Nitric oxide releasing articles with an omniphobic coating and methods for making and using the same

Abstract

Described herein are nitric oxide releasing articles with an omniphobic coating covalently bonded to the surface of the article. The articles described herein possess a uniquely engineered, combinatorial anti-biofouling design. The articles described herein include a nitric oxide releasing compound that provides a 'bioactive' avenue, which was further combined with an omniphobic (i.e., 'liquid-like') solid coating as the 'passive' anti-biofouling pathway. The articles described herein possess numerous advantageous properties including, but not limited to, high physical durability, aqueous chemical stability, and UV resistance, prolonged room temperature storage, cytocompatibility and impeccable anti-biofouling properties including anti-platelet adhesion and activation.

Description

T|H Docket: 222105-2390 NITRIC OXIDE RELEASING ARTICLES WITH AN OMNIPHOBIC COATING AND METHODS FOR MAKING AND USING THE SAME STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government support under grant number R01 HL134899 and R01 HL151473 awarded by the NIH. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 696,873, filed on September 20, 2024, the contents of which are incorporated by reference herein in their entireties. BACKGROUND

[0003] Surface fouling caused by the adsorption of microorganisms, biological molecules, and chemical substances / liquids is a widespread concern plaguing medical devices [1-2], water treatment plants [3], the food industry [4], and marine surfaces [5]. Conventional bioactive approaches such as the use of intrinsically bioactive bulk materials (e.g. silver, chitosan, bioactive glass or loaded with antibiotics) [6-8], grafting antimicrobial molecules (e.g. triclosan, chlorhexidine) [9-10], reactive oxygen species releasing polymers [11-12], photoactivated titanium dioxide coatings

[0013] , and nanostructured biomaterials [14-15] have been explored to combat surface biofouling. However, such conventional bioactive approaches suffer from limitations related to well-known antibiotic resistance

[0016] , leaching of metal ions causing toxicity

[0017] , lack of prolonged durability of the coatings

[0018] , and mechanically fragile nanostructures

[0019] . Nitric oxide (NO) is a well-known endogenously produced free radical gasotransmitter with anti-microbial and anti-thrombotic characteristics, used to fabricate bioactive antifouling biomaterials [20-22]. However, NO-derived biomaterials a) are unable to prevent protein adsorption on the surface that ultimately triggers the platelet adhesion followed by thrombosis,

[0023] and b) induces toxicity due to the leaching of the NO donor molecules, thus, restricting the translational ability of NO-based biomaterials [24,25].

[0004] Over the last decade, strategic permutation of chemistry and topography was investigated to develop nature-inspired, passive antifouling surfaces such as superhydrophobicity (SHP), and slippery liquid-infused porous surfaces (SLIPS) [26-30]. However, the temperature and pressure instability concerns related to SHP restricted theT|H Docket: 222105-2390 practical utility of this nature-inspired passive antifouling approach [40-41]. Moreover, the fabrication of durable SLIPS requires the development of micro / nano topography followed by an appropriate surface modification to stably hold the infused lubricant

[0042] , which demands sophisticated physical and chemical treatment processes [43-45]. Importantly, the infused lubricant is well-reported to be prone to migration, depletion and volatilization over time [43- 45], thus, limiting its prolonged utility under real-world scenarios. SUMMARY

[0005] Described herein are nitric oxide releasing articles with an omniphobic coating covalently bonded to the surface of the article. The articles described herein possess a uniquely engineered, combinatorial anti-biofouling design. The articles described herein include a nitric oxide releasing compound that provides a ‘bioactive’ avenue, which was further combined with an omniphobic (i.e., ‘liquid-like’) solid coating as the ‘passive’ anti-biofouling pathway. The articles described herein possess numerous advantageous properties including, but not limited to, high physical durability, aqueous chemical stability, and UV resistance, prolonged room temperature storage, cytocompatibility and impeccable anti- biofouling properties including anti-platelet adhesion and activation.

[0006] Other compositions, apparatus, methods, features, and advantages will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional compositions, apparatus, methods, features and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Further aspects of the present disclosure will be more readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings.

[0008] Figures 1A-1J. (A-B) Digital images depicting the restricted sliding behaviour of a water (A) and DMSO (B) droplet on the N-octyltriethoxylsilane (OTS) coated PDMS substrate. (C-F) Digital images depicting the sliding behaviour of a water (C-D) and DMSO (E-F) droplet on a PDMS substrate coated with the ‘liquid-like’ solid coating. (G) Graph accounting for the sliding behaviour of liquids with different surface tensions across the ‘liquid-like’ solid coating on PDMS. (H-I) Scanning electron microscopy (H) and atomic force microscopy, 10 µm X 10 µm (I) images of the ‘liquid-like’ solid coating on PDMS. (J) FTIR analysis accounting for the ‘liquid-like’ behaviour of OTS after addition of TMOS as the spacer molecule. Liquid droplet volume used = 15 µL.T|H Docket: 222105-2390

[0009] Figures 2A-2K. (A-C) Schematic depicting the blending of the multi-functional gaso-transmitter, S-nitroso-N-acetyl-D-penicillamine (SNAP) into the PDMS substrate and subsequent coating with the ‘liquid-like’ solid coating to obtain a nitric oxide releasing, solid slippery polymeric material (PDMS-SNAP-SS). (D-E) Scanning electron microscopy (D) and atomic force microscopy (E) images of the PDMS-SNAP material. (F-G) Digital images depicting the sliding behaviour of water (F) and DMSO (G) on PDMS-SNAP-SS. (H-I) Scanning electron microscopy (H) and atomic force microscopy (I) images of PDMS-SNAP- SS. (J) Graph accounting for the sliding behaviour of liquids with different surface tensions across PDMS-SNAP-SS. (K) Plot accounting for the nitric oxide release over a prolonged time from PDMS-SNAP and PDMS-SNAP-SS.

[0010] Figures 3A-3N. (A-B) Graph depicting the sliding angles on the ‘liquid-like’ solid coating on PDMS (PDMS-SS) at regular intervals during continuous exposure to aqueous phase up to 15 days (A) and thermal stability (B) at 100ºC up to 30 days. (C-L) Digital images depicting the tape peel test. (M) Graph depicting the change in sliding angles at regular intervals during the repetitive tape peel test for 50 cycles. (N) Graph depicting the variation in sliding angles on PDMS-SS and PDMS-SNAP-SS at regular intervals during the room temperature storage stability up to 60 days.

[0011] Figures 4A-4F show graph accounting for the E. coli (A) and S. aureus (B) adhered on the different sample types following a 24 h bacterial adhesion experiment. C-D) Graph accounting for the E. coli (A) and S. aureus (B) planktonic bacterial elimination following a 24 h experiment. E-F) Graph illustrating the E. coli (E) and S. aureus (F) biomass accumulation on the different sample types following a 72 h drip flow bioreactor experiment. *p ≤0.01, **p ≤0.01 and ****p ≤0.0001. All data are represented as mean ±SD.

[0012] Figures 5A-5D. (A) Graph depicting the relative cell viability (in percentage) of the different sample types against human fibroblasts and endothelial cells. (B) Graph accounting for the fibrinogen adsorbed on the surface PDMS-SNAP-SS in comparison to the controls. (C) Graph depicting the platelets adhered onto the surface of the different polymeric control samples and the combinatorial material (PDMS-SNAP-SS). (D) Bar diagram accounting for the hemolytic index (in percentage) for the polymeric materials. *p^≤^.01, **p ≤^0.01, ***p ≤^0.001, ****p ≤^.0001 and ns is non-significant. All data are represented as mean^±^SD.

[0013] Figures 6A-6O. (A-D) Digital images depicting the sliding behaviour of water (A,C) and DMSO (B,D) droplet on a polyvinylchloride (PVC) substrate blended without (A-B) and with SNAP (C-D) followed by application of the solid slippery (SS) coating. E-H) Digital images depicting the sliding behaviour of water (E,G) and DMSO (F,H) droplet on a ChronoSil substrate blended without (E-F) and with SNAP (G-H) followed by application of the solidT|H Docket: 222105-2390 slippery (SS) coating. I) Graph accounting for the sliding behaviour of liquids with different surface tensions across the ‘liquid-like’ solid coating on the different polymers. J) Graph accounting for the sliding behaviour of liquids with different surface tensions across the ‘liquid- like’ solid coating on the different polymers blended with SNAP. K) Graph accounting for the sliding behaviour of water and DMSO after performing tape peel test on the ‘liquid-like’ solid coating on the different polymers blended without (black) and with (green) SNAP. L-O) Digital images depicting the sliding behaviour of water (L,N) and DMSO (M,O) on a commercial grade silicone rubber coated with the solid slippery (SS) topcoat without (L-M) and with SNAP blending (N-O). Liquid droplet volume used = 15 µL.

[0014] Figures 7A-7E. Schematic depicting the formation of a random co-condensed network of organo-silanes i.e. tetramethyl orthosilicate (TMOS) and N-octyltriethoxysilane (OTS). The presence of TMOS as a spacer molecule provides the optimum spacing to the OTS functionalities to enable the free-rotational ability of the alkyl chains that can act as the ‘liquid-like’ solid lubricant. The organo-silane co-condensed mixture was covalently bonded onto a medical grade polymer that was pre-loaded with a bioactive agent. The combination of the ‘liquid-like’ solid slippery coating on a bioactive polymer provides a novel interface that can exhibit liquid repellence as well combat the biofouling of medical grade polymers.

[0015] Figure 8A-8E. Digital images (A-B) and contact angle images (C-D) depicting the sliding behaviour of a water and DMSO droplet on an uncoated PDMS substrate. E) AFM image of PDMS. (10 µm X 10 µm)

[0016] Figures 9A-9H. Digital images and contact angle images depicting the static (A-D) and sliding behaviour (E-H) of a water and DMSO droplet on a N-octyltriethoxysilane coated PDMS substrate.

[0017] Figures 10A-10H. Digital images (A-D) and static contact angle images (E-H) of liquids with varying surface tensions on the solid slippery coating on PDMS.

[0018] Figures 11A-11X. Digital images and contact angle images depicting the sliding behavior of liquids with varying surface tensions on the solid slippery coating on PDMS.

[0019] Figures 12A-12B. A) Graph depicting the change in sliding angles for different liquids on varying the volume of the impinged liquid droplet. B) Graph accounting for the optical transmittance of the solid slippery coating on a PDMS substrate (red) normalized with respect to an uncoated PDMS substrate (black).

[0020] Figures 13A-13D. A-D) Scanning electron microscopy images and energy dispersive X-ray analysis on the different types of samples.

[0021] Figures 14A-14D. Digital images (A-B) and contact angle images (C-D) depicting the sliding behaviour of a water and DMSO droplet on an PDMS-SNAP substrate.T|H Docket: 222105-2390

[0022] Figures 15A-15H. Digital images (A-D) and static contact angle images (E-H) of liquids with varying surface tensions on the PDMS-SNAP-SS.

[0023] Figures 16A-16L. A-L) Digital images and contact angle images depicting the sliding behavior of liquids with varying surface tensions on PDMS-SNAP-SS.

[0024] Figures 17A-17B. A) Bar Diagram accounting for the static water contact angles on the different sample types. B) Graph accounting for the percentage of SNAP remaining in the polymeric substrate over 7 days of continuous exposure to phosphate buffer.

[0025] Figure 18. Graphs accounting for the change in sliding angles of water and DMSO on PDMS-SS and PDMS-SNAP-SS after 24 hours of continuous exposure to UV irradiation (354 nm).

[0026] Figures 19A-19H. A-H) SEM images depicting the E. coli biomass accumulation on the different sample types after 72 h drip flow bioreactor experiment.

[0027] Figures 20A-20H. A-H) SEM images depicting the S. aureus biomass accumulation on the different sample types after 72 h drip flow bioreactor experiment.

[0028] Figures 21A-21D. A-D) Fluorescence microscopy images depicting the fibrinogen adsorption on the surface of the PDMS, PDMS-SS, PDMS-SNAP and the combinatorial material, PDMS-SNAP-SS.

[0029] Figures 22A-22L. A-L) Scanning electron microscopic images depicting the platelet adsorption and activation on the surface of the uncoated PDMS (A-C), PDMS-SS (D-F), PDMS-SNAP (G-I) and PDMS-SNAP-SS (J-L) after 30 mins of whole blood exposure.

