WO2014110511A1 - Protective barriers for preventing or reducing transfer of microorganisms - Google Patents

Protective barriers for preventing or reducing transfer of microorganisms Download PDF

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Publication number
WO2014110511A1
WO2014110511A1 PCT/US2014/011310 US2014011310W WO2014110511A1 WO 2014110511 A1 WO2014110511 A1 WO 2014110511A1 US 2014011310 W US2014011310 W US 2014011310W WO 2014110511 A1 WO2014110511 A1 WO 2014110511A1
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Prior art keywords
μιη
article
nm
method
surface
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PCT/US2014/011310
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French (fr)
Inventor
Benjamin Hatton
Joanna Aizenberg
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President And Fellows Of Harvard College
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Priority to US61/751,507 priority
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Publication of WO2014110511A1 publication Critical patent/WO2014110511A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B08CLEANING
    • B08BCLEANING IN GENERAL; PREVENTION OF FOULING IN GENERAL
    • B08B17/00Methods preventing fouling
    • B08B17/02Preventing deposition of fouling or of dust
    • B08B17/06Preventing deposition of fouling or of dust by giving articles subject to fouling a special shape or arrangement
    • B08B17/065Preventing deposition of fouling or of dust by giving articles subject to fouling a special shape or arrangement the surface having a microscopic surface pattern to achieve the same effect as a lotus flower
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/12Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Abstract

The present disclosure relates generally to protective barriers useful in reducing or preventing transfer of microorganisms from contaminated sources.

Description

Protective Barriers for Preventing or Reducing Transfer of

Microorganisms

Field of the Invention

[0001] The present disclosure relates generally to protective barriers useful in reducing or preventing transfer of microorganisms from contaminated sources.

Background

[0002] Contamination of surfaces by microbial attachment occurs very easily, and is the first step towards the development of bacterial bio films as multicellular communal superorganisms (O'Toole et al, Annu. Rev. Microbiol. 54, 49-79 (2000); De Beer et al, Prokaryotes 1, 904-937 (2006); O'Toole, J. Bacteriology 185, 2687-2689 (2003); the contents of which are hereby incorporated by reference in their entireties). An important consequence of bacterial contamination and population of surfaces is the infection of surgical instruments, biomedical materials and prosthetics such as catheters (Christensen et al., J. Clin. Microbiol. 22, 996-1006 (1985); Costerton et al, Ann. Rev. Microbiol. 41, 435-464 (1987); Gristina, Science 237, 1588-1595 (1987); Everaert et al, Colloids and Surfaces B: Biointerfaces 10, 179-190 (1998); Jacques et al, Microbial Ecology 13, 173-191 (1987); Hall et al, Public Health Records 79, 1021-1024 (1964); Druskin et al, J. Am. Med. Assoc. 185, 966-968

(1963) ; Bentley et al, J. Am. Med. Assoc. 206, 1749-1752 (1968); Corso et al, J. Am. Med. Assoc. 210, 2075-2077 (1969); Irwin et al, Yale J. Biol. Med. 46, 85-93 (1973); Michel et al, Am. J. Surgery 137, 745-748 (1979); and Shinozaki et al, J. Am. Med. Assoc. 249, 223-225 (1983); the contents of which are hereby incorporated by reference in their entireties).

Bloodstream infection caused by surgical instrument-, catheter- and implant-related bacterial contamination is a frequent serious complication associated with procedures involving catheters and implants (Christensen et al, J. Clin. Microbiol. 22, 996-1006 (1985); Costerton et al, Ann. Rev. Microbiol. 41, 435-464 (1987); Gristina, Science 237, 1588-1595 (1987); Everaert et al, Colloids and Surfaces B: Biointerfaces 10, 179-190 (1998); Jacques et al, Microbial Ecology 13, 173-191 (1987); Hall et al, Public Health Records 79, 1021-1024

(1964) ; Druskin et al, J. Am. Med Assoc. 185, 966-968 (1963); Bentley et al, J. Am. Med. Assoc. 206, 1749-1752 (1968); Corso et al, J. Am. Med. Assoc. 210, 2075-2077 (1969); Irwin et al, Yale J. Biol. Med. 46, 85-93 (1973); Michel et al, Am. J. Surgery 137, 745-748 (1979); and Shinozaki et al, J. Am. Med. Assoc. 249, 223-225 (1983); the contents of which are hereby incorporated by reference in their entireties).

[0003] Nosocomial-related infections are increasingly becoming problematic, causing serious increases to healthcare costs, stretching healthcare resources, and affecting patient health (Raad, I., Hanna, H. & Maki, D. Intravascular catheter-related infections: advances in diagnosis, prevention, and management. Lancet Infectious Diseases 7, 645-657 (2007);

Klevens, R.M., et al. Estimating health care-associated infections and deaths in US hospitals, 2002. Public Health Reports 122, 160 (2007); Peleg, A.Y. & Hooper, D.C. Hospital-acquired infections due to gram-negative bacteria. New England Journal of Medicine 362, 1804-1813 (2010); Graves, N. & McGowan Jr, J.E. Nosocomial infection, the Deficit Reduction Act, and incentives for hospitals. JAMA: the journal of the American Medical Association 300, 1577- 1579 (2008); Pittet, D., et al. Evidence-based model for hand transmission during patient care and the role of improved practices. The Lancet infectious diseases 6, 641-652 (2006); Maki, D., Stolz, S.M., Wheeler, S. & Mermel, L.A. Prevention of Central Venous Catheter-Related Bloodstream Infection by Use of an Antiseptic-Impregnated Catheter. Annals of Internal Medicine 127, 257-266 (1997); Maki, D.G., et al. An Attachable Silver-Impregnated Cuff for Prevention of Infection with Central Venous Catheters: A. Prospective Randomized

Multicenter Trial. American Journal of Medicine 85, 307-314 (1988); the contents of which are hereby incorporated by reference in their entireties). A patient (often already weak, with a compromised immune system) who acquires such an infection will be less likely to recover, and will also incur a great deal of hospital costs, resources, and time to limit the further transmission.

[0004] Bacteria can physically attach to a vast variety of surfaces, from hydrophilic to hydrophobic, by a variety of mechanisms (O 'Toole et al, Annu. Rev. Microbiol. 54, 49-79 (2000); De Beer et al, Prokaryotes 1, 904-937 (2006); O'Toole, J. Bacteriology 185, 2687- 2689 (2003); Christensen et al, J. Clin. Microbiol. 22, 996-1006 (1985); Costerton et al, Ann. Rev. Microbiol. 41, 435-464 (1987); Gristina, Science 237, 1588-1595 (1987); Everaert et al, Colloids and Surfaces B: Biointerfaces 10, 179-190 (1998); Jacques et al., Microbial Ecology 13, 173-191 (1987); the contents of which are hereby incorporated by reference in their entireties). The typical mechanisms include an initial deposition of proteins, known as conditioning layer, by physical or chemical adsorption, which precedes the attachment of the bacteria itself. Conditioning films, which may contain fibronectin, fibrinogen, collagen, and other proteins, coat a biomaterial surface almost immediately and provide receptor sites for bacterial or tissue adhesion (Gristina, Science 237, 1588-1595 (1987); the contents of which are hereby incorporated by reference in their entireties). The roles of these various macromolecules differs for different bacterial species. For example, Staphylococcus aureus has specific binding sites for collagen and fibronectin (Gristina, A.G. Biomaterial-Centered Infection: Microbial Adhesion Versus Tissue Integration. Science 237, 1588-1595 (1987); the contents of which are hereby incorporated by reference in their entireties). Bacteria (or tissue cells, such as bone, endothelial cells, or fibroblasts) that approach a biomaterial surface first encounter the glycoprotenacious conditioning layer.

[0005] The attachment of bacteria to typical medical surfaces can occur relatively easily. Materials used in medical environments {e.g., gloves, surgical instruments and intravascular devices (IVD) such as catheters) have many potential sources for infection. For example, conventional disposable medical gloves are typically made of polymers such as latex, nitrile rubber, vinyl and neoprene. These materials demonstrate a large degree of disordered roughness at the nanometer to 102 μιη length scales, which provides a large surface area for attachment of microorganisms. Accordingly, the adherence of microorganisms to the surface of a material is among the most important characteristics associated with the pathogenesis of infection.

[0006] The transfer of microbial organisms (bacteria, viruses, fungal spores, etc.) is frequently by physical contact. This contact most frequently involves hands, with or without gloves, from one place to another {e.g., from patient to doctor, to other patients). Standard medical gloves, and hand washing, only partially reduce the problems since bacteria quickly adhere to surfaces (and populate on skin very quickly). The physical transmission of bacteria to intravascular devices (IVD) such as catheters can lead to biofilm formation within the body; contamination outside of the body can lead to infection within the body.

