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EP2806905A2 - Textures superficielles biosélectives - Google Patents

Textures superficielles biosélectives

Info

Publication number
EP2806905A2
EP2806905A2 EP13702696.9A EP13702696A EP2806905A2 EP 2806905 A2 EP2806905 A2 EP 2806905A2 EP 13702696 A EP13702696 A EP 13702696A EP 2806905 A2 EP2806905 A2 EP 2806905A2
Authority
EP
European Patent Office
Prior art keywords
medical device
tissue
implantable medical
surface texture
texture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP13702696.9A
Other languages
German (de)
English (en)
Inventor
Lukas Bluecher
Michael Milbocker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bvw Invest Ag
Original Assignee
BVW Holding AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BVW Holding AG filed Critical BVW Holding AG
Publication of EP2806905A2 publication Critical patent/EP2806905A2/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth

Definitions

  • the present disclosure provides implantable medical devices comprising surface textures on a substrate that, upon implantation in a host tissue, create interfaces with liquids present in the host tissue.
  • the implants in certain embodiments advantageously prevent or reduce undesirable tissue adhesion, bacterial growth and/or biofllm formation while promoting the attachment or ingrowth of desired host tissue.
  • a hydrophobic surface repels water.
  • the hydrophobicity of a surface can be measured, for example, by determining the contact angle of a drop of water on a surface.
  • the contact angle can be measured in a static state or in a dynamic state.
  • a dynamic contact angle measurement can include determining an advancing contact angle or a receding contact angle with respect to an adherent species such as a water drop.
  • a hydrophobic surface having a small difference between advancing and receding contact angles i.e., low contact angle hysteresis presents clinically desirable properties.
  • red rose petal with a hierarchical structure of convex cell papillae ornamented with circumferentially arranged and axially directed ridges, which have a moderate contact angle and high angular contact difference.
  • the contact angle is a measure of the amount of water directly in contact with the implant surface, while the contact angle hysteresis is a measure of the degree to which water is mobile on a surface.
  • the evolutionary motivation for each of these states is quite distinct. In the case of lotus, and botanical leaves generally, minimal contact with water and high water mobility results in preferential adherence of the water to particulate contaminants, which are cleared from the leave as the water runs off. This serves to reduce to the amount of light absorbance by surface contaminants, and increase photosynthetic efficiency. In the case of the rose petal, and botanical petals generally, most pollinators are attracted to high tension water sources which provide ready accessibility without drowning the insect. Thus, high contact angle paired with high contact angle hysteresis is preferred where the evolutionary stimulus is reproduction in botanicals, and high contact angle paired with low contact angle hysteresis is preferred where the evolutionary stimulus is metabolism and growth.
  • the methods and embodiments of the disclosure are applicable to absorbable and permanent implantable materials, where absorbable materials are preferred.
  • the materials can be used in implantable medical devices.
  • One embodiment of the disclosure provides an implantable medical device comprising at least two surface textures on a substrate, wherein upon implantation in a host tissue the surface textures form interfaces with liquids present in the host tissue, wherein a first surface texture traps air between the device and the tissue to form a first interface; and a second surface texture does not trap air between the device and the host tissue to form a second interface; wherein the interfaces have a contact hysteresis angle of at least 5 degrees.
  • the disclosure further relates to physiologically absorbable, non-fibrogenic, hydrophilic materials that are made relatively hydrophobic during a first time interval by the addition of surface texture.
  • the disclosure relates to physiologically absorbable, generally fibrogenic, hydrophobic materials that are made relatively hydrophilic during a first interval by the addition of surface texture.
  • the disclosure relates to implantable, absorbable sheets which are hydrophilic, and possibly swell or even dissolve in situ, whereby the addition of a hydrophobic surface texture reduces the rate of absorption or conformal change in situ.
  • the disclosure relates to hydrophobic implantable sheets that do not absorb quickly in the body, which are made to absorb more quickly with the addition of a hydrophilic surface texture.
  • the disclosure relates to implantable devices comprising surface textures which favor one substance or living structure within a mammalian body over another substance or living structure.
  • a surface filtering effect can be achieved with the devices described herein, wherein a first substance or structure is brought into more intimate contact with the implant than another substance or structure.
  • the intimacy level is characterized by the spatial scale of interactions.
  • the disclosure describes a surface filter effect wherein one species characterized by scale or polarity is excluded and another species characterized by scale or polarity is attracted, or both are excluded, or both are attracted, on the same side or on opposite sides of a sheet implant.
  • an implant may comprise a side in which bacteria are excluded and a component of tissue is attracted and on the other side bacteria are excluded and a component of tissue is excluded.
  • the present disclosure further provides implantable materials comprising textures that initially create Cassie and Wenzel states when exposed to an aqueous environment in a mammalian body.
  • implantable materials comprised of textures that after a period of time create analogs to Wenzel and Cassie states that include a solid hydrophilic phase, a liquid hydrophobic phase, and a liquid hydrophilic phase.
  • the trapped phase analogous to the classical gaseous phase is the liquid hydrophobic phase.
  • implantable materials comprised of textures that later replace a gaseous with a liquid hydrophobic phase.
  • the disclosure provides implantable, absorbable sheets comprising a hydrophilic substrate that can possibly swell or even dissolve in the host tissue, whereby the addition of a hydrophobic surface texture reduces the rate of absorption or conformal change in the host tissue.
  • the disclosure further provides implantable absorbable sheets comprising a hydrophobic substrate that does not absorb quickly in a body and that can be made to absorb quickly with the addition of a hydrophilic surface texture.
  • the dominance of Wenzel over Cassie states, or the converse, or their analogues can evolve as a function of time as the outer surfaces of the device are removed by hydrolysis or enzymatic degradation in the host tissue.
  • a filter effect is created and one species characterized by scale or polarity is excluded and another species characterized by scale or polarity is attracted, or both are excluded, or both are attracted, on the same side or on opposite sides of the implant.
  • a first side excludes a first component of tissue and a second component of tissue is attracted and wherein a second side excludes bacteria and a component of tissue is excluded.
  • the rate of the first surface texture absorbance is chosen to mitigate tissue adhesion and bacterial colonization, especially biofilm formation in a first time interval, and to becomes a smooth, hydrophilic, rapidly absorbing and non-fibrogenic material in a second time interval.
  • accentuation of surface charge and surface energy of the substrate occurs such that water is always bonded to the substrate surface, even though any particular water molecule may have a short residence time on the surface.
  • the surfaces of the implantable medical device are both shielded from protein adhesion and also self-washing due to stochastic
  • a folding or rolling effect on bacterial colonies is induced, such that the external biofilm layer encapsulates and excludes the evolving bacterial colony from the surface of the medical device.
  • FIG. 1 General view of an implantable prosthetic of the present disclosure possessing a hierarchical surface.
  • FIG. 2c Schematic of minimum communication structure C - 0.
