Patent Application
20240101862
The present invention relates to a fabrication method of elastomer breath structure and an chemically or biologically treated and modified elastomer breath topographical structure, a patterned surface produced with it and a driveline as application product.
WO 2014/036290 A1 discloses a drug delivery device and a method of making such a drug delivery device based on single and multi-layer polymer films made by a breath figure technique having therapeutic agents associated therewith. For example, the devices may be a dual layer polymer film wherein the first layer includes a therapeutic agent incorporated into it by spin coating the first agent with a polymer solution and CH2Cl2 as solvent and the second agent is incorporated into the second layer by loading the agent into pores of the second layer after it is spin coated onto the first layer. In some cases one layer provides a burst release and the second layer provides a slow release drug delivery profile. The devices may take on the form of a surgical mesh with a slow release therapeutic drug.
EP 1 887 388 A2 discloses a type of optical film, processes for making such a film, and a backlight device containing the film. The film includes a substantially monolayer arrangement of beads partially submerged in a binder. Such a film is achieved by applying to a transparent substrate a coating comprising a carrier, an aqueous dispersible or soluble polymeric binder and a bead population of desired refractive index and low polydispersity, wherein the binder is selected to have a refractive index that substantially matches that of the beads upon removal of the carrier, and wherein the relative proportions of the coating components is sufficient to provide a substantially mono layer arrangement of the beads that is partially submerged in the binder upon removal of the carrier; and then removing the carrier from the coating to provide a substrate coated with a substantially mono layer arrangement of the beads that is partially submerged in the binder. Useful solvents for the polymer suspension process are those that dissolve the polymer, which are immiscible with water and which are readily removed from the polymer droplets such as, for example, chloromethane, dichloromethane, ethylacetate, vinyl chloride, methyl ethyl ketone, trichloromethane, carbon tetrachloride, ethylene chloride, trichloroethane, toluene, xylene, cyclohexanone, 2-nitropropane and the like.
A further application of the breath figure technique can be found in US 2017/096545 A1, where a solid state dye laser is prepared with the laser dye being incorporated in pores of the copolymer membrane.
The technology is broadly used as there exists a wikipedia article relating to Breath-figure self-assembly; https://en.wikipedia.org/wiki/Breath-figure self-assembly mainly edited and updated in 2018 and 2019. By casting a thin layer of solvent on the already cured polymer surface, the material will be softened. In a humid environment of limited control, water droplet condensation will be induced spontaneously due to the heat removed by the evaporation of solvent. The condensed droplets indent the soft surface by the effect of gravity and surface tension. The resultant topography is a honeycomb structure with sub-micrometer, mono-sized imprints. Endothelial cells (ECs) can sense and respond to the surface roughness associated with these topographies.
This breath figure technology is casting a solvent on the polymer and evaporates it to fabricate the uniform honeycomb topography with unit size <10 um. Since the process in humid environment is under little control unit sizes >10 um are seldomly produced.
Different solutions of driveline development become the starting point of percutaneous driveline infections, in short Olis. The number of patients experiencing such infections are steadily increasing. Such Olis are detected via either superficial symptoms such as redness, increased temperature, and purulent discharge at the exit site or as a clinically apparent abscess at the lower layers of the soft tissues (e.g. fascia and muscles).
Based on this prior art it is an object of the invention to provide a better controlled and better performing fabrication method of a breath topological structure, providing the possibility of creating unit sizes >50 um, allowing for secondary shallow craters, and/or imprints with certain size distributions which are features unknown with the prior art methods. There, the indented wells are densely packed without control of the inter-well distance.
A fabrication method of an elastomer breath structure or elastomer breath topological structure comprises the steps of applying a liquid elastomer onto a substrate, initial curing the liquid elastomer on the substrate partially into a partially cured polymer, condensation of water droplets from the environment onto the partially cured polymer and finishing curing of the partially cured polymer with parallel or sequential removal of the water droplets creating surface dimples on the cured elastomer. Within the fabrication method the condensation step can comprise controlling the original environment of the partially cured polymer as a humid chamber atmosphere with a relative humidity of between 20 and 100%, especially 40% and 100% and further especially 60 to 90%.