[0007] Antimicrobial products have become extensively used to combat microorganism contamination in these environments, with commercial products employing a wide variety of active chemical agents, or biocides, often delivered in liquid form and sometimes as vapor. Various other approaches exist to coat or impregnate the surface of a medical material {e.g., glove, tubing, or catheter) with an antiseptic or antimicrobial drug (Maki, D., Stolz, S.M., Wheeler, S. & Mermel, L.A. Prevention of Central Venous Catheter-Related Bloodstream Infection by Use of an Antiseptic-Impregnated Catheter. Annals of Internal Medicine 127, 257-266 (1997); Maki, D.G., et al. An Attachable Silver-Impregnated Cuff for Prevention of Infection with Central Venous Catheters: A. Prospective Randomized Multicenter Trial. American Journal of Medicine 85, 307-314 (1988); Mermel, L.A. Prevention of Intravascular Catheter-Related Infections. Annals of Internal Medicine 132, 391-402 (2000); Danese, P.N. Antibiofilm Approaches: Prevention of Catheter Colonization. Chemistry and Biology 9, 873- 880 (2002); Crnich, C.J. & Maki, D. The Promise of Novel Technology for the Prevention of Intravascular Device-Related Bloodstream Infection. I. Pathogenesis and Short-Term

Devices. Clinical Infectious Diseases 34, 1232-1242 (2002); Crnich, C.J. & G. Maki, D.G. The Promise of Novel Technology for the Prevention of Intravascular Device-Related Bloodstream Infection. II. Long-Term Devices. Clinical Infectious Diseases 34, 1362-1368 (2002); the contents of which are hereby incorporated by reference in their entireties).

Examples include silver particles or chlorhexidine. Other examples include photocatalytic Ti02 surfaces, to oxidize organic species. However, this approach to achieving

microorganism- free surfaces in a medical environment relies on killing bacteria after they attach. While this assists in providing materials which are sterile or free of microorganisms prior to use, even a single bacterium cell that successfully adheres to the surface can develop into a robust and infectious bacterial film and cause disease.

[0008] An alternative approach has been the development of liquid-repellent surfaces, inspired by the self-cleaning abilities of many natural surfaces on animals, insects, and plants. Water droplets on these natural surfaces maintain a near-spherical shape and roll off easily, carrying dirt away with them. The water-repellency function has been attributed to the presence of micro/nanostructures on many of these natural surfaces. These observations have led to enormous interest in the past decade in manufacturing biomimetic water-repellent surfaces, owing to their broad spectrum of potential applications, which range from water- repellent fabrics to friction reduction surfaces {see, e.g., Barthlott, W. & Neinhuis, C. Purity of the sacred lotus, or escape from contamination in biological surfaces. Planta 202, 1-8 (1997); Cassie, A. B. D. & Baxter, S. Wettability of porous surfaces. Trans. Faraday Soc. 40, 0546 - 0550 (1944); Cassie, A. B. D. & Baxter, S. Large contact angles of plant and animal surfaces. Nature 155, 21-22 (1945); Shafrin, E. G. & Zisman, W. A. Constitutive relations in the wetting of low energy surfaces and the theory of the retraction method of preparing monolayers. J. Phys. Chem. 64, 519-524 (1960); Nguyen, T. P. N., Brunet, P., Coffmier, Y. & Boukherroub, R. Quantitative testing of robustness on superomniphobic surfaces by drop impact. Langmuir 26, 18369-18373 (2010); Quere, D. Wetting and roughness. Annu. Rev. Mater. Res. 38, 71-99 (2008); Bocquet, L. & Lauga, E. A smooth future? Nature Mater. 10, 334-337 (2011); Tuteja, A. et al, Science 318, 1618-1622 (2007); Tuteja, A., et al, Proc. Natl. Acad. Sci. USA 105, 18200-18205 (2008); Ahuja, A., et al, Langmuir 24, 9-14 (2008); Li, Y., et al, Angew. Chem. Int. Ed. 49, 6129-6133 (2010); the contents of which are hereby incorporated by reference in their entireties). The use of superhydrophobic surfaces to resist microbial attachment has been proposed before (Genzer, J. & Efimenko, K. Recent developments in superhydrophobic surface marine fouling: a review. Biofouling 22, 339-360 (2006); the contents of which are hereby incorporated by reference in their entireties).

[0009] Despite over a decade of intense research, surfaces in the art are still plagued with problems that restrict their practical applications. For example, these surfaces exhibit limited oleophobicity with high contact angle hysteresis; fail under pressure; cannot self-heal when damaged; and are expensive to produce.

[0010] There exists a need for a surface capable of reducing or preventing transfer of microorganisms from a contaminated source.

Brief Description of the Drawings

[0011] FIG. 1A is a perspective view of an array of superhydrophobic posts 100.

[0012] FIG. IB is a schematic of the top of an array of a substrate 120 bearing superhydrophobic posts with a droplet 110 of an aqueous solution contacting the tops of the posts in the "Cassie" or "Cassie-Baxter" state, and FIG. lC-1 is a corresponding cross- sectional side view illustration which shows the droplet 110 contacting the tops of the posts 100. FIG. lC-2 is an exploded view of the vapor/liquid interface between the droplet 110 and the posts 100 that defines a contact angle Θ or Θ .

[0013] FIG. ID is a side view illustration of an array of posts 100 on a substrate 120 (bottom) with an aqueous 130 solution (top) in "Cassie" state and containing microorganisms that are only exposed to the tips of the structure.

[0014] FIG. IE is a side view illustration of an array of posts 100 on a substrate 120 (bottom) with an aqueous solution 140 (top) in partial or full transition to Wenzel (wetting) state and containing microorganisms, which adhere to posts wetted by the solution.

[0015] FIG. IF depicts an illustration of a substrate 150 having disordered raised structures in contact with an aqueous solution 140, and FIG. 1G depicts an illustration of a substrate 120 having uniform or regular raised structures 100, demonstrating that the contaminated liquid 140 (above the surface) is more efficiently excluded from the substrate subsurface by the uniform raised structures than by the disordered raised structures. [0016] FIG. 2 depicts perspective, top- and side-view schematic diagrams of round raised post (2A), raised channel ("wall") (2B) and raised closed-cell brick ("intersecting wall") (2C) structures with widths (w), pitch (p) and interstructure spacings (s) indicated.

[0017] FIG. 3 A is a side view illustration of a substrate having raised post structures having interstructure distances (s) less than about both the longest diameter dL and shortest transverse diameter ds of the microorganism which preclude microorganisms from contacting the substrate.

[0018] FIG. 3B is a micrograph of B. subtilis on a substrate having raised post structures having interstructure distances less than the transverse diameter of the B. subtilis cells, demonstrating that the B. subtilis cells reside on the tips of the post structures and do not contact the substrate.

[0019] FIG. 4 shows a schematic and scanning electron microscope (SEM) images of a conventional nitrile glove surface at different magnifications.

[0020] FIG. 5A-5H shows images demonstrating contamination results for E. coli bacteria in static contact with different surface structures.

[0021] FIG. 6 shows a bar graph of density counts for E. coli cells remaining on different surface structures after static contact and rinsing.

[0022] FIG. 7A1-7C is a schematic comparing a standard medical glove (left side) with a medical glove bearing a non- wetting surface structure (right side) for contamination by bacteria from surface contact with a contaminating droplet.

Summary

[0023] Disclosed herein are compositions and methods which reduce or prevent transfer of microorganisms from a contaminated source. Applicants have previously disclosed surfaces for repelling fluids of biological origin, and the conditions for which surfaces can remain effectively sterile (i.e. free of surface-bound bacteria, even after extended contact with bacteria-rich growth medium (e.g., 60 min) (see International Patent Application Publication Nos. WO 2011/094344, WO 2012/100100; the contents of which are hereby incorporated by reference in their entireties).

[0024] In one aspect, a method of reducing or preventing transfer of a microorganism from a contaminated source to a surface is disclosed, the method comprising providing an article comprising a protective barrier, wherein the protective barrier comprises a

superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers; contacting the superhydrophobic surface of the protective barrier with a contaminated source comprising at least one microorganism, wherein the contaminated source is dewetted from the protective barrier to provide a substantially sterile

superhydrophobic surface; and subsequently contacting the article with a surface, wherein transfer of a microorganism from the contaminated source to the surface is reduced or prevented.