  • FIG. 3a,b A method of manufacture of an implantable prosthetic of the present disclosure.
  • FIG. 4 Example of Sierpinski gasket surface texture.
  • FIG. 5 Example of Apollonian gasket surface texture.
  • FIG. 6 Example of diffusion limited aggregation surface texture.
  • FIG. 7. Example of Kock snowflake surface texture.
  • FIG. 8 Example of an absorbable hydophilic implantable made hydrophobic to reduce a foreign body response.
  • FIG. 9 Example of an absorbable hydrophilic implantable made hydrophobic to reduce the rate of absorption.
  • FIG. 10 Example of an absorbable hydrophobic implantable made hydrophilic to reduce a foreign body response.
  • FIG. 11 Example of an absorbable hydrophobic implantable made hydrophilic to increase the rate of absorption.
  • FIG. 13 Example of an implantable with at least one side immediately tissue adhesive,
  • FIG. 14 Example of an implantable with cell type filter effect surface.
  • FIG. 15 Example of an implantable with a tissue type filter effect surface.
  • FIG. 16 Example of an implantable with a bacterial adhesion resistance.
  • the present disclosure provides an implantable medical device comprising at least two surface textures on a substrate, wherein upon implantation in a host tissue the surface textures form interfaces with liquids present in the host tissue, wherein a first surface texture traps air between the device and the tissue to form a first interface; and a second surface texture does not trap air between the device and the host tissue to form a second interface; wherein the interfaces have a contact hysteresis angle of at least 5 degrees.
  • the medical devices may comprise the surface texture material, or the medical devices may comprise other materials commonly used in the art having the surface texture material disposed thereon.
  • the surface texture refers to a microscale texture or pattern disposed in the substrate material, for example, as described by the methods described herein below. In particular embodiments ,the surface texture comprises a hierarchical structure.
  • the contact hysteresis angle ranges from at least 5 degrees to about 90 degrees. In other embodiments, the contact hysteresis angle ranges from at least 5 degrees to about 75 degrees, while in further embodiments, the contact angle hysteresis ranges from about 10 degrees to about 75 degrees.
  • the interfaces comprise: a) a solid hydrophilic phase, b) a liquid hydrophobic phase, and c) a liquid hydrophilic phase.
  • the implantable medical device of claim 1 wherein the trapped air is replaced by a liquid hydrophobic phase after a period of time.
  • the period of time may be about 5 minutes to 12 hours, or more particularly, about 5 minutes to about 6 hours, or about 30 minutes to about 6 hours.
  • the surface textures comprise hydrophilic absorbable materials, wherein the hydrophilic absorbable materials are made less hydrophilic by the surface textures, and the surface textures reduce the rate of absorption or conformal change of the medical device in the host tissue.
  • the surface textures comprise hydrophobic absorbable materials, wherein the hydrophobic absorbable materials are made less hydrophobic by the surface textures, and the surface textures increase a rate of absorption or conformal change of the medical device in the host tissue.
  • At least one surface texture comprises absorbable materials, wherein the at least one surface texture is modified by absorption, such that the at least one surface texture becomes more wetting or less wetting as the medical device is absorbed.
  • the surface textures have a rate of absorbance in the host tissue that mitigates tissue adhesion, bacterial colonization, and/or biofilm formation during a first time interval, and wherein the surface textures become a smooth, hydrophilic, rapidly absorbing and non-fibrogenic material during a second time interval.
  • a first time interval may range from about 5 minutes to about 6 hours, or about 10 minutes to about 6 hours, about 10 minutes to about 3 hours, or about 10 minutes to about 30 minutes
  • a second time interval may range from about 30 minutes to about 12 hours, about 30 minutes to about 6 hours, about 1 hour to about 6 hours or about 3 hour to about 6 hours.
  • At least one surface texture comprises a smaller pitch of
  • the smaller surface textures traps the air, while the larger surface texture does not trap air.
  • the larger surface texture traps air and the smaller surface texture does not trap air.
  • the interfaces thus formed depend in part on the pitch size, the pattern of the texture, and/or the substrate material used to prepare the surface texture, as described in more detail hereinbelow.
  • the first interface excludes attachment of a first host derived substance and the second interface promotes attachment of a second host derived substance.
  • the first host derived substance may be a microbe and the second host derived substance may be host cells.
  • the first host derived substance is a protein and the second host derived substance is host tissue.
  • the first host derived substance is a host tissue and the second host derived substance is endothelial cells.
  • a surface charge of at least one surface texture increases such that water is more strongly bonded to the substrate surface, but not so strongly bonded so as to preclude exchange of water molecules bonded to said substrate surface with surrounding water in the host tissue.
  • a layer of water may adhere to the surface of the device and said water layer reduces the rate of protein molecule adsorption to said textured surface, relative to a device comprised of said substrate without surface texture.
  • a layer of water may adhere to the surface textures of the device, such that the water layer reduces a rate of protein molecule adsorption to the textured surface, relative to a device without the surface textures.
  • the substrate is porous.
  • the substrate may comprise three dimensionally interconnected pores.
  • the first surface texture forms a Cassie state when implanted in host tissue and the second surface texture forms a Wenzel state when implanted in host tissue.
  • at least one of the surface textures comprises fibers embedded in and protruding from the substrate, and the fibers are bifurcated at least once on at least one spatial scale different from a pitch of other surface textures of the device.
  • at least one of said surface textures is comprised of fibers embedded at both ends in said substrate and said fiber and protrude from said substrate, and said fibers form loops with at least one diameter different from the pitch of other surface textures of the medical device.
  • the surface textures may comprise or be similar to certain mathematical fractal shapes.
  • at least one surface texture comprises a Koch snowfiake pattern, a Sierpinski gasket pattern, Apollonian gasket pattern, or a diffusion limited aggregation pattern.
  • the aforementioned implantable medical devices comprises two sides, such as a sheet structure, wherein the two sides have different surface texture patterns.
  • the surface textures form interfaces with liquids present in host tissue, wherein at least one surface texture traps air between the device and tissue and at least one other surface texture does not trap air between the device and tissue, and wherein the resulting interfaces generate a contact hysteresis angle of at least 5 degrees on one side (for example, the contact angle hysteresis can be at least 5 degrees to about 90 degrees, at least 5 degrees to about 75 degrees, or about 10 degrees to about 75 degrees), and less than 5 degrees (for example, an angle of about 0.1 to less than 5 degrees, or more particular, about 0.5 to less than 5 degrees, or more particularly, about 0.5 to about 3 degrees) on the other side of the device.
  • a typically hydrophilic material can be rendered more hydrophobic by the addition of surface structure, but such addition does not require the surface to be superhydrophobic, by the usual definitions.
  • the contact angle for a water droplet on a smooth surface is dictated by the electronic structure of the molecules comprising the smooth surface.
  • the highest contact angle due to electronic structure alone is approximately 120 degrees.
