Nitric oxide-releasing/generating polymers for the development of implantable chemical sensors with enhanced biocompatibility (original) (raw)
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The current state-of-the-art with respect to the preparation, characterization and biomedical applications of novel nitric oxide (NO) releasing or generating polymeric materials is reviewed. Such materials show exceptional promise as coatings to prepare a new generation of medical devices with superior biocompatiblity. Nitric oxide is a well-known inhibitor of platelet adhesion and activation, as well as a potent inhibitor of smooth muscle cell proliferation. Hence, polymers that release or generate NO locally at their surface exhibit greatly enhanced thromboresistivity and have the potential to reduce neointimal hyperplasia caused by device damage to blood vessel walls. In this review, the use of diazeniumdiolates and nitrosothiols as NO donors within a variety polymeric matrixes are summarized. Such species can either be doped as discrete NO donors within polymeric films, or covalently linked to polymer backbones and/or inorganic polymeric filler particles that are often employed to enhance the strength of biomedical polymers (e.g., fumed silica or titanium dioxide). In addition, very recent efforts to create catalytic polymers possessing immobilized Cu(II) sites capable of generating NO from endogenous oxidized forms of NO already present in blood and other physiological fluids (nitrite and nitrosothiols) are discussed. Preliminary literature data illustrating the efficacy of the various NO release/ generating polymers as coatings for intravascular sensors, extracorporeal blood loop circuits, and arteriovenous grafts/shunts are reviewed. r
Preparation and characterization of implantable sensors with nitric oxide release coatings
Microchemical Journal, 2003
The widespread use of miniaturized chemical sensors to monitor clinically important analytes such as PO , PCO , 2 2 pH, electrolytes, glucose and lactate in a continuous, real-time manner has been seriously hindered by the erratic analytical results often obtained when such devices are implanted in vivo. One major factor that has influenced the analytical performance of indwelling sensors is the biological response they elicit when in contact with blood or tissue (e.g. thrombus formation on the device surface, inflammatory response, encapsulation, etc.). Nitric oxide (NO) has been shown to be a potent inhibitor of platelet adhesion and activation as well as a promoter of wound healing in tissue. Herein, we review recent work aimed at the development of hydrophobic NO-releasing polymers that can be employed to coat catheter-type amperometric oxygen sensors without interfering with the analytical performance of these devices. Such modified sensors are shown to exhibit greatly enhanced hemocompatibility and improved analytical performance when implanted within porcine carotid and femoral arteries for up to 16 h. Further, results from preliminary studies also demonstrate that prototype fluorescent oxygen sensors, catheter-style potentiometric carbon dioxide sensors and subcutaneous needle-type enzyme-based amperometric glucose sensors can also be fabricated with new NO-release outer coatings without compromising the analytical response characteristics of these devices. The NO-release strategy may provide a solution to the lingering biocompatibility problems encountered when miniature chemical sensors are implanted in vivo. ᮊ
Nitric oxide release for improving performance of implantable chemical sensors – A review
Applied Materials Today, 2017
Over the last three decades, there has been extensive interest in developing in vivo chemical sensors that can provide real-time measurements of blood gases (oxygen, carbon dioxide, and pH), glucose/lactate, and potentially other critical care analytes in the blood of hospitalized patients. However, clot formation with intravascular sensors and foreign body response toward sensors implanted subcutaneously can cause inaccurate analytical results. Further, the risk of bacterial infection from any sensor implanted in the human body is another major concern. To solve these issues, the release of an endogenous gas molecule, nitric oxide (NO), from the surface of such sensors has been investigated owing to NO's ability to inhibit platelet activation/adhesion, foreign body response and bacterial growth. This paper summarizes the importance of NO's therapeutic potential for this application and reviews the publications to date that report on the analytical performance of NO release sensors in laboratory testing and/or during in vivo testing.
