interface with minimized side effects. For that purpose, poly(styrene-alt-maleic-anhydride) copolymers were conjugated to heparin via coagulation-responsive linker peptides and shown to tightly adsorb onto poly(ethersulfone) (PES)-surfaces from aqueous solutions as monolayers. Coagulation-responsive release of unfractionated as well as low molecular weight heparins from the respective coatings was demonstrated to be functionally beneficial in human plasma and whole blood incubation with faster release kinetics resulting in stronger anticoagulant effects. Coated poly(ethersulfone)/poly(vinylpyrrolidone) (PES/PVP) flat membranes proved the technology to offer an easy, effective and robust anticoagulant interfacial functionalization of hemodialysis membranes. In perspective, the modularity of the adaptive release system will be used for inhibiting multiple activation processes.

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.

Dynamic matrices with DNA-encoded viscoelasticity for cell and organoid culture.

Three-dimensional cell and organoid cultures rely on the mechanical support of viscoelastic matrices. However, commonly used matrix materials lack control over key cell-instructive properties. Here we report on fully synthetic hydrogels based on DNA libraries that self-assemble with ultrahigh-molecular-weight polymers, forming a dynamic DNA-crosslinked matrix (DyNAtrix). DyNAtrix enables computationally predictable and systematic control over its viscoelasticity, thermodynamic and kinetic parameters by changing DNA sequence information. Adjustable heat activation allows homogeneous embedding of mammalian cells. Intriguingly, stress-relaxation times can be tuned over four orders of magnitude, recapitulating mechanical characteristics of living tissues. DyNAtrix is self-healing, printable, exhibits high stability, cyto- and haemocompatibility, and controllable degradation. DyNAtrix-based cultures of human mesenchymal stromal cells, pluripotent stem cells, canine kidney cysts and human trophoblast organoids show high viability, proliferation and morphogenesis. DyNAtrix thus represents a programmable and versatile precision matrix for advanced approaches to biomechanics, biophysics and tissue engineering.

A New In Vitro Blood Flow Model for the Realistic Evaluation of Antimicrobial Surfaces.

Device-associated bloodstream infections can cause serious medical problems and cost-intensive postinfection management, defining a need for more effective antimicrobial coatings. Newly developed coatings often show reduced bacterial colonization and high hemocompatibility in established in vitro tests, but fail in animal studies or clinical trials. The poor predictive power of these models is attributed to inadequate representation of in vivo conditions. Herein, a new single-pass blood flow model, with simultaneous incubation of the test surface with bacteria and freshly-drawn human blood, is presented. The flow model is validated by comparative analysis of a recently developed set of antiadhesive and contact-killing polymer coatings, and the corresponding uncoated polycarbonate surfaces. The results confirm the model's ability to differentiate the antimicrobial activities of the studied surfaces. Blood activation data correlate with bacterial surface coverage: low bacterial adhesion is associated with low inflammation and hemostasis. Shear stress correlates inversely with bacterial colonization, especially on antiadhesive surfaces. The introduced model is concluded to enable the evaluation of novel antimicrobial materials under in vivo-like conditions, capturing interactions between bacteria and biomaterials surfaces in the presence of key components of the ex vivo host response.

Advanced in vitro hemocompatibility assessment of biomaterials using a new flow incubation system.

Physiologically relevant in vitro hemocompatibility assessment of biomaterials remains challenging. We present a new setup that enables standardized whole blood incubation of biomedical materials under flow. A blood volume of 2 mL is recirculated over test surfaces in a custom-made parallel plate incubation system to determine the activation of hemostasis and inflammation. Controlled physiological shear rates between 125 s-1 and 1250 s-1 and minimized contact to air are combined with a natural-like pumping process. A unique feature of this setup allows tracing adhesion of blood cells to test surfaces microscopically in situ. Validation testing was performed in comparison to previously applied whole blood incubation methodologies. Experiments with the newly developed setup showed that even small obstacles to blood flow activate blood (independent of materials-induced blood activation levels); that adhesion of blood cells to biomaterials equilibrates within 5 to 10 min; that high shear rates (1250 compared to 375 s-1) induce platelet activation; and that hemolysis, platelet factor 4 (PF4) release and platelet loss - but not thrombin formation - depend on shear rate (within the range investigated, 125 to 1250 s-1).