[0030] Figures 23A-23P. Digital images depicting the sliding behavior of (A-B) uncoated Elast-EonTMpolymer film with water and DMSO, water (C-E) and DMSO (F-H) on a SNAP blended Elast-EonTMpolymer coated with the silane-derived solid slippery coating. Digital images depicting the sliding behavior of (I-J) uncoated polyvinylchloride polymer film with water and DMSO water (K-M) and DMSO (N-P) on a SNAP blended polyvinylchloride polymer further coated with the silane-derived solid slippery coating.

[0031] Figures 24A-24H. A-B) Digital images depicting the sliding behavior of water and DMSO on an uncoated ChronSsil substrate. C-H) Digital images depicting the sliding behavior of water and DMSO on the silane-derived solid slippery coating on ChronoSil.

[0032] Figures 25A-25F. A-F) Digital images depicting the sliding behavior of water (A-C) and DMSO (D-F) on a SNAP blended polyvinylchloride polymer coated with the silane-derived solid slippery coating.

[0033] The drawings illustrate only example embodiments and are therefore not to be considered limiting of the scope described herein, as other equally effective embodiments are within the scope and spirit of this disclosure. The elements and features shown in the drawingsT|H Docket: 222105-2390 are not necessarily drawn to scale, emphasis instead being placed upon clearly illustrating the principles of the embodiments. Additionally, certain dimensions may be exaggerated to help visually convey certain principles. In the drawings, similar reference numerals between figures designate like or corresponding, but not necessarily the same, elements. DETAILED DESCRIPTION

[0034] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0035] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0036] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0037] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0038] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing dateT|H Docket: 222105-2390 of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0039] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0040] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0041] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions

[0042] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” “having,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0043] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a polysiloxane” includes, but is not limited to, mixtures or combinations of two or more such polysiloxanes, and the like.T|H Docket: 222105-2390

[0044] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0045] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0046] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0047] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are notT|H Docket: 222105-2390 and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0048] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0049] Disclosed are the components to be used to prepare the compositions disclosed herein as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B- D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would beT|H Docket: 222105-2390 considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0050] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

[0051] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance and instances where it does not.

[0052] As used herein, the term “biocompatible,” with respect to a substance or fluid described herein, indicates that the substance or fluid does not adversely affect the short-term viability or long-term proliferation of a target biological particle within a particular time range.

[0053] The terms “antimicrobial” and “antimicrobial characteristic” refer to the ability to kill and / or inhibit the growth of microorganisms. A substance having an antimicrobial characteristic may be harmful to microorganisms or microbes (e.g., bacteria, fungi, virus, protozoans, algae, and the like). A substance having an antimicrobial characteristic can kill the microorganism and / or prevent or substantially prevent the growth or reproduction of the microorganism.

[0054] The terms “bacteria” or “bacterium” include, but are not limited to, gram positive and gram negative bacteria. Bacteria can include, but are not limited to, Abiotrophia, Achromobacter, Acidaminococcus, Acidovorax, Acinetobacter, Actinobacillus, Actinobaculum, Actinomadura, Actinomyces, Aerococcus, Aeromonas, Afipia, Agrobacterium, Alcaligenes, Alloiococcus, Alteromonas, Amycolata, Amycolatopsis, Anaerobospirillum, Anabaena affinis and other cyanobacteria (including the Anabaena, Anabaenopsis, Aphanizomenon, Camesiphon, Cylindrospermopsis, Gloeobacter Hapalosiphon, Lyngbya, Microcystis, Nodularia, Nostoc, Phormidium, Planktothrix, Pseudoanabaena, Schizothrix, Spirulina, Trichodesmium, and Umezakia genera) Anaerorhabdus, Arachnia, Arcanobacterium, Arcobacter, Arthrobacter, Atopobium, Aureobacterium, Bacteroides, Balneatrix, Bartonella, Bergeyella, Bifidobacterium, Bilophila Branhamella, Borrelia, Bordetella, Brachyspira, Brevibacillus, Brevibacterium, Brevundimonas, Brucella, Burkholderia, Buttiauxella, Butyrivibrio, Calymmatobacterium, Campylobacter, Capnocytophaga, Cardiobacterium,T|H Docket: 222105-2390 Catonella, Cedecea, Cellulomonas, Centipeda, Chlamydia, Chlamydophila, Chromobacterium, Chyseobacterium, Chryseomonas, Citrobacter, Clostridium, Collinsella, Comamonas, Corynebacterium, Coxiella, Cryptobacterium, Delftia, Dermabacter, Dermatophilus, Desulfomonas, Desulfovibrio, Dialister, Dichelobacter, Dolosicoccus, Dolosigranulum, Edwardsiella, Eggerthella, Ehrlichia, Eikenella, Empedobacter, Enterobacter, Enterococcus, Erwinia, Erysipelothrix, Escherichia, Eubacterium, Ewingella, Exiguobacterium, Facklamia, Filifactor, Flavimonas, Flavobacterium, Francisella, Fusobacterium, Gardnerella, Gemella, Globicatella, Gordona, Haemophilus, Hafnia, Helicobacter, Helococcus, Holdemania Ignavigranum, Johnsonella, Kingella, Klebsiella, Kocuria, Koserella, Kurthia, Kytococcus, Lactobacillus, Lactococcus, Lautropia, Leclercia, Legionella, Leminorella, Leptospira, Leptotrichia, Leuconostoc, Listeria, Listonella, Megasphaera, Methylobacterium, Microbacterium, Micrococcus, Mitsuokella, Mobiluncus, Moellerella, Moraxella, Morganella, Mycobacterium, Mycoplasma, Myroides, Neisseria, Nocardia, Nocardiopsis, Ochrobactrum, Oeskovia, Oligella, Orientia, Paenibacillus, Pantoea, Parachlamydia, Pasteurella, Pediococcus, Peptococcus, Peptostreptococcus, Photobacterium, Photorhabdus, Phytoplasma, Plesiomonas, Porphyrimonas, Prevotella, Propionibacterium, Proteus, Providencia, Pseudomonas, Pseudonocardia, Pseudoramibacter, Psychrobacter, Rahnella, Ralstonia, Rhodococcus, Rickettsia Rochalimaea Roseomonas, Rothia, Ruminococcus, Salmonella, Selenomonas, Serpulina, Serratia, Shewenella, Shigella, Simkania, Slackia, Sphingobacterium, Sphingomonas, Spirillum, Spiroplasma, Staphylococcus, Stenotrophomonas, Stomatococcus, Streptobacillus, Streptococcus, Streptomyces, Succinivibrio, Sutterella, Suttonella, Tatumella, Tissierella, Trabulsiella, Treponema, Tropheryma, Tsakamurella, Turicella, Ureaplasma, Vagococcus, Veillonella, Vibrio, Weeksella, Wolinella, Xanthomonas, Xenorhabdus, Yersinia, and Yokenella. Other examples of bacterium include Mycobacterium tuberculosis, M. bovis, M. typhimurium, M. bovis strain BCG, BCG substrains, M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium subspecies paratuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus equi, Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes, Listeria ivanovii, Bacillus anthracis, B. subtilis, Nocardia asteroides, and other Nocardia species, Streptococcus viridans group, Peptococcus species, Peptostreptococcus species, Actinomyces israelii and other Actinomyces species, and Propionibacterium acnes, Clostridium tetani, Clostridium botulinum, other Clostridium species, Pseudomonas aeruginosa, other Pseudomonas species, Campylobacter species, Vibrio cholera, Ehrlichia species, Actinobacillus pleuropneumoniae, Pasteurella haemolytica, Pasteurella multocida, other Pasteurella species, LegionellaT|H Docket: 222105-2390 pneumophila, other Legionella species, Salmonella typhi, other Salmonella species, Shigella species Brucella abortus, other Brucella species, Chlamydi trachomatis, Chlamydia psittaci, Coxiella burnetti, Escherichia coli, Neiserria meningitidis, Neiserria gonorrhea, Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species, Yersinia pestis, Yersinia enterolitica, other Yersinia species, Escherichia coli, E. hirae and other Escherichia species, as well as other Enterobacteria, Brucella abortus and other Brucella species, Burkholderia cepacia, Burkholderia pseudomallei, Francisella tularensis, Bacteroides fragilis, Fudobascterium nucleatum, Provetella species, and Cowdria ruminantium, or any strain or variant thereof. The gram-positive bacteria may include, but is not limited to, gram positive Cocci (e.g., Streptococcus, Staphylococcus, and Enterococcus). The gram-negative bacteria may include, but is not limited to, gram negative rods (e.g., Bacteroidaceae, Enterobacteriaceae, Vibrionaceae, Pasteurellae and Pseudomonadaceae).

[0055] The terms “fungus” or “fungi” include, but are not limited to yeasts such as, for example, Candida albicans or other Candida spp. including C. glabrata, C. rugosa, C. parapsilosis, C. tropicalis, or C. dubliniensis Fungi can also include dermatophytes such as, for example, Trichophyton spp. and Microsporum spp. (e.g., T. rubrum, T. interdigitale, T. tonsurans, T. violaceum, T. concentricum, T. schoenleinii, T. soudanense, T. mentagrophytes, T. equinum, T. erinacei, T. verrucosum, M. audouinii, M. ferrugineum, M. canis, M. gypseum, M. nanum, and / or M. cookie).

[0056] The term “antimicrobial effective amount” as used herein refers to that amount of the compound being administered / released that will kill microorganisms or inhibit growth and / or reproduction thereof to some extent (e.g. from about 5% to about 100%). In reference to the compositions or articles of the disclosure, an antimicrobial effective amount refers to that amount which has the effect of diminishment of the presence of existing microorganisms, stabilization (e.g., not increasing) of the number of microorganisms present, preventing the presence of additional microorganisms, delaying or slowing of the reproduction of microorganisms, and combinations thereof. Similarly, the term “antibacterial effective amount” refers to that amount of a compound being administered / released that will kill bacterial organisms or inhibit growth and / or reproduction thereof to some extent (e.g., from about 5% to about 100%). In reference to the compositions or articles of the disclosure, an antibacterial effective amount refers to that amount which has the effect of diminishment of the presence of existing bacteria, stabilization (e.g., not increasing) of the number of bacteria present, preventing the presence of additional bacteria, delaying or slowing of the reproduction of bacteria, and combinations thereof.T|H Docket: 222105-2390

[0057] As used herein, the term “subject” includes humans, mammals (e.g., cats, dogs, horses, etc.), birds, and the like. Typical subjects to which embodiments of the present disclosure may be administered will be mammals, particularly primates, especially humans. For veterinary applications, a wide variety of subjects will be suitable, e.g., livestock such as cattle, sheep, goats, cows, swine, and the like; and domesticated animals particularly pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals will be suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.

[0058] The terms “treat”, “treating”, and “treatment” are an approach for obtaining beneficial or desired clinical results. Specifically, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (e.g., not worsening) of disease, delaying or slowing of disease progression, substantially preventing spread of disease, amelioration or palliation of the disease state, and remission (partial or total) whether detectable or undetectable.

[0059] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0060] As used herein, the term “reduce” or “reducing” refers to deceasing the degree or amount of an event. For example, reducing biofilm formation can mean lower the amount of biofilm formation when using the compositions described herein when compared to the amount of biofilm formation when the compositions described herein are not used.

[0061] The term “omniphobic coating” and “omniphobic surface” is a coating or surface that repels water, oils, and a variety of organic solvents so that the liquid for the most part will not spread on the surface of the article.

[0062] The term "alkyl group" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl- substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.

[0063] In some embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer. Likewise, in some embodiments cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g. have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latterT|H Docket: 222105-2390 of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

[0064] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, having from one to ten carbons, or from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In embodiments described in the present application, preferred alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0065] In some embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer.

[0066] The term "fluoroalkyl group" refers to an alkyl group as defined herein where one or more hydrogen atoms on the alkyl group are substituted with a fluorine atom. In one aspect, all of the hydrogen atoms on the alkyl group are substituted with a fluorine atom.

[0067] The terms “alkoxy” and “alkoxyl” as used herein refer to an alkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or —OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl groups.