  • High surface energy substances tend to reduce the contact angle with a polar substance such as water.
  • Water when not in contact with a solid, is in its lowest energy state when it is in the shape of a sphere.
  • Lower surface area equates with lower surface energy, and for a given volume a sphere corresponds to the shape with minimum surface area.
  • a solid with low surface energy will not cause water to spread across its surface (increase its surface area) because the increase in energy needed to spread the water across the solid exceeds the available energy at the solid surface.
  • Molecules comprised of fluorine and carbon atoms typically have some of the lowest surface energies, for example, CF 3 groups have a low surface energy of 6.7 mJ/m2. Surfaces with lower surface energy are defined as superhydrophobic, with a water contact angle greater than 150 degrees. To achieve these high contact angles the solid surface must be textured.
  • the present disclosure employs hydrophilic materials with high surface energy that are made more hydrophobic (but typically not superhydrophobic) and less prone to bacterial colonization by employing hierarchical surface texture.
  • Os-g, Dl-s, and Dl-g represent the interfacial tensions of solid-gas, s-g, liquid-solid l-s, and liquid-gas, l-g interfaces, respectively.
  • a characterization of the Wenzel state can be obtained by generalizing the Young equation. To do so, we define an apparent contact angle Da, and relate Da to Dy by
  • r is termed the "roughness factor” and is defined as the ratio of the actual area of contact on a rough surface to the projected area of contact in the contact plane.
  • a characterization of the Cassie state can be obtained by generalizing the Young equation. To do so, we relate the apparent contact angle Da to Dy the apparent contact angle in the Cassie state is given by
  • contact angle hysteresis is defined here as the difference between association and disassociation contact angles. This hysteresis occurs due to the wide range of "metastable" states which can be observed as the liquid surface tension interacts with the surface of a solid at the phase interface.
  • the present disclosure discloses an implant that is absorbable, resistant to bacterial colonization, and is reversibly adhesive to tissue.
  • the adhesive aspect of a Cassie wettable state is one in which the energy to associate water with a surface is less than the energy required to disassociate that interface, even in cases where the overall surface energy is quite low (high contact angle).
  • the contact angle hysteresis is achieved by allowing one scale of roughness to be Wenzel and another scale of roughness to be Cassie. This condition is known as the "petal effect”.
  • 0a the apparent angle
  • Ql and Q2 represent the fraction of the surface covered by liquid/solid interface for each of the roughness scales characterized by contact angles ⁇ 1 and ⁇ 2.
  • ⁇ 1- ⁇ 2 is large (contact angle hysteresis)
  • 0a characterizes a petal effect and is generally adhesive.
  • 9a characterizes a lotus effect and is generally repulsive.
  • the contact angle is determined by both a) the hydrophobicity/hydrophilicity (surface electronic structure) of the substance comprising the surface and b) its texture.
  • the above equation assumes the solid surface is comprised of a single substance and represents only the hierarchical structure of the surface texture.
  • This equation is critical to the design of the implants of the present disclosure.
  • the surface of a solid is modified by relatively amphiphilic aqueous constituents.
  • the implant/tissue interfacial tension can be modified by amphiphilic constituent addition caused by the adsorption of amphiphilic proteins onto the implant and can be described by the Gibbs adsorption equation, which relates the surface excess concentration Ds to the interfacial tension ⁇ by
  • c p is the surface protein concentration
  • T is temperature
  • A3 ⁇ 4 is the Boltzmann constant
  • the present disclosure is directed to adapting the surface texture effects resulting in Wenzel and Cassie states under implant conditions, in particular, the adaptation of petal and lotus effects, and in particular wettable Cassie and dry Wenzel states, to an implant environment. Therefore, except where polymers are used which actively entrap a gas state on an implant surface, such as fluorocarbons, a gas state cannot be relied upon to create the desired in vivo states.
  • Biological fluids are far from homogeneous, and comprise discrete hydrophilic and hydrophobic components, suspended macromolecules, and several size scales of sub-cellular, cellular, and tissue structures.
  • the present disclosure teaches methods and devices which use surface texture induced states to organize constituents of a liquid biologic medium. These methods comprise the use of scale hierarchical surface geometry, scale hierarchical surface regions,
  • spatially hierarchical surfaces as regards their geometry, that is ones that are linearly and fractally arranged in a scale ranging from tens of micrometers down to several nanometers. Considering that only the outermost portions of individual hierarchic levels are wetted (contact water), such structures should be characterized by a very small surface of effective contact between the solid and bodily aqueous fluids, even below 1% of the coating surface.
  • the percentage of water association is critical, and not the absolute value of the amount of water association, such that at various fine scales the amount of water interaction with the surface may be very small but the clinical consequence could be great relative to the percentage of water at that particular scale which is interacting with the surface structure.
  • lipid constituents are preferentially attracted, particularly tissue constituents, which replace the regions occupied by air.
  • one embodiment of the present disclosure produces a dramatic reduction in surface area available for microbial attachment and foreign body response.
  • the result is that the film acts as a low energy surface which is energetically disfavored for protein attachment and microbial colonization.
  • one side of an implantable sheet can possess a Cassie wettable state for localizing the implant to tissue, and the other side can possess a pure Cassie state for resisting tissue adhesions.
  • the substrate material may have on one side a layer which is relatively rapidly absorbable and hydrophilic and on the other side is a layer which is relatively slowly absorbable and hydrophobic such that the texture on the two sides produce a Cassie wettable state on one side and a superhydrophobic pure Cassie state on the other side.
  • the tissue adhesive surfaces of the present disclosure bind to tissue spontaneously in the presence of water.
  • hydrophobic bonding is based on very-long-range attractive forces. These forces are due to lipid separation resulting in a phase-like transition in bodily fluid present at an implant site. This change is characterized by a sudden, strong attractive force and by the formation of lipid bridges. In contradistinction, implantables with long-range attractive forces are described.
  • such attractive forces between a textured implant surface and tissue are employed to (reversibly) bind an implant to a surgical site.
  • the surface texture of an implant may be chosen to induce a filtering effect, wherein certain molecules, cellular structures, or tissue components are attracted while others are repelled, and this attractive/repulsive effect varies across different surface texture spatial scales.
  • This filter effect can be employed to produce local separation of normally homogenous in vivo constituents wherein the separation occurs at different levels of the implant surface.
  • the surfaces of the present disclosure be they pure Cassie, pure Wenzel or
  • Cassie wettable, or analogues possess low surface energy, and the affinity of bacteria to bind to tissue or themselves is energetically favored over binding to the implant surface. More particularly, if microbes should colonize the implant surface the spreading of a protective biofilm is energetically disfavored. Consequently, an evolving biofilm would tend to take on a spherical shape, which turns the biofilm surface to encapsulate the bacterial colony and decrease the contact area with the implant surface.
  • the implant produces a folding or rolling effect on bacterial colonies, such that the external biofilm layer encapsulates and excludes the evolving bacterial colony.
