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The gold standard of care for coronary artery disease, a leading cause of death for in the world, is balloon angioplasty in conjunction with stent deployment. However, implantation injuries and long-term presence of foreign material often promotes significant luminal tissue growth, leading to a narrowing of the artery and severely restricted blood flow. A promising method to mitigate this process is the use of biodegradable metallic stents, but thus far they have either degraded too slowly (iron) or disappeared prematurely (magnesium). The present work investigates the use of a unique type of magnetic material, galfenol (iron-gallium), for postoperative wireless control of stent degradation rates. Due to its magnetoelastic property, galfenol experiences longitudinal micron-level elongations when exposed to applied magnetic fields, allowing generation of a microstirring effect that affect its degradation behavior. In vitro indirect cytotoxicity tests on primary rat aortic smooth muscle cells indicated that galfenol byproducts must be concentrated approximately seven times from collected 60 day degradation medium to cause ∼15% of death from all cells. Surface and cross-sectional characterization of the material indicate that galfenol (Fe80 Ga20 ) degradation rates (∼0.55% per month) are insufficient for stenting applications. While this material may not be ideal for comprising the entire stent, there is potential for use in combination with other materials. Furthermore, the ability to control degradation rates postimplantation opens new possibilities for biodegradable stents; additional magnetoelastic materials should be investigated for use in stenting applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 232-241, 2019.

Microgels that can generate antipathogenic levels of hydrogen peroxide (H 2 O 2 ) through simple rehydration in solutions with physiological pH are described herein. H 2 O 2 is a widely used disinfectant but the oxidant is hazardous to store and transport. Catechol, an adhesive moiety found in mussel adhesive proteins, was incorporated into microgels, which generated 1–5 mM of H 2 O 2 for up to four days as catechol autoxidized. The sustained release of low concentrations of H 2 O 2 was antimicrobial against both gram-positive ( Staphylococcus epidermidis ) and gram-negative ( Escherichia coli ) bacteria and antiviral against both non-enveloped porcine parvovirus (PPV) and enveloped bovine viral diarrhea virus (BVDV). The amount of released H 2 O 2 is several orders of magnitude lower than H 2 O 2 concentration previously reported for antipathogenic activity. Most notably, these microgels reduced the infectivity of the more biocide resistant non-envelope virus by 3 log reduction value (99.9% reduction in infectivity). By controlling the oxidation state of catechol, microgels can be repeatedly activated and deactivated for H 2 O 2 generation. These microgels do not contain a reservoir for storing the reactive H 2 O 2 and can potentially function as a lightweight and portable dried powder source for the disinfectant for a wide range of applications. Statement of Significance Researchers have designed bioadhesives and coatings using the adhesive moiety catechol to mimic the strong adhesion capability of mussel adhesive proteins. During catechol autoxidation, hydrogen peroxide (H 2 O 2 ) is generated as a byproduct. Here, catechol was incorporated into microgels, which can generate millimolar levels of H 2 O 2 by simply hydrating the microgels in a solution with physiological pH. The sustained release of H 2 O 2 was both antimicrobial and antiviral, inactivating even the more biocide resistant non-enveloped virus. These microgels can be repeatedly activated and deactivated for H 2 O 2 generation by incubating them in solutions with different pH. This simplicity and recyclability will enable this biomaterial to function as a lightweight and portable source for the disinfectant for a wide range of applications.