[0068] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula - OH. Nitric Oxide Releasing Articles with an Omniphobic Coating and Methods for Making and Using the Same

[0069] Described herein are nitric oxide releasing articles with an omniphobic coating covalently bonded to the surface of the article. The articles described herein possess a uniquely engineered, combinatorial anti-biofouling design. The articles described herein include a nitric oxide releasing compound that provides a ‘bioactive’ avenue, which was furtherT|H Docket: 222105-2390 combined with an omniphobic (i.e., ‘liquid-like’) solid coating as the ‘passive’ anti-biofouling pathway.

[0070] The methods for producing the articles described herein provide an extremely facile and economic synthetic process that can be extended to a wide range of substrates for widespread real-world applicability. In one aspect, the articles described herein are produced by the method comprising (a) functionalizing at least one surface of the article comprising the nitric oxide releasing compound with a plurality of hydroxyl groups to produce a pre-functionalized surface, and (b) contacting the pre-functionalized surface with a hydrolyzed polysiloxane, wherein the plurality of hydroxyl groups on the surface of the article reacts with the hydrolyzed polysiloxane to covalently bond the polysiloxane to the surface of the article.

[0071] The first step of the process involves functionalizing a surface of the article with a plurality of hydroxyl groups to produce a pre-functionalized surface. In one aspect, the surface of the article is exposed to plasma treatment such as, for example, air plasma. Plasma treatment generates surface hydroxyl groups, which permits the covalent bonding of a hydrolyzed polysiloxane on the surface of the article. Non-limiting procedures for functionalizing the surface of the article with plasma are provided in the Examples.

[0072] After the surface has been functionalized with a plurality of hydroxyl groups, the functionalized surface is contacted with a hydrolysed polysiloxane to covalently bond the polysiloxane to the surface of the article. In one aspect, the hydrolysed polysiloxane is produced by (a) reacting a compound having the structure I and II wherein R1, R2, and R3are independently an alkyl group or a fluoroalkyl group in a solvent followed by the addition of an acid to produce the hydrolysed polysiloxane.

[0073] In one aspect, each of R1and R2in structures I and II are a C1 to C5 alkyl group. In another aspect, R3in structure II is a C1to C10alkyl group. In another aspect, the polysiloxane is the hydrolyzed reaction product between octyltriethoxysilane and tetramethyl orthosilicate. In one aspect, the polysiloxane comprises the structure IIIT|H Docket: 222105-2390 wherein R3is aat least one of R3is a C1to C10alkyl group.

[0074] The reaction between the compounds having the structure I and II is conducted in a solvent. In one aspect, the solvent is an alcohol (e.g., ethanol). In one aspect, the reaction is conducted in the presence of an acid. In one aspect, the acid is a strong acid such as, for example, hydrochloric acid, sulfuric acid, and the like. In one aspect, the reaction is conducted at an elevated temperature to ensure the reaction between compounds having the structures I and II is complete and the hydrolyzed product is produced. Non-limiting procedures for producing the hydrolyzed polysiloxanes useful herein are provided in the Examples.

[0075] The hydrolysed polysiloxane can be applied to the pre-functionalized surface composed of a plurality of hydroxyl groups using techniques known in the art including, but not limited to, dipping, coating, or spraying the hydrolyzed polysiloxane on the pre- functionalized surface of the article. Exemplary non-limiting methods for applying the hydrolyzed polysiloxane on the pre-functionalized surface of the article are provided in the Examples.

[0076] The article used herein can be composed of a variety of different materials. In one aspect, the article is composed of glass. In another aspect, the article is composed of a polymer (e.g., polysiloxane such as polydimethylsiloxane, a polydiethylsiloxane, a polydipropylsiloxane, or a polydiphenylsiloxane) or a metal (e.g., aluminum or stainless steel). In one aspect, the article is composed of a silicone-polyurethane co-polymer (e.g., Elast- EonTM), a polycarbonate-based silicone elastomer (e.g., ChronoSil), or a thermoplastic co- polymer of vinyl chloride and vinyl acetate. In another aspect, the article is composed of a room temperature vulcanizing (RTV) silicone (e.g., DowsilTM).

[0077] The articles described herein include a nitric oxide releasing compound. In one aspect, nitric oxide releasing compound can be integrated or dispersed throughout the article. In one aspect, the article is composed of a polymeric material. For example, the polymeric material can be admixed with the nitric oxide releasing compound, and the resultingT|H Docket: 222105-2390 composition can be added to a mold to produce an article with a desired shape. Exemplary non-limiting methods for producing polymeric substrates with a nitric oxide releasing compound are provided in the Examples.

[0078] The nitric oxide releasing compound is a compound that possesses one or more nitric oxide groups, wherein nitric oxide can be released from the compound. In one aspect, the nitric oxide releasing compound is an S-nitrosothiol (RSNO) compound. In a further aspect, the nitric oxide compound is S-nitroso-N-acetylpenicillamine, S-nitroso-glutathione, S- nitroso-N-acetylcysteine, S-nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B,D-glucose, S-nitrosocaptopril, S-nitrosocysteamine, S-nitroso-3-mercapto-propanoic acid, S-nitroso-N- acetyl-l-cysteine ethyl ester (SNACET), S-nitroso-N-acetyl-L-methionine, S- nitrosomercaptoethanol, or any combination thereof. In another aspect, the nitric oxide releasing compound can be S-nitrosothiol conjugated polymers, S-nitrosothiol modified- dendrimers, S-nitrosothiol modified polysaccharides, S-nitrosothiol modified nano / microparticles, or S-nitrosothiol modified-proteins. The nitric oxide releasing compound can also include other NO-donors such as, for example, nitrates and N-diazeniumdiolates (NONOates).

[0079] In other aspects, the nitric oxide releasing compound includes a modified antibiotic compound including a nitric oxide release agent covalently attached to an antibiotic molecule. Having a single molecule with the combined functionalities of both of a stable NO donor and an antibiotic can be a very efficient approach for combating and preventing biofilm related infections. The modified antibiotic compound can be a synthetic RSNO covalently attached to an antibiotic molecule to create a novel dual functional antimicrobial agent, also referred to as a modified antibiotic compound. In other aspects, the nitric oxide releasing agent is S-nitroso- N-acetylpenicillamine (SNAP), S-nitroso-glutathione, S-nitroso-N-acetylcysteine, S- nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B,D-glucose, S-nitrosocaptopril, S- nitrosocysteamine, S-nitroso-3-mercapto-propanoic acid, or any combination thereof. In other aspects, the antibiotic molecule can be ampicillin, vancomycin, gentamicin, cephalexin, or any combination thereof. In further aspects, the modified antibiotic compound includes SNAP covalently bonded to ampicillin, referred to herein as SNAPicillin. SNAP can be represented by the following structure:T|H Docket: 222105-2390 SNAPicillin can be

[0080] In one be formed by covalently attaching a nitric oxidean attachment can be formed by mixing the nitric oxide release agent and the antibiotic molecule in a solvent and then nitrosating the mixture. The nitrosation can occur through the excess addition of t-butyl nitrite or an acidified sodium nitrite solution to the mixture. The excess addition can be about a 3 times molar excess of t-butyl nitrate with respect to the quantity of the antibiotic molecule, such as ampicillin. Methods for producing the modified antibiotic compound useful as nitric oxide releasing compounds are described in US Patent No.11,220,516, which is incorporated by reference in its entirety.

[0081] The articles described herein possess numerous advantageous mechanical and biological properties including. The omniphobic coating present on the articles described herein described herein are “slippery” liquids, which can reduce or prevent the adhesion of microbes on the surface of the article. In one aspect, the articles described herein have a sliding angle of less than 20.0 degrees for water or an organic solvent (e.g., DMSO). In another aspect, the coated articles described herein have a sliding angle of about 2.0 degrees, 4.0 degrees, 6.0 degrees, 8.0 degrees, 10.0 degrees, 12.0 degrees, 14.0 degrees, 16.0 degrees, 18.0 degrees, or 20.0 degree for water or an organic solvent, where any value can be a lower and upper endpoint of a range (e.g., 4.0 degrees to 16.0 degrees).T|H Docket: 222105-2390

[0082] The articles described herein are highly durable, which is an important consideration in practical settings and applications. In one aspect, the liquid sliding angle of the articles described herein is maintained under various conditions. In one aspect, the articles described herein have good water stability. In one aspect, the surface having the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is exposed to water for 15 days. Non-limiting procedures for determining water stability are provided in the Examples.

[0083] In one aspect, the articles described herein have good thermal stability. In one aspect, the surface having the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the article is stored at 20oC to 30oC for 60 days. In another aspect, the surface having the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is heated at 100oC for 30 days. Non-limiting procedures for determining thermal stability are provided in the Examples.

[0084] In one aspect, the articles described herein have good stability when exposed to UV irradiation. In one aspect, the surface having the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is exposed to UV irradiation for 24 hours. Non-limiting procedures for determining UV stability are provided in the Examples.

[0085] With the polysiloxane covalently bonded to the surface of the article, the articles are resistant mechanic force or pressure. In one aspect, the surface having the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is subjected to a tape peel test of 50 cycles. Here, the polysiloxane is not easily removed from the surface of the article. Non-limiting procedures for performing the tape peel test are provided in the Examples.

[0086] The articles described herein possess a uniquely engineered, combinatorial anti- biofouling design. The articles described herein include a nitric oxide releasing compound that provides a ‘bioactive’ avenue, which was further combined with an omniphobic (i.e., ‘liquid- like’) solid coating as the ‘passive’ anti-biofouling pathway. The articles described herein can be used where it is desirable to reduce or prevent biofouling (e.g. growth of bacteria, adhesion of platelets, adhesion of fibrinogen). Biofilm and thrombus formation on surfaces results in significant morbidity and mortality worldwide, which highlights the importance of the development of efficacious fouling-prevention approaches. Provided herein are multi- functional articles with outstanding multi-liquid repellency, bactericidal performance, and extremely low bacterial and blood adhesion.T|H Docket: 222105-2390

[0087] In one aspect, the articles described herein are useful in applications where it is desirable to reduce or prevent biofouling. In one aspect, the articles described herein are an implantable medical device. Implantable medical devices are a leading cause of infection such as nosocomial infections. Implantable devices described herein can reduce or prevent biofouling in a subject when the device is introduced into the subject. In one aspect, the implantable device is a urinary catheter, artificial heart valve, a vascular catheter, a graft, or a stent. In other aspects, the device is intended to contact human blood or tissue. In one aspect, the device is a hemodialysis device or a component thereof.

[0088] In one aspect, the articles described herein can prevent the adhesion of fibrinogen and other proteins on the article. The adsorption of proteins on a surface is the primary step towards platelets adhesion and activation that ultimately leads to thrombosis, hence, the protein repellence ability of biomaterials is of utmost importance. As demonstrated herein the articles described herein are effective in reducing or preventing the adhesion of proteins and ultimately platelets on the surface of the article. Non-limiting procedures for evaluating protein and platelet adhesion are provided in the Examples.

[0089] Additionally, as demonstrated herein, the articles are cytocompatible and hemocompatible, which makes them suitable for numerous medical applications (e.g., for use as implantable devices). In one aspect, the articles described herein are cytocompatible as determined by ISO-10993-5 toxicity assay. In another aspect, the articles described herein are hemocompatible, where the article has a hemolytic index of less than 0.5% as determined by NAMSA ASTM F756.

[0090] In other aspects, the articles described herein are useful in non-medical applications where it is desirable to reduce or prevent biofouling caused by the exposure to the environment. For example, the articles described herein can be used where the article is exposed to environmental elements such as rain, snow, salt water, or other conditions that can cause or promote biofouling. In one aspect, the articles described herein can be incorporated into automobile surfaces, boat hulls, or aircraft. Aspects

[0091] Aspect 1. An article comprising a polysiloxane covalently bonded to at least one surface of the article, wherein the article comprises a nitric oxide releasing compound.

[0092] Aspect 2. The article of Aspect 1, wherein the polysiloxane comprises the hydrolyzed reaction product between a compound having the structure I and IIT|H Docket: 222105-2390 OR1OR2R1O Si OR1R2O Si R3OR1OR2IIIwherein R1, R2, and R3are independently an alkyl group or a fluoroalkyl group.

[0093] Aspect 3. The article of Aspect 2, wherein each R1and R2are a C1to C5alkyl group.