[0025] In another aspect, a method of reducing or preventing transfer of a microorganism from a protective barrier to a surface is disclosed, the method comprising: providing an article comprising a protective barrier comprising a microorganism, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers; contacting the protective barrier with a liquid such that the liquid also contacts the microorganism, the liquid is dewetted from the protective barrier, thereby removing the microorganism from the protective barrier to provide a substantially sterile surface; and subsequently contacting the article with a surface, wherein transfer of a microorganism from the article to the surface is reduced or prevented.

[0026] In another aspect, an article comprising a protective barrier is disclosed, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers.

Detailed Description

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in accordance with the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the present disclosure will be apparent from the following detailed description, and from the claims.

[0028] The present disclosure describes methods of reducing or preventing transfer of a microorganism from a contaminated source to a surface by providing a protective barrier. The present disclosure also provides methods of reducing or preventing transfer of a microorganism from a surface that has been exposed to a contaminated source or to other secondary sources, such as patients and the medical devices that come into contact with patients. In some embodiments, the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures that is applied directly to a surface is at risk of exposure to a contamination source. In some embodiments, the raised structures energetically exclude microorganisms by reducing or preventing wetting of the surface by a contaminated liquid. In further embodiments, the interstructure spacing, dimension and geometry of raised structures are selected so as to further physically exclude microorganisms, providing an additional mechanism for inhibiting, reducing, or attenuating microorganism transfer.

[0029] In certain embodiments, the protective barrier is a superhydrophobic surface on a medical device, instrument, or implant. Nonlimiting examples include medical gloves, clamps, forceps, scissors, skin hooks, tubing (such as endotracheal or gastrointestinal tubes), needles, retractors, scalers, drills, chisels, rasps, saws, catheters including indwelling catheter (such as urinary catheters, vascular catheters, peritoneal dialysis catheter, central venous catheters), catheter components (such as needles, Leur-Lok connectors, needleless connectors), orthopedic devices, artificial heart valves, prosthetic joints, voice prostheses, stents, shunts, pacemakers, surgical pins, respirators, ventilators, and endoscopes. In one or more embodiments, raised structures are prepared and are attached to a device, such as a medical device. In other embodiments, the raised structures are molded directly into the device structure, or imprinted on the device surface.

[0030] Such medical devices, instruments or implants remain effectively sterile during use. The devices, instruments or implants comprise superhydrophobic surface structures, which are non- wetting surfaces to aqueous liquids. Microorganism attachment to these surfaces is reduced or prevented after liquid dewetting from the surface, thus reducing or inhibiting transfer of the microorganisms when such devices are further brought into contact with, for example, patients and other surfaces that come into contact with patients.

[0031] Medical gloves are a specific example of a surface that can be provided a protective barrier to both prevent initial attachment of microorganism and prevent or reduce further transfer of such microorganisms. In some embodiments, medical gloves comprise a protective barrier as disclosed herein. These medical gloves greatly reduce or prevent the surface attachment and contamination with bacteria, viruses and other microorganisms which originate from contact with a contaminating source, such as a liquid, and can thereby reduce or prohibit the potential for transfer of microorganisms. This design can be incorporated with existing molding techniques for gloves (or other surfaces), and combined with existing antibacterial material compositions. In some embodiments, the medical gloves are

disposable. In some embodiments, the medical gloves comprise a protective barrier on at least a portion of at least one exterior fingertip or pad or thumbtip or pad of the glove. In further embodiments, the medical gloves comprise a protective barrier on at least a portion of the exterior palm of the glove. In still further embodiments, the medical gloves comprise a protective barrier on at least an entire exterior face of the glove. In still further embodiments, the medical gloves comprise a protective barrier on the entire exterior surface of the glove.

[0032] In some embodiments, the medical device, instrument or implant directly incorporates a superhydrophobic surface structure into the molded structure of the device, instrument or implant itself. In some embodiments, the superhydrophobic surface covers the entire surface of the device, instrument or implant. In further embodiments, the

superhydrophobic surface covers only a portion of the device, instrument, or implant.

[0033] In some embodiments the device is a medical glove. In some embodiments, the superhydrophobic surface covers the entire surface of the gloves. In further embodiments, the superhydrophobic surface covers less than the entire surface of the gloves. In some embodiments, the superhydrophobic surface covers the fingertips of the glove. In further embodiments, the superhydrophobic surface covers the entire front (palm) surface of the gloves. In some embodiments, the disclosed medical gloves limit or prevent the attachment of microorganisms to the surface after contact with a contaminating source, thereby limiting or preventing transfer of microorganisms to another surface. In some embodiments, the glove is disposable.

[0034] In some embodiments, the contaminating source is a liquid. In some

embodiments, the contaminating source is an aqueous liquid. In some embodiments, the contaminating source is blood, exudate from a wound or sweat.

[0035] In some embodiments, the medical gloves disclosed herein comprise anti-bacterial, superhydrophobic surfaces which find immediate and important application in hospitals and various medical (or biological research) environments. The present disclosure demonstrates that these surfaces on the glove remain effectively sterile, and should greatly reduce the probability for bacterial, viral or fungal transfer from one surface to another. In some embodiments, these medical gloves are coated, or directly molded, with these kind of surface structures. In some embodiments, the gloves are disposable, which mitigates eventual mechanical erosion, wetting or contamination with dust or oil.

A. Definitions

[0036] The content of any publication cited herein is incorporated by reference.

[0037] As used herein, the term "superhydrophobic" means a surface that is highly hydrophobic and non- wetting, with the liquid/surface interface having a contact angle Θ of at least about 140°, and the liquid in the so-called "Cassie" state such that the liquid is only in contact with the tips of the raised surface features and is resting on a cushion of air. The contact angle (Θ), as seen in Figure 1C, is the angle at which the liquid- vapor interface meets the so lid- liquid interface. The tendency of a drop to spread out over a flat, solid surface increases as the contact angle decreases. Thus, the contact angle provides an inverse measure of wettability.

B. Embodiments

[0038] The present disclosure relates generally to compositions and methods which reduce or prevent transfer of microorganisms from a contaminated source.

[0039] In one aspect, a method of reducing or preventing transfer of a microorganism from a contaminated source to a surface is disclosed, the method comprising providing an article comprising a protective barrier, wherein the protective barrier comprises a

superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers; contacting the superhydrophobic surface of the protective barrier with a contaminated source comprising at least one microorganism, wherein the contaminated source is dewetted from the protective barrier to provide a substantially sterile

superhydrophobic surface; and subsequently contacting the article with a surface, wherein transfer of a microorganism from the contaminated source to the surface is reduced or prevented.

[0040] In another aspect, a method of reducing or preventing transfer of a microorganism from a protective barrier to a surface is disclosed, the method comprising: providing an article comprising a protective barrier comprising a microorganism, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers; contacting the protective barrier with a liquid such that the liquid also contacts the microorganism, the liquid is dewetted from the protective barrier, thereby removing the microorganism from the protective barrier to provide a substantially sterile surface; and subsequently contacting the article with a surface, wherein transfer of a microorganism from the article to the surface is reduced or prevented.

[0041] In another aspect, an article comprising a protective barrier is disclosed, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers.

[0042] In some embodiments, the distal widths are less than about 20 μιη, less than about

5 μιη, less than about 2 μιη, less than about 1.5 μιη, or less than about 1 μιη.

[0043] In some embodiments, the distal widths are between about 10 nm and about 5 μιη, between about 50 nm and about 5 μιη, between about 100 nm and about 2 μιη, between about

150 nm and about 1.5 μιη, or between about 1.5 μιη and about 2 μιη.

[0044] In some embodiments, the distal widths are greater than or equal to about 50 nm and less than about 5 μιη, greater than or equal to about 100 nm and less than about 2 μιη, greater than or equal to about 500 nm and less than about 2 μιη , greater than or equal to about 1 μιη and less than about 2 μιη, or greater than or equal to about 1.5 μιη and less than about 2 μιη.

[0045] In some embodiments, the distal widths are greater than or equal to about 1.5 μιη and less than about 2 μιη.

[0046] In some embodiments, the interstructure spacings are between about 10 nm and about 5 μιη, between about 10 nm and about 500 nm, between about 50 nm and about 450 nm, between about 10 nm and less than about 500 nm, between about between about 100 nm and about 2 μιη, between about 150 nm and about 1.5 μιη, between about 500 nm and about 1 μιη, between about 500 nm and about 1.5 μιη, between about 1 μιη and about 1.5 μιη, between about 1 μιη and about 2 μιη, or between about 1.5 μιη and about 2 μιη.

