<i>In Vivo</i>Pharmacokinetic and Hemocompatible Evaluation of Lyophilization Induced Nifedipine Solid-Lipid Nanoparticle

Nifedipine-solid-lipid nanoparticles lyophilized with trehalose (NI-SLN-Tre) were prepared by the high pressure homogenization of a roll mixture consisting of NI and hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol, and in vivo pharmacokinetic properties and their hemocompatibility were determined and compared with those of a NI-SLN suspension. The resulting pharmacokinetic data demonstrated that although no significant differences were observed between the time of peak concentration (Tmax), peak plasma concentration (Cmax), and the area under the curve (AUC0→∞) values of both administrated samples, NI tended to be absorbed to a much greater extent from the lyophilized NI-SLN-Tre suspensions because of the enhanced solvation of NI-SLN in gastrointestinal fluid, derived from formation of hydrogen bonds between the polar head groups of the lipids and the O-H groups of trehalose. Furthermore, the results of a hemolysis assay revealed that the NI-SLN and NI-SLN-Tre suspensions showed good hemocompatibility properties with hemolysis values of less than 5%. Taken together, the results of this study demonstrate that NI-SLN-Tre exhibits suitable pharmacokinetic properties and good biocompatibility.

Advanced hemocompatible polyethersulfone composite artificial lung membrane with efficient CO_(2)/O_(2)exchange channel constructed by modified carbon nanotubes network

Artificial lung membranes as the core module of the extracorporeal membrane oxygenation technology(ECMO)execute the function of extracorporeal blood-gas barrier accomplishing CO_(2)/O_(2)exchange with blood.However,the unsatisfactory hemocompatibility and difficulty in functionalization are the promi-nent challenges faced by current artificial lung membrane materials.In this study,polyethersulfone(PES)composite membranes with self-anticoagulant property and high gas exchange efficient are fabricated by blending PES matrix with poly(vinylamine)(PVAm)modified carboxylic carbon nanotubes(mCNTs)and citrate-based poly(octamethylene-citrate)(POC)pre-polymers.The mCNTs construct specific gas transfer channels within the composite membranes to enhance the gas permeability,while the POC pre-polymers provide anticoagulant property based on the chelation to blood Ca^(2+)and the inactivation effect to in-trinsic coagulation factors.Importantly,directed by the actual ECMO gas exchange mode,we design a gas-liquid convectional circulation device that could evaluate gas exchange efficiency for the composite membranes under mimetic ECMO state.Therefore,this strategy not only proposes a new design method of advanced artificial lung membranes to solve the practical challenges in the current ECMO technology,but also establishes a scientific testing method to evaluate the gas exchange performance for new-type artificial lung membrane materials in the future.

Large-Scale Surface Modification of Decellularized Matrix with Erythrocyte Membrane for Promoting In Situ Regeneration of Heart Valve

In situ regeneration is a promising strategy for constructing tissue engineering heart valves(TEHVs).Currently,the decellularized heart valve(DHV)is extensively employed as a TEHV scaffold.Nevertheless,DHV exhibits limited blood compatibility and notable difficulties in endothelialization,resulting in thrombosis and graft failure.The red blood cell membrane(RBCM)exhibits excellent biocompatibility and prolonged circulation stability and is extensively applied in the camouflage of nanoparticles for drug delivery;however,there is no report on its application for large-scale modification of decellularized extracellular matrix(ECM).For the first time,we utilized a layer-by-layer assembling strategy to immobilize RBCM on the surface of DHV and construct an innovative TEHV scaffold.Our findings demonstrated that the scaffold significantly improved the hemocompatibility of DHV by effectively preventing plasma protein adsorption,activated platelet adhesion,and erythrocyte aggregation,and induced macrophage polarization toward the M2 phenotype in vitro.Moreover,RBCM modification significantly enhanced the mechanical properties and enzymatic stability of DHV.The rat models of subcutaneous embedding and abdominal aorta implantation showed that the scaffold regulated the polarization of macrophages into the anti-inflammatory and pro-modeling M2 phenotype and promoted endothelialization and ECM remodeling in the early stage without thrombosis and calcification.The novel TEHV exhibits excellent performance and can overcome the limitations of commonly used clinical prostheses.