[0094] Aspect 4. The article of Aspect 2 or 3, wherein R3is a C1to C10alkyl group.

[0095] Aspect 5. The article of Aspect 1, wherein the polysiloxane comprises the hydrolyzed reaction product between octyltriethoxysilane and tetramethyl orthosilicate.

[0096] Aspect 6. The article of Aspect 1, wherein the polysiloxane comprises the structure III R3OH R3een3wh r i R is a C1to C10alkyl group, hydroxyl, or an alkoxy group, wherein at least one of R3is a C1to C10alkyl group.

[0097] Aspect 7. The article of any one of Aspects 1-6, wherein the nitric oxide releasing compound is a S-nitrosothiol conjugated polymer, a S-nitrosothiol modified-dendrimers; a S- nitrosothiol modified polysaccharide, a S-nitrosothiol modified nano / microparticle, a S- nitrosothiol modified-protein, a nitrate, a N-diazeniumdiolates (NONOate), or a S-nitrosothiol (RSNO).

[0098] Aspect 8. The article of any one of Aspects 1-6, wherein the nitric oxide releasing compound is a modified antibiotic compound comprising a nitric oxide release agent covalently attached to an antibiotic molecule

[0099] Aspect 9. The article of Aspect 8, wherein the nitric oxide release agent is S- nitroso-N-acetylpenicillamine, S-nitroso-glutathione, S-nitroso-N-acetylcysteine, S-T|H Docket: 222105-2390 nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B, D-glucose, S-nitrosocaptopril, S- nitrosocysteamine, and S-nitroso-3-mercapto-propanoic acid.

[0100] Aspect 10. The article of Aspect 8 or 9, wherein the antibiotic molecule is ampicillin, vancomycin, gentamicin, or cephalexin.

[0101] Aspect 11. The article of Aspect 10, wherein the modified antibiotic compound comprises S-nitroso-N-acetylpenicillamine covalently attached to ampicillin.

[0102] Aspect 12. The article of any one of Aspects 1-6, wherein the nitric oxide releasing compound is a S-nitrosothiol compound.

[0103] Aspect 13. The article of any one of Aspects 1-6, wherein the nitric oxide releasing compound is S-nitroso-N-acetyl-penicillamine, S-nitroso-N-acetylcysteine, S-nitroso-N-acetyl cysteamine, S-nitrosoglutathione, S-nitrosocysteamine-glutathione, methyl S- nitrosothioglycolate, nitrosated cysteine, S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), S-nitroso-L-homocysteine, S-nitroso-L-cysteine, S-nitroso-albumin, S-nitrosocaptopril, or any combination thereof.

[0104] Aspect 14. The article of any one of Aspects 1-6, wherein the nitric oxide releasing compound is S-nitroso-N-acetyl-penicillamine.

[0105] Aspect 15. The article of any one of Aspects 1-14, wherein the nitric oxide releasing compound is dispersed throughout the article.

[0106] Aspect 16. The article of any one of Aspects 1-15, wherein the polysiloxane is covalently bonded to the at least one surface of the article by a plurality of hydroxyl groups on the at least one surface of the article.

[0107] Aspect 17. An article comprising a polysiloxane covalently bonded to at least one surface of the article, wherein the article comprises a nitric oxide releasing compound, wherein the article is produced by the method comprising: (a) functionalizing the at least one surface of the article comprising the nitric oxide releasing compound with a plurality of hydroxyl groups to produce a pre-functionalized surface, and (b) contacting the pre-functionalized surface with a hydrolyzed polysiloxane, wherein the plurality of hydroxyl groups on the surface of the article react with the hydrolyzed polysiloxane to covalently bond the polysiloxane to the surface of the article.

[0108] Aspect 18. The article of Aspect 17, wherein step (a) comprises exposing the at least one surface of the article to plasma treatment.

[0109] Aspect 19. The article of Aspect 18, wherein the plasma treatment comprises air plasma.T|H Docket: 222105-2390

[0110] Aspect 20. The article of Aspect 17 or 18, wherein the hydrolyzed polysiloxane is produced by (a) reacting a compound having the structure I and II wherein R1, R2, and R3are independently an alkyl group or a fluoroalkyl group in a solvent followed by the addition of an acid to produce the hydrolyzed polysiloxane.

[0111] Aspect 21. The article of any one of Aspects 1-20, wherein the article comprises glass, a polymer, or a metal.

[0112] Aspect 22. The article of Aspect 21, wherein the metal is aluminum or stainless steel.

[0113] Aspect 23. The article of Aspect 21, wherein the polymer is a polysiloxane, a silicone-polyurethane co-polymer, a polycarbonate-based silicone elastomer, a thermoplastic co-polymer of vinyl chloride and vinyl acetate, or a room temperature vulcanizing (RTV) silicone.

[0114] Aspect 24. The article of any one of Aspects 1-20, wherein the article comprises a polymeric grade material, a medical device, a surface or article in a hospital or medical facility, a surface in an automobile, boat, or aircraft, or an electronic display screen.

[0115] Aspect 25. The article of any one of Aspects 1-20, wherein the article comprises an implantable medical device.

[0116] Aspect 26. The article of Aspect 25, wherein the implantable medical device comprises a urinary catheter, artificial heart valve, a vascular catheter, a graft, or a stent.

[0117] Aspect 27. The article of any one of Aspects 1-26, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees.

[0118] Aspect 28. The article of Aspect 27, wherein the organic solvent comprises water or DMSO.

[0119] Aspect 29. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is exposed to water for 15 days.T|H Docket: 222105-2390

[0120] Aspect 30. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is heated at 100oC for 30 days.

[0121] Aspect 31. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is exposed to UV irradiation for 24 hours.

[0122] Aspect 32. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is subjected to a tape peel test of 50 cycles.

[0123] Aspect 33. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the article is stored at 20oC to 30oC for 60 days.

[0124] Aspect 34. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface is cytocompatible.

[0125] Aspect 35. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface is hemocompatible.

[0126] Aspect 36. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces the growth of microbes on the article.

[0127] Aspect 37. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces biofilm formation on the article.

[0128] Aspect 38. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces the adhesion of fibrinogen on the article.

[0129] Aspect 39. The article of any one of Aspects 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces the adhesion and activation of platelets on the article. EXAMPLES

[0130] Now having described the embodiments of the disclosure, in general, the examples describe some additional embodiments. While embodiments of the present disclosure are described in connection with the example and the corresponding text and figures, there is no intent to limit embodiments of the disclosure to these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure.T|H Docket: 222105-2390

[0131] MATERIALS AND METHODS

[0132] Experimental Section: Trioctyl trimellitate, hydrochloric acid (HCl), sulphuric acid (H2SO4), sodium nitrate (NaNO3), triton-X, N-acetyl-D-penicillamine (NAP), sodium nitrite (NaNO2), phosphate buffer saline (PBS), polyvinyl chloride (PVC), nitric acid, sodium citrate dihydrate, methylene blue, oil red, Glutaraldehyde (50% aqueous solution), Yellow 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), tetrahydrofuran, Roche® Cytotoxicity Detection Kit, methanol and MTT reagent 3-(4,5-Dimethylthiazol-2-yl)-2,5- Diphenyltetrazolium Bromide) were purchased from Sigma-Aldrich (St. Louis, MO). N- octyltriethoxysilane (OTS) was purchased from Tokyo Chemical Industry, Japan. DowsilTM3- 1944 room temperature vulcanized silicone rubber was purchased from Ellsworth Adhesives (Germantown, WI). Hexamethyldisilazane (HMDS) was obtained from Electron Microscopy Sciences (Hatfield, PA). Tetramethyl orthosilicate (TMOS), diiodomethane, dimethyl sulfoxide (DMSO), Saint GobainTMTygonTMFormula 3350 silicone rubber tubing, ethylene glycol, ethanol, and fluorescein isothiocyanate was purchased from Fisher Scientific (Hampton, NH). Standard glass slides (11 cm × 6 cm) and double-sided adhesive tape were purchased from Amazon. The multi-drug resistant bacterial isolates Escherichia coli (AR 0089), Staphylococcus aureus (AR 1006) were gifted by the Center for Disease Control and Prevention (CDC, Atlanta, GA). The human fibroblast cells (BJ ATCCTMCRL-2522) were procured from the American Type Culture Collection (ATCC) and the human umbilical vein endothelial cells (HUVEC GibCoTMC-003-5C),) were procured from Thermo Fisher Scientific (Waltham MA, USA). Luria-Bertani Broth (LB) was procured from Fischer Bioreagents (Fair Lawn, NJ). Tryptic soy broth (TSB) was obtained from Millipore Sigma (Burlington, MA). Dulbecco’s Modified Eagle Medium (DMEM) was procured from Gibco, USA. Penicillin- Streptomycin antibiotic and fetal bovine serum was purchased from Avantor, VWR. Endothelial cell growth basal medium (EBMTM2) was purchased from Lonza. Human fibrinogen was purchased from Innovative Research (Novi, MI). Trypsin-EDTA was purchased from Corning (Manassas, VA). Calcium and magnesium-free PBS (1x) was purchased from Corning Incorporated. Drabkin’s reagent was purchased from Ricca Chemical Company. High-density polyethylene (HDPE) was purchased from eBay (.030" × 12" x 21.5"). Elast- EonTME2A was purchased from Biomerics. ChronoSil AL 75A was purchased from AdvanSource (Wilmington, MA).

[0133] General Considerations: Contact angles and sliding angles on the different surfaces were recorded using a contact angle goniometer and corresponding software from Ossila (Sheffield, UK) at three different locations for each sample. Plasma cleaner (TERGEO, PIE Scientific) was used to pre-treat the polymeric substrates prior to coating with the ‘liquid-T|H Docket: 222105-2390 like’ solid slippery formulation. The surface morphology of the samples was imaged using a scanning electron microscope (SEM Model: FEI TENEO) at an operating voltage of 10.00 kV. Chemical analysis and mapping were performed using the energy dispersive X-ray spectroscopy (EDX, Oxford Instruments) at an operating voltage of 20.00 kV. Leica sputter coater was used to coat the samples with gold-palladium (~10 nm) prior to imaging for SEM and EDX. For SEM analysis of the biomass accumulated on the surface, sample preparation was as follows; primarily samples were washed with PBS after the 72 h drip flow bioreactor studies followed by fixation with glutaraldehyde (3%) and stored at 4°C overnight. Thereafter, the samples were dehydrated in different concentrations (50%, 60%, 70%, 80%, 90%, 100%) of ethanol for 20 mins. In the final dehydration steps, the samples were immersed in a 2:1 ethanolic mixture of hexamethyldisilane (HMDS) for 15 minutes followed by immersion in 100% HMDS overnight. Thereafter, the air-dried samples were subjected to SEM analysis. Atomic force microscopy (Model: MultiMode 8-HR) was used to scan the surface roughness of the samples. Attenuated Total Reflection Fourier Transform Infrared Spectra was recorded with the PerkinElmer FT-IR Spectrometer Spectrum 3 at ambient conditions. The optical transmittance of the samples was measured using the UV-Spectrophotometer CARY 60, AGILENT Technologies. The nitric oxide release from the different sample types was quantified using the Zysense chemiluminescence nitric oxide analyzer (NOA) 280i (GE Analytical Instruments, Boulder, Colorado, USA) under nitrogen atmosphere at physiological conditions. The drip flow bioreactor apparatus was acquired from BioSurface Technologies Corporation (Model: DFR-110-6, Bozeman, MT, USA). S-nitroso-N-acetyl-D-penicillamine (SNAP) leaching, cell viability, fibrinogen adsorption, cytocompatibility, platelet adhesion and hemolytic index was quantified using a BioTeK Cytation 5 plate reader. Fluorescence microscopy images were analyzed using Advanced Microscopy Group’s EVOS FL Microscope (AMG, Mill Creek, WA). Digital images were acquired using iPhone 13.