Although significant advances have been made in the development of artificial vascular grafts, small-diameter grafts still suffer from excessive platelet activation, thrombus formation, smooth muscle cell intimal hyperplasia, and high occurrences of restenosis. Recent discoveries demonstrating the excellent blood-contacting properties of the natural elastic lamina have raised the possibility that an acellular elastic lamina could effectively serve as a patent blood-contacting surface in engineered vascular grafts. However, the elastic lamina alone lacks the requisite mechanical properties to function as a viable vascular graft. Here, we have screened a wide range of biodegradable and biostable medical-grade polymers for their ability to adhere to the outer surface of the elastic lamina and allow cellular repopulation following engraftment in the rat abdominal aorta. We demonstrate a novel method for the fabrication of elastic lamina-polymeric hybrid small-diameter vascular grafts and identify poly(ether urethane) (PEU 1074A) as ideal for this purpose. In vivo results demonstrate graft patency over 21 days, with low thrombus formation, mild inflammation, and the general absence of smooth muscle cell hyperplasia on the graft's luminal surface. The results provide a new direction for developing small-diameter vascular grafts that are mass-producible, shelf-stable, and universally compatible due to a lack of immune response and inhibit the in-graft restenosis response that is common to nonautologous materials.

Directly monitoring physiological analytes on a continuous, real-time basis may lead to improved patient outcomes. Although the technology to fabricate robust miniature sensors has existed for decades, these sensors fail to accurately track the true physiological status of patients after implantation in the human body. Nitric oxide (NO) may be employed to mediate the biological response toward the implanted sensors allowing the sensors to accurately and reliably monitor analytes of interest such that therapeutic decisions could be made based on sensor readings. This chapter discusses details of the biological response that results in senor failure and why NO may help control this response. Three approaches for NO production (N-diazeniumdiolates, S-nitrosothiols, and catalytic NO generation from endogenous S-nitrosothiols) and NO releasing materials that utilize these approaches which have been applied in sensor fabrication are presented. NO releasing sensors have shown greatly enhanced performance in blood contacting and tissue contacting applications in vivo.

A new type of nitric oxide (NO)-releasing material is described that utilizes S-nitrosothiols anchored to tiny fumed silica (FS) particles as the NO donor system. The synthetic procedures suitable for tethering three different thiol species (cysteine, N-acetylcysteine, and N-acetylpenicillamine) to the surface of FS polymer filler particles are detailed. The thiol-derivatized particles are converted to their corresponding S-nitrosothiols by reaction with t-butylnitrite. The total NO loading on the resulting particles range from 21-138 nmol/mg for the three different thiol-derivatized materials [S-nitrosocysteine-(NO-Cys)-FS, S-nitroso-N-acetylcysteine (SNAC)-FS, and S-nitroso-N-acetylpenicillamine (SNAP)-FS], with SNAP-FS yielding the highest NO loading. NO can be generated from these particles when suspended in solution via the addition of copper(II) ions, ascorbate, or irradiation with visible light. The SNAC-FS and SNAP-FS particles can be blended in polyurethane and silicone rubber matrixes to create films that release NO at controlled rates. Polyurethane films containing SNAC-FS submerged in phosphate-buffered saline (pH 7.4) generate NO surface fluxes approximately 0.1-0.7x10(-10) mol cm-2 min-1 and SNAP-FS films generate NO fluxes of approximately 0-7.5x10(-10) mol cm-2 min-1 upon addition of increasing amounts of copper ions. Silicone rubber films containing SNAC-FS or SNAP-FS do not liberate NO upon exposure to copper ions or ascorbate in phosphate-buffered saline solution. However, such films are shown to release NO at rates proportional to increasing intensities of visible light impinging on the films. Such photoinitiated NO release from these composite materials offers the first NO-releasing hydrophobic polymers with an external on/off trigger to control NO generation.

The in vivo biocompatibility and analytical performance of amperometric oxygen-sensing catheters prepared with a new type of nitric oxide (NO)-releasing silicone rubber polymer (DACA/N2O2 SR) is reported. The NO-release silicone rubber coating contains diazeniumdiolated secondary amine sites covalently anchored to a dimethylsiloxane matrix. Narrow diameter (0.9 mm, o.d.) silicone rubber tubing coated with this polymer can be employed to construct functional oxygen-sensing catheters that release NO continuously at levels1 x 10(-10) mol/cm2-min for more than 20 h. In vivo evaluation of such sensors within the carotid and femoral arteries of swine over a 16-h time period demonstrates that sensors prepared with the new NO-release coating exhibit no significant platelet adhesion or thrombus formation, but control sensors (non-NO release) implanted within the same animals do show a high propensity for cell adhesion and bulk clot formation. Furthermore, the in vivo analytical data provided by sensors fabricated with NO-release coatings (N = 9) are shown to be statistically equivalent to PO2 levels measured in vitro on discrete samples of blood. Control sensors (N = 9) placed within the same animals yield average PO2 values that are statistically different (por = 0.05) (lower) from both the levels measured on discrete samples and those provided by the NO-release sensors over a 16-h in vivo monitoring period.