Hemocompatible polyurethane/gelatin-heparin nanofibrous scaffolds formed by a bi-layer electrospinning technique as potential artificial blood vessels

In this paper,a scaffold,which mimics the morphology and mechanical properties of a native blood vessel is reported.The scaffold was prepared by sequential bi-layer electrospinning on a rotating mandrel-type collector.The tubular scaffolds(inner diameter 4 mm,length 3 cm)are composed of a polyurethane(PU)fibrous outer-layer and a gelatin-heparin fibrous inner-layer.They were fabricated by electrospinning technology,which enables control of the composition,structure,and mechanical properties of the scaffolds.The microstructure,fiber morphology and mechanical properties of the scaffolds were examined by means of scanning electron microscopy(SEM)and tensile tests.The PU/gelatinheparin tubular scaffolds have a porous structure.The scaffolds achieved a breaking strength(3.7±0.13 MPa)and an elongation at break(110±8%)that are appropriate for artificial blood vessels.When the scaffolds were immersed in water for 1 h,the breaking strength decreased slightly to 2.2±0.3 MPa,but the elongation at break increased to 145
21%.In platelet adhesion tests the gelatin-heparin fibrous scaffolds showed a significant suppression of platelet adhesion.Heparin was released from the scaffolds at a fairly uniform rate during the period of 2nd day to 9th day.The scaffolds are expected to mimic the complex matrix structure of native arteries,and to have good biocompatibility as an artificial blood vessel owing to the heparin release.

Fabrication of chitosan/silica hybrid coating on AZ31 Mg alloy for orthopaedic applications

Biocompatible conversion of chitosan and chitosan/silica hybrid coating were prepared to enhance the biocompatibility and corrosion resistance of biodegradable AZ31 Mg alloy. The coatings were optimized and analysed with potentiodynamic polarization, SEM, ATR-IR and XPS studies. Potentiodynamic polarization studies, revealed that the coatings exhibited high corrosion resistance. The surface morphology of the Ch-3/Si coating showed small globular rough structure. The presence of functional groups was confirmed by ATR-IR. For a better understanding of chitosan/silica hybrid coating, the chemical states were examined by XPS studies. The in-vitro bioactivity of the coated samples was evaluated in Earle’s solution, which formed a dense layer of coral-like structure and calcium-deficient apatite with less stoichiometric ratio than the hydroxyapatite. In-vitro cell culture studies exhibited a good cell proliferation rate and the fabricated Ch-3/Si coating was found to be non-hemolytic. The bacterial studies proved that Ch-3/Si coating possessed inherent antibacterial activity.

Biodegradable Protection for Medical Devices with Medical Drugs Controlled Separation

With the aim of creating biodegradable materials for medical devices clinical appointments with high hemocompatibility we have developed a new polymer product.The basis of this product is plasticized by polyethylene glycol bacterial copolymer of hydroxybutyrate and oxovalerate. A well-known antitbrombotic supplement--acetylsalicylic acid has been added to improve hemocompatibility in the polymer. The results of our studies showed a controlled prolonged separation of acetylsalicylic acid from polymeric material in the blood. We studied in vitro the dynamics of liberation of acetylsalicylic acid from polymeric coatings. It was shown that the concentration of polyethylene glycol and the thickness of the polymer layer can affect the rate of diffusion of acetylsalicylic acid from polymer films.

The facile method developed for preparing polyvinylidene fluoride plasma separation membrane via macromolecular interaction

The design of membrane pore is critical for membrane preparation. Polyvinylidene fluoride(PVDF) membrane exhibits outstanding properties in the water-treatment field. However, it is a huge challenge to prepare PVDF macro-pore plasma separation membrane by non-solvent induced phase separation(NIPS). Herein, a facile strategy is proposed to prepare PVDF macro-pore plasma separation membrane via macromolecular interaction. ATR-FTIR and ^(1)H NMR showed that the intermolecular interaction existed between polyethylene oxide(PEO) and polyvinylpyrrolidone(PVP). It could significantly affect the PVDF macro-pore membrane structure. The maximum pore of the PVDF membrane could be effectively adjusted from small-pore/medium-pore to macro-pore by changing the molecular weight of PEO. The PVDF macro-pore membrane was obtained successfully when PEO-200 k existed with PVP. It exhibited higher plasma separation properties than the currently used plasma separation membrane.Moreover, it had excellent hemocompatibility due to the similar plasma effect, hemolysis, prothrombin time, blood effect and complement C_(3a) effect with the current utilized plasma separation membrane,implying its great potential application. The proposed facile strategy in this work provides a new method to prepare PVDF macro-pore plasma separation membrane by NIPS.