  • the present patent introduces the concept of using structured surfaces consisting of non-communicating (closed cell) roughness elements to prevent the transition of a water droplet from the Cassie to the Wenzel state.
  • the resistance to the Cassie-Wenzel transition can be further increased by utilizing surfaces with nanostructured (instead of micro-structured) non- communicating elements, since the resistance is inversely related to the dimension of the roughness element.
  • One aspect of some embodiments of the present disclosure are dimpled or impressed surfaces that offer increased resistance to droplet transition to the Wenzel state compared to a dimensionally equivalent pillared surface.
  • the presence of air trapped inside the non-communicating craters and the resistance to fluid motion offered by the crater boundaries and corners are two sources of this increased resistance to the transition to a Wenzel state and enhance adhesiveness in vivo.
  • the impressed or concave textured surfaces of the present disclosure preferably possess a fractal structure or hierarchic structure wherein the forms of the first hierarchic level are located next to the coating substrate and the forms of each successive level are located on the surface of forms of the previous hierarchic level and the shape of forms of higher hierarchic levels reiterate the shapes of lower hierarchical levels and the structure contains forms of at least two hierarchical impressions.
  • the substrate of the biocompatible implants of the present disclosure are polymeric materials with possibly one or more nano-scale textures with dimensional spacing of 10 to several thousand nanometers and at least one micro-scale texture with dimensional spacing of 10 to about 100 microns.
  • the polymeric material is preferably heat meltable without decomposition or soluble in a solvent, so that the texture may be embossed in the melt state or cast in the solvent state.
  • texture refers to topographical and porosity elements, including elevations and depressions on the surface and mass distribution in the volume of a polymeric surface and of the layer comprising the surface.
  • the polymeric layer may be made of multiple polymer types, and may contain other material being embedded in the polymer and contributing to the topography,
  • non-polymeric or polymeric fibers or particulate may be dispersed on the surface of the polymer substrate, which matrix by itself may comprise more phases or components.
  • components with absorption rates in a mammalian body slower than the bulk polymer such that a desired texture is preserved for an extended period during the dissolution process.
  • these slower absorbing elements are embedded in the polymeric substrate homogeneously or on several levels such that several different topologies are presented during the course of dissolution.
  • the textured implants of this disclosure can have many variants and
  • the implant can have a homogenous bulk composition wherein grooves, ridges, protuberances or indentations are located, on at least two spatial scales, on the surface of implant.
  • the implant can have a porous substrate with three dimensionally interconnected pores.
  • the implant can have a solid substrate with interconnected channels or non-interconnected indentations on the implant surface.
  • the implant can have a first small scale texture embossed on a second larger scale structure, or a hierarchical arrangement of such scales.
  • the implant can have a first small scale texture that is concave and non-communicating embossed on a second larger scale structure that is convex and
  • the implant can have a first small scale texture that is Cassie embossed on a second larger scale structure that is Wenzel, or the reverse.
  • the implant can have grooves or ridges deployed in a step-like contour on larger scale convex protuberances.
  • the implant can have a semi-open structure wherein hierarchical texture is located on cross elements, such that the semi-open structure itself comprises a texture.
  • the implant can have fibers imbedded and protruding from the polymer substrate, said fibers can be bifurcated on a number of spatial scales in the manner of the fibers disposed on a Gecko foot.
  • the implant can have fibers attached by both ends in the polymeric substrate, thus determining loops, the radius of said loops of at least two length scales. The implant of any combination of the above.
  • a scale of interaction is defined by the surface texture of the implantable device, and is typically hierarchical, and characterized by at least two spatial scales, one on the order of micrometers (microns) and another on the order of nanometers.
  • the surface texture may induce one state with a large difference between preceding and receding contact angles (contact angle hysteresis), or alternatively another state with a small contact angle hysteresis.
  • States of interest, or their in situ analogues are known respectively as Wenzel and Cassie states.
  • Each of the hierarchical spatial scales may induce separately a Wenzel or Cassie state, such that combinations are possible on a multiplicity of spatial scales.
  • the present disclosure relates to implantable materials comprised of textures that initially create Cassie and Wenzel states when exposed to an aqueous environment in a mammalian body. These states evolve in situ, and their evolution analogues differ from typical Wenzel and Cassie states in that they involve a solid hydrophilic phase, a liquid hydrophobic phase, and a liquid hydrophilic phase or a solid hydrophobic phase, a liquid hydrophilic phase, and a liquid hydrophobic phase.
  • the trapped phase analogous to the classical gaseous phase is the liquid hydrophobic phase.
  • a trapped gaseous phase is preferentially replaced by a liquid hydrophobic phase.
  • Wenzel state the implant is reversibly adherent to tissue.
  • the implant In hybrid Cassie-Wenzel states, where one texture scale is Wenzel and the other is Cassie, the implant can be both localizing to a tissue surface and resistant to bacterial colonization and tissue adhesions. Opposite sides of an implant may be biased toward tissue localization on one side and resistance to tissue adhesion on the other side, while both sides may exhibit both properties to greater or lesser extent.
  • the dominance of Wenzel over Cassie, or the converse can evolve as a function of time as the outer surfaces are removed by hydrolysis or enzymatic degradation.
  • the spatial frequency of the various structure scales may be modulated at various implant depths, presenting a changing spatial frequency as the surface layers of the implant are removed.
  • the surface texture may be chosen to present to tissue on one side of the implant a high surface area relative to a second side with low surface area.
  • the surface texture may be chosen to modulate the hydrophobicity of a single implant material to control water absorbance, biodegradation, and drug elution differentially relative to regions or whole sides of the implant.
  • the rate of surface texture absorbance is chosen to mitigate tissue adhesion and bacterial colonization, especially biofilm formation in a first time interval and to reduce to a smooth, hydrophilic, rapidly absorbing and non-fibrogenic material in a second time interval.
  • the Wenzel state has the lower contact angle, higher contact angle hysteresis and lower mobility.
  • mixed Wenzel-Cassie states it is possible to have high contact angle and high contact angle hysteresis.
  • the hydrophobicity of a textured solid relative to the interacting liquid is very important.
  • Water possesses a dipole structure which makes it attractive to any other substance that is charged.
  • Implantable molecules with a charge surplus localized at a specific location on the molecule renders that molecule hydrophilic.
  • the charges can associate, and the bulk substance and possess a macroscopic charge. And in such macroscopic assemblages, such materials are strongly water attractive. And when those macroscopic charge localities are associated with surface texture, than a substance becomes super hydrophilic.
  • super hydrophilic has various meanings in the literature, and in many cases simply refers to the rendering of a substance more hydrophilic, or a decrease in contact angle relative to a flat surface of the same substance.
  • implant surface is both shielded from protein adhesion and also is self-washing due to the stochastic attachment/detachment of water molecules from the surface.
