Optimizing the Bacteriostatic and Cytocompatibility Properties of Poly(hexamethylene guanidine) Hydrochloride (PHMG) via the Guanidine/Alkane Ratio.

The emergence of "superbugs" is not only problematic and potentially lethal for infected subjects but also poses serious challenges for the healthcare system. Although existing antibacterial agents have been effective in some cases, the side effects and biocompatibility generally present difficulties. The development of new antibacterial agents is therefore urgently required. In this work, we have adapted a strategy for the improvement of poly(hexamethylene guanidine) hydrochloride (PHMG), a common antibacterial agent. This involves copolymerization of separate monomer units in varying ratios to find the optimum ratio of the hydrocarbon to guanidine units for antibacterial activity. A series of these copolymers, designated as PGB, was synthesized. By varying the guanidine/hydrophobic ratio and the copolymer molecular weight, a structure-optimized PGB was identified that showed broad-spectrum antibacterial activity and excellent biocompatibility in solution. In an antibacterial assay, the copolymer with the optimum composition (hydrophobic unit content 25%) inhibited >99% Staphylococcus aureus and was compatible with mammalian cells. A polyurethane emulsion containing this PGB component formed transparent, flexible films (PGB-PU films) on a wide range of substrate surfaces, including soft polymers and metals. The PGB-PU films showed excellent bacteriostatic efficiency against nosocomial drug-resistant bacteria, such as Pseudomonas aeruginosa and methicillin-resistant S. aureus (MRSA). It is concluded that our PGB polymers can be used as bacteriostatic agents generally and in particular for the design of antibacterial surfaces in medical devices.

Robust, anti-biofouling 2D nanogel films from poly(N-vinyl caprolactam-co-vinylimidazole) polymers.

In analogy with adsorbed protein films, we have fabricated a family of 2D nanofilms composed of poly(N-vinyl caprolactam-co-vinylimidazole) (PNVCL) nanogels. NVCL was copolymerized with 1-vinylimidazole (VIM), and then cross-linked with α,ω-dibromoalkanes with 2 to 8 carbons via quaternization to form the nanogels. The swelling ratio of the gels was precisely controlled by regulating the inter-chain spacing of the polymers at the level of the carbon atom chain length of the cross-linker. The short-chain alkanes used are relatively rigid and their dimensions provide an accurate estimate of the chain spacing in the nanogels. It was shown that small differences in the carbon atom number of the cross-linking agent led to significant differences in the mechanical properties of the nanogels, in particular in the softness, deformability, and contact area (in film form), all of which increased with increasing carbon number. Films of the softer gels not only showed good adhesion to a number of substrates, but were also mechanically robust. In addition, the films showed excellent light transmission and nontoxicity to L929 cells. Nanogels of intermediate softness were shown to inhibit the adhesion of bacteria and human umbilical vein smooth muscle cells (HUVSMCs), and to be resistant to the adsorption of the plasma protein fibrinogen, indicating strong anti-biofouling properties. Gels that were either too stiff or too soft showed somewhat weaker anti-fouling activity in terms both of HUVSMCs adhesion and protein adsorption.

One-step surface modification strategy with composition-tunable microgels: From bactericidal surface to cell-friendly surface.

As modifiers for biomaterial surfaces, soft colloidal particles not only have good film-forming properties, but can also contribute to the function of the biomaterial via their chemical and biological properties. This general approach has proven effective for surface modification, but little is known about methods to control the properties of the colloidal particles to regulate film formation and biological function. In this work, we prepared poly (N-isopropylacrylamide) microgels (ZQP) containing both a zwitterionic component (Z) to provide anti-fouling functionality, and a quaternary ammonium salt (Q) to give bactericidal functionality. Fine-tuning of the Z and Q contents allowed the preparation of microgels over a range of particle size, size distribution, charge, and film-forming capability. The films showed anti-adhesion and contact-killing properties versus Escherichia coli (E. Coli), depending on the chemical composition. They also showed excellent cytocompatibility relative to L929 cells. A variety of microgel-coated substrates (silicon wafer, PDMS, PU, PVC) showed long-term anti-bacterial activity and resistance to chemical and mechanical treatments. It is concluded that this approach allows the preparation of effective bactericidal, cytocompatible surfaces. The properties can be fine-tuned by regulation of the microgel composition, and the method is applicable universally, i.e., independent of substrate.