Preparation of functional coating on magnesium alloy with hydrophilic polymers and bioactive peptides for improved corrosion resistance and biocompatibility

Biodegradable magnesium alloy stents(MAS)have great potential in the treatment of cardiovascular diseases.However,too fast degradation and the poor biocompatibility are still two key problems for the clinical utility of MAS.In the present work,a functional coating composed of hydrophilic polymers and bioactive peptides was constructed on magnesium alloy to improve its corrosion resistance and biocompatibility in vitro and in vivo.Mg-Zn-Y-Nd(ZE21B)alloy modified with the functional coating exhibited moderate surface hydrophilicity and enhanced corrosion resistance.The favourable hemocompatibility of ZE21B alloy with the functional coating was confirmed by the in vitro blood experiments.Moreover,the modified ZE21B alloy could selectively promote the adhesion,proliferation,and migration of endothelial cells(ECs),but suppress these behaviors of smooth muscle cells(SMCs).Furthermore,the modified ZE21B alloy wires could alleviate intimal hyperplasia,enhance corrosion resistance and re-endothelialization in vivo transplantation experiment.These results collectively demonstrated that the functional coating improved the corrosion resistance and biocompatibility of ZE21B alloy.This functional coating provides new insight into the design and development of novel biodegradable stents for biomedical engineering.

Graft Copolymerization of N,N-Dimethylacrylamide to Cellulose in Homogeneous Media Using Atom Transfer Radical Polymerization for Hemocompatibility

In homogeneous media, N,N-Dimethylacrylamide (DMA) was grafted copolymerization to cellulose by a metal-catalyzed atom transfer radical polymerization (ATRP) process. First, cellulose was dissolved in DMAc/LiCl system, and it reacted with 2-bromoisobutyloyl bromide (BiBBr) to produce macroinitiator (cell-BiB). Then DMA was polymerized to the cellulose backbone in a homogeneous DMSO solution in presence of the cell-BiB. Characterization with FT-IR, NMR, and GPC measurements showed that there obtained a graft copolymer with cellulose backbone and PDMA side chains (cell-PDMA) in well-defined structure. The proteins adsorption studies showed that the cellulose membranes modified by the as-prepared cell-PDMA copolymer owns good protein adsorption resistancet.

Surface Modification of Polycarbonate Urethane by Covalent Linkage of Heparin with a PEG Spacer

Heparin was grafted onto polycarbonate urethane (PCU) surface via a three-step procedure utilizing α, ωdiamino-poly(ethylene glycol) (APEG, M n =2 000) as a spacer. In the first step, isocyanate functional groups were introduced onto PCU surface by the treatment of hexamethylene diisocyanate (HDI) in the presence of di-n-butyltin dilaurate (DBTDL) as a catalyst. In the second step, APEG was linked to the PCU surface to obtain the APEG conjugated PCU surface (PCU-APEG). In the third step, heparin was covalently coupled with PCU-APEG in the presence of N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylamidopropyl) carbodiimide (EDAC). The amount of heparin (1.639 μg/cm 2 ) covalently immobilized on the PCU-APEG surface was determined by the toluidine blue method. The modified surface was characterized by water contact angle, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The hemocompatibility was preliminarily studied by platelet adhesion test. The results indicated that heparin was successfully grafted onto the PCU surface, and meanwhile the hydrophilicity and hemocompatibility of the modified PCU surface were improved significantly compared with the blank PCU surface.

Relationship and improvement strategies between drug nanocarrier characteristics and hemocompatibility:What can we learn from the literature

This article discusses the various blood interactions that may occur with various types of nano drug-loading systems. Nanoparticles enter the blood circulation as foreign objects. On the one hand, they may cause a series of inflammatory reactions and immune reactions, resulting in the rapid elimination of immune cells and the reticuloendothelial system, affecting their durability in the blood circulation. On the other hand, the premise of the drug-carrying system to play a therapeutic role depends on whether they cause coagulation and platelet activation, the absence of hemolysis and the elimination of immune cells. For different forms of nano drug-carrying systems, we can find the characteristics, elements and coping strategies of adverse blood reactions that we can find in previous researches. These adverse reactions may include destruction of blood cells, abnormal coagulation system, abnormal effects of plasma proteins, abnormal blood cell behavior, adverse immune and inflammatory reactions, and excessive vascular stimulation. In order to provide help for future research and formulation work on the blood compatibility of nano drug carriers.