  • Gas in living tissue is not compatible with living cells, gas surrounding an implant effectively shields the implant from cellular attachment, and in most cases blocks a foreign body response by blocking the adsorption of signaling proteins.
  • gas surrounding an implant effectively shields the implant from cellular attachment, and in most cases blocks a foreign body response by blocking the adsorption of signaling proteins.
  • a chemically inert material if cells cannot deposit protein on an implant to mark it as a foreign body the body does not react to the implant. This results in low inflammation, low fibrosis and minimal encapsulation. In this case, fibrosis is largely due to surgical disruption of tissue and mechanical disruption of tissue subsequent to closure. Consequently, to maintain a benign implant condition, the implant must be inert, non-adhesive to cellular protein deposition, and be relatively well localized so that differential motion between implant and tissue does not occur.
  • a hydrophobic substance is a material with low surface energy. Cells attach to surfaces by reducing the surface energy of a material. High surface energy of a material causes cells to stick to a foreign body. On the other hand, a higher surface energy energetically favors water association over protein association. Thus, maximally biocompatible substances tend to be those that are either superhydrophobic or super hydrophilic. Intermediate or even amphiphilic conditions are more typical in vivo, and cellular mechanism have evolved to identify, and eliminate foreign bodies with such properties, resulting in an undesirable foreign body response.
  • the magnitude of the surface energy reduction is proportional to the magnitude of the adhesive strength between foreign body and deposited protein and associated cell.
  • the protein changes shape, it may or may not be bound to the foreign body surface, but once it has changed shape it in turn becomes a foreign body, signaling a cascade of responses, chief among them the release of reactive oxygen species, which then can significantly change the charge structure of the implant surface.
  • proteins are strongly denatured by hydrophobic surfaces. This is because proteins typically carry a charge that relates to its conformal state. Once a protein is denatured, it folds, and is seen as foreign, even though it may be only weakly attached to the foreign body. This can precipitate a sequence of cellular assaults that include macrophages, giant cells, histiocytes and any of the mononuclear phagocyte system, which begin to charge the foreign surface, preparing it for adhesion and encapsulation. If the implant surface is absorbable, the remodeling of the implant surface results in a prolonged attack by oxidizing species and resulting dense fibrosis.
  • Micro-layers of gas are ideal insulators from a foreign body response because from an evolutionary perspective, gas is almost never in the body and thus cellular mechanisms to ostracize it were never developed. This is primarily due to the fact that gas does not remain long in the gas phase in the body, and readily absorbs into fluids or is metabolized. Important in maintaining the Cassie-like state, is the replacement of gas by a similarly electronically structured constituent.
  • a particularly stable fluid readily found in the body is lipids.
  • Lipids are moderately hydrophobic and present an ever-changing surface, so protein attachment is inhibited.
  • Lipids also do not denature protein, since lipids are commonly found in the body, especially if such lipids are recruited from the body's own cellular environment.
  • lipids do not allow for the conductance of cells to the underlying implant surface.
  • Typical methods of converting material surfaces to become superhydrophobic include, for example: 1) Etching the existing surface to create specific nano-patterns (patterns which are in the nanometer size range), and subsequently coating the surface with a hydrophobic coating. 2) Roughening the substrate surface using techniques known in the art, and functionalizing the resulting surface by applying a hydrophobic coating. 3) Growing a rough (or porous) film from solutions containing nano-particles or polymers in a way which creates a rough and hydrophobic surface on the material. 5) Vapor deposition of carbon nano-rods on a substrate. 6) Lithography of a silicon substrate, or laser ablation of a polymeric substrate, and 7) Electro-spun fibers deposited on a substrate.
  • protuberance refers to any higher structure on a macroscopically planar surface and “depression” refers to any lower structure on a macroscopically planar surface.
  • protuberances and depressions are paired with respect to a specific spatial scale, and reported dimensions thereof are made pair- wise. For example, when a protuberance is reported to be 100 microns in height, that dimension is measured with respect to a near-by depression. In engineering parlance, the measurement is made peak to trough. Lateral measurements are typically made peak to peak or trough to trough, and are referred to as the pitch.
  • an implantable prosthetic 100 of the present disclosure possesses a hierarchical surface comprised of a micro-scale structure 102 with a plurality of protuberances 104 and depressions 106 disposed in a geometric pattern on at least one surface of a substrate 108, and a nano-scale structure 110 disposed on at least one surface of the micro-level structure 102.
  • the nano-scale structure 110 is similarly comprised of protuberances 112 and depressions 114.
  • the micro-scale protuberances 104 should be high enough so that a water drop does not touch the micro-scale depressions between adjacent protuberances 104.
  • the micro-scale protuberances 104 may comprise a height H of between about 1 to about 100 microns and a diameter D of between about 1 to about 50 microns, wherein the fraction of the surface area of the substrate 108 covered by the protuberances 104 may range from between about 0.1 to about 0.9.
  • the nano-scale protuberances 1 12 may comprise a height h of between 1 nanometer to about 1 micron and a diameter d of between 1 nanometer to about 0.5 microns, wherein the fraction of the surface area of the substrate 108 covered by the
  • protuberances 112 may range from between about 0.1 to about 0.9.
  • the nano-scale structure 1 10 may be disposed primarily on the micro-scale protuberances 104, or alternatively primarily on the micro-scale depressions 106, or primarily uniformly across micro-scale structure 1 10.
  • the pitch P between adjacent micro-scale protuberances 104 or depressions 106 may range from between about 1 and about 500 microns.
  • the pitch p between adjacent nano- scale protuberances 112 or depressions 114 may range from between 1 nanometer and about 1 micron.
  • the arrangement of hierarchical structures may be geometric or describable generally with a mathematical equation.
  • the hierarchical structures may be randomly disposed, possibly with varying pitch, which is more typical of natural structures.
  • the arrangement of hierarchical structure can generally be described by a fractal dimension, F.
  • a fractal dimension is a statistical quantity that gives an indication of how completely a collection of structures appears to fill space, in the present case a plane, as one examines that structure on a multiplicity of spatial scales. For example, a fractal dimension of 1 describes a pure geometric line and a fractal dimension of 2 describes a plane, and so on.
  • Specifying a fractal dimension which is statistical in nature, does not necessarily indicate that the hierarchical structure is well defined by a mathematical equation.
  • a random arrangement of structures within a specific scale possesses a higher fractal dimension than one in which the structure is mathematically described at all points on a surface.
  • a random structure may possess an advantage in the aspect that a synthetic structure of the present disclosure has greater utility when interacting with a natural surface such as tissue.
  • a higher fractal dimension within a specific spatial scale may be achieved by applying to a substrate multiple pitch arrangements. The protuberances and depressions may be locally scaled with respect to the local pitch.
  • the pitch may vary within a scale structure.
  • the variation of the pitch may be describable by a mathematical equation, for example, a sinusoidal variation of pitch, which would have utility in mimicking natural surfaces.