The humid chamber atmosphere can be controlled that the surface covered by water droplets is between 10% and 80%, especially 20 to 50%, of the polymer covered substrate surface.
The initial curing step of the liquid elastomer on the substrate into a partially cured polymer can be configured to obtain a partially cured polymer with a surface tension such that condensed water droplets sink in into the previous undisturbed surface by a depth of 1 to 100% before the finishing curing step evaporates the sunk in water droplets. In an application, the water droplets may have a size between 10 and 100 micrometres and sink in into the previous undisturbed surface by a depth of 1 to 10 micrometres before the finishing curing step evaporates these sunk in water droplets.
The aspect ratio of well width to well depth can be between 30 to 1 and 10 to 1.
The humidity and temperature of the humid environment (41′) can be controlled within the condensation step and the finishing curing step. By increasing humidity, the droplet size is increased, while inter-droplet distance is decreased. These results in larger well diameter and smaller inter-well distance. Raising the temperature increases the curing speed, resulting in smaller diameter. The final curing step which comprises the removal of droplets can be executed in different manners, especially through evaporation, washing or centrifuging to reveal the topography of the breath structures onto the elastomer.
The application step can be preceded by a step of mixing one or more liquid polymers, since a mix of different polymers provide more flexibility in the choice of the resulting well structure.
Such a mixing step can comprise mixing of one or more liquid polymers, especially room temperature vulcanizing silicones or silicones curing at temperatures between −10 and +60 degrees Celsius, optionally with polymers and copolymers having a different degree of miscibility.
The application step of the liquid polymer on the substrate can be conducted by a process from the group encompassing spin-coating, dip-coating, air spray or 3D-printing.
The finishing curing step can be followed by a chemical or biological treatment step to apply predetermined chemical compounds or biological cells into the surface dimples and on the in-between dimple surface which are steps towards a direct application of the created breath surface.
A patterned surface of a polymer can be fabricated according the above cited method having an aspect ratio of well width to well depth between 30 to 1 and 10 to 1.
Based on the prior art it is an aim of the present invention to provide percutaneous drivelines facilitating skin integration and reduce Dlis.
The object of the invention is tackled with an improved topographical modification of the percutaneous driveline according to the features described herein.
Such a percutaneous driveline is coated at least adjacent to the percutaneous portion with a patterned surface according to the invention, wherein predetermined chemical compounds or biological cells are in the surface dimples and/or on the in-between dimple surface.
Similarly, an effective transfer of topographical cues that secures the infection-free application of percutaneous drivelines will also benefit a wide range of medical devices that require access to blood (i.e. dialysis), different tissues (i.e. tissue monitoring), body cavities (i.e. prosthetic urethra), and internal prosthetic parts (i.e. corneal implant).
Focusing on a different set of applications, the transfer of tunable topographical cues on biomedical devices can alleviate the negative effects from adverse foreign body (FB) responses. The present fabrication method uniquely fulfills scale up requirements when covering large surfaces of biomedical devices (e.g. the entire luminal surface of cardiovascular devices). Similarly, the invention manages to successfully transfer the selected topographies on non-conventional three-dimensional (3D) surfaces which are regularly encountered in biomedical equipment and instrumentation.
To this end, the claimed method of imprinting selected topographies offers a solution to obtain endothelialization over artificial surfaces with complex 3D geometries. Overall, this free-form imprinting technology constitutes a new method to efficiently introduce breath structures on surfaces that are engineered to reduce tissue morbidity and improve the lifestyle of the patients.