[0134] Synthesis of S-nitroso-N-acetyl-D-penicillamine (SNAP): The synthesis of SNAP was performed following our previously reported protocol [1,2]. Primarily, 5 g acetylated penicillamine (NAP) was added to 60 mL methanol in a 1 L beaker followed by addition of 5 mL concentrated H2SO4and 20 mL concentrated HCl. The solution was stirred until NAP dissolved (reaction setup in an ice bath). Next, 5 g sodium nitrite dissolved in 40 mL distilled water was added dropwise to the NAP containing solution till the color of the solution turned dark green. The reaction was allowed to continue for ~6 h under nitrogen flow until the green colored SNAP crystals precipitated out. The crystals were collected following vacuum filtration and dried in a desiccator for 24 h to remove any residual solvents. During the entire synthesis process, the reaction vessel was shielded from light. Prior to blending the SNAP with theT|H Docket: 222105-2390 different polymers, the purity of the synthesized SNAP was performed using the nitric oxide analyzer. Purity greater than 90% was considered acceptable for further experiments.

[0135] Fabrication of Polymeric Substrates without and with blended SNAP: To prepare the polydimethylsiloxane polymeric substrate, 3.75 g of DowsilTM3-1944 room temperature vulcanized silicone rubber was weighed out in a 20 mL glass vial followed by addition of 15 mL THF. The solution was sonicated for half an hour followed by stirring at room temperature for 2 h. Thereafter, the solution was casted in a 6×6 mm Teflon mold followed by room temperature drying. The resultant films in the Teflon molds were transferred into a desiccator for 24 h to eliminate any residual solvents. For fabricating the SNAP blended Dowsil films, 10 wt% SNAP was added to the Dowsil / THF solution followed by sonication and stirring at room temperature (2 h). Thereafter, the resultant films in Teflon molds were transferred into a desiccator kept under dark conditions for 24 h to eliminate any residual solvents. Films of the desired size can be prepared by changing the dimensions of the Teflon molds and optimizing the concentrations of Dowsil and SNAP accordingly.

[0136] Similarly, other medically relevant polymers such as Elast-EonTM, PVC, ChronoSil were fabricated into films of the desired size following the polymer solution casting into Teflon molds with polymer concentrations of 50 mg mL-1(in THF) and 10 wt% SNAP. For the PVC substrates, 4% v / v of the plasticizer (trioctyl trimellitate) was used.

[0137] ‘Liquid-Like’ Solid Coating on Polymeric Substrates: The polymeric substrates blended without and with SNAP were coated with the ‘liquid-like’ solid formulation to obtain the solid slippery polymeric substrates. Primarily, 0.41 mL tetramethyl orthosilicate (TMOS) and 0.29 mL n-octyltriethoxysilane (OTS) were mixed in 2 mL ethanol followed by addition of 0.25 mL of HCL (0.01 M). The reaction mixture was allowed to stir for 12 h at 60°C. Next, the polymers i.e. Polydimethylsiloxane, ChronoSil, PVC, Elast-EonTMwere subjected to air plasma treatment at 75 watts for 4 mins to generate the surface hydroxyl groups. Thereafter, the reaction mixture was dip coated / doctor bladed on the different polymers followed by air drying. The SNAP blended polymers were dried in the dark to avoid the degradation of the s-nitroso thiol linkage and subsequent loss of nitric oxide. The resultant solid slippery polymeric substrates without and with SNAP were examined for its liquid sliding angles.

[0138] Durability Analysis: The robustness of the embedded ‘liquid-like’ slippery property on the different polymeric substrates were examined following standard durability tests as discussed in detail below.

[0139] Tape Peel Test: The tape peel test was performed on the different polymers i.e. Polydimethylsiloxane, Elast-EonTM, ChronoSil and PVC (blended with and without SNAP) that were further coated with the ‘liquid-like’ slippery formulation. Briefly, an adhesive tape wasT|H Docket: 222105-2390 fixed onto the surface of the polymeric substrate with a 500 g load on top to ensure uniform contact between the adhesive tape and the underlying substrate. After 5 mins, the tape was peeled off from the substrate followed by examination of the liquid sliding angles. The tape peeling was repeated for 50 cycles with replacement of the tape at regular intervals.

[0140] Thermal Stability: The polydimethylsiloxane polymeric substrate coated with the ‘liquid-like’ slippery formulation (PDMS-SS) was subjected to continuous thermal treatment at 100°C up to 30 days with examination of the liquid sliding angles for water and DMSO at regular intervals.

[0141] Storage Stability: The polydimethylsiloxane polymeric substrate without and with SNAP coated with the ‘liquid-like’ slippery formulation (i.e. PDMS-SS and PDMS-SNAP-SS) was examined for its room temperature stability up to 60 days with investigation of the liquid sliding angles for water and DMSO at regular intervals.

[0142] Aqueous Stability: The polydimethylsiloxane polymeric substrate coated with the ‘liquid-like’ slippery formulation (PDMS-SS) was subjected to continuous exposure to tap water up to 15 days with examination of the liquid sliding angles for water and DMSO at regular intervals.

[0143] Stability under UV Irradiation: The polydimethylsiloxane polymeric substrate without and with SNAP coated with the ‘liquid-like’ slippery formulation (i.e. PDMS-SS and PDMS-SNAP-SS) was subjected to continuous UV irradiation (354 nm) up to 24 hours with investigation of the liquid sliding angles for water and DMSO at regular intervals.

[0144] Investigation of Nitric Oxide Release under Physiological Conditions: The nitric oxide analyzer (NOA) was used to investigate the nitric oxide (NO) release from the SNAP blended samples. Briefly, the SNAP blended samples were immersed in an amber vial containing PBS buffer (1x, pH = 7.4) with EDTA (100 mm) at 37°C. The amber vial prevented the light-assisted degradation of SNAP. The NO released from the samples was directed from the amber chamber into the reaction cell by a continuous nitrogen flow at 200 mL / min. Inside the reaction cell, NO reacts with ozone (O3) to produce an excited state of nitrogen dioxide (NO2*). Following the return of NO2*to the ground state, the released photon is multiplied and converted to voltage. Subsequently, the NO release is obtained in parts per billion (ppb). The final NO flux (× 10-10mol cm-2min-1) was calculated using the NOA constant (mol ppb-1s-1) and the surface area (cm2) of the samples. The NO analysis was performed in triplicates at regular time intervals and the samples were always maintained in the dark at 37°C submerged in PBS.

[0145] S-nitroso-N-acetyl-D-penicillamine (SNAP) Leaching Studies: The SNAP blended samples namely, PDMS-SNAP and PDMS-SNAP-SS were investigated for its SNAPT|H Docket: 222105-2390 leaching. Briefly, the samples (n=3) were immersed in PBS at 37°C and the leaching was evaluated at several timepoints (BioTek Cytation 5 Plate Reader) via spectral analysis of the collected leachates at 340 nm. A standard curve of SNAP in PBS at known concentrations was plotted to calculate the SNAP leached (in mg) from each sample. Thereafter, the amount of SNAP loaded initially was used to calculate the percentage of SNAP remaining in each sample over 7 days.

[0146] Anti-microbial Evaluation (Adhesion and Planktonic Bacteria): The anti- microbial properties of PDMS, PDMS-SS, PDMS-SNAP and PDMS-SNAP-SS were evaluated against clinical isolates of Gram-positive S. aureus (AR-1006) and Gram-negative E. coli (AR- 0089) in a 24 h assay. Tryptic soy and Luria Bertini medium were used to culture S. aureus and E. coli respectively. The bacterial isolates were revived from frozen cryopreserved vials and cultured at 37°C in a shaker incubator (150 rpm). Bacterial cultures in the exponential growth phase were collected and washed with sterile PBS by centrifuging at 4400 rpm for 7 mins under ambient conditions. The bacterial suspensions were adjusted to approximately 1 × 108CFU mL-1in respective media at 10% concentration and exposed to the polymeric samples in sterile 24 well plates. The samples were pre-sterilized by exposing to UV irradiation for 30 mins on each side. The plates were sealed and incubated for 24 h at 37°C in a shaker incubator (150 rpm) protected from light. After incubation, the adhered bacterial cells were collected by homogenizing the samples in fresh PBS for 1 min followed by vortexing for 30 seconds. Planktonic bacteria were collected with rigorous pipetting to achieve a homogenous suspension. Both adhered and planktonic bacterial suspensions were serially diluted with sterile PBS and plated on agar plates using a using Spiral plater (Eddy Jet 2W, IUL Instruments). The bacterial plates were incubated at 37°C overnight to allow colony formation. Individual colonies were counted using a colony counter (Sphere Flash, IUL Instruments), and the colony forming units (CFUs) were calculated using the equation given below: Number of colonies × Dilution factor × Volume of suspension Total CFUs (mL) × 100

[0147] Total CFUs obtained were normalized to the sample surface area, and bacterial reduction was calculated using the equation given below. Bacterial Reduction = CFUcontrol - × 100%T|H Docket: 222105-2390 CFUcontrol

[0148] Drip Flow Bioreactor: Thecapabilities of the polymeric films were evaluated using a DFR-110-6 Drip Flow Biofilm Reactor following previous reports [3,4]. A drip flow bioreactor is a physiologically relevant model for evaluating biofilm formation with a continuous media inlet and outlet that excludes any effects form accumulated metabolites or media limitation [5] Bacterial suspensions were prepared as discussed above followed by exposure to pre-sterilized polymeric samples (3 inches × 1 inch). The reactors were incubated at 37°C in a batch phase (for 6 h) to allow the initial bacterial adherence to the surface. After incubation, the reactor was inclined at an angle of 10° to allow the bacterial media flow for 72 h continuously with a constant flow rate of 0.80 ± 0.03 mL min-1. The reactor was placed inside an incubator maintained at 37°C, and the dripping medium (10% v / v) was warmed at 37 ± 2 °C on a magnetic hot plate with continuous stirring. After incubation, the polymeric samples were removed and gently rinsed with sterile PBS prior to biofilm analysis. The adhered bacteria were quantified as discussed above via homogenization and plating followed by colony counting. The gross morphology of the formed biofilm was visualized via scanning electron microscopy after fixation and dehydration.

[0149] Cytocompatibility Analysis: The cytocompatibility of the polymeric films i.e. PDMS, PDMS-SS, PDMS-SNAP and PDMS-SNAP-SS was evaluated in an indirect toxicity assay following the International Organization for Standardization (ISO-10993-5) [6]. Human fibroblast and HUVEC cells were revived from frozen stocks and subsequently cultured in DMEM (supplemented with 10% FBS) and endothelial media respectively at 37°C with 5% CO2in a humidified incubator. The cells were grown in tissue culture-treated flasks and harvested using trypsin-EDTA at around 80% confluency. The cells were collected by centrifuging at 500 g for 5 mins at room temperature. The cells were seeded on tissue-culture- treated 24-well plates (1 × 104cells per well) and incubated overnight. Next, the films (n = 5) were sterilized via UV exposure for 30 mins on each side and exposed to the cell monolayer using tissue culture hanging inserts. The plates were incubated at 37°C with 5% CO2for another 24 h. After incubation, the samples and cell culture inserts were removed, and the media was replaced with MTT solution (1 mg mL-1) followed by another 4 h incubation at 37°C. MTT is a water-soluble dye that forms an insoluble formazan product in the presence of mitochondrial enzymes. The intensity of the color is directly proportional to the number of metabolically active cells [7,8]. The MTT solution was carefully removed, and the formazan product was dissolved in DMSO followed by recording the absorbance at 570 nm. TheT|H Docket: 222105-2390 absorbance of the untreated cells was assigned 100% viability and used as the control. The percentage cell viability was calculated using the following equation: Absorbance of sample Cell Viability (%) = × 100% Absorbance of untreated controls

[0150] Fibrinogen Adsorption Analysis: Following our previous protocol,[9] the samples namely PDMS, PDMS-SS, PDMS-SNAP and PDMS-SNAP-SS were analyzed for human fibrinogen (Fg) adsorption characteristics under physiological conditions PBS (1x) at 37°C. Fluorescein isothiocyanate (FITC-Fg) tagged Human Fg (purified) was mixed 1:10 (by mass) with unlabelled Fg to a final concentration of 4 mg mL-1. All the samples were incubated in a 12 well glass bottom black polystyrene well plate for 30 mins in PBS (1x) at 37°C with surface area: volume ratio of 3cm2mL-1. After equilibration, the samples were treated with a Fg solution to achieve a final exposure concentration of 2 mg mL-1. Thereafter, all the sample types were incubated for 90 mins at 37°C with protection from light. Next, the wells were washed thoroughly with PBS (1x) for 10 times (100 µL used each time) to remove any unadhered fibrinogen. The resultant Fg-treated samples were suspended in 100 µL PBS for fluorescence spectral analysis to analyze the Fg adsorption. The results (n=6) have been reported as the mean mass of adsorbed Fg normalized to exposed surface area (mg cm-2). Furthermore, fluorescence microscopy was performed to investigate the surface coverage of Fg on the different sample surfaces.