Electroanalysis, 2021
The real‐time, continuous monitoring of glucose/lactate, blood gases and electrolytes by implantable electrochemical sensors holds significant value for critically ill and diabetic patients. However, the wide‐spread use of such devices has been seriously hampered by implant‐initiated host responses (e. g., thrombus formation, inflammatory responses and bacterial infection) when sensors are implanted in blood or tissue. As a result, the accuracy and usable lifetime of in vivo sensors are often compromised. Nitric oxide (NO) is an endogenous gas molecule able to inhibit platelet adhesion/activation, inflammatory responses and bacterial growth. As such, the release of NO from the surfaces of in vivo sensors is a promising strategy for enhancement of their biocompatibility and analytical performance. In this review, the physiological functions of NO to improve the biocompatibility of implantable electrochemical sensors are introduced, followed by a brief analysis of chemical approaches ...
Journal of biomedical materials research. Part A, 2007
Nitric oxide (NO) is released by endothelial cells that line the inner walls of healthy blood vessels at fluxes ranging from 0.5 x 10(-10) to 4.0 x 10(-10) mol cm(-2) min(-1), and this continuous NO release contributes to the extraordinary thromboresistance of the intact endothelium. To improve the biocompatibility of blood-contacting devices, a biomimetic approach to release/generate NO at polymer/blood interfaces has been pursued recently (with NO donors or NO generating catalysts doped within polymeric coatings) and this concept has been shown to be effective in preventing platelet adhesion/activation via several in vivo animal studies. However, there are no reports to date describing any quantitative in vitro assay to evaluate the blood compatibilities of such NO release/generating polymers with controlled NO fluxes. Such a methodology is desired to provide a preliminary assessment of any new NO-releasing material, in terms of the effectiveness of given NO fluxes and NO donor am...
Free Radical Biology and Medicine, 2004
The synthetic methods used recently in this laboratory to prepare a variety of novel nitric oxide (NO)releasing hydrophobic polymers are reviewed. Nitric oxide is a well known inhibitor of platelet adhesion and activation. Thus, such NO release polymers have potential applications as thromboresistant coatings for a large number of bloodcontacting biomedical devices (e.g., in vivo sensors, arteriovenous grafts, stents, catheters, extracorporeal circuits). The approaches taken to prepare NO releasing poly(vinyl chloride) (PVC), silicone rubber (SR), polymethacrylate (PM), and polyurethane (PU) materials are grouped into three categories: (1) dispersion/doping of discrete diazeniumdiolated molecules within the polymeric films; (2) chemical derivatization of polymeric filler microparticles (e.g., silicon dioxide, titanium dioxide) to possess NO release chemistry and then their dispersion within the hydrophobic polymers; and (3) covalent attachment of NO release moieties to polymer backbones. Specific chemical examples of each of these approaches are summarized and the advantages and disadvantages of each are discussed. Other related work in the field of NO release polymers is also cited. It is further shown that several of the NO-releasing polymeric materials already prepared exhibit the expected improved thromboresistivity when tested in vivo using appropriate animal models.
J. Mater. Chem. B, 2014
Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/activation. Nitric oxide releasing (NOrel) materials can be prepared by doping an NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N 2 O 2 ), within a polymer coating. The inherent hemocompatibility properties of the base polymer can also influence the efficiency of such NO release coatings. In this study, four biomedical grade polymers were evaluated in a 4 h rabbit model of thrombogenicity for their effects on extracorporeal circuit thrombus formation and circulating platelet count. At the end of 4 h, Elast-Eon E2As was found to preserve 58% of baseline platelets versus 48, 40, and 47% for PVC/DOS, Tecophilic SP-60D-60, and Tecoflex SG80A, respectively. Elast-Eon also had significantly lower clot area of 5.2 cm 2 compared to 6.7, 6.1, and 6.9 cm 2 for PVC/DOS, SP-60D-60, and SG80A, respectively. Based on the results obtained for the base polymer comparison study, DBHD/ N 2 O 2 -doped E2As was evaluated in short-term (4 h) rabbit studies to observe the NO effects on prevention of clotting and preservation of platelet function. Platelet preservation for this optimal NO release formulation was 97% of baseline after 4 h, and clot area was 0.9 cm 2 compared to 5.2 cm 2 for controls, demonstrating that combining E2As with NO release provides a truly advanced hemocompatible polymer coating for extracorporeal circuits and potentially other blood contacting applications.