[0047] In some embodiments, the distal widths are between about 10 nm and about 5 μιη and said interstructure spacings are between about 50 nm and about 5 μιη. [0048] In some embodiments, the distal widths are greater than or equal to about 1.5 μιη and less than about 2 μιη and said interstructure spacings are between about 10 nm and about 1 μιη.

[0049] In some embodiments, the interstructure spacings are between about 10 nm and less than about 500 nm.

[0050] In some embodiments, the interstructure spacings are between about 50 nm and about 450 nm.

[0051] In some embodiments, the raised structures are fluorinated.

[0052] In some embodiments, the protective barrier has a contact angle in the range of about 140° to about 180°.

[0053] In some embodiments, the basal width is greater than the distal width.

[0054] In some embodiments, the distal widths are selected to be less than three times the largest dimension of the microorganism in that contacts the article.

[0055] In some embodiments, the raised structures are posts.

[0056] In some embodiments, the raised structures define channels, grooves or closed-cell structures, which are optionally round-bottomed.

[0057] In some embodiments, the raised structures define closed-cell structures, and said closed-cell structures are honeycombs or bricks.

[0058] In some embodiments, the interstructure spacings are less than about 5 μιη; and the interstructure spacings are selected to be less than the largest dimension of said microorganism.

[0059] In some embodiments, the microorganism is a bacterium, virus or fungus.

[0060] In some embodiments, the protective barrier contacts the contaminated liquid or the surface for less than about 5 minutes.

[0061] In some embodiments, the article comprises a medical device. In some

embodiments, the medical device is selected from the group consisting of gloves, clamps, forceps, scissors, skin hooks, tubing, needles, retractors, scalers, drills, chisels, rasps, saws, catheters including indwelling catheter, catheter components, orthopedic devices, artificial heart valves, prosthetic joints, voice prostheses, stents, shunts, pacemakers, surgical pins, respirators, ventilators, and endoscopes.

[0062] In some embodiments, the article comprises a glove. In some embodiments, the glove is disposable. In some embodiments, at least a portion of at least one exterior fingertip or finger pad or thumbtip or thumb pad comprises a protective barrier. In some embodiments, at least one exterior face of the glove comprises a protective barrier.

C. Superhydrophobic Raised Structures

[0063] In some embodiments, the present disclosure describes methods of reducing or preventing transfer of a microorganism from a contaminated source to a surface by providing a protective barrier. In some embodiments, the protective barrier comprises a

superhydrophobic surface comprising a plurality of raised structures. Such raised structures reduce or prevent the transfer of microorganisms from a contaminated source by imbuing the surface with superhydrophobic properties. The contact between the contaminated source and protective barrier can be static due to simple exposure to a contaminated source or dynamic, such as contact due to splashing or pouring of a microorganism-containing liquid. In some embodiments, the transfer is inhibited or reduced following temporary contact of the substrate with the contaminated source. In certain embodiments, the contact lasts a few milliseconds to a few minutes.

[0064] In some embodiments, the superhydrophobic surface comprises raised

superhydrophobic structures which energetically exclude microorganisms by reducing or preventing wetting of the surface by a contaminated liquid. In further embodiments, the superhydrophobic surface also physically excludes microorganism, providing an additional mechanism for inhibiting, reducing, or attenuating microorganism attachment, resulting in a surface with additional mechanisms to reduce or prevent transfer of microorganisms from a contaminated source.

[0065] In some embodiments, the raised structures are posts. In further embodiments, the raised structures are channels. In still further embodiments, the raised structures are closed- cell structures. In still further embodiments, the raised structures are a combination of the above. The raised structures can be uniformly or regularly spaced on a base or subsurface, e.g., post arrays, regularly spaced channels and brick-like closed structures. In other embodiments, the structures are randomly spaced. In some embodiment, the structures have a width of less than about 5 μιη to reduce or prevent bacterial attachment and less than about 15 μιη to reduce or prevent fungal attachment, thereby reducing or preventing transfer of microorganisms from a contaminated source.

[0066] In some embodiments, the width of the raised structures are selected to reduce or prevent or discourage microorganism attachment to the surface, thereby reducing or preventing transfer of microorganisms from a contaminated source. In some embodiments, the width of the raised structures are less than or about 5 μηι for bacteria or viruses. For fungal organisms, the feature width can be less than or about 10 μιη. In some embodiments, the width of the raised structures are less than or about 2 μιη. In some embodiments, the width of the raised structures is in the range of about 5 μιη to about 100 nm, or about 2 μιη to about 300 nm. In some embodiments, the width of the raised structures are less than about the smallest axis of a microorganism. In further embodiments, the width of the raised structures are less than about the length of a microorganism or less than about the diameter of a microorganism.

[0067] In one aspect, an article comprising a protective barrier is disclosed, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends, wherein the article is a glove and wherein the distal widths are between about 10 nm and less than 2 μικη, and said interstructure spacings are between about 10 nm and less than about 1 μιη.

[0068] In some embodiments, the distal widths are between about 50 nm and about 1 μιη. In some embodiments the interstructure spacings are between about 1.5 μιη and less than about 2 μιη. In some embodiments, the distal widths are between about 50 nm and about 1 μιη and the interstructure spacings are between about 1.5 μιη and less than about 2 μιη.

[0069] More specifically, the physically-excluding surfaces should have interstructure spacings and structure widths that are smaller than the size of the microorganism contained in the contaminated solution or medium. These sizes should be tailored to the application and the specific species expected in the contaminated environment.

[0070] FIG. 1 A shows exemplary superhydrophobic surface having an array of posts 100. The posts are hydrophobic, e.g., they can be made of a material that is hydrophobic or coated or chemically treated to provide a hydrophobic surface. Liquids, e.g., water, bead up and do not wet the surface of the superhydrophobic surface. FIG. IB shows non- wetting water droplet 110 on a superhydrophobic surface 120 made up, for example, of an array of posts 100, such as are shown in FIG. 1A. FIG. lC-1 shows a cross-sectional view of the water droplet as it rests on the microstructured superhydrophobic surface. FIG. lC-2 provides a magnified view of the relative positions of the liquid phase (L), vapor (V) on a substrate. In this figures, Θ is the contact angle for a Cassie state liquid, and Θ is the apparent contact angle which corresponds to the stable equilibrium state. Superhydrophobic surfaces are known in the art, and are known to be influenced by factors such as, but not limited to, the surface composition, the widths, heights, and interstructure spacings of the raised surfaces. One of skill in the art will appreciate how these factors influence the contact angle exhibited by a surface.

[0071] FIG. 2A shows a post array having posts 20 on subsurface 10 in perspective, plan and cross-sectional views. The raised structures in this embodiment typically have heights of 0.1 μιη to 100 μιη (preferably 1 μιη to 25 μιη and most preferably 2 μιη to 10 μιη). For embodiments where the raised structures energetically exclude microorganisms from the substrate surface by anti-wetting properties under dynamic conditions, the raised structures have widths at their distal ends of 0.01 μιη to 5 μιη, and pitches of 0.05 μιη to 50 μιη

(preferably 0.1 μιη to 20 μιη and most preferably 0.5 μιη to 10 μιη). For embodiments where the raised structures physically exclude microorganisms from the substrate subsurface by controlling interstructure spacings and by limiting the available width for adhesion, and where the microorganisms are contacting only the top surface with reduced contact area, the raised structures have interstructure spacings of 0.01 μιη to 10 μιη (preferably 0.1 μιη to 2 μιη), and widths at their distal ends of 0.01 μιη to 5 μιη.

[0072] FIG. 2B shows a channel array having walls 40 on subsurface 30 in

perspective, plan and cross-sectional views. The raised structures in this embodiment typically have heights of 0.1 μιη to 100 μιη (preferably 1 μιη to 25 μιη and most preferably 2 μιη to 10 μιη). For embodiments where the raised structures energetically exclude microorganisms from the substrate surface by anti-wetting properties under dynamic conditions, the raised structures have widths at their distal ends of 0.01 μιη to 5 μιη, and pitches of 0.05 μιη to 50 μιη (preferably 0.2 μιη to 20 μιη and most preferably 0.5 μιη to 10 μιη). For embodiments where the raised structures physically exclude microorganisms from the substrate subsurface by controlling interstructure spacings, the raised structures have interstructure spacings of 0.01 μιη to 10 μιη (preferably 0.1 μιη to 2 μιη), and widths at their distal ends of 0.01 μιη to 5 μιη. More specifically, the physically-excluding surfaces should have interstructure spacings and structure widths that are smaller than the size of the microorganism contained in the contaminated solution or medium.