Hemocompatibility of cellulose phosphate aerogel membranes with potential use in bone tissue engineering.

Cellulose is an appealing material for tissue engineering. In an attempt to overcome some obstacles with cellulose II cell scaffolding materials related to insufficient biomineralization, lack of micron-size porosity, and deficiency in surface charge, respective solutions have been proposed. These included covalent phosphorylation of different cellulose materials targeting relatively low degrees of substitution (DS 0.18-0.23) and processing these cellulose derivatives into scaffolding materials by a dissolution/coagulation approach employing the hitherto rarely used TBAF/DMSO/H2O system for cellulose dissolution. Here, we report bioactivity and preliminary hemocompatibility testing of dual-porous cellulose phosphate aerogels (contrasted with the phosphate-free reference) obtained via coagulation (water/ethanol), solvent exchange and scCO2 drying. Deposition of hydroxyapatite from simulated body fluid (7 days of immersion) revealed good bioactivity (1.5-2.2 mg Ca2+ per mg scaffold). Incubation of the scCO2-dried and rehydrated scaffolding materials in heparin anticoagulated human whole blood was conducted to study selected parameters of hemostasis (prothrombin F1+2 fragment, PF4, count of thrombocyte-leukocyte conjugates) and inflammatory response (C5a fragment, leukocyte activation marker CD11b). Adhesion of leukocytes on the surface of the incubated substrates was assessed by scanning electron and fluorescence microscopy (DAPI staining). The results suggest that phosphorylation at low DS does not increase platelet activation. However, a significant increase in platelet activation and thrombin formation was observed after a certain fraction of the negative surface charges had been compensated by Ca2+ ions. The combination of both phosphorylation and calcification turned out to be a potent means for controlling the inflammatory response, which was close to baseline level for some of the studied samples.

A "built-up" composite film with synergistic functionalities on Mg-2Zn-1Mn bioresorbable stents improves corrosion control effects and biocompatibility.

Control of premature corrosion of magnesium (Mg) alloy bioresorbable stents (BRS) is frequently achieved by the addition of rare earth elements. However, limited long-term experience with these elements causes concerns for clinical application and alternative methods of corrosion control are sought after. Herein, we report a "built-up" composite film consisting of a bottom layer of MgF2 conversion coating, a sandwich layer of a poly (1, 3-trimethylene carbonate) (PTMC) and 3-aminopropyl triethoxysilane (APTES) co-spray coating (PA) and on top a layer of poly (lactic-co-glycolic acid) (PLGA) ultrasonic spray coating to decorate the rare earth element-free Mg-2Zn-1Mn (ZM21) BRS for tailoring both corrosion resistance and biological functions. The developed "built-up" composite film shows synergistic functionalities, allowing the compression and expansion of the coated ZM21 BRS on an angioplasty balloon without cracking or peeling. Of special importance is that the synergistic corrosion control effects of the "built-up" composite film allow for maintaining the mechanical integrity of stents for up to 3 months, where complete biodegradation and no foreign matter residue were observed about half a year after implantation in rabbit iliac arteries. Moreover, the functionalized ZM21 BRS accomplished re-endothelialization within one month.

Hemocompatibility tuning of an innovative glutaraldehyde-free preparation strategy using riboflavin/UV crosslinking and electron irradiation of bovine pericardium for cardiac substitutes.

Hemocompatibility tuning was adopted to explore and refine an innovative, GA-free preparation strategy combining decellularization, riboflavin/UV crosslinking, and low-energy electron irradiation (SULEEI) procedure. A SULEEI-protocol was established to avoid GA-dependent deterioration that results in insufficient long-term aortic valve bioprosthesis durability. Final SULEEI-pericardium, intermediate steps and GA-fixed reference pericardium were exposed in vitro to fresh human whole blood to elucidate effects of preparation parameters on coagulation and inflammation activation and tissue histology. The riboflavin/UV crosslinking step showed to be less efficient in inactivating extracellular matrix (ECM) protein activity than the GA fixation, leading to tissue-factor mediated blood clotting. Intensifying the riboflavin/UV crosslinking with elevated riboflavin concentration and dextran caused an enhanced activation of the complement system. Yet activation processes induced by the previous protocol steps were quenched with the final electron beam treatment step. An optimized SULEEI protocol was developed using an intense and extended, trypsin-containing decellularization step to inactivate tissue factor and a dextran-free, low riboflavin, high UV crosslinking step. The innovative and improved GA-free SULEEI-preparation protocol results in low coagulant and low inflammatory bovine pericardium for surgical application.