Dual-Functional Surfaces Based on an Antifouling Polymer and a Natural Antibiofilm Molecule: Prevention of Biofilm Formation without Using Biocides.

Pathogenic biofilms formed on the surfaces of implantable medical devices and materials pose an urgent global healthcare problem. Although conventional antibacterial surfaces based on bacteria-repelling or bacteria-killing strategies can delay biofilm formation to some extent, they usually fail in long-term applications, and it remains challenging to eradicate recalcitrant biofilms once they are established and mature. From the viewpoint of microbiology, a promising strategy may be to target the middle stage of biofilm formation including the main biological processes involved in biofilm development. In this work, a dual-functional antibiofilm surface is developed based on copolymer brushes of 2-hydroxyethyl methacrylate (HEMA) and 3-(acrylamido)phenylboronic acid (APBA), with quercetin (Qe, a natural antibiofilm molecule) incorporated via acid-responsive boronate ester bonds. Due to the antifouling properties of the hydrophilic poly(HEMA) component, the resulting surface is able to suppress bacterial adhesion and aggregation in the early stages of contact. A few bacteria are eventually able to break through the protection of the anti-adhesion layer leading to bacterial colonization. In response to the resulting decrease in the pH of the microenvironment, the surface could then release Qe to interfere with the microbiological processes related to biofilm formation. Compared to bactericidal and anti-adhesive surfaces, this dual-functional surface showed significantly improved antibiofilm performance to prevent biofilm formation involving both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus for up to 3 days. In addition, both the copolymer and Qe are negligibly cytotoxic, thereby avoiding possible harmful effects on adjacent normal cells and the risk of bacterial resistance. This dual-functional design approach addresses the different stages of biofilm formation, and (in accordance with the growth process of the biofilm) allows sequential activation of the functions without compromising the viability of adjacent normal cells. A simple and reliable solution may thus be provided to the problems associated with biofilms on surfaces in various biomedical applications.

Ultrahigh Efficiency and Minimalist Intracellular Delivery of Macromolecules Mediated by Latent-Photothermal Surfaces.

Intracellular delivery of exogenous macromolecules by photothermal methods is still not widely employed despite its universal and clear effect on cell membrane rupture. The main causes are the unsatisfactory delivery efficiency, poor cell activity, poor cell harvest, and sophisticated operation; these challenges stem from the difficulty of simply controlling laser hotspots. Here, we constructed latent-photothermal surfaces based on multiwall carbon nanotube-doped poly(dimethyl siloxane), which can deliver cargoes with high delivery efficiency and cell viability. Also, cell release and harvest efficiencies were not affected by coordinating the hotspot content and surface structure. This system is suitable for use with a wide range of cell lines, including hard-to-transfect types. The delivery efficiency and cell viability were shown to be greater than 85 and 80%, respectively, and the cell release and harvest efficiency were greater than 95 and 80%, respectively. Moreover, this system has potential application prospects in the field of cell therapy, including stem cell neural differentiation and dendritic cell vaccines.

A Pumpless Microfluidic Neonatal Lung Assist Device for Support of Preterm Neonates in Respiratory Distress.

