Preparation of materials having controlled morphologies using self-regulating technology

Abstract

The present disclosure relates to methods of forming porous polymer films, such as surgical meshes, utilizing reaction-diffusion phenomena.

Description

[0001] PREPARATION OF MATERIALS HAVING CONTROLLED MORPHOLOGIES USING SELF-REGULATING TECHNOLOGY

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims benefit of priority of U.S. Provisional Application No. 63 / 653,180, filed May 29, 2024, which is incorporated herein by reference in its entirety.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with government support under grant / contract no. 2023-31100-01417 awarded by United States Department of Agriculture. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] The self-regulating biochemical processes that take place in living organisms are of extreme complexity. Although the exact quantitative and qualitative analysis of all the reactions that occur even in a single cell is nearly impossible, there is a long history of attempts that targeted the description and characterization of the phenomena that shape living organisms. The first article that had a profound influence on the physicochemical theories of self-organization was written by Alan Turing in 1952 (A. Turing, The chemical basis of morphogenesis, Philos Trans R Soc Lond B Biol Sci. 237 (1952) 37-72). Turing was a true modern polyhistor: although he is mainly renowned for his contribution to breaking the Enigma code and for being a pioneer in computer science and artificial intelligence, he also laid the foundations of mathematical biology. In his 1952 article, ‘The chemical basis of morphogenesis’, Turing hypothesized that pattern formation in living organisms could be explained by considering only two parallel phenomena: reaction and diffusion. Despite the availability of high-performance computers, Turing correctly predicted what the patterns formed by parallel reaction and diffusion will look like. Figs. 1A-1B.

[0008] Although Turing’s work in this field is now regarded as groundbreaking, his contemporaries did not receive his ingenious ideas well. Waddington, one of the most prominent developmental biologists of the post-war era, explicitly opposed the inclusion of Turing’s concept in scientific discourse. As a result, reaction-diffusion models were largely overlooked for the next two decades. In 1972, Gierer and Meinhard practically re-discovered the idea of reaction-diffusion models and proposed a mathematical method that can predict the formation of patterns observable in nature. Gierer and Meinhardt’s second pivotal contribution to this field was the empirical validation of reaction-diffusion models. Their model organism was a freshwater polyp hydra (Hydra atteriuata). Later, Yamaguchi carried out similar experiments with zebrafish (Danio rerid) and proved that the Gierer-Meinhardt model can be used to describe the formation of patterns on vertebrates as well.

[0009] Although the Gierer-Meinhardt model and its derivatives are widely accepted among biologists, the importance of reaction-diffusion phenomena is certainly not limited to biology. In the past few decades, several other models have emerged that can describe a variety of processes not related to biology or biochemistry in any way. The list of notable examples includes the Brusselator model, FitzHugh-Nagumo model, and, most importantly, the Gray-Scott model. Since its first appearance in 1983, the Gray-Scott model has gained popularity across a surprisingly large number of scientific fields. Chemists mainly use it to optimize batch reactors and plug-flow reactors. Bhattacharjee reported that the model can also provide a basis for the numerical analysis of hydrodynamics of reactive mixtures. Recently, the model was successfully applied to simulate the structure of carbide composites.

[0010] Besides being able to simulate or predict, the Gray-Scott model can also inspire: Hankins argued that biomimetic design for composites could enhance their properties and generated bioinspired patterns with the Gray-Scott model. While the articles cited above discuss comparatively simple processes with only a few components, the model was proven to be ableto describe reactions in extremely complex environments. A notable example is its application in neurosciences, or for the purpose of building gene networks.

[0011] The number and diversity of the articles cited above highlight the immense potential offered by reaction-diffusion models. Interestingly, in the field of polymer science, their impact is still marginal. Although many manufacturing techniques could be based on the patternforming capabilities of reaction-diffusion phenomena, none of the processing methods proposed in the literature or applied by the industry leverage this potential. There are numerous polymeric products composed of regular or semi-regular patterns that are manufactured by conventional processing technologies. Notable examples are surgical meshes, which are widely used in regenerative medicine. Products that have received regulatory approval and are currently in use are often manufactured by knitting or weaving. Both techniques require complex instrumentation that is also rather expensive to operate. Therefore, new methods that can output nonwoven fabrics have also emerged. The most relevant examples are electrospinning and 3D printing. Although these techniques are promising, they have not yet proliferated in the market and are, in most cases, still in the development stage. Consequently, the biomedical industry could certainly benefit from a new method that does not require expensive instrumentation and can also be upscaled easily and rapidly to satisfy the demand of the market.

[0012] SUMMARY

[0013] Meshes and porous mats are widely used in regenerative medicine. In the past decades, several technologies have been developed that facilitate the production of meshes for biomedical applications. However, these technologies generally require a complex infrastructural background and expensive instrumentation that makes their manufacturing costly in terms of both money and time. In order to accelerate mesh production and reduce costs, alternative manufacturing techniques have emerged recently, such as electrospinning or halospinning. However, even if the most cost-efficient technologies (e.g., halospinning) are used, production- related prices exceed $1000 per square meter, which can negatively impact the industrial relevance of the product and its proliferation in the market.

[0014] Described herein are alternative methods for the preparation of materials having controlled morphologies (e.g., porous mats, thin films, meshing, and other materials having controlled pore size and / or porosity). These methods utilize reaction-diffusion phenomena and leverage the pattern-forming capabilities and self-regulating nature of parallel reaction and diffusion.

[0015] By way of example, poly(styrene-b-isobutylene-b-styrene) (SIBS) can precipitated in a controlled manner. Owing to the pattern-forming capabilities of reaction-diffusion processes, the resulting polymer film (mesh) can contain evenly distributed pores of diameters falling in a narrow range. Furthermore, by fine-tuning the parameters of the process, the pore size of the resulting thin film can be adjusted and tailored to fit the requirements of the intended area of application. The technology is robust and enables the creation of surgical meshes from a wide variety of elastomers.

[0016] Apart from the above-mentioned SIBS, other thermoplastic elastomeric polymers (TPEs), such as other polyisobutylene block copolymers (e.g., poly(alloocimene-b-isobutylene- b-alloocimene), AIBA), can be used. Depending on the intended area of application, the properties of the polymer can be adjusted by the addition of an additive, such as an inorganic additives (e.g., zinc oxide) or a polymeric additive (e.g., a polyalkylene oxide such as PEG). The presence of the additive can impact but not hinder the formation of periodic reaction-diffusion patterns. Therefore, the production of surgical meshes remains attainable even if additives are present. Further, the additives can be introduced to alter the morphology of the porous polymer film formed by the methods described herein. In addition, additives such as active agents (e.g., therapeutic agents, diagnostic agents, and / or prophylactic agents) can be introduced into the porous polymer film (from which they can be subsequently eluted when the film is in use).

[0017] Another advantage of the comparatively simple and robust experimental setup of this method is that production can be scaled up easily. Instead of carrying out the controlled precipitation on a static plate, the solution of the polymer is to be continuously distributed on a conveyor belt, from where the porous polymer can be removed after the precipitation is completed.

[0018] In accordance with the purposes of the disclosed materials and methods, as embodied and broadly described herein, the disclosed subject matter, in one aspect, relates to methods of forming porous polymer films utilizing reaction-diffusion phenomena. In particular, methods of forming porous polymer films utilizing reaction-diffusion phenomena are provided that comprise: dissolving a thermoplastic elastomeric polymer (TPE) in a first solvent to form a polymer solution; contacting a layer of the polymer solution with a layer of a precipitator medium; and allowing diffusion to occur between the polymer solution and the precipitator medium, thereby inducing precipitation of a porous polymer film comprising the TPE.

[0019] Also provided herein are porous polymer films (e.g., surgical meshes) prepared by the methods described herein.

[0020] Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0021] DESCRIPTION OF DRAWINGS

[0022] FIGS. 1A-1B illustrate the formation of reaction-diffusion patterns in one-dimension (FIG. 1 A) and two-dimensions (FIG. IB), as presented in Turing’s article. In the original paper, these diagrams lack the names of axes. Each axis represents spatial coordinates except the vertical axis of (FIG. 1 A), which represents concentration.