  • structures can be described as sharp-edged or rounded, and this feature is not typically captured by a fractal dimension.
  • a Fourier decomposition of such structures would provide a fractal-like dimension.
  • a sharp-edged structure would require a greater number of sinusoidal waveforms to describe such a structure in superposition.
  • This corner roundness can be characterized by a radius (R,r), and generally may be different in a direction x relative to a direction y in the plane of the implant.
  • Another structural aspect not addressed by the above descriptive parameters is the degree of communication between structures.
  • communication it is meant that a structure, such as a protuberance or a depression, has a spatial extent greater than the pitch.
  • a valley surrounding a protuberance may be connected to another valley surrounding another protuberance, thus the depressions are said to be communicating whereas the protuberances are not.
  • the communication can vary across the surface of the substrate. The communication may range from 1 to about 1000, more particularly the communication may extend over the entire surface of the substrate.
  • structures of low communication can be constructed for both depressions and protuberances where reference to a flat, non-textured level is made.
  • a texture may be impressed into a flat planar surface wherein some of these textures are protuberances and other textures are depressions, separated by regions of flat planar surface.
  • Structures can be created wherein the depressions possess a high communication ratio and the protuberances possess a low communication ratio, and conversely.
  • Such structures are difficult to create by an etching or casting method, but can readily be created by an embossing method that entails folding of a structure.
  • the Wenzel state can be discouraged by the use of curving communications between structures as opposed to straight line communication. In most cases, higher hydrophobicity equates with lower propensity for a Wenzel transition.
  • the hydrophobicity of a surface is enhanced by the placement of exterior comers around depressions. In some embodiments, this is achieved by the creation of additional pairs of adjacent depression walls that project into and are joined at the interior of the depression. In some embodiments this is achieved by designing an ordered array of depressions of a first hierarchy (examples: triangular, rectangular, pentagonal, or hexagonal shapes, regular or irregular; and further polygonal shapes defined generally by straight line segments). A second feature of smaller size and different hierarchical order is then superimposed on the depression wall of the first pattern.
  • the method employed in creating such a structure may involve first emboss a nano-structure and then secondarily emboss a micro-structure.
  • electronic structure of the substrate may be hydrophobic.
  • Hydrophobic substances suitable for implantation include polyesters made from aliphatic or aromatic dicarboxylic acids and aliphatic and/or aromatic diols, e.g.: polyesters synthesized from aliphatic dialcohols having 2 to 18 carbon atoms, e.g., propanediol, butanediol, hexanediol, and dicarboxylic acids having 3 to 18 carbon atoms, such as adipic acid and decanedicarboxylic acid; polyesters synthesized from bisphenol A and the above mentioned dicarboxylic acids having 3 to 18 carbon atoms; and polyesters synthesized from terephthalic acid, aliphatic dialcohols having 2 to 18 carbon atoms, and dicarboxylic acids having from 3 to 18 carbon atoms.
  • polyesters made from aliphatic or aromatic dicarboxylic acids and aliphatic and/or aromatic diols e.g.: polyesters synthesized from alipha
  • polyesters may optionally be terminated by long-chain monoalcohols having
  • polyesters 4 to 24 carbon atoms, such as 2-ethyl hexanol or octadecanol.
  • the polyesters may be terminated by long-chain monocarboxylic acids having 4 to 24 carbon atoms, such as stearic acid. In most cases, hydrophobicity is reduced by the presence of polar pendant groups, such as hydroxy Is.
  • polymers containing urethane (carbamate) or urea links or combinations of these can be made hydrophobic by varying the number of these links relative to the molecular weight of the amorphous phase backbone, as well as varying the hydrophobicity of the backbone.
  • such polymers are formed by combining diisocyanates with alcohols and/or amines. For example, combining toluene diisocyanate with a diol and a diamine under polymerizing conditions provides a polyurethane/polyurea composition having both urethane linkages and urea linkages.
  • Such materials are typically prepared from the reaction of a diisocyanate and a polymer having a reactive portion (diol, diamine or hydroxyl and amine), and optionally, a chain extender.
  • Suitable diisocyanates include both aromatic and aliphatic diisocyanates.
  • aromatic diisocyanates examples include toluene diisocyanate, 4,4'-diphenylmethane diisocyanate, 3,3'-dimethyl-4,4'-biphenyl diisocyanate, naphthalene diisocyanate and paraphenylene diisocyanate.
  • Suitable aliphatic diisocyanates include, for example, 1,6- hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMDI), trans- 1,4- cyclohexane diisocyanate (CHDI), 1,4-cyclohexane bis(methylene isocyanate) (BDI), 1,3- cyclohexane bis(methylene isocyanate), isophorone diisocyanate (IPDI) and 4,4'- methylenebis(cyclohexyl isocyanate).
  • HDI 1,6- hexamethylene diisocyanate
  • TMDI trimethylhexamethylene diisocyanate
  • CHDI trans- 1,4- cyclohexane diisocyanate
  • BDI 1,4-cyclohexane bis(methylene isocyanate)
  • IPDI isophorone diisocyanate
  • the alcoholic or amine ⁇ containing polymer can be a diol, a diamine or a combination thereof.
  • the diol can be a poly(alkylene)diol, a polyester-based diol, or a polycarbonate diol.
  • poly(alkylene)diol refers to polymers of alkylene glycols such as poly(ethylene)diol, poly(propylene)diol and polytetramethylene ether diol.
  • polyester-based diol refers to a polymer such as ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, 2,2-dimethyl-l,3-propylene, and the like.
  • diester portion of the polymer can also vary.
  • the present disclosure also contemplates the use of succinic acid esters, glutaric acid esters and the like.
  • the polymers of the present disclosure may be combined with biofunctional substances.
  • implants with a texture-induced bacteriostatic functionality may be beneficially augmented by addition of a bacteriocidal group.
  • bacteriocides include silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds, in addition to the clinically useful antibiotics.
  • the methods of manufacture of the implantable prosthetics of the present disclosure include lithography, casting, extrusion/embossing, and any of several methods for transferring a texture to a surface.
  • a preferred method is embossing.
  • a polymeric substance is heated to a molten state and passed through dual rollers, at least one of which contains a negative image of the desired embossed structure.
  • a nano-scale texture 302 is embossed on a formed planar sheet 300, as depicted in FIG. 3a. As depicted in FIG.
  • formed sheet 300 is heated to a malleable but not fluid state and passed through dual rollers 304 possessing a micro-scale texture 306 which impresses an inverse image.
  • the micro-scale texture 306 is large relative to the nano-scale texture 302, thus the impression of the micro-scale texture 306 folds the nano-scale texture 302, making possible involute structures 308 which would ordinarily not be possible with lithography or casting methods.
  • the method depicted in FIG. 3 may be improved by heating from the non-textured side, so that the textured side is cooler and the nano-scale texture is less likely to be deformed by impressing the micro-scale texture over the nano-scale texture.