Premature neonates suffer from respiratory morbidity as their lungs are immature, and current supportive treatment such as mechanical ventilation or extracorporeal membrane oxygenation causes iatrogenic injuries. A non-invasive and biomimetic concept known as the "artificial placenta" (AP) would be beneficial to overcome complications associated with the current respiratory support of preterm infants. Here, a pumpless oxygenator connected to the systemic circulation supports the lung function to relieve respiratory distress. In this paper, the first successful operation of a microfluidic, artificial placenta type neonatal lung assist device (LAD) on a newborn piglet model, which is the closest representation of preterm human infants, is demonstrated. This LAD has high oxygenation capability in both pure oxygen and room air as the sweep gas. The respiratory distress that the newborn piglet is put under during experimentation, repeatedly and over a significant duration of time, is able to be relieved. These findings indicate that this LAD has a potential application as a biomimetic artificial placenta to support the respiratory needs of preterm neonates.

Dual Pathway for Promotion of Stem Cell Neural Differentiation Mediated by Gold Nanocomposites.

The neural differentiation of embryonic stem cells (ESCs) is of great value in the treatment of neurodegenerative diseases. On the basis of the two related signaling pathways that direct the neural differentiation of ESCs, we used gold nanoparticles (GNP) as a means of combining chemical and physical cues to trigger the neurogenic differentiation of stem cells. Neural differentiation-related functional units (glyco and sulfonate units on glycosaminoglycans, GAG) were anchored on the GNP surface and were then transferred to the cell membrane surface via GNP-membrane interactions. The functional units were able to activate the GAG-related signaling pathway, in turn promoting differentiation and maturation of stem cells into neuronal lineages. In addition, using the photothermal effect of GNP, the differentiation-inducing factor retinoic acid (RA), could be actively delivered into cells via laser irradiation. The RA-related intracellular signaling pathway was thereby further triggered, resulting in strong promotion of neurogenesis with a 300-fold increase in mature neural marker expression. The gold nanocomposites developed in this work provide the basis for a new strategy directing ESCs differentiation into nerve cells with high efficiency and high purity by acting on two related signaling pathways.

Precise regulation of particle size of poly(N-isopropylacrylamide) microgels: Measuring chain dimensions with a "molecular ruler".

HYPOTHESIS: Poly(N-isopropylacrylamide) microgels are used extensively in the design of drug carriers, surfaces for control of cell adhesion, and optical devices. Particle size is a key factor and has a significant influence in many areas. EXPERIMENTS: In this work, precise control of the particle size of poly(N-isopropylacrylamide) microgels was achieved by controlling the separation distance of the poly(N-isopropylacrylamide) chains. Dibromoalkanes of different size were used as an adjustable "molecular ruler" to measure molecular dimensions in poly(N-isopropylacrylamide) nanoaggregates at the critical crosslinking temperature. FINDINGS: We find that the chain separation distance decreases as the temperature increases with a sharp decrease over the 55-to-65 °C interval. Based on the observed relationships between chain separation and crosslinker, the particle size of poly(N-isopropylacrylamide) microgels can be regulated by changing the length of the "molecular ruler" (crosslinker) at the same temperature. Furthermore, for partly crosslinked poly(N-isopropylacrylamide) microgels that contain free crosslinkable sites, the particle size can be reduced still more by further crosslinking ("re-crosslinking") with crosslinkers of different size. It is shown that the particle size can be regulated by adjusting the length of "molecular ruler" and the degree of crosslinking. This work provides a "molecular level" method for precise control of poly(N-isopropylacrylamide) microgel particle size.

Modular Polymers as a Platform for Cell Surface Engineering: Promoting Neural Differentiation and Enhancing the Immune Response.