[0023] FIGS. 2A-2B show photographs of patterns created from a 4 m / m% solution (FIG. 2 A), and a 5 m / m% solution (FIG. 2B). The precipitator medium was isopropanol in both cases. FIGS. 3A-3B show the results of individual measurements (FIG. 3 A), and the normalized average curve (FIG. 3B). Note that the conversion converges to 100% with saturation-like kinetics.

[0024] FIGS. 4A-4B show pattern as a function plotted in real space (FIG. 4 A), and in reciprocal space (FIG. 4B). Only one dominant peak can be observed on the spectrum, i.e., the pattern can be characterized by one spatial frequency.

[0025] FIGS. 5A-5B show the results of the analysis of kinetics (FIG. 5 A), results of the measurement of dominant spatial frequency (FIG. 5B).

[0026] FIGS. 6A-6C show the results of modeling the process in one dimension.

[0027] FIGS. 7A-7D show the results of modeling the process in two dimensions.

[0028] FIGS. 8A-8B shows spectra of the concentration profile near the beginning of the experiment (FIG. 8A), and in the final (static) state (FIG. 8B). The self-regulating process functions as a filter that retains only one frequency and attenuates the rest.

[0029] FIGS. 9A-9B show surgical meshes with holes / pores shaped and distributed uniformly by self-regulation. FIG. 9A shows an example mesh with an average pore size of ~2 mm. FIG. 9B shows an example mesh with an average pore size of -200 pm.

[0030] FIG. 10 graphically illustrates an overall approach which utilizes the pattern-forming capabilities and self-regulating nature of parallel reaction and diffusion to generate materials having controlled morphologies.

[0031] FIG. 11 shows a photo of a surgical mesh containing polymer only.

[0032] FIG. 12 shows a photo of a drug-loaded surgical mesh taken immediately after the mesh is created.

[0033] FIG. 13 shows a photo of a drug-loaded surgical mesh taken a week after its creation.

[0034] FIG. 14 shows a photo of a drug-loaded surgical mesh containing 3 wt% Crystal Violet (CV), a model drug.

[0035] FIG. 15 shows the chemical structure of crystal violet (CV). Note that the equilibrium shown is formed only in aqueous solutions.

[0036] FIG. 16 is a photo showing the TLC sheet taken immediately after 15 pl of each solution has been applied onto its surface.

[0037] FIG. 17 is a plot showing the result of fitting the calibration curve onto the surface integral values (squares) calculated from the image showing the wet TLC sheet. The R2of the regression line was 0.9769.

[0038] FIG. 18 is a photo showing the appearance of the release medium immediately after the mesh containing CV was placed in it, FIG. 19A is a plot showing the release profile (in weight) of the CV from the surgical mesh over time.

[0039] FIG. 19B is a plot showing the release profile (in weight) of the CV from the surgical mesh over time.

[0040] Like reference symbols in the various drawings indicate like elements.

[0041] DETAILED DESCRIPTION

[0042] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiments. Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed methods and compositions and devices used therein pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0043] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0044] As can be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0045] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0046] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0047] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0048] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0049] Definitions

[0050] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, nonlimiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.

[0051] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an electrode”, “a polyester”, or “a solvent”, includes, but is not limited to, two or more such electrodes, polyesters, or solvents, and the like.

[0052] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it can be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0053] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of Tess than x’, less than y’, and Tess than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0054] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0055] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0056] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0057] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0058] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R-) or (5-) configuration. The compounds provided herein may either be enantiomerically pure, or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its ( / -) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5-) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0059] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas-chromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Both traditional and modern methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers.

[0060] Methods of Forming Porous Polymer Films

[0061] The present disclosure provides methods for forming porous polymer films utilizing reaction-diffusion phenomena. These methods can leverage the pattern-forming capabilities and self-regulating nature of parallel reaction and diffusion to form porous polymer film comprising a population of pores having controlled pore sizes. These methods can comprise dissolving a thermoplastic elastomeric polymer (TPE) in a first solvent to form a polymer solution; contacting a layer of the polymer solution with a layer of a precipitator medium; and allowing diffusion to occur between the polymer solution and the precipitator medium, thereby inducing precipitation of a porous polymer film comprising the TPE.

[0062] In some embodiments, the layer of the precipitator medium has a first volume and the layer of the polymer solution has a second volume; and the ratio of the first volume to the second volume is from 2.5: 1 to 100: 1, such as from 2.5: 1 to 50: 1, from 2.5: 1 to 25: 1, from 5: 1 to 100: 1, from 5: 1 to 50: 1, or from 5: 1 to 25: 1. In some embodiments, the precipitator medium has a volume of at least 5 or at least 10 times greater than a volume of the polymer solution;

[0063] In some embodiments, the layer of the polymer solution has a thickness of from 0.1 mm to 10 mm, such as from 0.5 mm to 5 mm. In some embodiments, the layer of a resulting mat has a thickness of from 0.01 mm to 1 mm, such as from 0.05 mm to 0.5 mm.

[0064] In some embodiments, the layer of the precipitator medium has a thickness of from 0.5 mm to 25 mm, such as from 1 mm to 25 mm.

[0065] In some embodiments, the first solvent has a higher density than the precipitator medium.

[0066] In some embodiments, the first solvent comprises a non-polar solvent or a polar aprotic solvent. In certain examples, the first solvent comprises a Ci-6 haloalkane, such as a Ci-4 haloalkane. For example, the first solvent can comprise 1,1,2,2-tetrachloroethane, chloroform, carbon tetrachloride, dichloromethane, or a combination thereof.

[0067] In some embodiments, the precipitator medium comprises a polar, protic solvent or a polar aprotic solvent. In certain examples, the precipitator medium comprises an alcohol, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or t-butyl alcohol. In certain examples, the precipitator medium comprises acetonitrile, acetone, or a combination thereof.

[0068] In some embodiments, the first solvent has a density of greater than 1.1 g / mL and the precipitator medium has a density of less than 1.0 g / mL. In some embodiments, the layer of the polymer solution is contacted with a layer of the precipitator medium on a static plate. In other embodiments, the layer of the polymer solution is contacted with the layer of a precipitator medium on a conveyor belt. In some embodiments, the method comprises a continuous process. For example, the layer of the polymer solution and the layer of the precipitator medium can be continuously distributed on the conveyor belt, and the porous polymer film can be continuously formed and removed from the conveyor belt.

[0069] In some embodiments, the porous polymer film comprises a population of pores having an average pore size of from 50 pm to 5 mm, such as from 100 pm to 5 mm, from 100 pm to 2 mm, from 200 pm to 5 mm, or 200 pm to 2 mm.

[0070] In some embodiments, the population of pores is monodisperse. As used herein, a monodisperse pore size distribution refers to pore size distributions in which 80% of the distribution (e.g., 85% of the distribution, 90% of the distribution, or 95% of the distribution) lies within 20% of the median pore size (e.g., within 15% of the median pore size, within 10% of the median pore size, or within 5% of the median pore size).

[0071] In some embodiments, the porous polymer film has a thickness of from 0.01 mm to 2.5 mm, such as from 0.1 mm to 2.5 mm, from 0.01 mm to 1.0 mm, from 0.1 mm to 1.0 mm, from 0.01 mm to 0.5 mm, from 0.05 mm to 0.5 mm, or from 0.1 mm to 0.5 mm.

[0072] In some embodiments, the TPE is present in the polymer solution at a concentration of from 1% by weight to 25% by weight, based on the total weight of the polymer solution, such as from 2.5% by weight to 25% by weight, from 2.5% by weight to 20% by weight, from 2.5% by weight to 15% by weight, or from 2.5% by weight to 10% by weight.

[0073] In some embodiments, the polymer solution further comprises an additive. In some embodiments, the additive comprises a polymeric additive, such as a hydrophilic polymer. The hydrophilic polymer can comprise a polyalkylene oxide, such as polyethylene glycol or a copolymer thereof. In some embodiments, the additive comprises an inorganic additive, such as a metal oxide (e.g., zinc oxide). In some embodiments, the additive comprises an active agent (e.g., a therapeutic agent, a prophylactic agent, or a diagnostic agent).