[0073] Lastly, FIG. 2C shows a closed-cell array having long walls 60 and transverse short walls 65 on subsurface 50 in perspective, plan and cross-sectional views.

[0074] The raised structures in this embodiment typically have heights of 0.1 μιη to 100 μιη (preferably 1 μιη to 25 μιη and most preferably 2 μιη to 10 μιη). [0075] For embodiments where the raised structures energetically exclude

microorganisms from the substrate surface by anti-wetting properties under dynamic conditions, the raised structures have widths at their distal ends of 0.01 μιη to 5 μιη, and shortest wall-to-wall distances within each compartment of 0.02 μιη to 50 μιη (preferably 0.2 μιη to 20 μιη and most preferably 0.5 μιη to 10 μιη).

[0076] For embodiments where the raised structures physically exclude microorganisms from the substrate subsurface by controlling interstructure spacings, the raised structures have interstructure spacings of 0.01 μιη to 10 μιη (preferably 0.1 μιη to 2 μιη), and widths at their distal ends of 0.01 μιη to 5 μιη. More specifically, the physically-excluding surfaces should have interstructure spacings and structure widths that are smaller than the size of the microorganism contained in the contaminated solution or medium. These sizes should be tailored to the application and the specific species expected in the contaminated environment. Because the microorganisms are physically excluded from the subsurface, it is not required that the surface be hydrophobic.

[0077] As used herein, "width" (w) refers to the shortest transverse distance of the distal ends of a raised surface. For example, FIG. 2 shows that the width of the distal end of a raised circular post surface is its diameter at its distal end (2A), and the width of the distal end of a raised surface defining channels or closed-cell structures is the width of the wall defining the channel or closed-cell structure at its distal end (2B and 2C, respectively).

[0078] As used herein, "pitch" (p), or periodicity, refers to the distance between the centers of adjacent raised structures. For example, FIG. 2 shows that the pitch between posts is the distance between the centers of adjacent posts (2A), the pitch between raised structures defining channels is the average distance between the centers of adjacent lateral walls (2B), and the pitch between raised structures defining closed-cell structures is the average distance (per compartment) between the centers of the wall or opposite walls delimiting the closed-cell structure (e.g., for some symmetric compartments such as those exhibiting square, hexagonal, octagonal, etc. geometry, the interstructure spacings would be equal to the distance between the centers of oppositely facing lateral walls; for non-symmetric compartments: px and py).

[0079] As used herein, "interstructure spacing" (s) refers to the shortest lateral dimension of the available space/gap between adjacent raised structures. FIG. 2A-B show that the interstructure spacing is equal to the pitch minus width of the structures. For structures with varying interstructure spacings, such as non-uniformly spaced posts, non-symmetric compartments, and non-symmetric channels, interstructure spacing is better defined as the average shortest available space/gap between adjacent raised structures per compartment.

[0080] In some embodiments, a protective barrier as disclosed herein includes raised structures that can vary in dimensions, shape, and spatial arrangement. In some

embodiments, the heights and widths of the raised structures on the substrate are uniform. In further embodiments, the heights and widths of the raised structures vary across the substrate. In some embodiments, the heights of the raised structures change gradually across the substrate, e.g., creating a gradient of heights. In further embodiments, the heights of the raised structures vary randomly across the substrate. Similarly, in some embodiments the widths of the raised structures on the substrate are uniform. In further embodiments, the widths of the raised structures vary across the substrate. In some embodiments, the widths of the raised structures change gradually across the substrate, e.g., creating a gradient of widths. In further embodiments, the widths of the raised structures vary randomly across the substrate. In some embodiments, the shapes of the raised structures on the substrate are uniform. In further embodiments, the shapes of the raised structures vary across the substrate. In some embodiments, the shapes of the raised structures change gradually across the substrate, e.g., creating a gradient of shapes. In further embodiments, the shapes of the raised structures vary randomly across the substrate. In some embodiments, the interstructure spacings of the raised structures on the substrate are uniform or regular. In further

embodiments, the interstructure spacings of the raised structures vary across the substrate. In some embodiments, the interstructure spacings of the raised structures change gradually across the substrate, e.g., creating a gradient of interstructure spacings. In further

embodiments, the interstructure spacings of the raised structures vary randomly across the substrate. In some embodiments, the raised structures are distributed in an ordered fashion, e.g., symmetrically arranged. In further embodiments, the raised structures are randomly positioned.

[0081] In some embodiments, the raised structures are either isolated or interconnected. Thus, different surface patterns, including periodic patterns, are formed of raised structures having different dimensions, shapes, and spatial arrangements. The contaminated liquid (above the surfaces) is more efficiently excluded from the substrate subsurface by the uniform raised structures than by the disordered raised structures, as shown in Fig. 1F-G; therefore, uniform raised structures are preferred. [0082] In certain embodiments, the raised structures are generally vertically oriented to the substrate (e.g., perpendicular). In further embodiments, the raised structures are oriented oblique to the substrate.

[0083] In some embodiments, the raised post structures comprise mechanically reinforced posts, having branched cross-sections for mechanical stability. For example, such posts can have branched T-shaped, Y-shaped, or X-shaped cross-sections, or branched I-beam shapes, known to be used in construction due to their maximum mechanical stability. In further embodiments, posts can be S-shaped in cross section.

[0084] In some embodiments, the raised structures comprise mechanically reinforced structures, having basal widths greater than their distal widths.

[0085] In some embodiments, the raised structures are prepared as a coating on a device, such as a medical device, to prevent, inhibit, or reduce the attachment of microorganisms on to the device, thereby reducing or preventing transfer of microorganisms from a contaminated source. In further embodiments, the surface itself is structured so as to define the raised structures described herein.

[0086] The raised structures of the present invention can be produced by numerous different techniques, such as photolithography, projection lithography, e-beam writing or lithography, depositing nanowire arrays, growing nanostructures on the surface of a substrate, soft lithography, replica molding, solution deposition, solution polymerization,

electropolymerization, electrospinning, electroplating, vapor deposition, contact printing, etching, transfer patterning, microimprinting, self-assembly, and the like.

[0087] In certain embodiments, the raised superhydrophobic structures are prepared from a hydrophobic material, and/or include a hydrophobic coating. In some embodiments, the raised superhydrophobic structures are fluorinated. Further detail on preparation of raised structures can be found in International Patent Application Publication Nos. WO

201 1/094344, the contents of which are incorporated by reference in their entireties.

Energetic Exclusion of Microorganisms

[0088] The invention is based in part on the discovery that the transfer of microorganisms from a surface that has been exposed to a contaminated liquid containing microorganisms can be inhibited or reduced by providing that surface with superhydrophobic raised structures having defined feature sizes.

[0089] When the feature diameters are at or less than the dimensions of the

microorganism, the microorganisms have difficulty attaching to the tops of the raised surface features, and are thus limited in their ability to be transferred from a contaminated source. When the surface is in a Cassie state so the contact angle of liquids is high and the contact area is low, the ability of the microorganisms to attach and proliferate on the surface, and potentially transfer to other surfaces is further hindered. In particular embodiments, the raised superhydrophobic structures (or the array of raised superhydrophobic structures) have a contact angle of greater than about 140°, such as between about 150° and about 180°. In some embodiments, raised structures having widths of less than about 2 microns result in effectively sterile surfaces after contact with a contaminated liquid). In further embodiments, raised structures having widths of between about 2 and about 20 microns result in surfaces exhibiting limited or reduced contamination after contact with a contaminated liquid).

[0090] FIG. ID shows a superhydrophobic surface having raised posts 100 on a subsurface 120 and illustrates the confining effect of a superhydrophobic surface on microorganism attachment. Microbial organisms in solution 130 only have limited contact with the surface (FIG. ID). However, extended exposure times can cause partial or complete wetting 140 of the surface (FIG. IE). Therefore, the lifetime of the "Cassie" state can be limited, and the prospects of the non- wetting contact of contaminating liquids (i.e. liquids containing microorganisms) can also be limited.

[0091] Since there exists an induction time for microorganism attachment (i.e. the time required for a microorganism to attach to the raised surface or substrate), conditions for which water droplets bounce off a surface before microorganism attachment occurs can be created. Contaminated liquid droplets bounce off a patterned superhydrophobic surface and their contact time with the surface is shorter than the time required for microorganism attachment. In contrast, contaminated liquid droplets typically do not bounce off unpattemed hydrophobic surfaces, or patterned or unpattemed hydrophilic surfaces. As a result, such droplets can remain in contact with unpattemed hydrophobic or any hydrophilic surfaces and provide sufficient opportunity for microorganisms to attach to these surfaces.