[0151] Investigation of Blood Compatibility

[0152] Collection and Processing pf Porcine Whole Blood: Protocols pertaining to the use of porcine whole blood (WB) and its products were approved by the University of Georgia’s Institutional Animal Care and Use Committee. Porcine WB was drawn into vials containing 3.2% sodium citrate aqueous solution and were assessed for hematological parameters including cell counts and hemoglobin (Hg) levels. WB was centrifuged (280 rcf, 2 min) to fractionate platelet-rich plasma (PRP). WBwas further centrifuged (3000 rcf, 2 min) to obtain platelet poor plasma (PPP). All blood compatibility experiments were performed within 4 h of the WB draw.

[0153] In vitro analysis of Platelets Adhesion: Investigation of platelet adhesion was performed in accordance to previously reported protocols [9]. PRP was diluted with PPP to obtain a platelet count of 2 × 108platelets mL-1which was subjected to reverse anti- coagulation with calcium chloride solution (2.5 mM) to obtain the final platelet working solution.T|H Docket: 222105-2390 The samples (normalized with respect to surface area, 1 cm2) were incubated in the platelet working solution (1 cm2mL-1) for 90 min with gentle rocking. After incubation, the samples were gently washed with sterile PBS (1x) to remove the non-adhered platelets. Next, the adherent platelets on the surface of the samples were lysed with 2% (v / v) Triton-X in PBS (1x, 125 mL). Thereafter, the lysates were processed with the Roche Cytotoxicity Detection Kit, which measures the activity of released lactate dehydrogenase in the lysate via redox cycling and conversion of tetrazolium salt to its formazan product. Standard curves were plotted for assay normalization. Final results (n=6) have been reported as the number of platelets adhered per unit surface area (platelets cm-2).

[0154] Hemolysis: The modified NAMSA protocol was followed to investigate the hemolytic index. Primarily, porcine WB was diluted with calcium and magnesium free PBS (CMF-PBS) to obtain the final WB concentration of 10 ± 1.0 mg mL-1. Next, 1 mL porcine WB was diluted with 7 mL deionized water to be considered as the positive control or 7 mL CMF- PBS as the blank. According to NAMSA ASTM F756 protocol, 1 cm2high density polyethylene (HDPE) coupons were considered as the negative controls. Thereafter, each of the samples along with negative control were incubated in the diluted porcine WB for 3 h with inversions every 30 mins at 37°C. Positive control was incubated under similar conditions. Following incubation, the samples were centrifuged at 800 gravity for 15 min. The supernatant from the different samples (n=6) were combined with Drabkin’s reagent in 1:1 ratio and incubated for 15 min at room temperature followed by analyzing the absorbance at 540 nm. Percent hemolysis was calculated using the following equation: Absorbancesample -Absorbanceblank Hemolysis (%) =Absorbancediluted blood- Absorbanceblank × 100%

[0155] Statistical Analysis: All the data has been represented as mean ± standard deviation unless specified otherwise. All statistical analysis were performed using GraphPad Prism Software (Version: 10.1.0). Outliers were eliminated through Grub’s test and the results of the optimized combination sample was compared with the control sample types using one- way ANOVA followed by Tukey’s test. Results with p < 0.05 were considered statistically significant.

[0156] RESULTS AND DISCUSSION

[0157] In the current work, we exploited n-octyltriethoxysilane (OTS) as the hydrophobic alkyl-silane and tetramethyl orthosilicate (TMOS) as the molecular spacer to obtain an organo-T|H Docket: 222105-2390 silane co-polymerised network as shown in Figure 7A-7C The organo-silane co-polymerised network was covalently bonded with plasma-treated medical-grade polymeric substrates that were pre-loaded with the anti-bacterial and anti-thrombotic, NO-releasing molecule i.e. S- nitroso-N-acetyl-D-penicillamine as shown in Figure 7D. The ‘liquid-like’ solid coating on the surface of the bioactive polymers resulted in an overall antibiofouling avenue that repelled the beaded liquid droplets as well as the bio-foulants as shown in Figure 7E. Primarily, we investigated the feasibility of applying OTS on medical-grade polymers. The hydrophobic, room-temperature vulcanized silicone rubber (abbreviated PDMS) that inherently doesn’t exhibit any liquid sliding behaviour (Figure S1A-D) was chosen as the model polymeric substrate owing to its vast applicability in medical settings. As shown in Figure 1A-B and Figures 9A-9H, OTS coating on the plasma-treated PDMS substrate failed to exhibit any liquid sliding behaviour (water and dimethylsulfoxide, DMSO) owing to the rigid (solid-like) conformation of the alkyl chains of OTS. The plasma treatment generated surface hydroxyl groups on PDMS that allowed the covalent bonding of the organo-silane co-polymerised network with the underlying substrate following the hydroxyl condensation reaction. However, on coating the surface of plasma-treated PDMS with the organo-silane co-polymerised network (abbreviated as PDMS-SS), sliding of the beaded liquid droplets was observed at sliding angles 16^ and 12^ for water and DMSO respectively (liquid droplet volume: 15 ^L), thus, achieving an omniphobic solid slippery coating on a medical-grade polymeric substrate as shown in Figure 1C-F. Moreover, liquid sliding characteristics was observed on PDMS-SS for a wide range of liquids with varying surface tension as accounted in Figure 1G and Figures 10A-10H and 11A-11X. The liquid sliding characteristics were also investigated with different volumes of the liquid droplet with higher sliding angles observed for smaller droplet volume (5 ^L) as shown in Figure 12A. Further, the transmittance of the underlying PDMS substrate was maintained even after application of the solid slippery coating as shown in Figure 12B.

[0158] The scanning electron microscopy (SEM) images revealed the smooth, featureless morphology of the solid slippery coating on PDMS (Figure 1H). The surface morphology was further characterized through AFM analysis which exhibited a surface roughness of ^2.5 nm for uncoated PDMS (Figure 8E) and ^0.71 nm for PDMS-SS as shown in Figure 1I, thus, indicating the physical homogeneity on application of the solid slippery coating. Moreover, the surface chemical composition was evidenced through energy dispersive X-ray spectroscopy, depicting the primary presence of silicon (Si), oxygen (O) and carbon (C) on PDMS and PDMS-SS as shown in Figure 13A-B respectively.

[0159] The progress of the reaction between TMOS and OTS to form the organo-silane co-polymerised network resulting in the omniphobic solid slippery coating was monitoredT|H Docket: 222105-2390 through FTIR analysis. The spectra corresponding to OTS exhibited the characteristic Si-O-C stretching peak at 1100 cm-1and the CH2asymmetric vibration at 2920 cm-1indicating the solid-like (all trans) conformation of the alkyl groups of the OTS molecule as shown in Figure 1J (red spectra)

[0056] . However, introducing TMOS as the spacer led to a distinct decrease in the peak intensity at 2920 cm-1and an increase in CH2 asymmetric vibration at 2930 cm-1that indicates the induction of the ‘liquid-like’ (trans-gauche) conformation of the alkyl groups on the addition of the spacer molecule as shown in Figure 1J (black spectra). Moreover, the Si- O-Si stretching peak at 1080 cm-1indicates the presence of the co-polymerized silane network.

[0160] Thus, we have successfully examined and characterized the applicability of the organosilane derived solid slippery coating on a medical-grade polymer without requiring any complicated fabrication process or post-treatment.

[0161] Characterization of the Solid Slippery Behaviour on Bioactive Polymer:

[0162] In this work, the organosilanes-derived solid slippery coating as discussed in the previous section was applied to medical-grade polymers to assess the sustenance of the embedded liquid repellence behaviour and the combinatorial effect of the bioactive and passive antibiofouling avenue. Primarily, PDMS substrates were in-situ blended with the widely known anti-bacterial and anti-thrombotic, hydrophobic NO-releasing molecule (SNAP) followed by casting into the desired shape and drying under dark conditions (Figure 2A-B). The PDMS-SNAP substrates inherently restricted the sliding of the beaded liquid droplets as shown in Figures 14A-14D which can be attributed to the rough surface morphology as evident through SEM images (Figure 2D) and AFM imaging with surface roughness ^11 nm (Figure 2E). However, on coating the surface of the plasma-treated PDMS-SNAP with the solid slippery network (abbreviated as PDMS-SS-SNAP), sliding of the beaded liquid droplets were observed at sliding angles 20^ and 14^ for water and DMSO respectively (liquid droplet volume: 15 ^L), thus, achieving an omniphobic solid slippery coating on a bioactive medical- grade polymeric substrate as shown in Figure 2C,F-G and Figures 15A-15H and 16A-16L. Moreover, liquid sliding characteristics was observed on PDMS-SNAP-SS for a wide range of liquids with varying surface tensions as shown in Figure 2J. Further, the scanning electron microscopy (SEM) images revealed that the solid slippery coating on the bioactive polymeric substrate rendered the surface smooth and featureless (Figure 2H). The AFM revealed a decrease in surface roughness from ^11 nm for PDMS-SNAP to ^2 nm for PDMS-SNAP-SS as shown in Figure 2I, thus, indicating the restoration of physical homogeneity on application of the solid slippery coating on PDMS-SNAP. Moreover, the surface chemical composition on PDMS-SNAP and PDMS-SNAP-SS was evidenced through energy-dispersive X-ray spectroscopy, depicting the primary presence of silicon (Si), oxygen (O) and carbon (C) alongT|H Docket: 222105-2390 with nitrogen (N) and sulfur (S) owing to the incorporation of SNAP as shown in Figures 13C- D.

[0163] The Nobel prize-winning discovery of endothelial-derived relaxation led to extensive research towards understanding the pivotal function of nitric oxide (NO) in physiological systems [20-22]. Over the years, different types of NO-donor molecules have been reported such as organic nitrates, nitrites, S-nitrosothiols (RSNOs), metal-NO complexes, N-diazeniumdiolates, and nitrosamines

[0060] . Amongst the various types of donors, RSNOs that are known to be the physiological carrier of NO in vivo and marked with ease of synthesis, storage stability, sterilization stability, and biocompatibility, have been widely explored to fabricate NO-releasing biomaterials for applications in wound healing, urinary catheters, cardiovascular devices etc

[0061] . Exposure to physiological conditions, heat or light initiates the homolytic cleavage of the S-N bond of RSNOs to generate a thiyl radical and the free radical gasotransmittter, NO [20-22,60-61]. Recently, NO-releasing biomaterials have been integrated with SHP

[0062] and SLIPS [37-39] to obtain antibiofouling materials exhibiting excellent bacteria and platelet repellence, however, these reports severely lack in-depth durability investigation and vaguely reported the protein repellence ability as accounted in Table S1, thus, demanding further comprehensive analysis to support clinical translation.

[0164] Herein, for the first time, we report the integration of a NO-releasing polymer with a solid slippery coating to obtain a combinatorial antibiofouling avenue comprising of both a bioactive and passive avenue. Primarily, the NO release under physiological conditions (pH = 7.4, 37^C) was evaluated from the SNAP-containing PDMS substrates with and without the solid slippery coating. As shown in Figure 2K, the NO release from PDMS-SNAP and PDMS- SNAP-SS was observed to be ^ 1.5 × 10-10mol min-1cm-2and ^ 0.7 × 10-10mol min-1cm-2respectively. The higher flux for PDMS-SNAP-SS can be attributed to the presence of the silane-based coating which has been shown in the past to selectively facilitate water vapor permeability while exhibiting hydrophobicity (water contact angles as shown in Figure 17A) [63-64]. Over a period of 7 days, the NO flux for PDMS-SNAP-SS is comparable to PDMS- SNAP, thus, indicating that the solid slippery coating doesn’t hinder the spontaneous release of the small gaseous molecule, NO. Moreover, even at day 7, the NO flux is above the physiologically recognized limit of > 0.5 × 10-10mol min-1cm-2that is required to exhibit anti- bacterial activity, thus, establishing the potential of the as-reported material for clinical applications [20-22, 60-61]. Moreover, to rule out the potential possibility of excessive leaching of the NO-donor molecule that can raise toxicity concerns [24,25], we investigated the SNAP leaching from PDMS-SNAP and PDMS-SNAP-SS over 7 days. It was observed that even after 7 days of exposure to physiological conditions (pH = 7.4, 37^C), PDMS-SNAP retained 87%T|H Docket: 222105-2390 of SNAP in the polymer while PDMS-SNAP-SS retained 89% of the SNAP as shown in Figure 17B, thus, ruling out unwanted leaching of the donor molecule.