The surfaces of different biomedical devices (e.g. drivelines and luminal surfaces) can be modified with the method according to the invention with selected surface chemistry and rationally developed microscale surface topography. Specifically, a silicone formulation that favors low infection, enhanced tissue integration, and non-cytotoxic behaviour is used. The incorporated silicone layer covers substrates of various geometries, that span from thin copper wires to flat membranes to curved tubes and is subject to further modification by imprinting selected surface topographies. The imprint procedure develops by a free-form process following the condensation of water droplets on top of the uncured silicon surface.
This method obtains selected topographical patterns of breath morphology that resembles micrometer-sized circular wells. In this manner, fine control of the diameter, depth and distance between the wells of the breath topography by just tuning the curing time preceding the condensation step is obtained.
The effects of breath topography can be alternatively modulated with the incorporation of selected chemical and biological molecules (e.g. polymers, DNA molecules, peptides, antibodies, matrix proteins). Orthogonal control of breath topography and presented chemistry can expand the combinations of instructive cues to account for the different mechanisms involved in a variety of tissue responses involved such as wound healing, skin integration, and endothelialization.
The present invention uses a known silicon formulation as the substrate material. However, then a selected topography is applied on top of the silicon in contrast with prior art lacking control of surface topography, especially on the inter-well distance.
According to the present invention a random spatial distribution of features with disperse imprint sizes and depths in the micrometer range is achieved. The unit imprint can house 1˜2 endothelial cells. The invention also differs from the existing condensation-imprint technology by the absence of any organic solvent. The condensation is enforced during the silicone curing process, in which the silicone undergoes a liquid-to-solid transition process.
The curing process is hence divided into two sequential parts: initial curing and finish curing. The condensation is induced by controlling environmental temperature and humidity instead of solvent evaporation.
The present invention overcomes problems inherent to current methods for imprinting breath topography on synthetic biomedical surfaces, offering a new therapeutic avenue by triggering select tissue responses in the human body. Instead of using regular chemical and biological factors, the present technology harnesses the physical characteristics of the imprinting breath topography to promote therapeutic cell and tissue responses. That is, the breath topographies produced according to the invention can exert physically instructive signals to biological tissues with therapeutic benefits for the patient.
The present invention presents a surface topography with certain size distribution and (diameter-to-thickness) aspect ratio, which can be controlled by the two-step curing method. The size distribution and tunable aspect ratio suits better in cell cultivation, because size distributions and large aspect ratio resembles more closely the natural morphology of most cells. The present invention also includes a new degree of freedom, namely the inter-well distance, which is not presented in the prior arts. The tuning of inter-well distance will control the percentage coverage of the topography on the surface, which can be further treated for culturing cells individually or in clusters.
Further embodiments of the invention are laid down in the dependent claims.
The process according to the invention is different to the prior art in both chemistry and physics. From the chemistry point of view, there is no reagent (e.g. polymer) dissolution employed in the method according to the invention. In contrast, the method uses a two-step curing process (before and after droplet formation) to control the interfacial force balance between the water droplet and the curing polymer without dissolving neither the curing polymer nor the curing polymer substrate. In effect of these steps in the fabrication process, the present method is more economic, environmentally friendly, toxicity-free, and sustainable. From the physics point of view, what prior art utilize is a liquid-liquid interaction.
In contrast, the present method relies on a liquid-(soft)solid interaction.
Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,
The method starts with a mixing step 10. The used components of room temperature vulcanizing (RTV) silicones are sufficiently mixed. In other embodiments silicones are mixed which crosslink to form elastomers at lower or higher temperatures, especially between −20 to +60 degree C. Different temperature vulcanizing silicones are associated with working solutions of variant viscosity, mediating the efficiency of coverage of the coated surface and the final thickness of the spread silicone layer. Higher temperature will in general result in a faster curing, hence reducing the fabrication time, while lower temperature in general slows down the curing process, results in a longer handling time, more homogeneous spread on surfaces.