[0074] In some examples, the active agent is selected from the group consisting of proteins or peptides, nucleic acids, lipids, sugars or polysaccharides, small molecules, or combinations thereof. In some examples, the active agent is present in an amount of from between 0.5% and 70% weight / weight, between 1% and 50% weight / weight, or between 5% and 30% weight / weight in the polymer solution. In some embodiments, the method can further comprise altering the composition of the first solvent, the precipitator medium, or a combination thereof to alter the average pore size of pores present in the porous polymer film.

[0075] In some embodiments, the method can further comprise altering the concentration of the TPE present in the polymer solution to alter the average pore size of pores present in the porous polymer film.

[0076] In some embodiments, the layer of the precipitator medium has a first volume and the layer of the polymer solution has a second volume; and the method further comprises altering the ratio of the first volume to the second volume to alter the average pore size of pores present in the porous polymer film.

[0077] Thermoplastic Elastomeric Polymers (TPEs)

[0078] A variety of suitable TPE components can be utilized in conjunction with the methods herein. Examples of suitable TPEs include thermoplastic polyurethanes (TPU), styrenic block copolymers (TPS (TPE-s)), thermoplastic polyolefmelastomers (TPO (TPE-o)), thermoplastic vulcanizates (TPV (TPE-v or TPV)), thermoplastic copolyesters (TPC (TPE-E)), thermoplastic polyamides (TPA (TPE-A)), and copolymers and blends thereof. The TPE component can have any suitable structure, such as a linear, star, arborescent, comb, brush, centipede, hyperbranched, or dendritic structure. In some embodiments, the TPE can be biocompatible.

[0079] In some embodiments, the TPE component can comprise a block copolymer having at least one elastomeric block. For example, the TPE component can comprise a polystyrenepolyisobutylene block copolymer, polystyrene-polybutadiene block copolymer, polystyrenepolyisoprene block copolymer, polystyrene-poly(ethylene-butylene block copolymer, polystyrene-poly(ethylene-propylene) block copolymer, a thermoplastic polyolefin (TPO), a dynamically vulcanized TPV, or a blend or copolymer thereof.

[0080] In some embodiments, the TPE component can comprise a styrene-olefin thermoplastic elastomer. The styrene-olefin thermoplastic elastomer is a block copolymer having a soft segment and a hard segment within a molecule. The soft segment is a unit that is obtained from polymerization of an olefin, e.g., a polyisobutylene block, a polybutadiene block or a polyisoprene block. The component constituting the hard segment is a unit of styrene block, for example, that is obtained from a compound having one or at least two types selected from styrene and its derivatives, e.g., a.-methyl styrene, vinyl toluene, p-tertiary butyl styrene, 1,1- diphenyl ethylene and others.

[0081] Specific examples of the styrene-olefin thermoplastic elastomers include: styrene- isobutylene-styrene block copolymer (SIBS); styrene-butadiene-styrene block copolymer (SBS); styrene-ethylene-butylene-styrene block copolymer (SEBS); styrene-isoprene-styrene block copolymer (SIS); styrene-ethylene-propylene-styrene block copolymer (SEPS); styrene- ethylene-ethylene-propylene-styrene block copolymer (SEEPS structure); and modified block copolymers thereof. The content of styrene (or its derivatives) in each of the SIBS, SBS, SEBS, SIS, SEPS and SEEPS structures is preferably in a range of 10-50 wt. %, and more preferably in a range of 15-45 wt. % within the copolymer. A particular example is SIBS with about 17 wt % styrene.

[0082] In some embodiments, the TPE component can comprise a terpene-olefin thermoplastic elastomer. Such copolymers can comprise block copolymers comprising one or more blocks derived from a terpene or terpenoid monomer and at least one elastomeric polyolefin (e.g., polyisobutylene) block.

[0083] In certain embodiments, the TPE component can comprise a polyisobutylene-based TPE (i.e., a block copolymer having at least one elastomeric polyisobutylene block). Examples of such polyisobutylene-based TPEs include polystyrene-polyisobutylene-polystyrene (SIBS). Linear triblock SIBS TPEs were introduced commercially in 2003 by Kaneka Co. of Japan. Such TPEs are described, for example, in U.S. Patent No. 4,946,899 and 4,946,899, each of which is hereby incorporated herein by reference in its entirety. Star-branched SIBS were subsequently developed, and considered the second generation with improved properties. The third generation, arborescent (dendritic, tree-like) SIBS TPEs were introduced in 2002. Such TPEs are described, for example, in U.S. Patent No. 6,747,098 and 8,748,530, each of which is hereby incorporated herein by reference in its entirety. A fourth generation of PIB-based TPEs (poly(alloocimene-isobutylene-alloocimene) or AIBA for short) have also been developed. Such TPEs are described, for example, in U.S. Patent No 9,790,301, which is hereby incorporated herein by reference in its entirety. Any of these polyisobutylene-based TPEs are suitable.

[0084] In some embodiments, the TPE component can comprise a linear polyisobutylene TPE, a star polyisobutylene TPE, or an arborescent polyisobutylene TPE.

[0085] In certain embodiments, the TPE component can comprise a linear polyisobutylene TPE that comprises an elastomeric midblock of polyisobutylene with a number average molecular weight of from about 10,000 to about 200,000 and a molecular weight distribution of from about 1.05 to about 1.6 and two plastomeric endblocks of at least one polymerized C8 to C12 monovinylidene aromatic monomer which may bear at least one Cl to C4 alkyl substituent or a bromine or chlorine atom on the aromatic ring comprising from about 5 to about 50 weight percent of a total of 100 weight percent of the linear triblock copolymer. In specific embodiments, the TPE component can comprise a linear polyisobutylene TPE that comprises an elastomeric midblock of polyisobutylene having a number average molecular weight of from about 35,000 to about 100,000 and a molecular weight distribution of from about 1.05 to about 1.6 and two plastomeric endbocks of polystyrene comprising from about 5 to about 50 weight percent of a total of 100 weight percent of the linear triblock copolymer.

[0086] In certain embodiments, the TPE component can comprise a star-shaped polyisobutylene TPE that comprises from three to six arms that comprise inner elastomeric blocks of polyisobutylene with a number average molecular weight of from about 10,000 to about 200,000 and outer plastomeric blocks of at least one polymerized C8 to C12 monovinylidene aromatic monomer which may bear at least one Cl to C4 alkyl substituent or a bromine or chlorine atom on the aromatic ring comprising from about 10 to about 55 weight percent of a total of 100 weight percent of the star-shaped block copolymer. In specific embodiments, the TPE component can comprise a star-shaped polyisobutylene TPE that comprises three arms that comprise inner elastomeric blocks of polyisobutylene with a number average molecular weight of from about 35,000 to about 100,000 and outer plastomeric blocks of polystyrene comprising from about 10 to about 55 weight percent of a total of 100 weight percent of the star-shaped block copolymer.

[0087] In some embodiments, the TPE component can comprise a linear polyisobutylene TPE, a star polyisobutylene TPE, an arborescent polyisobutylene TPE, a linear poly(isobutylene(OH)-b- (isobutylene-co-para-methylstyrene), a star poly(isobutylene(OH)-b-(isobutylene-co-para- m ethyl styrene), an arborescent poly(isobutylene(OH)-b-(isobutylene-co-para-methylstyrene), a linear poly(styrene-b-isobutylene-b-styrene), a star poly(styrene-b-isobutylene-b-styrene), an arborescent poly(styrene-b-isobutylene-b-styrene), a linear poly(isobutylene-OH-co-para- m ethyl styrene), a star poly(isobutylene-OH-co-para-methylstyrene), an arborescent poly(isobutylene-OH-co-para-methylstyrene), a linear poly(alloocimene-b-isobutylene-b- alloocimene), a star poly(alloocimene-b-isobutylene-b-alloocimene), or an arborescent poly(alloocimene-b-isobutylene-b-alloocimene). In one example, the TPE component can comprise an arborescent PIB-based TPE with poly (para-methyl styrene) end blocks (arbPIB- MS). In certain embodiments, the TPE component can comprises a linear triblock polystyrene- polyisobutylene-polystyrene copolymer (L SIBS).