Nitric Oxide-Releasing Fluorescence-Based Oxygen Sensing Polymeric Films
Analytical Chemistry, 2002
The in vitro analytical performance of fluorescence-based oxygen sensing polymeric films prepared with silicone rubbers that spontaneously release nitric oxide (NO) is examined. The use of NO-release polymers for fabricating functional optical sensors is proposed as a potential solution to lingering biocompatibility and concomitant performance problems encountered with prototype intravascular optical oxygen sensors. Plasticized silicone rubber films formulated with two distinct types of diazeniumdiolate NO donors release NO for more than 24 h. The optical oxygen sensing films prepared by doping these NO release polymeric materials with oxygen indicators (pyrene/ perylene donor/acceptor pair) display different analytical responses, as compared to controls without NO release capability. Nonlinear Stern-Volmer behavior is observed for single-layer NO release oxygen sensors owing to heterogeneous environments for the pyrene/perylene pair and a concomitant quenching of the fluorescence by excess amine sites in such films. In contrast, a dual-layer configuration using an underlying NO-release silicone rubber layer covered with a second polymeric layer containing the fluorescent indicators is shown to yield identical sensitivity and linearity toward oxygen as conventional non-NO-releasing oxygen sensing films, while still providing surface NO fluxes necessary to yield more thromboresistive devices. Recent studies in this laboratory 1,2 and elsewhere 3,4 have demonstrated the potential utility of nitric oxide (NO)-releasing polymers in creating more thromboresistant material/blood interfaces. Indeed, NO is well-known to be a potent inhibitor of both platelet adhesion and aggregation and is, in fact, continuously released at low levels (1 × 10-10 mol cm-2 min-1) by the vascular endothelium.
Biosensors and Bioelectronics, 2011
Intravenous amperometric needle-type enzymatic glucose/lactate sensors intended for continuous monitoring are prepared with a novel nitric oxide (NO) releasing layer to improve device hemocompatibility. To create an underlying NO release coating, the sensors with immobilized enzymes (either glucose oxidase or lactate oxidase) are prepared with a thin layer of poly(lactideco-glycolide) (PLGA) loaded with lipophilic diazeniumdiolate species that slowly release NO via a proton driven reaction. An outer thin layer (ca. 30 µm) of PurSil (polyurethane/dimethylsiloxane copolymer) limits the flux of glucose and lactate to the inner layer of enzyme, to provide the desired linear amperometric response. A 30 µm coating of PLGA containing 33 wt% of the appropriate NO donor (N-diazeniumdiolated dibutylhexanediamine, DBHD/N 2 O 2 ) can release NO at a physiologically relevant rate > 1 × 10 −10 mol min −1 cm −2 for at least 7 d without influencing the analytical performance of the glucose/lactate sensors. In vitro, the sensors exhibit relatively stable amperometric response over a one-week period with high selectivity over interferences (e.g., ascorbic acid) required for blood monitoring applications. Glucose sensors implanted in the veins of rabbits for 8 h exhibit significantly enhanced hemocompatibility for the NO release sensors vs. corresponding controls (without NO release in same animals), with greatly reduced thrombus formation on their surfaces. Further, the analytical performance of the NO release glucose sensors are superior to controls placed in the veins of the same animals, with a greater accuracy in measuring blood glucose levels as evaluated using a Clark error grid type analysis.
Biomaterials science, 2016
Biomedical devices are essential for patient diagnosis and treatment; however, when blood comes in contact with foreign surfaces or homeostasis is disrupted, complications including thrombus formation and bacterial infections can interrupt device functionality, causing false readings and/or shorten device lifetime. Here, we review some of the current approaches for developing antithrombotic and antibacterial materials for biomedical applications. Special emphasis is given to materials that release or generate low levels of nitric oxide (NO). Nitric oxide is an endogenous gas molecule that can inhibit platelet activation as well as bacterial proliferation and adhesion. Various NO delivery vehicles have been developed to improve NO's therapeutic potential. In this review, we provide a summary of the NO releasing and NO generating polymeric materials developed to date, with a focus on the chemistry of different NO donors, the polymer preparation processes, and in vitro and in vivo ...