[0092] The property of fast droplet de-wetting and ejection from a surface, in combination with superhydrophobic raised structures of defined feature size that interferes with the ability of bacteria, viruses or fungi, contained within such a droplet, to physically attach to the surface, provides a surface that is resistant to cell attachment and biofilm formation, and which therefore reduces or prevents transfer of microorganisms from a contaminated source. Therefore, after droplet de-wetting and ejection from the surface by a contaminated liquid, there are either no or very few loosely attached or poorly organized microorganisms left behind. As a result, the complete or substantial absence of microbial organisms means the transfer of microorganisms from the contaminated source is substantially reduced or inhibited.

Physical Exclusion of Microorganisms

[0093] Further, it has been discovered that mterstructure spacing, dimension and geometry of raised structures can be used to inhibit, reduce, or attenuate microorganism attachment, thereby reducing or preventing transfer of microorganisms from a contaminated source. In conjunction with a superhydrophobic surface, the physical exclusion of microorganisms further prevents transfer of microorganisms from a contaminated source.

[0094] In some embodiments, the raised structures have mterstructure spacings of less than about the length and/or transverse diameter of the microorganism contained in the contaminated liquid, which physically exclude microorganisms from the substrate subsurface. In these embodiments, the mterstructure spacing is too small to permit the microorganisms to enter the mterstructure space and attach to the base surface, and they are instead constrained to the upper surface of the raised structures. For example, FIG. 3A shows a side view of a substrate 740 having raised post structures 700 with mterstructure distances s less than about the transverse diameter d of a microorganism, 725, so that the microorganism is precluded from contacting the substrate. An aspected microorganism 720 is also shown, having a shortest transverse diameter ds and a longest diameter dL. As microorganisms 720 and 725 are constrained to the upper surface of the raised structures, these microorganisms are more susceptible to biological or chemical attack, as they can be accessed from both the top 770 and the available space below 760. FIG. 3B is a micrograph of B. subtilis microorganisms on such a substrate, where the cells 750 reside on the tips of the post structures and do not contact the substrate. Thus, even when there is a possibility of surface wetting, so that the liquid contacts the surface for a time sufficient to permit attachment, little or only weak attachment occurs.

[0095] In some embodiments, the mterstructure spacings of the raised structures are less than about the smallest axis of a microorganism. In further embodiments, the mterstructure spacings of the raised structures are less than about the length and greater than about the transverse diameter of a microorganism. In further embodiments, as the mterstructure spacings of the raised structures decrease and are less than about the shortest dimension of a microorganism, the microorganism contacts the tips of the structures and does not contact the substrate.

[0096] As noted above, the diameters of the raised features can also be selected to discourage microorganism adhesion. Typically, a rod-shaped microorganism has a length of about 0.1 μιη to about 10 μιη or longer and a transverse diameter of about 0.1 μιη to about 5 μιη or wider. A spherical microorganism can have a diameter of about 0.1 μιη to about 1 μιη. Accordingly, raised structures disposed on substrates can have widths based on the lengths and/or diameters of a particular microorganism. For example, Pseudomonas aeruginosa (strain PA14), the cause of most hospital-acquired diseases, has a lateral length of about 1 μιη to about 2 μιη and a transverse diameter of about 0.5 μιη to about 1 μιη. For this

microorganism, a substrate having raised structures with widths of less than about 2 μιη inhibit or reduce the attachment of this microorganism, while a substrate having raised structures with interstructure spacings of less than about 0.5 μιη would control the

microorganism such that the microorganism would be confined to the tops of the raised structures.

[0097] In certain embodiments, the surface is a superhydrophobic surface having raised features with diameters of less than about 10 μιη (for fungus) or less than about 5 μιη (for bacteria or viruses) or less than or about 2 μιη, so that the surface contact area is low and liquid have low residence times of the surface. Microorganism adhesion is further reduced or prevented by providing an interstructure spacing of less than about 2 μιη inhibit or with interstructure spacings of less than about 0.5 μιη to confine the microorganism to the tops of the raised structures. The particular features of the antibiofilm surface is dependent on the microbial system. Surface features having a distal width of 5 μιη or less will work for most bacterial systems (and therefore fungal, as fungi are larger than bacteria). However, depending on the nature of the exposure, additional feature sizes may be preferred.

Methods of Making

[0098] The raised structures of the present invention can be produced by any known method for depositing raised structures onto substrates. Nonlimiting examples include conventional photolithography, projection lithography, e-beam writing or lithography, depositing nanowire arrays, growing nanostructures on the surface of a substrate, soft lithography, replica molding, solution deposition, solution polymerization,

electropolymerization, electrospinning, electroplating, vapor deposition, contact printing, etching, transfer patterning, microimprinting, self-assembly, and the like. For example, a silicon substrate having a post array, a brick array, a channel or "blade" array, a box array, or a honeycomb array can be fabricated by photolithography using the Bosch reactive ion etching method (as described in Plasma Etching: Fundamentals and Applications, M.

Sugawara, et. al , Oxford University Press, (1998), ISBN-10: 019856287X), hereby incorporated by reference in its entirety. Further exemplary methods are described in WO 2009/158631, the contents of which are incorporated by reference in their entireties.

[0099] Patterned surfaces can also be obtained as replicas (e.g. , epoxy replicas) by a soft lithographic method (see, e.g., Pokroy et al, Advanced Materials, 2009, 21, 463, , hereby incorporated by reference in its entirety [Patterned surfaces having round-bottoms (e.g., a round-bottomed brick array) can be obtained by a combination of the Bosch reactive ion etching method and the isotropic reactive etching technique described in Plasma Etching: Fundamentals and Applications, M. Sugawara, et. al, Oxford University Press, (1998), ISBN- 10: 019856287X, the contents of which are incorporated by reference in their entireties.

[0100] Polymer films with patterned surfaces can be fabricated by means known in the art (e.g., roll-to-roll imprinting or embossing).

[0101] A patterned surface thus formed, if not fabricated from an innately hydrophobic material, can be coated with a hydrophobic material, such as low-surface-energy

fluoropolymers (e.g., polytetrafluoroethylene), and fluorosilanes (e.g., heptadecylfluoro- 1,1,2,2-tetra-hydrodecyl-trichlorosilane). Surface coating can be achieved by methods well known in the art, including plasma assisted chemical vapor deposition, solution deposition, and vapor deposition.

[0102] Note that the patterned surface can either be an integral part of the substrate or a separate layer on the substrate. For example, a patterned surface can be fabricated from a material (e.g., a silicon wafer or a polymer film) and used to cover another material (e.g., an aluminum plate). This can be useful when it is easier to fabricate a patterned surface from a material other than that of the substrate. Also, to obtain a large patterned surface on a large substrate, it is often necessary to fabricate smaller patterned surfaces and then place them on the large substrate.

[0103] To cover a substrate with a patterned surface, one can use standard methods (e.g., tiling, embossing, and rolling with a patterned roller, etc.), as described in Whitesides et al, Chem. Review, 2005, 105, 1171-1196, the contents of which are incorporated by reference in their entireties. To analyze the topology of a patterned surface, one can use well-known methods, such as scanning electron microscopy (SEM) and atomic force microscopy (AFM). As mentioned above, a water droplet on a hydrophobic surface for use in this invention displays a contact angle of more than 90°, preferably more than 140°. The actual contact angle can be determined by methods well known in the art (e.g. , with a contact angle goniometer).

[0104] The raised structures described herein can also be fabricated using molding techniques, such as those described in WO 2009/158631 , published December 30, 2009, the contents of which are incorporated by reference in their entireties. These techniques involve making an original replica mold using any known techniques, followed by forming a negative replica mold using suitable replica material. Finally, a replica is made using the negative replica as a mold. These replicas can then coat any flat or curved surface (including the inner or outer side of pipes as shown in Such curved patterned tubes are of particular importance in applications related to catheters or vascular tubing.

[0105] The raised structures described herein can also be fabricated using

electrodeposition techniques, such as those described in International Patent Application Nos. PCT/US1 1/22620, filed January 26, 201 1 and PCT/US 1 1/44553, filed July 19, 201 1 and U.S. Patent Application No. 13/575,688, filed July 27, 2012, the contents of which are

incorporated by reference in their entireties. In particular, the raised structures described herein can be fabricated by in situ deposition of conducting organic polymers by either electrochemical deposition or electroless direct solution deposition. In these methods, the morphology of the conducting organic polymers can be controlled by varying the deposition conditions such as the concentration of monomer, the types of electrolytes and buffers, the deposition temperature and time, and the electrochemical conditions such as voltage and current. The morphology of conducting organic polymers can be finely controlled from nanometer to over micrometer scales. Therefore, surface coatings with precisely controlled morphology can be produced by simple modifications, which promise the customization of various surface properties by design and control of the morphology.