[0088] In some embodiments, the TPE component can be present in the composite in an amount of at least about 10% by weight (e.g., at least about 15% by weight, at least about 20% by weight, at least about 25% by weight, at least about 30% by weight, at least about 35% by weight, at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, at least about 55% by weight, at least about 60% by weight, at least about 75% by weight, at least about 80% by weight, or at least about 85% by weight), based on the total weight of the composite. In some embodiments, the TPE component can be present in the composite in an amount of about 90% by weight or less (e.g., about 85% by weight or less, about 80% by weight or less, about 75% by weight or less, about 70% by weight or less, about 65% by weight or less, about 60% by weight or less, about 55% by weight or less, about 50% by weight or less, about 45% by weight or less, about 40% by weight or less, about 35% by weight or less, about 30% by weight or less, about 25% by weight or less, about 20% by weight or less, or about 15% by weight or less), based on the total weight of the composite.

[0089] The TPE component can be present in the component in an amount ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the TPE component can be present in an amount from about 10% to about 90% by weight (e.g., from about 25% to about 90% by weight, from about 30% to about 65% by weight, or from about 40% to about 60% by weight), based on the total weight of the composite.

[0090] In one example, the composite can comprise a blend of butyl elastomers and block copolymers of polyisobutylene, such as the blends described in U.S. Patent No. 5,276,094, which is hereby incorporated herein by reference in its entirety.

[0091] Copolymers of polyisobutylene are of particular interest for several reasons. Firstly, members of this polymer family meet the requirements of implant materials. They are inert, biocompatible, do not trigger allergic or hypersensitivity reactions, and are also easily sterilizable. Secondly, both SIBS, AIBA and other copolymers and composites have been proven to be able to function as a drug carrier matrix, a quality often expected of modern implants. Furthermore, their mechanical properties are well-suited for long-term use as a surgical mesh. If the technology arrives at the stage of scaling up, the price of the polymer also becomes a critical factor. The production of SIBS has already been scaled up. Manufacturers, such as Kaneka, typically offer SIBS at 6-8 $ / kg, making it affordable even if large volumes are to be purchased.

[0092] Further, polyisobutylene-based copolymers have been shown to be suitable for implantation given their current application as a coating of a coronary stent. The Boston Scientific Corporation introduced its SIBS-based coronary stent into the market as early as 2002 under the trade name TAXUS. Since then, the stent has been implanted into millions of patients, which highlights and proves that SIBS can be used safely in the human body.

[0093] A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. Active Agents

[0094] As discussed above, in some embodiments, the polymer solution can further comprise an active agent. The resulting active agent can then become incorporated in the polymer film, and ultimately the active agent can be eluted when the polymer film is in use (e.g., when the polymer film / surgical mesh is implanted in a subject).

[0095] Useful bioactive agents include without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body. A biologically active agent is a substance used for, for example, the treatment, prevention, diagnosis, cure, or mitigation of disease or disorder, a substance that affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0096] The active agent can comprise any suitable active agents, including therapeutic, diagnostic, prophylactic, nutraceutical, and / or prognostic agents. Any chemical compound to be administered to an individual can, in principle, by incorporated as an active agent provided the compound has suitable properties (e.g., hydrophobicity / hydrophilicity, stability, etc.) to allow the agent to be dissolved in the first solvent, dispersed in the TPE, and to be released from the TPE (if desired or needed for activity) while retaining activity of the active agent. For example, the agent may be a small molecule, organometallic compound, radionuclide, nucleic acid, protein, peptide, polynucleotide, carbohydrate, lipid, metal, isotopically labeled chemical compound, drug, vaccine, immunological agent, contrast agent, etc. In certain embodiments, an agent to be delivered is a small molecule (e.g., a compound having a molecular weight of less than 1,000 Daltons).

[0097] Bioactive agents include biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body, and in certain examples include agents that promote healing and the regeneration of host tissue, and also therapeutic agents that prevent, inhibit or eliminate infection.

[0098] In some embodiments, the resulting polymer film comprising an active agent is characterized by linear or zero-order release of the one or more bioactive agents or drugs. In some embodiments, the polymer film comprising an active agent does not release a burst of the one or more bioactive agents or drugs.

[0099] The one or more active agents or drugs will typically be released over a period of at least 3 days, 7 days, 21 days, at least one month, at least three months, or at least six months. In some embodiments, a linear release of the one or more active agents or drugs is observed following implantation in a patient. Examples of active agents include, but are not limited to, small-molecule drugs, antiinflammatory agents, immunomodulatory agents, molecules that promote cell migration, molecules that promote or retard cell division, molecules that promote or retard cell proliferation and differentiation, molecules that stimulate phenotypic modification of cells, molecules that promote or retard angiogenesis, molecules that promote or retard vascularization, molecules that promote or retard extracellular matrix disposition, signaling ligands, platelet rich plasma, peptides, proteins, glycoproteins, anesthetics, hormones, antibodies, antibiotics, antimicrobials, antiparasitic agents, growth factors, fibronectin, laminin, vitronectin, integrins, steroids, hydroxyapatite, silver particles or silver ions, vitamins, non-steroidal anti-inflammatory drugs, chitosan and derivatives thereof, alginate and derivatives thereof, collagen, sugars, polysaccharides, nucleotides, oligonucleotides, lipids, lipoproteins, anti-adhesion agents, hyaluronic acid and derivatives thereof, allograft material, xenograft material, ceramics, medical glass, bio-active glass, nucleic acid molecules, antisense molecules, aptamers, siRNA, nucleic acids, and combinations thereof.

[0100] In some examples, the active agent can comprise an antimicrobial agents. Antimicrobial agents include, but are not limited to, antibacterial drugs, antiviral agents, antifungal agents, and antiparasitic drugs. Antimicrobial agents include substances that kill or inhibit the growth of microbes such as microbicidal and microbiostatic agents.

[0101] Antimicrobial agents include, but are not limited to: rifampin; minocycline and its hydrochloride, sulfate, or phosphate salt; triclosan; chlorhexidine; vancomycin and its hydrochloride, sulfate, or phosphate salt; tetracycline and its hydrochloride, sulfate, or phosphate salt, and derivatives; gentamycin; cephalosporin antimicrobials; aztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin and its sodium salt; cefazolin and its sodium salt; cefaclor, ceftibuten and its sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodium salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodium salt; cephalexin; cefamandole nafate; cefepime and its hydrochloride, sulfate, and phosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodium salt; cefixime and its sodium salt; cefpodoxime proxetil; meropenem and its sodium salt; imipenem and its sodium salt; cilastatin and its sodium salt; azithromycin; clarithromycin; dirithromycin; erythromycin and hydrochloride, sulfate, or phosphate salts, ethyl succinate, and stearate forms thereof, clindamycin; clindamycin hydrochloride, sulfate, or phosphate salt; lincomycin and hydrochloride, sulfate, or phosphate salt thereof, tobramycin and its hydrochloride, sulfate, or phosphate salt; streptomycin and its hydrochloride, sulfate, or phosphate salt; neomycin and its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole; colistimethate and its sodium salt; quinupristin; dalfopristin; amoxicillin; ampicillin and its sodium salt; clavulanic acid and its sodium or potassium salt; penicillin G; penicillin G benzathine, or procaine salt; penicillin G sodium or potassium salt; carbenicillin and its disodium or indanyl disodium salt; piperacillin and its sodium salt; ticarcillin and its disodium salt; sulbactam and its sodium salt; moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin; gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate; trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride, sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate, or phosphate salt; oxytetracycline and its hydrochloride, sulfate, or phosphate salt; chlortetracycline and its hydrochloride, sulfate, or phosphate salt; metronidazole; dapsone; atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride, sulfate, or phosphate salt; sulfacetamide and its sodium salt; clarithromycin; and silver ions, salts, and complexes.