The RTV cures by polyaddition reaction of silicone reactivegroups (—SiH) with silicone unsaturated polymers (such as —Si—CH—CH2), under the platinum catalyst environment. Component A (containing platinum catalyst) and component Bare mixed in various ratios (including 1:1 ratio). The mixing ratio and the curing temperature affect the extend of crosslinking during the first step of curing. In turn, this influences the interfacial force balance and the associated droplet-induced deformation, which together determine the size and aspect ratio of the breath structures obtained.
Similar to RTV silicones, other silicone-based polymers can be recruited to promote the formation of breath figures by using the described method. Polydimethylsiloxane (PDMS), PDMS-based (e.g. Polydimethylsiloxane-diacrylamide, Poly(dimethylsiloxane), diglycidyl ether terminated) and PDMS copolymers (e.g. Poly(dimethylsiloxane-co-alkylmethylsiloxane), Poly[dimethylsiloxane-co-(2-(3,4-epoxycyclohexyhethyhmethylsiloxane], Poly(dimethylsiloxane-co-methylphenylsiloxane)) can be used separately or mixed in different combinations with RTV silicones to affect the characteristics of the breath figures.
RTV silicones can also be used in the presence of other polymers such as blends of diblock-copolymers (e.g. polysiloxane-poly(oxyalkylene), poly(dimethylsiloxane)-poly(oxydimethylsilylene), polycarbonate-PDMS) multiblock copolymers, homopolymers, which demonstrate different degree of miscibility with RTV silicones. Similarly, RTV silicones can be controllably blended with different type of surfactants that bear a miscible hydrophobic part and a polar counterpart. The number density, the chemistry, and the architecture of these secondary components correlates with the rate of crosslinking, the 35 mechanical properties, and the surface tension of the silicone elastomer, and eventually directing the physical and chemical characteristics of the breath figures. The volume fraction (0.01-1% v/v), the chemistry (molecular similarity with RTV) of these secondary components will affect the degree of partial curing at the two-step curing process before and after water condensation. The distribution of surfactants in the partially cured elastomer will also affect the Vsw and consequently the shape and the size distribution of the breath structures.
Other suitable formulations involve blends of RTV silicones with different components of organic/polymeric (e.g. polystyrene, poly-ethylene glycol, Teflon, poly(lactic-co-glycolic acid) and inorganic (e.g. silicon, metallic, carbon-based) micro- and nano-particles (or powders). The number density, the chemistry, and the architecture of the used particles can be selected to control the rate of crosslinking, the mechanical properties, and the surface tension of the silicone elastomer and consequently tune the characteristics of the breath figures. The volume fraction (0.01-1% v/v), the chemistry (hydrophilic) of these particle components in the partially cured elastomer will affect the Vsw and consequently the shape and size distribution of the breath structures.
The above mentioned pre-mixed liquid state polymer component(s) are applied in application step 12 to a substrate. RTV silicones (and other silicone based polymers) used in the method for breath figure formation can be cast on different materials (e.g. wax, gypsum, low melt alloys, metals, urethane, polyester resins, polystyrene and other substrates) composing flat (2-D) and curved (3-D) surfaces.
The application step 11 itself can be executed through various methods of deposition of RTV silicones, e.g. spin-coating the select material (e.g. RTV silicone) over different surfaces with various centrifugation speeds (100-2000 rpm) and centrifugation time. The speed and time is tuned to control the thickness of the deposited layer with further effects on the deformability of the silicone elastomer and finally the breath figures topography. The thickness of the coating layer 22 varies between tens of micrometers to a few hundreds of micrometers. As an example, a 60 um thickness coating was achieved by 700 rpm for 90 s on a flat surface. In general, an increased centrifugation speed and increased time will result in a smaller coating thickness. The reduced thickness in turn increases the boundary effect of the underlying substrate 51, oftentimes stiff material, hence decrease the deformability of the silicone elastomer.
In other embodiments the application step 11 is provided with casting and dip-coating of RTV silicones on-top of such select surfaces. The drawing speed of dip coating or the other relevant parameters of casting can be tuned to control the thickness of the deposited layer.