  • compositions of the present disclosure can comprise, consist of, or consist essentially of the essential elements and limitations of the embodiments described herein, as well as any additional or optional ingredients, components or limitations described herein or otherwise useful in implantable medical devices.
  • variables x and y denote orthogonal coordinates in the plane of a surface of the device or contacting tissue surface.
  • a variable associated with another variable in parentheses denotes the first variable is a function of a second variable, for example F(x) denotes the fractal dimension varies as a function of the spatial dimension x.
  • R,r corner radius, x and y values
  • H(x,y) Asin(x,y), where sin(x,y) can denote any of sin(x) + sin(y), sin(x)sin(y), sin(xy), sin(x
  • step 2 Place a conical protuberance or valley centered on each of the middle segments of step 2
  • the cell at the center of the circle is the location of the seed point. Now pick a square on the perimeter of the grid and place a random function on that square. Randomly, advance the state of the function to one of the four adjacent squares. If this function leaves the implant surface another seed point is started, chosen randomly at the edge. When the function arrives at one of four squares adjacent to the seed point, it stops there forming a cluster of two seed points, each releasing a new function. Continuing in this way, builds an aggregate, illustrated in FIG. 6. Now replace the linear trace with either a protuberance or a valley, generally these structures are inscribed on a larger scale structure of conical protuberances or valleys.
  • hydrophobic effect of hydrophobic materials is the dominant force for folding of globular protein in water.
  • the folding occurs due to relatively hydrophobic side chains on protein molecules.
  • the hydrophobic interaction is characterized in a large entropy gain, which typically results in the release of water molecules from the hydrophobic component with a relatively small enthalpy change.
  • a hydrophilic material possesses a surface texture that induces the hydrophobic effect the second part of the reaction, the release of water, is inhibited by polar interactions between water and the hydrophilic material.
  • a textured surface 800 interfaced with tissue 801 comprises first scale protuberances 802 and second scale protuberances 804.
  • Water layer 806 fills the valleys 808 of the first scale.
  • Air 810 and later lipids 812 surround the second scale features.
  • Proteins 814 interact with the hydrophobic air 810 or lipid 812 tips and fold 816. Protein adsorption is inhibited by reduction of the surface energy of the textured surface 800, since water 806 is strongly held in the valleys 808.
  • EXAMPLE 10 Absorbable hydrophilic implantables made hydrophobic to reduce the rate of absorption
  • the disclosure relates to implantable, absorbable sheets which are hydrophilic, and possibly swell or even dissolve in situ, whereby the addition of a hydrophobic structure reduces the rate of absorption or conformal change in situ.
  • a textured surface 900 interface with tissue 901 comprises first scale depressions 902 and first scale protuberances 903 and second scale depressions 904.
  • Water layer 906 interacts only with ridges 908 formed by the first scale 902 and second scale 904 structures. Air 910 and later lipids 912 surround the second scale features. Thus the surface area presented to water is significantly reduced.
  • the disclosure relates to physiologically absorbable, generally fibrogenic, hydrophobic materials that are made relatively hydrophilic during a first interval by the addition of surface texture. Structures of this type resemble corals.
  • a textured surface 1000 comprises first scale ridges 1002 and orthogonally arranged second scale ridges 1004.
  • Water layer 1006 wicks 1008 first into small scale ridges 1004 which drains 1010 into large scale ridges 1002.
  • the entire implant surface is coated with a thin layer of water, which without the surface texture would have been coated by protein.
  • EXAMPLE 12 Absorbable hydrophobic implantables made hydrophilic to increase the rate of absorption
  • a textured surface 1100 interacting with tissue 1001 comprises first scale pillars 1102 and between these second scale pillars 1104.
  • the first scale pillars form spaces 1 106 which induce a capillary effect 1 108, and actively draw water 1108 into the spaces 1 106 as the implant material dissolves into the water 11 10.
  • the second scale pillars 1104 form smaller spaces 1112 that further drive water 1 114 deeper into the substrate. Hence, the surface area in contact with water is significantly increased.
  • EXAMPLE 13 Implantables with one side more absorbable than the other side
  • An implant with one side with a surface texture of EXAMPLE 10 and the other side with a surface texture of EXAMPLE 12 is provided.
  • EXAMPLE 14 Implantables with one side more resistant to adhesion than the other
  • EXAMPLE 15 Implantables with at least one side immediately tissue adhesive
  • Surgical barrier implants block tissue adhesions between adjacent layers of tissue.
  • a Cassie wetting texture 1300 interacting with tissue 1301 is comprised of first scale protuberances 1302 and second scale ridges 1304 oriented axially with protuberances 1302 and distributed circumferentially.
  • the ridges 1304 enter the Wenzel state when placed on tissue. The Wenzel state is prevented from moving in the plane of the implant by the adjacent Cassie states created by the protuberances 1302.
  • EXAMPLE 16 Implantables with lipophilic/hydrophilic filter effect surface
  • a surface filtering effect wherein a first substance or structure is brought into more intimate contact with the implant than another substance or structure.
  • the intimacy defined by the spatial scale of interactions.
  • the heterogeneous liquid comprised of water and lipids segments separate such that the water fraction is localized to the Wenzel sites and the lipid fraction is localized to the Cassie sites.
  • thermodynamic hypothesis heterotypic cells in mixed aggregates can sort out into isotypic territories based on surface chemistry and texture.
  • the hypothesis treats tissue as a viscoelastic liquid, and as such each cell type possesses a characteristic tissue surface tension.
  • the differing surface tensions give rise to a sorting behavior.
  • Tissue type with a higher surface tension occupy an internal position on the implant surface relative to a tissue with a lower surface tension.
  • Quantitative differences in homo and heterotypic adhesion are supposed to be sufficient to account for this phenomenon without the need to postulate cell type specific adhesion systems.
  • This property can be applied to bacterial species as well as cell types. So where a certain cell type is desired and other cell types not desire, the surface texture can be impressed with the appropriate surface energy signature. For example, in an application where
  • inflammatory cells such as macrophages, giant cells, generally of a spherical shape are to be excluded in favor of generally cylindrical cells such as muscle cells and endothelial cells.
  • the cylindrical cells typically possess a higher surface tension than the spherical cells. Accordingly, we can create a sorting surface with a generally more axial structure than a spherical structure, such that cylindrical cells are energetically favored for attachment.
  • a cell sorting surface 1400 is comprised of centers 1402 that are generally semi-spherical protuberances with a central dimple 1404 and radial, closely spaced ridges 1406.
  • the centers 1402 are arranged in rows 1408 separated by a first characteristic distance A.
  • the centers 1402 within a row 1408 are regularly spaced a second characteristic distance B.
  • the distance between ridges 1406 is a third characteristic dimension C.
  • a combination of characteristic distances A, B, C determines which cell type associates with the implant surface.
  • the centers 1402 are connected by ridges 1406 with orthogonal smaller scale ridges.