[0102] Methods of Use

[0103] In some embodiments, the porous polymer films described herein are used as surgical meshes or implantable materials. In some examples, the porous polymer films are used in procedures such as hernia repair, breast reconstruction and augmentation, mastopexy, orthopedic repairs, wound management, pelvic floor reconstruction, including treatment of pelvic organ prolapse, including treatment of cystocele, urethrocele, uterine prolapse, vaginal fault prolapse, enterocele and rectocele, surgical treatments for incontinence, stenting, heart valve surgeries, dental procedures and other surgical procedures or plastic surgeries. Other examples of applications for the polymer films described herein include wound closure device, patch, wound healing device, wound dressing, burn dressing, ulcer dressing, skin substitute, tracheal reconstruction device, organ salvage device, dural patch or substitute, nerve regeneration or repair device, hernia repair device, hernia mesh, hernia plug, device for temporary wound or tissue support, tissue engineering scaffold, guided tissue repair / regeneration device, antiadhesion membrane or barrier, tissue separation membrane, retention membrane, sling, device for pelvic floor reconstruction, including treatment of pelvic organ prolapse, including treatment of cystocele, urethrocele, uterine prolapse, vaginal fault prolapse, enterocele and rectocele, urethral suspension device, device for treatment of urinary incontinence, bladder repair device, bulking or filling device, bone marrow scaffold, fixation device for an implant, ligament repair device or augmentation device, anterior cruciate ligament repair device, tendon repair device or augmentation device, rotator cuff repair device, meniscus repair or regeneration device, articular cartilage repair device, osteochondral repair device, spinal fusion device, cardiovascular patch, catheter balloon, vascular closure device, intracardiac septal defect repair device, including but not limited to atrial septal defect repair devices and PFO (patent foramen ovale) closure devices, left atrial appendage (LAA) closure device, pericardial patch, vein valve, heart valve, vascular graft, myocardial regeneration device, periodontal mesh, guided tissue regeneration membrane for periodontal tissue, ocular cell implant, imaging device, cochlear implant, anastomosis device, cell seeded device, cell encapsulation device, controlled release device, drug delivery device, plastic surgery device, breast lift device, mastopexy device, breast reconstruction device, breast augmentation device (including devices for use with breast implants), breast reduction device (including devices for removal, reshaping and reorienting breast tissue), devices for breast reconstruction following mastectomy with or without breast implants, facial reconstructive device, forehead lift device, brow lift device, eyelid lift device, face lift device, rhytidectomy device, thread lift device (to lift and support sagging areas of the face, brow and neck), rhinoplasty device, device for malar augmentation, otoplasty device, neck lift device, mentoplasty device, cosmetic repair device, and device for facial scar revision.

[0104] The porous films described herein can also be used to form enclosures, pouches, holders, covers, meshes, films, clamshells, casings, and other receptacles that partially or fully encase, surround or hold implantable medical devices. Implantable medical devices that can be partially or fully encased include cardiac rhythm management (CRM) devices (including pacemakers, defibrillators, and pulse generators), implantable access systems, neurostimulators, ventricular access devices, infusion pumps, devices for delivery of medication and hydration solutions, intrathecal delivery systems, pain pumps, and other devices to provide drugs or electrical stimulation to a body part.

[0105] By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below.

[0106] EXAMPLES

[0107] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variants of the present invention, which are apparent to one skilled in the art.

[0108] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0109] Example 1. Preparation of surgical meshes using self-regulating technology based on reaction-diffusion processes.

[0110] Summary

[0111] While reaction-diffusion processes are utilized in multiple scientific fields, these phenomena have seen limited practical application in the polymer industry. Although selfregulating processes driven by parallel reaction and diffusion can lead to patterned structures, most polymeric products with repeating subunits are still prepared by methods that require complex and expensive instrumentation. A notable, high-added-value example is surgical mesh, which is often manufactured by weaving or knitting. In our present work, we demonstrate how the polymer and the biomedical industry can benefit from the pattern-forming capabilities of rection-diffusion. We would like to propose a self-regulating method that facilitates the creation of surgical meshes from biocompatible polymers. Since the control of the process assumes a thorough understanding of the underlying phenomena, the theoretical background, as well as a mathematical model that can accurately describe the empirical data, is also introduced and explained. Our method offers the benefits of conventional techniques while introducing additional advantages not attainable with them. Most importantly, the method proposed in this example enables the rapid creation of meshes with an average pore size that can be adjusted easily and tailored to fit the intended area of application.

[0112] Introduction

[0113] We would like to propose self-regulating reaction-diffusion processes that were shown to be able to produce patterns very similar to that of surgical meshes already used in regenerative medicine.

[0114] Besides the technique, the polymer is also to be selected. We aim to demonstrate the potential of our method using poly(styrene-Z>-isobutylene-Z>-styrene), abbreviated as SIBS. SIBS is an elastic block copolymer that consists of a rubbery phase containing polybutadiene segments and a glassy phase containing polystyrene segments. This polymer has been selected for multiple reasons. Firstly, SIBS is a perfect candidate for the role of an implant material. It is inert, biocompatible, does not trigger allergic or hypersensitivity reactions, and is also easily sterilizable. Secondly, SIBS has been proven to be able to function as a drug carrier matrix, a quality often expected of modem implants. Furthermore, its mechanical properties are well- suited for long-term use as a surgical mesh. The mechanical characteristics of SIBS have been extensively studied and many characteristics including modulus, tensile strength, and elongation at break values, surpass those specified as a requirement for surgical meshes. Due to the continuous, repetitive movement of the human body, the implant must also be able to withstand cyclic mechanical load. The dynamic fatigue properties of SIBS have also been studied and this polymer meets these requirements as well.

[0115] Practical considerations also influenced our choice. The first one is price: if the technology arrives at the stage of scaling up, the price of the polymer becomes a critical factor. Manufacturers, such as Kaneka, typically offer this polymer at 6-8 $ / kg, making it affordable even if large volumes are to be purchased. The last and maybe the most important factor that highlights the suitability of SIBS for the role of an implant is its current application as a coronary stent. The Boston Scientific Corporation introduced its SIBS-based coronary stent into the market as early as 2002 under the trade name TAXUS. Since then, the stent has been implanted into millions of patients. By using the methods described herein, the self-regulating production of surgical meshes also becomes possible.

[0116] Experimental Methods

[0117] Experiments that target the analysis of pattern formation. SIBS (courtesy of Kaneka) was supplied under the trade name SIB Star 073 T. According to the datasheet of the product, the polystyrene content of this grade is 30%, while the average molecular weight is below 100,000 Da. First, the polymer was dissolved in chloroform (Molar Chemicals Ltd.) at the boiling point of the solvent (approximately 62 °C); the dissolution lasted an hour under constant reflux and stirring at 300 RPM. Solutions of two different concentrations were prepared: 4 and 5 m / m% with respect to the polymer. Prior to the preparation of reaction-diffusion patterns, the solutions were cooled down to room temperature, as increased temperatures could alter the process of pattern formation drastically. Therefore, reaction-diffusion patterns were created at room temperature by using the method implemented as follows. A Petri dish of 5 cm inner diameter was filled with the precipitator medium; for this purpose, methanol, ethanol, n-propanol, i- propanol, and tert-butanol were used. All alcohols were supplied by Molar Chemicals Ltd. except tert-butanol, which was purchased from Fluka Chemicals.

[0118] Then, 300 pl of the solution of the polymer was dispensed from a 1000 pl pipette tip at the very bottom of the precipitator medium, i.e., the pipette tip was lowered to touch the center of the circular bottom of the Petri dish. In this position, the solution of the polymer was dispensed in approximately 3 s. Due to the high density of the solution (~1.4 g / ml), it spread out under the less dense precipitator medium (-0.8 g / ml, depending on the aliphatic chain of the alcohol) without visible precipitation in the first few seconds. Then, the precipitation and the formation of patterns started, which was monitored by a camera placed above the Petri dish. In order to maximize contrast, black paper was laid under the Petri dish and served as a background of the white polymer. In addition to the video that recorded the process of pattern formation, a static photo was also taken one hour after the start of the experiment. This photo was considered to represent the ‘after infinite amount of time’ state of the pattern formation.