Regulating cell behavior and cell fate are of great significance for basic biological research and cell therapy. Carbohydrates, as the key biomacromolecules, play a crucial role in regulating cell behavior. Herein, "modular" glycopolymers were synthesized by reversible addition-fragmentation chain transfer polymerization. These glycopolymers contain sugar units (glucose), anchoring units (cholesterol), "guest" units (adamantane) for host-guest interaction, and fluorescent labeling units (fluorescein). It was demonstrated that these glycopolymers can insert into cell membranes with high efficiency and their residence time on the membranes can be regulated by controlling their cholesterol content. Furthermore, the behavior of the engineered cells can be controlled by modifying with different functional ß-cyclodextrins (CD-X) via host-guest interactions with the adamantane units. Host-guest interactions with the modular polymers were demonstrated using CD-RBITC (X = a rhodamine B isothiocyanate). The glycopolymers were modified with CD-S (X = seven sulfonate groups) and CD-M (X = seven mannose groups) and were then attached, respectively, to the surfaces of mouse embryonic stem cells for the promotion of neural differentiation and to the surfaces of cancer cells for the enhancement of the immune response. The combination of multiple anchors and host-guest interactions provides a widely applicable cell membrane modification platform for a variety of applications.

Rapid antibacterial effect of sunlight-exposed silicon nanowire arrays modified with Au/Ag alloy nanoparticles.

The continuing emergence of antibiotic-resistant bacteria due to the excessive use of antibiotics has produced a strong demand for novel strategies and new materials that do not lead to bacterial resistance. In the present work silicon nanowire arrays modified with gold-silver alloy nanoparticles (SN-Au/Ag) was investigated as a photo-induced antibacterial material. It was shown that SN-Au/Ag can kill bacteria with high efficiency under sunlight in times of the order of a few minutes, and this is achieved through synergism between photothermal and photocatalytic effects. It appears that the combined effect of heat and reactive oxygen species (ROS) causes bacteria killing through damage to the cell membrane and leakage of cytoplasm contents. Both gold and silver in the alloy nanoparticles are required for the observed bactericidal action. Moreover, the SN-Au/Ag material can be "recycled" without loss of bactericidal activity. It is concluded that the silicon nanowire arrays modified with gold-silver alloy nanoparticles developed in this work has promise as an antibacterial nanomaterial for the development of novel antibiotics.

An ultra-thin, all PDMS-based microfluidic lung assist device with high oxygenation capacity.

Preterm neonates with immature lungs require a lung assist device (LAD) to maintain oxygen saturation at normal levels. Over the last decade, microfluidic blood oxygenators have attracted considerable interest due to their ability to incorporate unique biomimetic design and to oxygenate in a physiologically relevant manner. Polydimethylsiloxane (PDMS) has become the main material choice for these kinds of devices due to its high gas permeability. However, fabrication of large area ultrathin microfluidic devices that can oxygenate sufficient blood volumes at clinically relevant flow rates, entirely made of PDMS, have been difficult to achieve primarily due to failure associated with stiction of thin PDMS membranes to each other at undesired locations during assembly. Here, we demonstrate the use of a modified fabrication process to produce large area ultrathin oxygenators entirely made of PDMS and robust enough to withstand the hydraulic conditions that are encountered physiologically. We also demonstrate that a LAD assembled from these ultrathin double-sided microfluidic blood oxygenators can increase the oxygen saturation level by 30% at a flow rate of 30 ml/min and a pressure drop of 21 mm Hg in room air which is adequate for 1 kg preterm neonates. In addition, we demonstrated that our LAD could withstand high blood flow rate of 150 ml/min and increase oxygen saturation by 26.7% in enriched oxygen environment which is the highest gas exchange reported so far by any microfluidic-based blood oxygenators. Such performance makes this LAD suitable to provide support to 1 kg neonate suffering from respiratory distress syndrome.

The blood compatibility challenge. Part 2: Protein adsorption phenomena governing blood reactivity.