  • the larger scale ridges 1406 are arranged to approximate equal distance spacing. This results in a parallel structure 1410 in the space between centers 1402 and a radial structure 1412 in the space proximal to centers 1402.
  • the centers 1402 are connected by ridges 1406.
  • the connectivity is characteristically directed, for example in the direction of row 1408, but they could also be directed orthogonally, and diagonally.
  • EXAMPLE 18 Implantables with a tissue type filter effect surface
  • texture is disposed, such that relatively hydrophobic tissue structures are attracted and hydrophilic tissue structures are repelled.
  • relatively hydrophobic tissue constituents of protein and fat are attracted and hydrophilic structure such as serum, exudate, and the generally lubricating and largely aqueous constituents are repelled so as to localize an implant in situ.
  • textured surface 1500 comprises hexagonal depressions
  • depression 1502 separated by relative narrow ridges 1504.
  • the interior of depression 1502 rapidly becomes circular on its surface on which are placed a multiplicity of equally space, concentric, undulating concentric ridges 1506 with a generally circular profile.
  • a petal structure 1508 with the number of petals corresponding to the number of cycles in the adjacent ridge structure 1506.
  • ridges 1504 On the ridges 1504 is a circumferential ridge 1510 broken into circular ridges 1512, the circular ridges 1512 corresponding to a period 1514 of adjacent undulating ridges 1506.
  • the space between ridges 1506 may be optionally ornamented with orthogonal fine scale ridge structures 1516.
  • EXAMPLE 19 Implantables with a bacterial adhesion resistance
  • Biomaterials and medical devices immediately and spontaneously acquire a layer of host proteins prior to interacting with host cells and microbes.
  • attention is directed to limiting microbial adhesion, but the principle can be equally applied to reduced tissue adhesion surfaces.
  • the types, levels, and surface conformations of the adsorbed proteins are critical determinants of what kind of living substances adheres to the implant surface. Conversely, the types, concentrations, and conformations of these surface-adsorbed proteins are dependent on biomaterial surface properties that dictate the adhesion and survival of cells, especially microbes, monocytes, and macrophages.
  • the interaction of adsorbed proteins with adhesion receptors present on microbes and inflammatory cell populations constitutes the major recognition system of biologies to implantable synthetic materials.
  • the presence of adsorbed proteins such as albumin, fibrinogen, complement, fibronectin, vitronectin, ⁇ globulin, and others mediate microbial colonization, inflammatory cell interactions and tissue adhesion.
  • Major driving forces behind protein adsorption include: surface energy, intermolecular forces, hydrophobicity, and ionic or electrostatic interaction - all of which are modified by surface texture.
  • the four fundamental classes of forces and interaction in protein adsorption are: 1) ionic or electrostatic interaction, 2) hydrogen bonding, 3) hydrophobic interaction (largely entropically driven), and 4) interactions of charge-transfer or particle electron donor/acceptor type.
  • cellular/bacterial adhesion is largely mediated by surface energy. That is to say, initiating a response is insufficient to maintain a response.
  • the goal of a bacterial resistant implant is to shift the surface energy equations, to promote affinity of bacteria to bind to tissue or themselves. Binding to tissue needs to be energetically favored over binding to the implant surface. More particularly, if microbes should colonize the implant surface the spreading of a protective biofilm is preferably energetically disfavored. In a disfavored scenario, an evolving biofilm tends to take on a spherical shape, which turns the biofilm surface to encapsulate the bacterial colony and decrease the contact area of the bacterial colony with the implant surface.
  • the anti-microbial surface 1600 is comprised of multiple depressions 1602 which may be any conformation, e.g., cylindrical, conical, square, hexagonal.
  • the interior surface of the depressions 1602 are ornamented with nano-scale structures that maximize the hydrophobicity and minimize the surface energy, such that while microbial attachment is preferred in the depressions because they shield the microbes from macrophages, the surface energy is so reduced within the depressions that the microbes are only tenuously adhered. Furthermore, attachment of microbes within the depressions changes the local surface energy and directs macrophages to the occupied depression.
  • a macrophage can easily infiltrate the depressions and eliminate the nascent microbial colony.
  • the nanoscale structures are ridges 1604 circumferentially and axially arranged, these surfaces enhance the hydrophobicity of the interior surfaces of depressions 1602.
  • Surrounding the depressions 1602 are circular ridges 1606 embossed with sinusoidal ridges 1608.
  • the sinusoidal structure mitigates a circular contact interface (low energy) between a biogel evolving out of depressions 1602 and the implant surface, thus making it energetically disfavored and unstable. In particular, propagation of the biofilm is inhibited.
  • the regions between depressions circumscribed by sinusoidal ridges may be ornamented with any of the above examples.
  • EXAMPLE 20 Implantables with a bacterial adhesion resistance
  • An anti-microbial surface wherein the surface filter effect is employed, wherein one species characterized by scale or polarity is excluded and another species characterized by scale or polarity is attracted, or both are excluded, or both are attracted, on the same side or on opposite sides of a sheet implant.
  • one species characterized by scale or polarity is excluded and another species characterized by scale or polarity is attracted, or both are excluded, or both are attracted, on the same side or on opposite sides of a sheet implant.
  • an implant side in which bacteria are excluded and a component of tissue is attracted and on the other side bacteria are excluded and a component of tissue is excluded.
  • any of the above implants with fibers imbedded and protruding from the polymer substrate said fibers can be bifurcated on a number of spatial scales in the manner of the fibers disposed on a Gecko foot.
  • a limited shear test was performed with a small quantity of positive image PLA sheets. The procedure consisted of forming a negative pyroxylin cast, pouring PLA acetone solution over the negative cast, and dissolving away with ethanol the pyroxylin portion.
  • peal strength was exceptionally low. The discovery that the peal strength is exceptionally low is not surprising given that it is far easier to pluck a droplet from a petal surface than roll in across its surface.

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Abstract

La présente invention concerne des surfaces texturées biosélectives qui médient la réponse aux corps étrangers, l'adhésion bactérienne et l'adhérence tissulaire sur des dispositifs implantés dans un corps de mammifère. On utilise des niveaux hiérarchiques de texture, qui pour certains sont capables d'établir un état Wenzel et pour d'autres, un état Cassie, afin d'agir en tant qu'interface avec des structures vivantes, soit pour favoriser, soit pour entraver une réponse/interaction biologique. Étant donné qu'un état gazeux est classiquement requis pour établir un état Cassie ou Wenzel, et que les gaz ne restent pas longtemps dans un tissu vivant, on décrit des interactions tissu/dispositif analogues aux états précités avec le constituant normalement représenté par un gaz remplacé par un constituant corporel, ce qui produit la séparation des constituants tissulaires et l'évolution d'un état d'interaction désiré.
EP13702696.9A 2012-01-24 2013-01-18 Textures superficielles biosélectives Pending EP2806905A2 (fr)

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