[0119] Experiments that target the preparation of surgical meshes. Surgical meshes were prepared by a method similar to that described above, with the exception of using an additive. The formation of evenly distributed holes in the mesh was aided by polyethylene glycol (PEG). In our experiments, PEG with an average molecular weight of 6000 g / mol was used; the product was supplied by Sigma-Aldrich. The preparation of the solution that contained this additive was carried out as described above, except for the addition of PEG6000 to the mixture prior to the start of the reflux. The best results were achieved with a solution that contained 94 m / m% chloroform, 4 m / m% SIBS, and 2 m / m% PEG6000. Since surgical meshes that are currently available in the market usually have rectangular shapes, these samples were not created in a circular Petri dish. Instead, we let the solution of the polymers spread on rectangular glassware. Once the pattern formation finished, the sample was immersed in an aqueous bath, which made the removal of the polymer from the surface of the glass significantly easier.

[0120] Results and Discussion

[0121] The results are discussed in multiple sections. First, the process of pattern formation will be presented. In this section, the time and spatial coordinate dependence of the patterns will also be thoroughly characterized. Next, we will propose a mathematical model for the process that explains the regularity observed in the pattered samples. Lastly, we will demonstrate how the results of the pattern analysis, as well as the conclusions of the modeling, can be used to develop a method that enables the self-regulating formation of surgical meshes.

[0122] Analysis of pattern formation. The patterns obtained as a result of the experiments described above are demonstrated in FIGS. 2A-2B. The reaction-diffusion patterns observed in these figures are the result of two parallel processes. In these experiments, the reaction is the precipitation of the polymer, whereas the diffusion is that of the macromolecules that have not precipitated yet. Although the technology is rather robust and patterns similar to those shown in FIGS. 2A-2B can be created easily, the geometrical characteristics of the final pattern are very sensitive to environmental factors, including contaminations in the precipitator medium or on the surface of the Petri dish. In general, the same pattern cannot be created twice: repeated experiments yield similar, but not identical patterns. While contaminations or impurities cannot be controlled directly, the parameters of the polymer solution and the characteristics of the precipitator medium can. A comparison of FIG. 2A and FIG. 2B reveals that increasing the polymer concentration by 1 m / m% shifts the appearance of the sample from a stripe-dominated pattern to a dot-dominated pattern.

[0123] The photos shown in FIGS. 2A-2B represent the final (static) stage of pattern formation. Besides static images, videos of the process were also recorded. The video demonstrates the time-dependence of two patterns. Both experiments were carried out with the same parameters: 4 m / m% polymer solution precipitated in isopropanol. Accordingly, the precipitation starts at the same time and completes at the same time. Likewise, the precipitation starts near the perimeter of the Petri dish and gradually progresses towards its center. Despite the parallel nature of the measurements, different patterns were formed. This difference highlights again that the process is very sensitive even to minor perturbations. An additional advantage of recording a video of the precipitation is that in this way, the kinetics of the process can also be analyzed. As a first step, we converted the video to a sequence of images; then, the images were converted from the red-green-blue (RGB) color space to hue-saturation-value (HSV) color space. In HSV color space, the third parameter (value) correlates positively with the lightness of the investigated pixel. The more polymer is precipitated at the investigated point, the brighter the pixel, i.e., the larger the lightness value. Accordingly, the state of the process can be monitored by plotting the lightness values against time. We averaged the lightness value of all pixels where the polymer was expected to appear (i.e., in the Petri dish), and plotted the averages. FIG. 3A demonstrates this plot for five parallel measurements.

[0124] Due to the noise superimposed on the raw data, the tendency is difficult to discern. Therefore, the curves were averaged, which reduced the noise significantly. The averaged curve converges to a constant value; this value can be attributed to 100% conversion. The averaged values are to be multiplied by the ratio of 100% and the lightness value the averaged curve converges to. The time-conversion diagram normalized in this way is presented in FIG. 3B. The process follows saturation-like kinetics: at the beginning, the rate of precipitation is at its maximum. Then it decelerates, and the rate gradually converges to zero.

[0125] In addition to the time dependence of the process, the spatial coordinate dependence of the patterns was also analyzed. Even though parallel experiments lead to differently shaped patterns, a very important parameter of patterns yielded by parallel experiments does not depend on stochastic factors. This parameter is the spatial frequency, which, in this case, can be defined as the number of stripes (FIG. 2A) or dots (FIG. 2B) per unit distance. Spatial frequency can be calculated by Fourier transformation. Although in many engineering fields Fourier transformation is applied to signals to convert them from the time domain to the (complex) frequency domain, this mathematical apparatus can also facilitate the conversion of spatial functions from real space to reciprocal space.

[0126] In our study, we aim to use the Fourier transformation as a sophisticated mathematical tool to calculate the frequencies of periodic shapes, such as strips or dots. Technically, Fourier transformation could be performed directly on photos depicted in FIGS. 2A-2B. However, this step would yield two-dimensional spectra, which are challenging to interpret and process further. Consequently, we opted for a different approach. Instead of transforming the entire image, we have extracted small portions of the pattern, such as the one shown in FIG. 4A. This sampling was done in a representative manner, i.e., samples were taken from uniformly distributed locations. The lightness value - spatial coordinate function of a sample obtained in this way is also shown in FIG. 4A. Then, this function was transformed into the reciprocal space by onedimensional Fourier transformation; see FIG. 4B.

[0127] By using the methods introduced and explained above, we have analyzed the time and spatial coordinate dependence of these patterns thoroughly. The results are compiled in FIGS. 5A-5B

[0128] A convenient way to quantize the rate of the conversion graphically represented in FIG. 3B is the calculation of the slope of the regression curve at the beginning of the process. The value obtained in this way is plotted on the vertical axis of FIG. 5A. As an independent variable, the length of the aliphatic chain in the alcohol was used, i.e., the scale ranges from methanol to butanol. The sequence of points outlines a clear tendency: the longer the aliphatic chain, the slower the precipitation. This tendency is due to the chemical potential of SIBS across the homologous series of aliphatic alcohols. The chemical potential of the polymer is the largest in methanol. Accordingly, the precipitation occurs very rapidly here. As the length of the aliphatic chain increases, the chemical potential of the polymer in the alcohol decreases, which also means that the thermodynamic driving force of the material transport becomes reduced. Thus, there is a negative correlation between the rate of process and the length of the aliphatic chain, as proven empirically by FIG. 5A.

[0129] FIG. 5B is dedicated to the second measured parameter, i.e., the spatial frequency of the patterns. Rather than the length of the aliphatic chain, the diffusion coefficient of the alcohol was selected here as an independent variable. Experiments carried out in methanol are omitted because the rapid precipitation leads to patterns that are challenging to analyze accurately. Instead, both n-propanol and i-propanol are represented in this diagram. The tendency outlined by the empirical data reveals that the faster the diffusion of the alcohol, the larger the spatial frequency of the pattern will be. In practice, this means that the number of characteristic geometrical elements (such as stripes or dots) per unit length can be increased by selecting a precipitator medium with a shorter aliphatic chain. The positive correlation demonstrated by Fig 5B also enables the control of the spatial frequency of the pattern.

[0130] Modeling of the process. The first model that was discussed in the introduction was proposed by Gierer and Meinhardt. Although this approach can provide a surprisingly accurate mathematical representation of the reactions that take place in living organisms, we have found that the activator-inhibitor approach the Gierer-Meinhardt model relies on does not comply with the process we are investigating here. In contrast, the Gray-Scott model assumes consecutive reactions, which aligns well with the gradual precipitation of the polymer. Therefore, we opted for the application of the Gray-Scott model, which is generally expressed in the following form:

[0131] In our experimental arrangement, A and B represent the amount of dissolved polymer and the polymer being precipitated, respectively. Parameter f stands for a rate of material transport: the translation of alcohol molecules into the solution of the polymer that continuously increases the number of macromolecules that will be precipitated. Parameter k marks the rate of precipitation, whereas DA and DB are the diffusion coefficients. The nabla operator represents the partial derivative with respect to spatial coordinates; the second independent variable (time) is denoted by t. First, the differential equation system was solved in one dimension. For this purpose, our research team wrote a purpose-specific software in MATLAB. The time and spatial coordinate dependence of the solution is shown in FIGS. 6A-6C and is also illustrated by a video.