Inflammation-Controlled Anti-Inflammatory Hydrogels.

While autoregulative adaptation is a common feature of living tissues, only a few feedback-controlled adaptive biomaterials are available so far. This paper herein reports a new polymer hydrogel platform designed to release anti-inflammatory molecules in response to the inflammatory activation of human blood. In this system, anti-inflammatory peptide drugs, targeting either the complement cascade, a complement receptor, or cyclophilin A, are conjugated to the hydrogel by a peptide sequence that is cleaved by elastase released from activated granulocytes. As a proof of concept, the adaptive drug delivery from the gel triggered by activated granulocytes and the effect of the released drug on the respective inflammatory pathways are demonstrated. Adjusting the gel functionalization degree is shown to allow for tuning the drug release profiles to effective doses within a micromolar range. Feedback-controlled delivery of covalently conjugated drugs from a hydrogel matrix is concluded to provide valuable safety features suitable to equip medical devices with highly active anti-inflammatory agents without suppressing the general immunosurveillance.

Adhesive and Self-Healing Polyurethanes with Tunable Multifunctionality.

Many polyurethanes (PUs) are blood-contacting materials due to their good mechanical properties, fatigue resistance, cytocompatibility, biosafety, and relatively good hemocompatibility. Further functionalization of the PUs using chemical synthetic methods is especially attractive for expanding their applications. Herein, a series of catechol functionalized PU (C-PU-PTMEG) elastomers containing variable molecular weight of polytetramethylene ether glycol (PTMEG) soft segment are reported by stepwise polymerization and further introduction of catechol. Tailoring the molecular weight of PTMEG fragment enables a regulable catechol content, mobility of the chain segment, hydrogen bond and microphase separation of the C-PU-PTMEG elastomers, thus offering tunability of mechanical strength (such as breaking strength from 1.3 MPa to 5.7 MPa), adhesion, self-healing efficiency (from 14.9% to 96.7% within 2 hours), anticoagulant, antioxidation, anti-inflammatory properties and cellular growth behavior. As cardiovascular stent coatings, the C-PU-PTMEGs demonstrate enough flexibility to withstand deformation during the balloon dilation procedure. Of special importance is that the C-PU-PTMEG-coated surfaces show the ability to rapidly scavenge free radicals to maintain normal growth of endothelial cells, inhibit smooth muscle cell proliferation, mediate inflammatory response, and reduce thrombus formation. With the universality of surface adhesion and tunable multifunctionality, these novel C-PU-PTMEG elastomers should find potential usage in artificial heart valves and surface engineering of stents.

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.

Real-Time Monitoring of Blood Parameters in the Intensive Care Unit: State-of-the-Art and Perspectives.

The number of patients in intensive care units has increased over the past years. Critically ill patients are treated with a real time support of the instruments that offer monitoring of relevant blood parameters. These parameters include blood gases, lactate, and glucose, as well as pH and temperature. Considering the COVID-19 pandemic, continuous management of dynamic deteriorating parameters in patients is more relevant than ever before. This narrative review aims to summarize the currently available literature regarding real-time monitoring of blood parameters in intensive care. Both, invasive and non-invasive methods are described in detail and discussed in terms of general advantages and disadvantages particularly in context of their use in different medical fields but especially in critical care. The objective is to explicate both, well-known and frequently used as well as relatively unknown devices. Furtehrmore, potential future direction in research and development of realtime sensor systems are discussed. Therefore, the discussion section provides a brief description of current developments in biosensing with special emphasis on their technical implementation. In connection with these developments, the authors focus on different electrochemical approaches to invasive and non-invasive measurements in vivo.

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.

Platelet Membrane-Coated Nanocarriers Targeting Plaques to Deliver Anti-CD47 Antibody for Atherosclerotic Therapy.