Bioreactivity of Stent Material: <i>In Vitro</i>Impact of New Twinning-Induced Plasticity Steel on Platelet Activation

A current challenge concerns developing new bioresorbable stents that combine optimal mechanical properties and biodegradation rates with limited thrombogenicity. In this context, twinning-induced plasticity (TWIP) steels are good material candidates. In this work, the hemocompatibility of a new TWIP steel was studied in vitro via hemolysis and platelet activation assessments. Cobalt chromium (CoCr) L605 alloy, pure iron (Fe), and magnesium (Mg) WE43 alloy were similarly studied for comparison. No hemolysis was induced by TWIP steel, pure Fe, or L605 alloy. Moreover, L605 alloy did not affect CD62P exposure, αIIbβ3 activation at the platelet surface, or phosphorylation of protein kinase C (PKC) substrates upon thrombin stimulation. In contrast, TWIP steel and pure Fe significantly decreased platelet response to the agonist. Given that similar inhibitory effects were obtained when using a conditioned medium previously incubated with TWIP steel, we postulated TWIP steel corrosion to be likely to release components counteracting platelet activation. We showed that the main ion form present in the conditioned medium is Fe3+. In conclusion, TWIP steel resorbable scaffold displays anti-thrombogenic properties in vitro, which suggests that it could be a promising platform for next-generation stent technologies.

Hemocompatibility of Albumin Nanoparticles as a Drug Delivery System—An in Vitro Study

As a major plasma protein, albumin has a distinct advantage compared with other materials for nanoparticle preparation. It is cheap and easily available. The present work aimed to prepare bovine albumin nanoparticles (BAN) with a simple coacervation method and to test their hemocompatibility. The albumin nanoparticles obtained by this method had a range of sizes from 250 - 350 nm at pH = 7.4. In vitro hemocompatibility tests of the prepared (BAN) were conducted after the incubation of BAN with normal blood for 2 h at 37&degC. Hemocompatibility tests showed that the reduction in the hemolysis percentage of erythrocytes was due to exposure to BAN. The other blood parameters such as hemoglobin (HG), mean corpuscle hemoglobin (MCH), and mean corpuscle hemoglobin concentration (MCHC) were in the normal range. The prothrombin time (PT) and erythrocyte sedimentation rate (ESR) decreased as the concentration of BAN increased. The results obtained in this study demonstrated that BAN could be used safely and without abnormal effect when interacted with blood through many biomedical applications.

Comparison on Hemocompatibility of MWCNTs and Hydroxyl Modificated MWCNTs

Objective: To study and compare the hemocompatibility of MWCNTs and hydroxyl modificated MWCNTs (MWCNTs-OH). Methods: MWCNTs and MWCNTs-OH were characterized by scanning electron microscope, Fourier transform infrared spectroscopy, water contact angle assays, platelet-adhesion and hemolytic rate assays. Results: The results showed that the two MWCNTs had a similar surface topography and MWCNTs-OH were functionalized with hydroxyl groups on their surfaces. Water contact angle assays indicated that MWCNTs were hydrophobic materials, whereas MWCNTs-OH was hydrophilic. The platelet-adhesion assays displayed that the platelet-adhesion rate of MWCNTs-OH was much lower than MWCNTs. The hemolytic rate assays showed that the hemolytic rates of both MWCNTs were lower than the standard value of 5%. Conclusion: MWCNTs-OH shows superior anticoagulant capacity over MWCNTs. Both MWCNTs and MWCNTs-OH are nonhemolytic materials.

Advances in Enhancing Hemocompatibility of Hemodialysis Hollow‑Fiber Membranes

Hemodialysis,the most common modality of renal replacement therapy,is critically required to remove uremic toxins from the blood of patients with end-stage kidney disease.However,the chronic inflammation,oxidative stress as well as throm-bosis induced by the long-term contact of hemoincompatible hollow-fiber membranes(HFMs)contribute to the increase in cardiovascular diseases and mortality in this patient population.This review first retrospectively analyzes the current clini-cal and laboratory research progress in improving the hemocompatibility of HFMs.Details on different HFMs currently in clinical use and their design are described.Subsequently,we elaborate on the adverse interactions between blood and HFMs,involving protein adsorption,platelet adhesion and activation,and the activation of immune and coagulation systems,and the focus is on how to improve the hemocompatibility of HFMs in these aspects.Finally,challenges and future perspectives for improving the hemocompatibility of HFMs are also discussed to promote the development and clinical application of new hemocompatible HFMs.