[0165] Thus, we have introduced the novel combination of a solid slippery surface coating with an underlying bioactive polymeric substrate with unperturbed liquid repellence behaviour and prolonged NO releasing ability for potential biomedical utility.

[0166] Durability Analysis: PDMS-SS was subjected to 15 days of continuous aqueous exposure and 30 days of thermal treatment (at 100^C) with regular measurement of the liquid sliding behaviour and it was observed that the embedded solid slippery property remained unperturbed with water and DMSO sliding angles <20^ as shown in Figure 3A and Figure 3B respectively. Next, PDMS-SS and PDMS-SNAP-SS was subjected to the adhesive tape peel test (Figures 3C-3L) for 50 repetitive cycles followed by examination of the liquid sliding property. As shown in Figure 3M, the sliding angles for both water and DMSO was observed to be <20^ for PDMS-SS and PDMS-SNAP-SS. Further, storage stability is another important criteria that needs to be fulfilled in order to qualify a biomaterial useful for prolonged practical applications. The embedded solid slippery behaviour on PDMS-SS and PDMS-SNAP-SS was monitored at regular intervals over a period of 60 days with insignificant variations in liquid sliding angle for water and DMSO as shown in Figure 3N. For biomedical applications, every functional material is subjected to UV sterilization to remove any unwanted microbial contamination on the surface. Thus, we exposed PDMS-SS and PDMS-SNAP-SS to UV irradiation (354 nm) for 24 hours and observed that the liquid sliding property remained intact with sliding angles <20^ as shown in Figure 18. Hence, the aqueous, physical, thermal, UV and storage stability tests inflicted on the organosilane derived solid slippery coating on the polymeric substrate failed to perturb the embedded liquid repellence property. Pertinent to note here, our group has reported that the NO-donor i.e. SNAP, is highly stable and releases physiologically relevant NO flux even after storage in room temperature storage / -20^C / -4^C / 37^C up to 6 months and withstands degradation against UV / ethylene oxide / hydrogen peroxide sterilization [24-25,65]. Thus, the durability of the bioactive agent in our combinatorial material is unparalleled and already proven in our previous works.

[0167] The covalent bonding of the solid slippery coating with the underlying polymeric substrate and the presence of the inorganic silica network is responsible for imparting robustness to the as-reported organosilane derived solid slippery coating on PDMS [55,66]. Thus, to conclude, the durability tests demonstrated the sustenance of the embedded solid slippery behaviour in our combinatorial material supported by the previously reported durability examination of the loaded SNAP.T|H Docket: 222105-2390

[0168] Anti-biofouling Characteristics of the Combinatorial Material: Biofouling on the surface of medical devices and implants remains one of the major cause of patient fatalities in the United States

[0067] . The non-specific adsorption of microbial and / or thrombotic species triggers a host of complications such as inflammation, bacterial infection and thrombosis

[0068] . Modulating the surface chemistry or morphology to obtain bio-inspired anti-wetting and antifouling passive pathways or incorporation of bioactive molecules are the general approaches adopted to combat biofouling of medical devices [26-36,49-55]. However, none of these approaches have witnessed successful translation due to inherent limitations associated with durability of the biomaterial and sustenance of the embedded liquid wettability, ease of fabrication etc as discussed in the previous sections. Thus, in the current work, we envisioned a combinatorial approach integrating ‘liquid-like’ solid coatings with bioactive polymeric substrates to obtain an overall antibiofouling avenue that would overcome the limitations of the existing approaches with potential for practical biomedical utility.

[0169] Investigating the Biomass Accumulation on PDMS-SNAP-SS: Blood- contacting medical devices associated bacterial infections are one of the major causes of patient mortality in the United States [67-68]. The free-floating bacteria (planktonic bacteria) from the surrounding can adhere to any suitable surface and trigger the formation of microbial microcolonies producing the extracellular polymeric substances (EPS) that eventually lead to unwanted biofilm formation on the surface

[0069] . The conventional methods to tackle bacterial infections of medical devices include antibiotics administration or removal of the infected devices [9-10], however, antibiotic resistance renders the conventional treatment strategies futile and removal of medical devices can be traumatic to the patient

[0016] . To date, solid slippery coatings have been shown to exhibit anti-bacterial performance by inhibiting the adhesion of bacteria / biofilm on the surface. However, the literature reported lacks the integration of solid slippery surfaces with bioactive agents to ensure the killing and repellence of the adhered as well as planktonic bacteria and ultimately thwart biofilm formation to ensure prolonged performance of the medical devices in clinical settings.

[0170] Nitric oxide (NO) is a widely-studied gaso transmitter molecule with impeccable anti-inflammatory, antibacterial and anti-thrombotic properties [20-22]. The production of reactive oxygen species and reactive nitrogen species on reaction of NO with oxygen and oxygenated derivatives such as superoxide and hydrogen peroxide, is the primary reason for NO-mediated bacterial killing and biofilm removal [60-61]. The as-produced free radical species lead to cellular damage, DNA mutation, protein conformational changes and lipid peroxidation in the bacterial strains, thus, inducing multiple ways of killing / inhibiting the bacterial growth. Over the years, NO-derived biomaterials integrated with bio-inspired liquidT|H Docket: 222105-2390 wettability such as SHP

[0062] and SLIPS [37-39] have been reported but the durability of these biomaterials (to render it useful for practical utility) remains to be investigated along with the lack of protein repellence ability (Table S1).

[0171] Herein, we investigated the anti-bacterial characteristics of our combinatorial material against clinically relevant gram-negative Escherichia coli and gram-positive Staphylococcus aureus bacterial strains. As shown in Figure 4A-B, the combinatorial effect of PDMS-SNAP-SS exhibited ~2.5 log reduction in bacterial adhesion against E. coli and ~3.5 log reduction against S. aureus adhesion in comparison to PDMS control. Further, PDMS- SNAP-SS exhibited ~1.5 log reduction in bacterial adhesion against E. coli and ~ 3.5 log reduction against S. aureus compared to PDMS-SS. In comparison to PDMS-SNAP, >1.3 log reduction in adhesion was observed for both E. coli and S. aureus for PDMS-SNAP-SS. Thus, the combined effect of NO as the bioactive antibacterial component and the low surface energy solid slippery surface is responsible for imparting impeccable antibacterial characteristics to the combination material. The low surface energy surface masks any possible covalent / physical interactions between the surface and the bio-foulants, thus, inhibiting the adhesion / growth of bacteria on the surface. Moreover, the combinatorial material was also tested for its ability to inhibit planktonic bacterial growth as shown in Figure 4C-D. PDMS-SNAP-SS exhibited >1 log reduction in planktonic bacterial growth against E. coli and >2 log reduction against planktonic S. aureus in comparison to PDMS control and PDMS-SS. The increase in planktonic killing for Polymer-SNAP-SS in comparison to Polymer-SNAP can be attributed to the higher initial NO flux of the combinatorial material (refer to Fig.2K) The facile permeability of NO as a free-radical, gaso-transmitter molecule to the surrounding environments is primarily accountable for the killing of the planktonic bacteria, thus, classifying the as-reported combinatorial material superior to the existing ones.

[0172] The irreversible formation of biofilms on the surface of blood contacting medical devices lead to complications such as inflammation, uncontrolled sepsis and even patient mortality [67-68]. The structured accumulation of bacterial cells that forms the biofilms impedes the diffusion of antibiotics thus, failing the vigorous treatment approaches leading to severe device and health complications

[0069] . Thus, the prevention of biofilm growth on the surface of medical devices is of utmost importance. We evaluated the biofilm inhibition performance of our developed material as against the controls in a 72 h drip flow bioreactor study where the samples were exposed to static bacterial media for 6 h followed by exposure to dynamic conditions for 72 h. The PDMS-SNAP-SS exhibited ~82% and ~70% reduction in the biomass accumulation for the clinical strains of E.coli and S. aureus respectively in comparison to the controls as shown in Figure 4E-F. The scanning electron microscopyT|H Docket: 222105-2390 images depicts the biofilm coverage on the surface of PDMS and the combinatorial material (PDMS-SNAP-SS) for the clinical strains of E.coli (Figure 19A-19H) and S. aureus (Figures 20A-20H) wherein the combinatorial material successfully inhibits the growth of biofilms. The inherent bacterial killing efficiency and the bacterial repellence characteristics of NO and solid slippery surface respectively is responsible for the successful thwarting of the biofilm formation.

[0173] Thus, we have introduced a unique combinatorial material which exploits both the bioactive and passive antibiofouling avenues to kill and inhibit the growth of the adhered and planktonic bacteria as well as significantly diminish the growth of biofilm on the surface of a medically relevant polymeric material, thus, displaying the potential of the reported approach for practical applications.

[0174] Cyto-compatibility Assessment: Biomaterial cytocompatibility (greater than 70%) is the primary criterion to classify any biomaterial safe for practical clinical applications

[0070] . In our work, the cytocompatibility investigation on PDMS, PDMS-SS, PDMS-SNAP and PDMS-SNAP-SS was performed using human fibroblasts and human endothelial cells following the indirect cytotoxicity method (ISO Standards). The UV-sterilized samples were exposed to a monolayer of the cells for 24 h at 37^C using cell culture inserts such that the leachates from the samples were directly in contact with the cells throughout the experiment. Subsequently, tetrazolium dye (CCK-8 reagent) was used to quantify the metabolically active cells to account for the cell viability

[0071] . As shown in Figure 5A, PDMS-SNAP-SS along with the other sample types exhibited cytocompatibility greater than 70% against both human fibroblasts and human endothelial cells, thus, indicating that the solid slippery components and SNAP used for fabricating the resultant combinatorial material is safe for biological applications.

[0175] Plasma Protein Repellence Behaviour: The protein adhesion on a surface through Van der Waals force or ionic interactions is known to be influenced by surface morphology and chemistry

[0072] . The adsorption of proteins is the primary step towards platelets adhesion and activation that ultimately leads to thrombosis, hence, the protein repellence ability of biomaterials is of utmost importance [67-68]. NO-releasing biomaterials exhibit superior anti-bacterial and anti-thrombotic characteristics [20-22, 60-61], however, the inability of NO-releasing surfaces to inhibit protein adhesion on the surface demands the incorporation of a secondary antifouling mechanism

[0023] . The reported NO-releasing SHP and SLIPS lacks in-depth protein antifouling investigation as accounted in Table S1. Thus, in our current work, we quantified the human fibrinogen for the as-reported combinatorial material. As shown in Figure 5B, PDMS-SNAP-SS exhibited significant reduction (>65%) in humanT|H Docket: 222105-2390 fibrinogen adhesion on the surface as compared to PDMS and PDMS-SNAP. The enhanced fibrinogen adhesion on PDMS-SNAP can be attributed to the increased surface roughness (ra~11 nm, Figure 2E) wherein it has been reported in the past that NO-releasing surfaces affect fibrinogen adhesion based on the surface roughness, wettability and composition [23,73]. However, there wasn’t any significant difference in protein adhesion on PDMS-SNAP-SS and PDMS-SS which indicates that the homogenous and featureless, low surface energy ‘liquid- like’ coating (Figure 2H-I) is primarily responsible for the protein repellence characteristics exhibited by the combinatorial material by masking any possible interaction between the proteins and the surface (lewis acid-base, ionic interactions, Lifshitz-van der waals) [74,75]. Further, fluorescence imaging was performed to support the quantitative fibrinogen data as shown in Figures 21A-21D.