The adsorption of proteins is the initiating event in the processes occurring when blood contacts a "foreign" surface in a medical device, leading inevitably to thrombus formation. Knowledge of protein adsorption in this context has accumulated over many years but remains fragmentary and incomplete. Moreover, the significance and relevance of the information for blood compatibility are not entirely agreed upon in the biomaterials research community. In this review, protein adsorption from blood is discussed under the headings "agreed upon" and "not agreed upon or not known" with respect to: protein layer composition, effects on coagulation and complement activation, effects on platelet adhesion and activation, protein conformational change and denaturation, prevention of nonspecific protein adsorption, and controlling/tailoring the protein layer composition. STATEMENT OF SIGNIFICANCE: This paper is part 2 of a series of 4 reviews discussing the problem of biomaterial associated thrombogenicity. The objective was to highlight features of broad agreement and provide commentary on those aspects of the problem that were subject to dispute. We hope that future investigators will update these reviews as new scholarship resolves the uncertainties of today.

One-step preparation of gold nanovectors using folate modified polyethylenimine and their use in target-specific gene transfection.

Gene transfection, as an effective treatment for inherited and acquired life threatening diseases caused by genetic deficiencies and abnormalities, has evolved as a promising therapeutic strategy for cancer and other intractable diseases. Non-target-specific vectors will affect normal cells as well as pathogenic cells, resulting in a relative decrease in transfection efficiency and unnecessary cytotoxicity. In the present work, gold nanoparticles (AuNPs) functionalized with folate (FA)-modified polyethylenimine (PEI-FA) were prepared by a single step method (without additional reducing agent) for targeted gene transfection in tumor cells. Moreover, an improved compound vector system was developed by mixing PEI-AuNPs and PEI-FA-AuNPs. It was shown that the compound vector system not only greatly increased transfection efficiency in HeLa cells, but also reduced cytotoxicity. By comparison, the transfection efficiency in L929 cells lacking folate receptor, was clearly lower than in tumor cells. The specific gene transfection of HeLa cells using this vector system could be clearly observed by confocal laser scanning microscopy in a co-culture system of HeLa cells and L929 cells. This transfection system with high-efficiency, high-specificity and low-toxicity appears to have potential in targeted cancer treatment and drug delivery.

BloodSurf 2017: News from the blood-biomaterial frontier.

From stents and large-diameter vascular grafts, to mechanical heart valves and blood pumps, blood-contacting devices are enjoying significant clinical success owing to the application of systemic antiplatelet and anticoagulation therapies. On the contrary, research into material and device hemocompatibility aimed at alleviating the need for systemic therapies has suffered a decline. This research area is undergoing a renaissance fueled by recent fundamental insights into coagulation and inflammation that are offering new avenues of investigation, the growing recognition of the limitations facing existing therapeutic approaches, and the severity of the cardiovascular disorders epidemic. This Opinion article discusses clinical needs for hemocompatible materials and the emerging research directions for fulfilling those needs. Based on the 2017 BloodSurf conference that brought together clinicians, scientists, and engineers from academia, industry, and regulatory bodies, its purpose is to draw the attention of the wider clinical and scientific community to stimulate further growth. STATEMENT OF SIGNIFICANCE: The article highlights recent fundamental insights into coagulation, inflammation, and blood-biomaterial interactions that are fueling a renaissance in the field of material hemocompatibility. It will be useful for clinicians, scientists, engineers, representatives of industry and regulatory bodies working on the problem of developing hemocompatible materials and devices for treating cardiovascular disorders.

An ultra-thin highly flexible microfluidic device for blood oxygenation.

Many neonates who are born premature suffer from respiratory distress syndrome (RDS) for which mechanical ventilation and an extracorporeal membrane oxygenation (ECMO) device are used in treatment. However, the use of these invasive techniques results in higher risk of complications like bronchopulmonary dysplasia or requires surgery to gain vascular access. An alternative biomimetic approach is to use the umbilical cord as a vascular access and to connect a passive device to the baby that functions like a placenta. This concept, known as the artificial placenta, provides enough oxygenation and causes minimal distress or complications. Herein, we have developed a new artificial placenta-type microfluidic blood oxygenator (APMBO) with high gas exchange, low priming volume and low hydraulic resistance such that it can be operated only by pressure differential provided by the baby's heart. Mimicking the placenta, we have made our new device ultra-thin and flexible so that it can be folded into a desired shape without losing its capability for gas exchange and achieve a compact form factor. The ability to fold allowed optimization of connectors and reduced the overall priming volume to the sub-milliliter range while achieving a high oxygen uptake which would be sufficient for preterm neonates with a birth-weight of around 0.5 kg.