Effect ofβ-cyclodextrin on the hemocompatibility of heparin-modified PMP hollow fibrous membrane for Extracorporeal Membrane Oxygenation(ECMO)

In this paper,modified membranes containingβ-cyclodextrin(β-CD)and heparin coatings were prepared on the surface of poly-4-methyl-1-pentene(PMP)hollow fibrous membrane using the high strength adhesion of polydopamine(PDA).In this paper,β-CD was added to increase the hemocompatibility of the PMP hollow fibrous membranes and the stability of the heparin coating.The uniformity of the heparin coating withβ-CD addition was better than that of the groups withoutβ-CD.After seven days of saline rinsing,the surface of the modified membranes withβ-CD addition still had a large amount of heparin present,which was more stable compared to the control group.After surface modification,the modified membrane changed from hydrophobic to hydrophilic.Importantly,the protein adsorption,platelet adhesion,and hemolysis rates of the modified membranes were significantly reduced compared with the pristine membranes.The APTT values were also significantly increased.The results showed that the modified membranes with the addition ofβ-CD had better hydrophilicity,can maintain the stability of heparin coating for a long time,and finally showed good hemocompatibility.

Hemocompatibility and cytocompatibility of diblock copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide)-based micelles

A synthetic diblock copolymer poly（2-ethyl-2-oxazoline）-poly（D,L-lactide） （PEOz-PLA） can self-assemble into micelles with an increased efficiency of drug delivery. However, the interactions of blood-micelles and cell-micelles remain unclear. In the present study, we aimed to assess the hemocompatibility and cytocompatibility of PEOz-PLA micelles in order to clarify its potentials as carriers for drug delivery. Blood compatibility of the micelles was evaluated by hemolysis analysis, coagulation test, platelet activation investigation and assessment of their interaction with protein. The results revealed that PEOz-PLA micelles had a favorable blood compatibility. In addition, PEOz-PLA micelles showed a good cytocompatibility through SRB assay, presenting only negligible cytotoxicity when incubated with KBv cells. Taken together, PEOz-PLA micelles could be used as a hemocompatible and cytocompatible drug carrier for intravenous administration.

Preparation and Characterization of Controlled Heparin Release Waterborne Polyurethane Coating Systems

In this study, to improve hemocompatibility of biomedical materials, a waterborne polyurethane （WPU）haepafin release coating system （WPU/heparin） is fabricated via simply blending biodegradable WPU emulsions with heparin aqueous solutions. The surface compositions and hydrophilicity of these WPU/heparin blend coatings are characterized by attenuated total reflectance infrared spectroscopy （ATR-FTIR） and water contact angle measurements. These WPU/heparin blend coatings show effectively controlled release of heparin, as determined by the toluidine blue method. Furthermore, the biocompatibility and anticoagulant activity of these blend coatings are evaluated based on the protein adsorption, platelet adhesion, activated partial thromboplastin time （APTT）, thrombin time （TT）, hemolysis, and cytotoxicity. The results indicate that better hemocompatibility and cytocompatilibity are obtained due to blending heparin into this waterborne polyurethane. Thus, the WPU/heparin blend coating system is expected to be valuable for various biomedical applications.

Polydopamine/poly(sulfobetaine methacrylate)Co-deposition coatings triggered by CuSO_(4)/H_(2)O_(2)on implants for improved surface hemocompatibility and antibacterial activity

Implanted biomaterials such as medical catheters are prone to be adhered by proteins,platelets and bacteria due to their surface hydrophobicity characteristics,and then induce related infections and thrombosis.Hence,the development of a versatile strategy to endow surfaces with antibacterial and antifouling functions is particularly significant for blood-contacting materials.In this work,CuSO_(4)/H_(2)O_(2)was used to trigger polydopamine(PDA)and poly-(sulfobetaine methacrylate)(PSBMA)co-deposition process to endow polyurethane(PU)antibacterial and antifouling surface(PU/PDA(Cu)/PSBMA).The zwitterions contained in the PU/PDA(Cu)/PSBMA coating can significantly improve surface wettability to reduce protein adsorption,thereby improving its blood compatibility.In addition,the copper ions released from the metal-phenolic networks(MPNs)imparted them more than 90%antibacterial activity against E.coli and S.aureus.Notably,PU/PDA(Cu)/PSBMA also exhibits excellent performance in vivo mouse catheter-related infections models.Thus,the PU/PDA(Cu)/PSBMA has great application potential for developing multifunctional surface coatings for blood-contacting materials so as to improve antibacterial and anticoagulant properties.