Atherosclerosis, the principle cause of cardiovascular disease (CVD) worldwide, is mainly characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Atherogenesis is associated with the upregulation of CD47, a key antiphagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or "efferocytosis." Here, we have developed platelet membrane-coated mesoporous silicon nanoparticles (PMSN) as a drug delivery system to target atherosclerotic plaques with the delivery of an anti-CD47 antibody. Briefly, the cell membrane coat prolonged the circulation of the particles by evading the immune recognition and provided an affinity to plaques and atherosclerotic sites. The anti-CD47 antibody then normalized the clearance of diseased vascular tissue and further ameliorated atherosclerosis by blocking CD47. In an atherosclerosis model established in ApoE-/- mice, PMSN encapsulating anti-CD47 antibody delivery significantly promoted the efferocytosis of necrotic cells in plaques. Clearing the necrotic cells greatly reduced the atherosclerotic plaque area and stabilized the plaques reducing the risk of plaque rupture and advanced thrombosis. Overall, this study demonstrated the therapeutic advantages of PMSN encapsulating anti-CD47 antibodies for atherosclerosis therapy, which holds considerable promise as a new targeted drug delivery platform for efficient therapy of atherosclerosis.

Poly(2-alkyl-2-oxazoline)-Heparin Hydrogels-Expanding the Physicochemical Parameter Space of Biohybrid Materials.

Poly(ethylene glycol) (PEG)-glycosaminoglycan (GAG) hydrogel networks are established as very versatile biomaterials. Herein, the synthetic gel component of the biohybrid materials is systematically varied by combining different poly(2-alkyl-2-oxazolines) (POx) with heparin applying a Michael-type addition crosslinking scheme: POx of gradated hydrophilicity and temperature-responsiveness provides polymer networks of distinctly different stiffness and swelling. Adjusting the mechanical properties and the GAG concentration of the gels to similar values allows for modulating the release of GAG-binding growth factors (VEGF165 and PDGF-BB) by the choice of the POx and its temperature-dependent conformation. Adsorption of fibronectin, growth of fibroblasts, and bacterial adhesion scale with the hydrophobicity of the gel-incorporated POx. In vitro hemocompatibility tests with freshly drawn human whole blood show advantages of POx-based gels compared to the PEG-based reference materials. Biohybrid POx hydrogels can therefore enable biomedical technologies requiring GAG-based materials with customized and switchable physicochemical characteristics.

The innate immune response of self-assembling silk fibroin hydrogels.

Silk has a long track record of use in humans, and recent advances in silk fibroin processing have opened up new material formats. However, these new formats and their applications have subsequently created a need to ascertain their biocompatibility. Therefore, the present aim was to quantify the haemocompatibility and inflammatory response of silk fibroin hydrogels. This work demonstrated that self-assembled silk fibroin hydrogels, as one of the most clinically relevant new formats, induced very low blood coagulation and platelet activation but elevated the inflammatory response of human whole blood in vitro. In vivo bioluminescence imaging of neutrophils and macrophages showed an acute, but mild, local inflammatory response which was lower than or similar to that induced by polyethylene glycol, a benchmark material. The time-dependent local immune response in vivo was corroborated by histology, immunofluorescence and murine whole blood analyses. Overall, this study confirms that silk fibroin hydrogels induce a similar immune response to that of PEG hydrogels, while also demonstrating the power of non-invasive bioluminescence imaging for monitoring tissue responses.

Bioresponsive starPEG-heparin hydrogel coatings on vascular stents for enhanced hemocompatibility.

Hydrogel coatings can improve the biocompatibility of medical devices. However, stable surface bonding and homogeneity of hydrogel coatings are often challenging. This study exploits the benefits of biohybrid hydrogels of crosslinked four-armed poly(ethylene glycol) and heparin to enhance the hemocompatibility of cobalt­chromium (CoCr) vascular stents. A bonding layer of dual silane and poly(ethylene-alt-maleic anhydride) (PEMA) treatment was applied to the stent to provide covalent immobilization and hydrophilicity for the homogeneous spreading of the hydrogel. A spray coating technology was used to distribute the aqueous solution of the reactive hydrogel precursors onto the sub-millimeter struts of the stents, where the solution polymerized to a homogeneous hydrogel film. The coating was mechanically stable on the stent after ethanol dehydration, and the stents could be stored in a dry state. The homogeneity and stability of the coating during stent expansion were verified. Quasistatic and dynamic whole blood incubation experiments showed substantial suppression of the pro-coagulant and inflammatory activity of the bare metal by the coating. Translation of the technology to industrial coating devices and future surface modification of stents with anti-inflammatory hydrogels are discussed.