Despite the documented potential to leverage nitric oxide generation to improve in vivo performance of implanted devices, a key limitation to current NO releasing materials tested thus far is that there has not been a means to modulate the level of NO release after it has been initiated. We report the fabrication of a wireless platform that uses light to release NO from a polymethylmethacrylate (PMMA) optical fiber coated with an S -nitroso- N -acetylpenicillamine derivatized polydimethylsiloxane (SNAP-PDMS). We demonstrate that a VAOL-5GSBY4 LED ( λ dominant = 460 nm) can be used as a dynamic trigger to vary the level of NO released from 500 μm diameter coated PMMA. The ability to generate programmable sequences of NO flux from the surface of these coated fibers offers precise spatial and temporal control over NO release and provides a platform to begin the systematic study of in vivo physiological response to implanted devices. NO surface fluxes up to 3.88 ± 0.57 × 10 −10 mol cm −2 min −1 were achieved with ∼100 μm thick coatings on the fibers and NO flux was pulsed, ramped and held steady using the wireless platform developed. We demonstrate the NO release is linearly proportional to the drive current applied to the LED (and therefore level of light produced from the LED). This system allow the surface flux of NO from the fibers to be continuously changed, providing a means to determine the level and duration of NO needed to mediate physiological response to blood contacting and subcutaneous implants and will ultimately lead to the intelligent design of NO releasing materials tailored to specific patterns of NO release needed to achieve reliable in vivo performance for intravascular and subcutaneous sensors and potentially for a wide variety of other implanted biomedical devices.

Previous studies have shown that many S-nitrosothiols (RSNOs) rapidly degrade, with half-lives from minutes to seconds in aqueous solution [1]. The research presented in this paper presents data that the RSNO 1,3-benzenedinitrosothiol has been relatively stable for over 1 year. This RSNO still releases nitric oxide (NO) when subjected to ultraviolet light and has the same characteristic absorbance peak as a freshly made RSNO. Developing this stable RSNO potentially provides a venue for further investigation into using this NO donor to improve the biocompatibility of implanted optical sensors.

Measuring the blood gases of patients in the intensive care unit or undergoing major surgical procedures in real time would help healthcare providers diagnose and manage base excess and base deficient disorders. Optical fibers provide a platform upon which an intravascular blood gas sensor may be built and has been by various companies. Unfortunately, thrombosis on the sensor surface interferes with the blood gas measurements and also poses the risk of creating emboli. Nitric oxide inhibits platelet adhesion and activation, which can reduce thrombus formation on the sensor surface. An optically based pH sensor is fabricated as a first step to show that nitric oxide can be used with blood gas sensors to reduce thrombosis and not interfere with the measurements. pH sensors fabricated using glass microscope slides suffered from leaching of the dye from the sol-gel matrix. The dye readily leached out when the dye was in its appropriate protonated or deprotonated form. To reduce the leaching of the dye, methods of covalently linking the dye to fumed silica have been investigated, and one is presented here.