[0132] The solution takes the form of a surface function, as one dependent variable (concentration) is attributed to two independent variables (spatial coordinate and time). The surface function is shown in FIG. 6A. A more adequate representation of how the concentration profile evolves over time could be based on the selection of only a few time coordinates. FIG. 6B demonstrates that even if the concentration profile is irregular around t=0 min, it gradually transforms into an almost perfectly sinusoidal curve; see the profile at t=2 min. The self- regulating process and the transformation that will ultimately lead to a sinusoidal function are also presented in a more conventional, two-dimensional diagram; see FIG. 6C. Videos can offer a more sophisticated method to depict time dependence. Therefore, a video was also prepared that portrayed the self-regulation animatedly

[0133] Although the diagrams presented in FIGS. 6A-6C and the animations in the video we prepared highlight the self-regulating nature of the investigated reaction-diffusion phenomena, one-dimensional simulations have little practical significance. Therefore, the equation system that consists of Eqs. 1 and 2 was solved in two dimensions as well. The results are presented in FIGS. 7A-7D and a supplementary video. FIGS. 7A and 7C demonstrate the final state of a simulation that started with perfectly regular initial conditions. Conversely, the pattern observed in FIGS. 7B and 7D are not symmetric, owing to the irregular nature of the initial conditions this simulation was carried out with. Besides the geometry of the patterns, the time dependence of the process is also similar to that observed in actual experiments. The precipitation starts at the perimeter of the sample holder and gradually progresses towards the center. This tendency is demonstrated in a video.

[0134] Utilization of self-regulation and creation of surgical meshes. The most important conclusion of the simulations discussed above is that the self-regulating process leads to patterns that can be characterized by one spatial frequency - regardless of the initial conditions. We would like to draw attention to the progress displayed in FIG. 6C again: the final profile is a sinusoidal function, which can be represented by one constant wavelength. Even if the initial concentration profile was irregular, the final profile is always a regular sinusoidal of one frequency. Mathematically, self-regulation functions as a bandpass filter: it reduces the amplitude of all frequencies except for a specific one, which it allows to pass. This bandpass filter effect is graphically represented in FIGS. 8A-8B. The spectrum of the concentration profile attributed to t=0 min is a red noise: it has many components; those belonging to higher frequencies have attenuated amplitudes (FIG. 8A). In comparison, the concentration profile in the final (static) state is almost a perfect harmonic function. Accordingly, its spectrum consists of only one component: one dominant peak appears at the frequency of the sinusoidal function (FIG. 8B) The amplitudes of the remaining peaks are marginal, i.e., the self-regulating process acts as a very effective bandpass filter.

[0135] A comparison of FIG. 8B and FIG. 4B also reveals that the results of the modeling presented above can describe empirical data very well. Consequently, we can safely assume that an experimental plan can rely on the bandpass filter effect displayed in FIGS. 8A-8B. Therefore, we decided to utilize this concept in practice and created meshes with holes yielded by parallel precipitation and diffusion. Due to self-regulation and the filter effect discussed above, the holes that formed during the experiment are evenly distributed and have a narrow distribution of diameters; see FIG. 9A. Regarding this figure, we would like to point out that this kind of hole formation will be achieved if the solution of the polymer contains an additive (PEG; see the experimental section). PEG is fully biocompatible and is already used extensively under in vivo conditions [44-46], Therefore, the presence of this additive will not hinder the application of surgical meshes manufactured with our method.

[0136] Another advantage of the method we propose here is that the average size of the holes can also be adjusted and tailored to the desired application. The faster the process of precipitation, the smaller the holes will be. Therefore, if a mesh with holes smaller than those displayed in FIG. 9B is required, the rate of precipitation is to be increased. A convenient and straightforward way of accelerating the precipitation is to apply less solution of the polymer onto the surface of the glassware. In this way, after the solution spreads, the thickness of the layer will be thinner, which will speed up the process. By fine-tuning the thickness of the layer of the polymer solution, we were able to achieve an average pore size as little as -200 pm; see FIG.

[0137] 9B

[0138] FIGS. 9A-9B reveal that our method facilitates the creation of surgical meshes with an average hole / pore size falling in the 2 mm - 200 pm range. Several publications [24,39,47] mention the importance of this parameter and report that the optimal value is in the -100 pm - few millimeters range (the exact value depends on the intended area of application [24,39,47]). Since the meshes created with our method cover most of this interval, they appear to be an ideal candidate for medical applications. Furthermore, these meshes do not consist of individual fibers, unlike the ones currently available for the biomedical industry. Due to the fibrous composition and direction-dependent mechanical characteristics of contemporarily applied meshes, the surgeon must pay very close attention to their orientation during implanting [48,49], In contrast, the meshes shown in FIGS. 9A-9B do not consist of woven or knitted fibers. Therefore, their mechanical properties are orientation-independent, which potentially simplifies surgical procedures and reduces associated risks.

[0139] Conclusion

[0140] The controlled precipitation of SIBS yields reaction-diffusion patterns. The geometrical characteristics of the patterns, such as the relative amounts of dots, stripes, and holes, can be adjusted by varying the parameters of the precipitation. Pattern formation is very susceptible to minor perturbations; therefore, the same pattern cannot be created twice. In contrast, the macroscopic characteristics of the patterns, most importantly the dominant spatial frequency, are fully deterministic and easily reproducible. Spatial frequency can be measured by processing the data extracted from the photos of the patterns with Fourier transformation. The deterministic nature of dominant spatial frequency can also be modeled mathematically. The time and the spatial coordinate dependence of the concentration of each component can be described by numerically solving the partial differential equation system of the model. Modeling reveals that the process acts as a bandpass filter: the final concentration profiles will always be sinusoidal, regardless of the irregularities in the initial conditions. In practice, this means that the dominant geometric elements, e.g., dots, stripes, or holes, will be distributed uniformly. This kind of selfregulation can be utilized to create surgical meshes with evenly distributed holes that have a narrow distribution of diameters. Therefore, meshes created with our method rival the uniformity and regularity of those manufactured by weaving or knitting. In addition to meeting the industry standards for meshes currently available in the market, our technique offers further benefits. By varying the parameters of pattern formation, the average pore size of the surgical mesh can be adjusted, which facilitates the rapid tailoring of the process to the intended area of application.

[0141] References

[0142] [1] S. Roth, Mathematics and biology: a Kantian view on the history of pattern formation theory, Dev Genes Evol. 221 (2011) 255-279.

[0143] [2] A. Turing, The chemical basis of morphogenesis, Philos Trans R Soc Lond B Biol Sci. 237 (1952) 37-72.

[0144] [3] C.H. Waddington, Principles of embryology / by C.H. Waddington., Macmillan, New York; 1956.

[0145] [4] A. Gierer, H. Meinhardt, A theory of biological pattern formation, Kybemetik. 12 (1972) 30-39.

[0146] [5] H. Meinhardt, Turing’s theory of morphogenesis of 1952 and the subsequent discovery of the crucial role of local self-enhancement and long-range inhibition, Interface Focus. 2 (2012) 407-416.

[0147] [6] H. Meinhardt, A. Gierer, Pattern formation by local self-activation and lateral inhibition, BioEssays. 22 (2000) 753-760.

[0148] [7] H. Meinhardt, A Model for Pattern Formation of Hypostome, Tentacles, and Foot in Hydra: How to Form Structures Close to Each Other, How to Form Them at a Distance, Dev Biol. 157 (1993) 321-333.

[0149] [8] H. Meinhardt, Models of Biological Pattern Formation: From Elementary Steps to the Organization of Embryonic Axes, in: 2008: pp. 1-63. [9] A. Gierer, S. Berking, H. Bode, C.N. David, K. Flick, G. Hansmann, H. Schaller, E. Trenkner, Regeneration of Hydra from Reaggregated Cells, Nat New Biol. 239 (1972) 98-101.

[0150]

[0010] M. Yamaguchi, E. Yoshimoto, S. Kondo, Pattern regulation in the stripe of zebrafish suggests an underlying dynamic and autonomous mechanism, Proceedings of the National Academy of Sciences. 104 (2007) 4790-4793.