[0176] Platelet Repellence and Hemolysis: The current work is the first-time investigation of platelet repellence ability of a combinatorial anti-biofouling material comprised of solid slippery and NO releasing characteristics for prospective application in blood contacting medical devices. To assess the platelet adherence property, the different sample types were exposed to platelet poor plasma (2 X 108platelets mL-1) for 90 mins followed by examination of the lysed platelets from the surface of the samples using the Roche Cytotoxicity Detection Kit. As shown in Figure 5C, our combinatorial material PDMS-SNAP-SS decreases the platelet adhesion on the surface by >50% in comparison to both PDMS-SS and PDMS- SNAP and >80% in comparison to PDMS which clearly indicates the combined effect of the ‘liquid-like’ solid coating and active NO release in repelling the surface-contacting platelets. Further, the extent of platelet adhesion and activation on the surfaces was examined through scanning electron microscopy after exposure to porcine whole blood for 30 mins. The surface of PDMS and PDMS-SS shows the characteristic spread filopodia of activated platelets (Figures 22A-22F)

[0031] . However, the surface of PDMS-SNAP and PDMS-SNAP-SS lacked any visibly activated platelets as shown in Figure 22G-22L. The platelets found on PDMS- SNAP and PDMS-SNAP-SS were round suggesting a resting and nonactivated state.

[0177] The platelets anti-adhesion / activation results complement the fibrinogen repellence ability of the combinatorial material wherein it is well-established that fibrinogen adsorption is the preliminary step prior to platelet adhesion [60-61,67-68]. Thus, a surface that can repel fibrinogen should be able to inhibit platelet adhesion to be used successfully for blood contacting medical devices.

[0178] Further, to translate biomaterials for real-world applications, the investigation of the hemolytic index in addition to cyto-compatibility is an important criterion. Following the NAMSA ASTM F756, materials with 2-5% hemolytic index is considered to be slightly hemolytic andT|H Docket: 222105-2390 >5% is hemolytic. The as-developed PDMS-SNAP-SS exhibited hemolytic index <0.5% and thus, can be classified as non-hemolytic as shown in Figure 5D. Thus, the robust combinatorial material developed in the current work was found to be cyto-compatible and hemo-compatible with excellent biofilm, protein and platelet repellence behaviour without any complicated fabrication processes therefore, qualifying the as-developed material for real-world clinical utility.

[0179] Extending the Combinatorial Strategy to Different Types of Polymers:

[0180] Bio-inspired combinatorial antibiofouling strategies have been extensively reported on a wide range of substrates ranging from fibrous to planar [26-36], however, limitations related to the durability of the bio-inspired anti-wetting states remains a concern. In that context, solid slippery coatings possess potential as antibiofouling clinical surfaces without requiring any topography or complicated chemistry [49-54]. There are very few reports that have investigated solid slippery coatings as durable, passive antibiofouling avenues on polymers with major translational limitations as already discussed in the previous sections.

[0181] In that context, we extended our facile combinatorial antibiofouling approach on a wide range of medically relevant polymers such as the silicone-polyurethane co-polymer (Elast-EonTM), polycarbonate-based silicone elastomer (ChronoSil) and the thermoplastic co- polymer made of vinyl chloride and vinyl acetate (Polyvinyl chloride, PVC). The polymers chosen for the demonstration inherently lacks any liquid sliding characteristics as shown in Figure 23A-B, I-J and Figure 24A-B. However, the ‘liquid-like’ omniphobic solid coating on PVC blended without (Figure 6A-B and Figure 23K-P) and with SNAP (Figure 6C-D) exhibited liquid sliding behaviour with sliding angles less than 16^. Similarly, ChronoSil (Figure 6E-H, Figure 24C-H and Figure 25G-L) and Elast-EonTM(Figure 17C-H and Figure 25A-F) blended without and with SNAP followed by application of the ‘liquid-like’ omniphobic solid coating exhibited liquid sliding angles less than 18^ as graphically accounted in Figure 6I-J. Moreover, to examine the robustness of the ‘liquid-like’ omniphobic solid coating on the polymers blended with and without SNAP, the different polymeric substrates were subjected to tape peeling test for 50 cycles. The liquid sliding angles were observed to be less than 20^ even after the repetitive tape peeling cycles as shown in Figure 6K. Further, to examine the translational ability of our combinatorial approach, commercially available silicone rubber tubing was swelled with SNAP

[0076] followed by application of the ‘liquid-like’ omniphobic solid coating. It was observed that the liquid behaviour remained undeterred for water and DMSO without and with SNAP as shown in Figure 6L-O, thus, realizing the potential of the as-reported combinatorial approach for clinical utility.T|H Docket: 222105-2390

[0182] Therefore, we have introduced a facile chemical approach that can combine bioactive and passive antibiofouling avenues on wide range of clinically utilized polymers to combat biofouling at hospital settings.

[0183] CONCLUSION

[0184] The current work is a unique combinatorial anti-biofouling avenue for combating medical device associated biofouling. Herein, the surface of the medical grade siloxane polymer i.e. polydimethylsiloxane (PDMS) was coated with the co-condensed silica network of tetramethyl orthosilicate and n-octyltriethoxysilane to obtain a ‘liquid-like’ omniphobic solid coating on the polymeric surface (PDMS-SS). The resultant PDMS-SS exhibited liquid sliding angles less than 18^ for liquids with various surface tensions and withstood prolonged physical and chemical abrasions. The ‘liquid-like’ omniphobic solid coating was extended to a PDMS substrate that was blended with a NO releasing small molecule (S-nitroso-N-acetyl-D- penicillamine, SNAP) to obtain a NO releasing-solid slippery polymeric substrate (PDMS- SNAP-SS) with liquid sliding angles less than 20^ even after prolonged (60 days) room temperature storage, UV irradiation and physical abrasion. The combinatorial polymeric material exhibited >2 log reduction in bacterial growth (adhered and planktonic) and >80% reduction in biofilm formation (72 h drip flow bioreactor) for both E. coli and S. aureus. Moreover, cytocompatible and hemocompatible PDMS-SNAP-SS exhibited >65% reduction in human fibrinogen adhesion and >80% repellence in platelet adhesion. Reports of such combinatorial avenue exploiting NO-releasing medical grade polymers and ‘liquid-like’ omniphobic solid coating is unprecedented in literature. Furthermore, the robust combinatorial anti-biofouling concept was extended to other medically relevant polymers such as ChronoSil, Polyvinyl Chloride, Elast-EonTMand commercially available silicon rubber wherein the polymeric substrates were blended with the NO-releasing SNAP molecule followed by the ‘liquid-like’ solid surface coating. Thus, the current work provides a promising, integrated bioactive and passive avenue for combating the widespread concern of clinical device biofouling.

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Claims

T|H Docket: 222105-2390 CLAIMS 1. An article comprising a polysiloxane covalently bonded to at least one surface of the article, wherein the article comprises a nitric oxide releasing compound.

2. The article of claim 1, wherein the polysiloxane comprises the hydrolyzed reaction product between a compound having the structure I and II OR1OR2R1O Si OR1R2O Si R3OR1OR2IIIwherein R1, R2, and R3are independently an alkyl group or a fluoroalkyl group.

3. The article of claim 2, wherein each R1and R2are a C1to C5alkyl group.

4. The article of claim 2, wherein R3is a C1to C10alkyl group.

5. The article of claim 1, wherein the polysiloxane comprises the hydrolyzed reaction product between octyltriethoxysilane and tetramethyl orthosilicate.

6. The article of claim 1, wherein the polysiloxane comprises the structure III R3OH R3H wheein3r R is a C1to C10alkyl group, hydroxyl, or an alkoxy group, wherein at least one of R3is a C1to C10alkyl group.

7. The article of claim 1, wherein the nitric oxide releasing compound is a S-nitrosothiol conjugated polymer, a S-nitrosothiol modified-dendrimers; a S-nitrosothiol modified polysaccharide, a S-nitrosothiol modified nano / microparticle, a S-nitrosothiol modified- protein, a nitrate, a N-diazeniumdiolates (NONOate), or a S-nitrosothiol (RSNO).

8. The article of claim 1, wherein the nitric oxide releasing compound is a modified antibiotic compound comprising a nitric oxide release agent covalently attached to an antibiotic moleculeT|H Docket: 222105-2390 9. The article of claim 8, wherein the nitric oxide release agent is S-nitroso-N- acetylpenicillamine, S-nitroso-glutathione, S-nitroso-N-acetylcysteine, S- nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B,D-glucose, S-nitrosocaptopril, S- nitrosocysteamine, and S-nitroso-3-mercapto-propanoic acid.

10. The article of claim 8, wherein the antibiotic molecule is ampicillin, vancomycin, gentamicin, or cephalexin.

11. The article of claim 10, wherein the modified antibiotic compound comprises S-nitroso- N-acetylpenicillamine covalently attached to ampicillin.

12. The article of claim 1, wherein the nitric oxide releasing compound is a S-nitrosothiol compound.

13. The article of claim 1, wherein the nitric oxide releasing compound is S-nitroso-N- acetyl-penicillamine, S-nitroso-N-acetylcysteine, S-nitroso-N-acetyl cysteamine, S- nitrosoglutathione, S-nitrosocysteamine-glutathione, methyl S-nitrosothioglycolate, nitrosated cysteine, S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), S-nitroso-L- homocysteine, S-nitroso-L-cysteine, S-nitroso-albumin, S-nitrosocaptopril, or any combination thereof.

14. The article of claim 1, wherein the nitric oxide releasing compound is S-nitroso-N- acetyl-penicillamine.

15. The article of claim 1, wherein the nitric oxide releasing compound is dispersed throughout the article.

16. The article of claim 1, wherein the polysiloxane is covalently bonded to the at least one surface of the article by a plurality of hydroxyl groups on the at least one surface of the article.

17. An article comprising a polysiloxane covalently bonded to at least one surface of the article, wherein the article comprises a nitric oxide releasing compound, wherein the article is produced by the method comprising: (a) functionalizing the at least one surface of the article comprising the nitric oxide releasing compound with a plurality of hydroxyl groups to produce a pre- functionalized surface, and (b) contacting the pre-functionalized surface with a hydrolysed polysiloxane, wherein the plurality of hydroxyl groups on the surface of the article react with the hydrolyzed polysiloxane to covalently bond the polysiloxane to the surface of the article.

18. The article of claim 17, wherein step (a) comprises exposing the at least one surface of the article to plasma treatment.T|H Docket: 222105-2390 19. The article of claim 18, wherein the plasma treatment comprises air plasma.

20. The article of claim 17, wherein the hydrolysed polysiloxane is produced by (a) reacting a compound having the structure I and II wherein R1, R2, and R3are independently an alkyl group or a fluoroalkyl group in a solvent followed by the addition of an acid to produce the hydrolysed polysiloxane.

21. The article of claim 1, wherein the article comprises glass, a polymer, or a metal.

22. The article of claim 21, wherein the metal is aluminum or stainless steel.

23. The article of claim 21, wherein the polymer is a polysiloxane, a silicone-polyurethane co-polymer, a polycarbonate based silicone elastomer, a thermoplastic co-polymer of vinyl chloride and vinyl acetate, or a room temperature vulcanizing (RTV) silicone.

24. The article of claim 1, wherein the article comprises a polymeric grade material, a medical device, a surface or article in a hospital or medical facility, a surface in an automobile, boat, or aircraft, or an electronic display screen.

25. The article of claim 1, wherein the article comprises an implantable medical device.

26. The article of claim 25, wherein the implantable medical device comprises a urinary catheter, artificial heart valve, a vascular catheter, a graft, or a stent.

27. The article of claim 1, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees.

28. The article of claim 27, wherein the organic solvent comprises water or DMSO.

29. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is exposed to water for 15 days.

30. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is heated at 100oC for 30 days.

31. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is exposed to UV irradiation for 24 hours.T|H Docket: 222105-2390 32. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the surface is subjected to a tape peel test of 50 cycles.

33. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface has a liquid sliding angle of less than 20.0 degrees when the article is stored at 20oC to 30oC for 60 days.

34. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface is cytocompatible.

35. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface is hemocompatible.

36. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces the growth of microbes on the article.

37. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces biofilm formation on the article.

38. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces the adhesion of fibrinogen on the article.

39. The article of any one of claims 1-28, wherein the surface comprising the polysiloxane covalently bonded to the surface prevents or reduces the adhesion or activation of platelets on the article.

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