[0106] The raised structures described herein can be made of any suitable material.

Nonlimiting examples of such materials include polymers such as epoxy, polypropylene (PP), polyethylene (PE), polyvinylalcohol (PVA), poly methyl methacrylic acid (PMMA), and various hydrogels and biological macromolecules (e.g., alginates, collagen, agar); metals and alloys, such as Au metal and Ti alloys; and ceramics including A1203, Ti02, Hf02, Si02, ZrO, and BaTi03. Other polymeric materials, metals, alloys and ceramics can also be used. [0107] In some embodiments, the material is any biocompatible material capable of being formed into a raised structure described herein.

Hydrophobic Coatings

[0108] In some embodiments, after fabrication, the raised structures are then treated with a hydrophobic coating to render the raised structures superhydrophobic. For example, as discussed above, hydrophobic surface coatings can be applied using fluorinated silanes, either by solution or vapor deposition treatment.

[0109] In some embodiments, the raised structures are rendered superhydrophobic by treatment with a silicone fluid, such as a polysiloxane, an alkyl silane, or an alkyl silazane. Nonlimiting examples of suitable polysiloxanes include a linear, branched or cyclic polydimethylsiloxane; polysiloxanes having a hydroxyl group in the molecular chain such as silanol-terminated polydimethylsiloxane, silanol-terminated polydiphenylsiloxane, diphenylsilanol-terminated polydimethylphenylsiloxane, carbinol-terminated

polydimethylsiloxane, hydroxypropyl-terminated polydimethylsiloxane and polydimethyl- hydroxyalkylene oxide methylsiloxane; polysiloxanes having an amino group in the molecular chain such as bis(aminopropyldimethyl)siloxane, aminopropyl-terminated polydimethylsiloxane, aminoalkyl group-containing, T-structured polydimethylsiloxane, dimethylamino-terminated polydimethylsiloxane and bis(aminopropyldimethyl)siloxane; polysiloxanes having a glycidoxyalkyl group in the molecular chain such as glycidoxypropyl- terminated polydimethylsiloxane, glycidoxypropyl-containing, T-structured

polydimethylsiloxane, polyglycidoxypropylmethylsiloxane and a

polyglycidoxypropylmethyldimethylsiloxane copolymer; polysiloxanes having a chlorine atom in the molecular chain such as chloromethyl-terminated polydimethylsiloxane, chloropropyl-terminated polydimethylsiloxane, polydimethyl-chloropropylmethylsiloxane, chloro-terminated polydimethylsiloxane and l,3-bis(chloromethyl)tetramethyldisiloxane; polysiloxanes having a methacryloxyalkyl group in the molecular chain such as

methacryloxypropyl-terminated polydimethylsiloxane, methacryloxypropyl-containing, T- structured polydimethylsiloxane and polydimethyl-methacryloxypropylmethylsiloxane;

polysiloxanes having a mercaptoalkyl group in the molecular chain such as mercaptopropyl- terminated polydimethylsiloxane, polymercaptopropylmethylsiloxane and mercaptopropyl- containing, T-structured polydimethylsiloxane; polysiloxanes having an alkoxy group in the molecular chain such as ethoxy-terminated polydimethylsiloxane, polydimethylsiloxane having trimethoxysilyl on one terminal and a polydimethyloctyloxymethylsiloxane copolymer; polysiloxanes having a carboxyalkyl group in the molecular chain such as carboxylpropyl-terminated polydimethylsiloxane, carboxylpropyl-containing, T-structured polydimethylsiloxane and carboxylpropyl-terminated, T-structured polydimethylsiloxane; polysiloxanes having a vinyl group in the molecular chain such as vinyl-terminated polydimethylsiloxane, tetramethyldivinyldisiloxane, methylphenylvinyl-terminated polydimethylsiloxane, a vinyl-terminated polydimethyl-polyphenylsiloxane copolymer, a vinyl-terminated polydimethyl-polydiphenylsiloxane copolymer, a polydimethyl- polymethylvinylsiloxane copolymer, methyldivinyl-terminated polydimethylsiloxane, a vinyl terminated polydimethylmethylvinylsiloxane copolymer, vinyl-containing, T-structured polydimethylsiloxane, vinyl-terminated polymethylphenetylsiloxane and cyclic

vinylmethylsiloxane; polysiloxanes having a phenyl group in the molecular chain such as a polydimethyl-diphenylsiloxane copolymer, a polydimethyl-phenylmethylsiloxane copolymer, polymethylphenylsiloxane, a polymethylphenyl-diphenylsiloxane copolymer, a

polydimethylsiloxane-trimethylsiloxane copolymer, a polydimethyl- tetrachlorophenylsiloxane copolymer and tetraphenyldimethylsiloxane; polysiloxanes having a cyanoalkyl group in the molecular chain such as polybis(cyanopropyl)siloxane,

polycyanopropylmethylsiloxane, a polycyanopropyl-dimethylsiloxane copolymer and a polycyanopropylmethyl-methyphenylsiloxane copolymer; polysiloxanes having a long-chain alkyl group in the molecular chain such as polymethylethylsiloxane, polymethyloctylsiloxane, polymethyloctadecylsiloxane, a polymethyldecyl-diphenylsiloxane copolymer and a polymethylphenetylsiloxane-methylhexylsiloxane copolymer; polysiloxanes having a fluoroalkyl group in the molecular chain such as polymethyl-3,3,3-trifluoropropylsiloxane and polymethyl-l,l,2,2-tetrahydrofluorooctylsiloxane; polysiloxanes having a hydrogen atom in the molecular chain such as hydrogen-terminated polydimethylsiloxane,

polymethylhydrosiloxane and tetramethyldisiloxane; hexamethyldisiloxane; and a

polydimethylsiloxane-alkylene oxide copolymer. Many polysiloxanes are commercially available as water repellents, such as Super Rain X formed mainly of polydimethylsiloxane (supplied by Unelko) and Glass Clad 6C formed mainly of polydimethylsiloxane whose terminal groups are replaced with chlorine atom (supplied by Petrarch Systems Inc.). These polysiloxanes can be used alone or in combination. Other suitable polysiloxanes are those organic polysiloxanes disclosed in U.S. Pat. No. 5,939,491, which is hereby incorporated by reference in its entirety. [0110] Suitable alkyl silanes include, but are not limited to, n-butyltrimethoxysilane, n- decyltrimethoxysilane, isobutyltrimethoxysilane, n-hexyltrimethoxysilane, and

cyclohexylmethyldimethoxysilane. Alkyl silanes can be used separately or in a mixture of two or more. Alternatively, a fluorinated hydrophobic silane can be used such as

perfluorinated alkyl, ether, ester, urethane, or other chemical moiety possessing fluorine and a hydrolyzable silane. Other exemplary fluorosilanes that can be used to coat raised structures are described in U.S. Pat. Nos. 5,081,192; 5,763,061; and 6,227,485, hereby incorporated by reference in their entireties.

[0111] The raised structures can be totally coated or partially coated, such as the vertical end of the raised structure opposite the substrate. In some embodiments, the raised nanostructures and the substrate are coated with the hydrophobic coating. The coating can be applied at a thickness of about 1 nm to about 30 nm.

[0112] If the structures are made out of hydrophobic material, no additional hydrophobic coating is required.

[0113] The superhydrophobicity can be quantified by measuring the contact angle between a droplet of a contaminated liquid and the surface of an array of raised

superhydrophobic structures using known methods. In particular embodiments, the array has a contact angle of greater than about 140°, or greater than about 150°, or greater than about 155° or greater than about 160°, or greater than about 165° or greater than about 170°, or greater than about 175°.

Experimental

[0114] The attachment of bacteria to typical medical surfaces can occur relatively easily. Conventional disposable medical gloves are typically made of polymers such as latex, nitrile rubber, vinyl and neoprene. FIG. 4 shows SEM images of the surface of a standard nitrile medical glove, showing the large degree of disordered roughness, from the nanometer to 102 μιη length scales. The upper image shows 1,000 times magnification, while the lower image shows 10,000 times magnification. This large surface area allows bacteria to remain adherent to a conventional glove surface after contact with contaminated source.