An artificial placenta type microfluidic blood oxygenator with double-sided gas transfer microchannels and its integration as a neonatal lung assist device.

Preterm neonates suffering from respiratory distress syndrome require assistive support in the form of mechanical ventilation or extracorporeal membrane oxygenation, which may lead to long-term complications or even death. Here, we describe a high performance artificial placenta type microfluidic oxygenator, termed as a double-sided single oxygenator unit (dsSOU), which combines microwire stainless-steel mesh reinforced gas permeable membranes on both sides of a microchannel network, thereby significantly reducing the diffusional resistance to oxygen uptake as compared to the previous single-sided oxygenator designs. The new oxygenator is designed to be operated in a pumpless manner, perfused solely due to the arterio-venous pressure difference in a neonate and oxygenate blood through exposure directly to ambient atmosphere without any air or oxygen pumping. The best performing dsSOUs showed up to ∼343% improvement in oxygen transfer compared to a single-sided SOU (ssSOU) with the same height. Later, the dsSOUs were optimized and integrated to build a lung assist device (LAD) that could support the oxygenation needs for a 1-2 kg neonate under clinically relevant conditions for the artificial placenta, namely, flow rates ranging from 10 to 60 ml/min and a pressure drop of 10-60 mmHg. The LAD provided an oxygen uptake of 0.78-2.86 ml/min, which corresponded to the increase in oxygen saturation from 57 ± 1% to 93%-100%, under pure oxygen environment. This microfluidic lung assist device combines elegant design with new microfabrication methods to develop a pumpless, microfluidic blood oxygenator that is capable of supporting 30% of the oxygen needs of a pre-term neonate.

Sulfonate Groups and Saccharides as Essential Structural Elements in Heparin-Mimicking Polymers Used as Surface Modifiers: Optimization of Relative Contents for Antithrombogenic Properties.

Blood compatibility is a long sought-after goal in biomaterials research, but remains an elusive one, and in spite of extensive work in this area, there is still no definitive information on the relationship between material properties and blood responses such as coagulation and thrombus formation. Materials modified with heparin-mimicking polymers have shown promise and indeed may be seen as comparable to materials modified with heparin itself. In this work, heparin was conceptualized as consisting of two major structural elements: saccharide- and sulfonate-containing units, and polymers based on this concept were developed. Copolymers of 2-methacrylamido glucopyranose, containing saccharide groups, and sodium 4-vinylbenzenesulfonate, containing sulfonate groups, were graft-polymerized on vinyl-functionalized polyurethane (PU) surfaces by free radical polymerization. This graft polymerization method is simple, and the saccharide and sulfonate contents are tunable by regulating the feed ratio of the monomers. Homopolymer-grafted materials, containing only sulfonate or saccharide groups, showed different effects on cell-surface interactions including platelet adhesion, adhesion and proliferation of vascular endothelial cells, and adhesion and proliferation of smooth muscle cells. The copolymer-grafted materials showed effects due to both sulfonate and saccharide elements with respect to blood responses, and the optimum composition was obtained at a 2:1 ratio of sulfonate to saccharide units (material designated as PU-PS1M1). In cell adhesion experiments, this material showed the lowest platelet and human umbilical vein smooth muscle cell density and the highest human umbilical vein endothelial cell density. Among the materials investigated, PU-PS1M1 also had the longest plasma clotting time. This material was thus shown to be multifunctional with a combination of properties, suggesting thromboresistant behavior in blood contact.