In general, a faster drawing speed results in a thinner coating. The thickness of the layer varies between tens of micrometers to a few hundreds of micrometers.
It is also contemplated that the application step comprises a 3-D printing of RTV-silicones. Here, in case of two or more polymers, it is possible to print and mix the polymers in situ instead of the mixing step 10.
The application step 11 can be summarized in that the aforementioned liquid polymer mixture is applied to a target surface, by the means of spin coating, dip coating, air spray 10 or other liquid deposition methods. The thickness of polymer layer is controlled accordingly by the deposition process parameter, e.g. rotational speed in spin coating, drawing speed in dip coating, air flow rate in air spray, etc. The thickness of the layer varies between tens of micrometers to a few hundreds of micrometers.
The curing itself happens in two curing steps. The application step 11 is followed by an initial partial curing step 12, within which the aforementioned polymer surface layer is partially cured under controlled temperature. The curing target can be set by fixing amount of time, or in-situ testing of mechanical property on a reference piece. The mechanical property criteria, including but not limited to Young's modulus and viscosity, affect directly 20 the diameter and the depth of the breath topography. The initial Young's modulus (very small) and viscosity (6000 mPa*s) in general result in smaller size (<10 um), small inter-well distance 72 (more closely packed) and lower diameter 71 to depth 73 aspect ratio (<10:1). On the other extreme, the almost cured Young's modulus (500 kPa) and viscosity (very high) will result in large size (>100 um), large inter-well distance 72 and large diameter 71-to-25 depth 73 aspect ratio (>30:1). In-between conditions can be seen as interpolation between two conditions. The curing target can be continuously selected to meet specific environment.
After the initial partial curing step 12 (not shown in
The inter-well distance can induce distinct effects on biological applications that involve presentation of breath structures. For instance, the inter-well distance will affect the organization and cohesion properties of adhering cell layers with subsequent effects on their capacity to perform inherent biological functions.
Specifically, the water droplet composition can be assisted by the following means in the condensation step 13: decreasing polymer temperature prior to condensation increases the well diameter 71, increases the inter-well distance 73 and the depth 72 of the breath figures; higher vapor pressure and/or temperature increases well diameter 71, inter-well distance 73 and well depth 72.
The more extended the final curing step 14 leading to a larger Young's modulus and higher viscosity of the liquid polymer prior to the condensation of droplets, the larger the diameter, the inter-well distance, but smaller the well depth of the breath figures.
As mentioned above, the condensation conditions in condensation step 13 and the curing conditions in curing step 14 directly influence the distribution of the wells after evaporation of the water droplets 40 and shown in
Treatment step 15 is relating to applying the cured polymer with its specific topography on substrates of various chemistries, 2-D and 3-D geometries for biomedical and flow control purpose. Examples of the substrates are electrical drivelines, fluid drivelines, implants, catheters, stents, artificial arteries etc. Different configurations of the device setup are schematically shown in
So portion (B) of
The different systems emanating from the breath topography (B), (C.1), (C.2) and (C.3) can instruct biological processes, such as endothelialization, wound healing, cell migration, proliferation, under in vitro or in vivo (and ex vivo) conditions or various of biological tissues (human body). Such biological processes initiated through the topography are symbolized with the rectangle with tissue elements 85 shown in (D.1). These can be subject to different profiles of physiological and non-physiological flow as indicated with arrow 86 in (D.2).
| Number | Date | Country | Kind |
|---|---|---|---|
| 20208958.7 | Nov 2020 | EP | regional |
This application is the United States national phase of International Patent Application No. PCT/EP2021/081325 filed Nov. 11, 2021, and claims priority to European Patent Application No. 20208958.7 filed Nov. 20, 2020, the disclosures of which are hereby incorporated by reference in their entireties.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/081325 | 11/11/2021 | WO |