[0115] A series of demonstration experiments were performed to test the effectiveness of various unstructured (control) and structured, superhydrophobic surfaces to allow bacterial contamination after being exposed for 5 min to a droplet (50 μί) of an Escherichia coli (wild type) bacterial growth solution (grown in lysogeny broth (LB) medium overnight, to optical density 0.4), then rinsed with deionized water. The control surfaces were a cut piece of nitrile medical glove, and a flat (unstructured) polyurethane (PU, Norland Optical 86). The non- wetting surfaces were posts arrays of 50 μιη, 3 μιη, 1 μιη diameter and 300 nm post diameters, cast in PU. All PU surfaces were treated with a hydrophobic silane ((heptadecafluoro-l,l,2,2-tetrahydrodecyl)trichlorosilane, Gelest) after oxygen plasma treatment, and the post arrays were superhydrophobic to deionized water.

[0116] As demonstrated by the contamination results for E. coli shown in FIG. 5, bacterial attachment is a function of the feature size of the superhydrophobic surface structure. FIG. 5 shows contamination results where E. coli (fixed and stained with fluorescent dye) were placed in static contact with different surface structures for 5 minutes, followed by rinsing. The surfaces shown are a) a nitrile glove; b) flat polyurethane (PU); c) 50 μιη posts on PU; d) 3 μιη posts on PU; e) 1 μιη posts on PU; f) 300 nm posts on PU. This figure demonstrates that only the posts of 1.5 μιη and 300 nm appeared to cause a complete lack of bacterial attachment, meaning that the 50 μιη and 3 μιη posts were too large to prevent surface attachment. FIGs. 5(g)-(h) illustrate schematics of a proposed mechanism for the data, where droplets fully wet a flat surface as shown in FIG. 5(g), but when exposed to a structured surface, are suspended on the tips of posts, unable to wet the surface as shown in FIG. 5(h).

[0117] FIG. 6 shows density counts for E. coli cells remaining on the surfaces after 5 minutes static contact and rinsing (from fluorescence counts), showing the dramatic difference for 1 μιη and 300 nm diameter posts. FIG. 6 shows that these large post sizes had similar densities of bacterial attachment as for the flat PU and glove materials, but that the 1.5 μιη and 300 nm samples had densities that were less by about three orders of magnitude. Accordingly, these surfaces are more sterile and less likely to transfer of microorganisms from a contaminated source.

[0118] FIG. 7 is a schematic comparing the ability of a standard medical glove (left side) and a medical glove given a protective barrier as described herein (right side) to reduce or inhibit transfer of a microorganism from a contaminated source. FIG. 7 shows how a glove that is coated, or directly molded, with a non- wetting surface structure having sufficiently small feature sizes could effectively prevent the attachment of bacterial cells after contact with a contaminating fluid on a surface. As a result, such a glove remains effectively sterile, and greatly reduce the probability of transferring bacteria (or other microorganisms) from one surface to another. Specifically, FIG. 7A-1 shows both gloves prior to contact with the contaminated source, with FIG. 7A-2 showing an exploded view of an area of the glove bearing a non-wetting surface structure with raised features. FIG. 7B shows the gloves in direct contact with the contaminated source. FIG. 7C shows the gloves after losing direct contact, where the non-wetting (structured) glove does not transfer the contaminated source and microorganisms from the surface after de-wetting, in contrast with the standard medical glove, which transfers these materials.

Equivalents

[0119] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:
1. A method of reducing or preventing transfer of a microorganism from a contaminated source to a surface, the method comprising: i) providing an article comprising a protective barrier, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers; ii) contacting the superhydrophobic surface of the protective barrier with a
contaminated source comprising at least one microorganism, wherein the contaminated source is dewetted from the protective barrier to provide a substantially sterile superhydrophobic surface; and iii) subsequently contacting the article with a surface, wherein transfer of a
microorganism from the contaminated source to the surface is reduced or prevented.
2. A method of reducing or preventing transfer of a microorganism from a protective barrier to a surface, the method comprising: i) providing an article comprising a protective barrier comprising a
microorganism, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers; ii) contacting the protective barrier with a liquid such that the liquid also contacts the microorganism, the liquid is dewetted from the protective barrier, thereby removing the microorganism from the protective barrier to provide a substantially sterile surface; and ii) subsequently contacting the article with a surface, wherein transfer of a
microorganism from the article to the surface is reduced or prevented.
3. An article comprising a protective barrier, wherein the protective barrier comprises a superhydrophobic surface comprising a plurality of raised structures on a face of the protective barrier, the raised structures defined by interstructure spacing, width at their basal ends, and width at their distal ends and wherein the distal widths are less than about 50 micrometers.
4. The method or article of any of the preceding claims, wherein said distal widths are less than about 20 μιη, less than about 5 μιη, less than about 2 μιη, less than about 1.5 μιη, or less than about 1 μιη.
5. The method or article of claim 4, wherein said distal widths are between about 10 nm and about 5 μιη, between about 50 nm and about 5 μιη, between about 100 nm and about 2 μιη, between about 150 nm and about 1.5 μιη, or between about 1.5 μιη and about 2 μιη.
6. The method or article of claim 5, wherein said distal widths are greater than or equal to about 50 nm and less than about 5 μιη, greater than or equal to about 100 nm and less than about 2 μιη, greater than or equal to about 500 nm and less than about 2 μιη , greater than or equal to about 1 μιη and less than about 2 μιη, or greater than or equal to about 1.5 μιη and less than about 2 μιη.
7. The method or article of claim 6, wherein said distal widths are greater than or equal to about 1.5 μιη and less than about 2 μιη.
8. The method or article of any of the preceding claims, wherein the interstructure spacings are between about 10 nm and about 5 μιη, between about 10 nm and about 500 nm, between about 50 nm and about 450 nm, between about 10 nm and less than about 500 nm, between about between about 100 nm and about 2 μιη, between about 150 nm and about 1.5 μιη, between about 500 nm and about 1 μιη, between about 500 nm and about 1.5 μιη, between about 1 μιη and about 1.5 μιη, between about 1 μιη and about 2 μιη, or between about 1.5 μιη and about 2 μιη.
9. The method or article of any of the preceding claims, wherein said distal widths are between about 10 nm and about 5 μιη and said interstructure spacings are between about 50 nm and about 5 μιη.
10. The method or article of claim 9, wherein said distal widths are greater than or equal to about 1.5 μιη and less than about 2 μιη and said interstructure spacings are between about 10 nm and about 1 μιη.
11. The method or article of claim 10, wherein said interstructure spacings are between about 10 nm and less than about 500 nm.
12. The method or article of claim 11, wherein said interstructure spacings are between about 50 nm and about 450 nm.
13. The method or article of any of the preceding claims, wherein said raised structures are fluorinated.
14. The method or article of any of the preceding claims, wherein said protective barrier has a contact angle in the range of about 140° to about 180°.
15. The method or article of any of the preceding claims, wherein the basal width is greater than the distal width.
16. The method or article of any of the preceding claims, wherein said distal widths are selected to be less than three times the largest dimension of the microorganism in that contacts the article.
17. The method or article of any of the preceding claims, wherein said raised structures are posts.
18. The method or article of any of claims 1 - 16, wherein said raised structures define channels, grooves or closed-cell structures, which are optionally round-bottomed.
19. The method or article of claim 18, wherein said raised structures define closed-cell structures, and said closed-cell structures are honeycombs or bricks.
20. The method or article any of the preceding claims, wherein said interstructure spacings are less than about 5 μιη; and said interstructure spacings are selected to be less than the largest dimension of said microorganism.
21. The method or article of any of the preceding claims, wherein the microorganism is a bacterium, virus or fungus.
22. The method or article of any of the preceding claims, wherein the protective barrier contacts the contaminated liquid or the surface for less than about 5 minutes.
23. The method or article of any of the preceding claims, wherein the article comprises a medical device.
24. The method or article of claim 23, wherein the medical device is selected from the group consisting of gloves, clamps, forceps, scissors, skin hooks, tubing, needles, retractors, scalers, drills, chisels, rasps, saws, catheters including indwelling catheter, catheter components, orthopedic devices, artificial heart valves, prosthetic joints, voice prostheses, stents, shunts, pacemakers, surgical pins, respirators, ventilators, and endoscopes.
25. The method or article of any of the preceding claims, wherein the article comprises a glove.
26. The method or article of claim 25, wherein the glove is disposable.
27. The method or article of claim 25, wherein at least a portion of at least one exterior fingertip or finger pad or thumbtip or thumb pad comprises a protective barrier.
28. The method or article of claim 25, wherein at least one exterior face of the glove comprises a protective barrier.
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