"Hearing Loss" in QCM Measurement of Protein Adsorption to Protein Resistant Polymer Brush Layers.

Accurate quantification of nonspecific protein adsorption on biomaterial surfaces is essential for evaluation of their antifouling properties. The quartz crystal microbalance (QCM) is an acoustic sensor widely used for the measurement of protein adsorption. However, although the QCM is highly sensitive, it does have performance limitations when working with surfaces modified with thick viscous layers. In the case of polymer brush surfaces, factors such as the thickness and viscosity of the brush may bring such limitations. In the present work, three types of antifouling molecules were used to explore the applicability of QCM for the evaluation of the protein resistance of hydrophilic polymer brush surfaces. Adsorption was also measured by surface plasmon resonance (SPR) as a reference. It was shown that the detection of adsorbed protein requires that protein be located within a critical distance from the QCM chip surface, determined by the viscosity of polymer brush. For larger proteins like fibrinogen, adsorption is expected to occur mainly "on top" of the polymer brush, and brush thickness determines whether protein is located in the "detectable zone". For smaller proteins like lysozyme, adsorption is expected to occur mainly at the chip surface and within the polymer brush layer and to be detectable by QCM. However, the quantity of adsorbed lysozyme may be underestimated when secondary adsorption also occurred. It is concluded that QCM data suggesting very low protein adsorption on polymer brush surfaces should take account of these considerations and should be treated generally with caution.

Stirred, shaken, or stagnant: What goes on at the blood-biomaterial interface.

There is a widely recognized need to improve the performance of vascular implants and external medical devices that come into contact with blood by reducing adverse reactions they cause, such as thrombosis and inflammation. These reactions lead to major adverse cardiovascular events such as heart attacks and strokes. Currently, they are managed therapeutically. This need remains unmet by the biomaterials research community. Recognized stagnation of the blood-biomaterial interface research translates into waning interest from clinicians, funding agencies, and practitioners of adjacent fields. The purpose of this contribution is to stir things up. It follows the 2014 BloodSurf meeting (74th International IUVSTA Workshop on Blood-Biomaterial Interactions), offers reflections on the situation in the field, and a three-pronged strategy integrating different perspectives on the biological mechanisms underlying blood-biomaterial interactions. The success of this strategy depends on reengaging clinicians and on the renewed cooperation of the funding agencies to support long-term efforts.

A multifunctional surface for blood contact with fibrinolytic activity, ability to promote endothelial cell adhesion and inhibit smooth muscle cell adhesion.

Blood compatible materials are required for a wide variety of medical devices. Despite many years of intensive effort, however, the blood compatibility problem, in particular the ability to prevent thrombosis, remains unsolved. Based on the knowledge that the vascular endothelium, the ultimate blood contacting surface, draws on several mechanisms to maintain blood fluidity, it seems reasonable that analogous multifunctionality should be the goal for blood compatible biomaterials. In the present work, a polyurethane surface was modified with the terpolymer poly(2-hydroxyethyl methacrylate-co-6-amino-2-(2-methacylamido)-hexanoic acid-co-1-adamantan-1-ylmethyl methacrylate) (poly(HEMA-co-LysMA-co-AdaMA)), referred to as PU-PHLA. Poly(HEMA) and poly(LysMA) were intended to provide, respectively, resistance to non-specific protein adsorption and the ability to lyse incipient clots. The heparin-like moiety, sulfonated ß-cyclodextrin was immobilized on the PU-PHLA via host-guest interactions with the poly(AdaMA). This component is expected to inhibit coagulation and smooth muscle cell proliferation and to promote endothelialization. The resulting materials were shown to have multifunctionalities including fibrinolytic activity, anticoagulant activity and the ability to promote endothelial cell adhesion and inhibit smooth muscle cell adhesion. This work provides a new strategy for the development of multifunctional, endothelial-mimicking, biomaterials for blood contacting applications.