Biomedical devices that contact blood and tissue universally inspire a host response that often compromises the function of the device (i.e., intravascular sensors become coated with thrombi, artificial vascular grafts become coated with thrombi, artificial vascular grafts become occluded with thrombus formation and neointimal hyperplasia). Nitric oxide (NO) has been shown to be a potent inhibitor of platelet adhesion and activation and has been implicated in mediating the inflammatory response and promoting would healing. We are currently developing NO-releasing compounds based on S-nitrosothiols derived from substituted aromatic compounds that utilize light as an external on/off trigger capable of releasing precisely controlled surface fluxes of NO. The level of NO generated is dependent on the wavelength and intensity of light shown on the compounds. Data will be presented that show the synthesis and NO-release properties of three novel compounds, S-nitroso-2-methoxybenzene, S-nitroso-3-methoxybenzene and S-nitroso-2-chlorobenzene. Ultimately, these compounds will be tethered to the surface of polymer fillers that will then be blended into hydrophobic polymers and used as coatings on biomedical devices. A model system that will be used to demonstrate the utility of this approach will be a multi-element fiber optic sensors that will contain sensing elements capable of measuring blood gases and NO-releasing fibers that locally generate enough NO to inhibit clot formation on the sensor surface, thus allowing the sensor to function reliably in vivo.

Nitric Oxide (NO) is small, free radical gas that has been shown to have a wide variety of physiological functions, including the ability to hinder tumor angiogenesis at high, but non lethal, concentrations [1]. Previous work suggests that if NO could be effectively delivered in vivo to tumors of patients currently undergoing chemotherapy treatments at the appropriate levels, less damaging chemotherapy treatments could be used against cancer [2]. This could increase the overall survivability of cancer patients, especially in those prone to the harmful effects of chemotherapy: children, elderly, and those of weak immune systems. If NO is especially successful at preventing and eliminating tumor growth, angiogenesis, and carcinogenesis the need for stressful chemotherapy treatments could be eliminated altogether. This project is focused on developing novel photosensitive NO donors that can be incorporated into polymeric systems and used in a fiber optic drug delivery system. Development of these NO-releasing polymers will allow continued investigation of NO's role in tumor death by precisely controlling the surface flux of NO that cells are exposed to. Generating specific surface fluxes of NO from polymer films has been demonstrated by using polymer films that contain photoinitiated NO donors [3], prepared by synthesizing S-nitrosothiol (RSNO) derivitized polymer fillers that are blended into hydrophobic polymers and cast into a film. These films generate and sustain a surface flux of NO based on the wavelength and intensity of light used [3]. Polymers releasing NO are more promising as an NO donor than simply injecting NO into samples because they allow for spatial and temporal control of NO delivery. The specific concentration of NO needed to produce desirable effects on tumor cells (i.e., apoptosis) is not known. Data will be presented that show the synthesis and NO-release properties of novel RSNOs based on the nitrosation of benzyl mercaptan thiols. Specifically, UV-Vis spectrum of benzyl mercaptan in toluene and S-nitrosobenzyl mercaptan after the addition of t-butyl nitrite will be presented. We are currently investigating the effects of varying NO-surface fluxes generated from photolytic NO donating polymer films on aortic smooth muscle cell cultures obtained from mice. Once we have established that we can quantitatively determine the effects of different levels of NO on the proliferation of smooth muscle cell cultures, work will begin to apply this methodology and these novel NO-releasing polymeric systems to begin investigating what durations and surface fluxes of NO are necessary to have tumorcidal effects on specific cancer cells.

Publisher Summary This chapter describes the procedure employed to construct functional NO-releasing catheter-type amperometric oxygen sensors, including coating the sensor with NO-release materials, assembly of the sensor itself, and in vivo evaluation of the analytical performance and hemocompatibility of the device. The procedure describing the specific fabrication of an intravascular catheter-type sensor that is introduced into an artery via a 14-gauge, 1.16-in. angiocath isdiscussed. In this procedure, the sensor is fixed into a four-way stopcock to allow a means to attach the sensor to the catheter securely and to introduce a saline drip to prevent blood from pooling in the catheter. The length and diameter of the sensor can be adjusted by selecting tubing of the appropriate diameters and adjusting lengths of wires and the sensor body to accommodate a wide variety of sizes and specific methods of introducing the sensor into the blood vessel or tubing to be monitored. Material and procedure for coating sensor sleeves, sensor fabrication, and concepts related to sensor calibration and use are also described.