[0151]

[0011] J.-G. Lian, H.-K. Zhang, Stability of t-periodic solution on the extended simplified Brusselator model, International Journal of Biomathematics. 01 (2008) 19-27.

[0152]

[0012] M.E. Rahman, A. Kumar, S. Singh, On the nonlinear characteristics of two-phase flow system as modified Fitzhugh-Nagumo model, Int J Heat Mass Transf. 207 (2023) 123963.

[0153]

[0013] P. Gray, S.K. Scott, Autocatalytic reactions in the isothermal, continuous stirred tank reactor, Chem Eng Sci. 38 (1983) 29-43.

[0154]

[0014] D. Ming, D. Glasser, D. Hildebrandt, Application of attainable region theory to batch reactors, Chem Eng Sci. 99 (2013) 203-214.

[0155]

[0015] W. Chaivorapoj, I. Birol, A. Cinar, F. Teymour, Feedback Control of a Continuous-Flow Stirred Tank Reactor with Competing Autocatalators, Ind Eng Chem Res. 42 (2003) 3765-3785.

[0156]

[0016] A.A. Kiss, C.S. Bildea, A.C. Dimian, PD. ledema, State multiplicity in PFR-separator- recycle polymerization systems, Chem Eng Sci. 58 (2003) 2973-2984.

[0157]

[0017] A.K. Bhattacharjee, K. Balakrishnan, A.L. Garcia, J.B. Bell, A. Donev, Fluctuating hydrodynamics of multi-species reactive mixtures, J Chem Phys. 142 (2015).

[0158]

[0018] VYa. Shevchenko, M.M. Sychev, A.I. Makogon, Modeling Reaction-Diffusion Processes of the Formation of Diamond-Silicon Carbide Composites, Glass Physics and Chemistry. 47 (2021) 289-296.

[0159]

[0019] VYa. Shevchenko, S.K. Gordeev, A.S. Oryshchenko, V.N. Sokolov, L.A. Lebedev, M.M. Sychev, N.A. Khristyuk, On the Formation of the Minimal-Energy Surface in the Solid-State Reactions of the Formation of Chromium Carbide, Glass Physics and Chemistry. 44 (2018) 518— 523.

[0160]

[0020] S.N. Hankins, R.S. Fertig, Methodology for optimizing composite design via biological pattern generation mechanisms, Mater Des. 197 (2021) 109208.

[0161]

[0021] S. Wang, X. Wang, M.A. Holland, Multi-physics modeling and finite-element formulation of neuronal dendrite growth with electrical polarization, Brain Multiphys. 4 (2023) 100071.

[0162]

[0022] R. Bauer, F. Zubler, A. Hauri, D.R. Muir, R.J. Douglas, Developmental Origin of Patchy Axonal Connectivity in the Neocortex: A Computational Model, Cerebral Cortex. 24 (2014) 487-500.

[0023] H. Hardway, Gene network models robust to spatial scaling and noisy input, Math Biosci. 237 (2012) 1-16.

[0163]

[0024] K. Bayion, P. Rodriguez-Camarillo, A. Elias-Zuniga, J. Diaz-Elizondo, R. Gilkerson, K. Lozano, Past, Present and Future of Surgical Meshes: A Review, Membranes (Basel). 7 (2017) 47.

[0164]

[0025] M.W. Laschke, J.M. Haufel, H. Thorlacius, M.D. Menger, New experimental approach to study host tissue response to surgical mesh materialsin vivo, J Biomed Mater Res A. 74A (2005) 696-704.

[0165]

[0026] U. Klinge, B. Klosterhalfen, A.P Ottinger, K. Junge, V. Schumpelick, PVDF as a new polymer for the construction of surgical meshes, Biomaterials. 23 (2002) 3487-3493.

[0166]

[0027] X. Wang, C. Han, X. Hu, H. Sun, C. You, C. Gao, Y. Haiyang, Applications of knitted mesh fabrication techniques to scaffolds for tissue engineering and regenerative medicine, J Meeh Behav Biomed Mater. 4 (2011) 922-932.

[0167]

[0028] X. Wang, P. Wu, X. Hu, C. You, R. Guo, H. Shi, S. Guo, H. Zhou, Y. Chaoheng, Y. Zhang, C. Han, Polyurethane membrane / knitted mesh-reinforced collagen-chitosan bilayer dermal substitute for the repair of full-thickness skin defects via a two-step procedure, J Meeh Behav Biomed Mater. 56 (2016) 120-133.

[0168]

[0029] B. Aghaei-Ghareh-Bolagh, S.M. Mithieux, M.A. Hiob, Y. Wang, A. Chong, A.S. Weiss, Fabricated tropoelastin-silk yams and woven textiles for diverse tissue engineering applications, Acta Biomater. 91 (2019) 112-122.

[0169]

[0030] D.A. Raptis, B. Vichova, J. Breza, J. Skipworth, S. Barker, A Comparison of Woven Versus Nonwoven Polypropylene (PP) and Expanded Versus Condensed Polytetrafluoroethylene (PTFE) on Their Intraperitoneal Incorporation and Adhesion Formation, Journal of Surgical Research. 169 (2011) 1-6.

[0170]

[0031] F. Corduas, D.A. Lamprou, E. Mancuso, Next-generation surgical meshes for drug delivery and tissue engineering applications: materials, design and emerging manufacturing technologies, Biodes Manuf. 4 (2021) 278-310.

[0171]

[0032] D.H. Ballard, U. Jammalamadaka, K. Tappa, J. A. Weisman, C.J. Boyer, J.S. Alexander, PK. Woodard, 3D printing of surgical hernia meshes impregnated with contrast agents: in vitro proof of concept with imaging characteristics on computed tomography, 3D Print Med. 4 (2018) 13.

[0172]

[0033] D.S. Morgan, T.J. Kaper, Axisymmetric ring solutions of the 2D Gray-Scott model and their destabilization into spots, Physica D. 192 (2004) 33-62.

[0034] L. Pinchuk, G.J. Wilson, J.J. Barry, R.T. Schoephoerster, J.-M. Parel, J.P. Kennedy, Medical applications of poly(styrene-block-isobutylene-block-styrene) (“SIBS”), Biomaterials. 29 (2008) 448-460.

[0173]

[0035] M. El Fray, P. Prowans, J.E. Puskas, V. Altstadt, Biocompatibility and Fatigue Properties of Polystyrene-Polyisobutylene-Polystyrene, an Emerging Thermoplastic Elastomeric Biomaterial, Biomacromolecules. 7 (2006) 844-850.

[0174]

[0036] J.E. Puskas, L.G. Munoz-Robledo, R.A. Hoerr, J. Foley, S.P. Schmidt, M. Evancho- Chapman, J. Dong, C. Frethem, G. Haugstad, Drug-eluting stent coatings, WIREs Nanomedicine and Nanobiotechnology. 1 (2009) 451-462.

[0175]

[0037] P. Antony, J.E. Puskas, M. Kontopoulou, Investigation of the rheological and mechanical properties of a polystyrene-polyisobutylene-polystyrene triblock copolymer and its blends with polystyrene, Polym Eng Sci. 43 (2003) 243-253.

[0176]

[0038] J.E. Puskas, M. El Fray, M. Tomkins, L.M. Dos Santos, F. Fischer, V. Altstadt, Dynamic stress relaxation of thermoplastic elastomeric biomaterials, Polymer (Guildf). 50 (2009) 245- 249.

[0177]

[0039] T. Saha, X. Wang, R. Padhye, S. Houshyar, A review of recent developments of polypropylene surgical mesh for hernia repair, OpenNano. 7 (2022) 100046.

[0178]

[0040] A.L. Gergely, J.E. Puskas, Synthesis and characterization of thermoplastic elastomers with polyisobutylene and polyalloocimene blocks, J Polym Sci A Polym Chem. 53 (2015) 1567— 1574.

[0179]

[0041] K.R. Kamath, J.J. Barry, K.M. Miller, The TaxusTM drug-eluting stent: Anew paradigm in controlled drug delivery, Adv Drug Deliv Rev. 58 (2006) 412-436.

[0180]

[0042] J.E. Puskas, Y. Kwon, P. Antony, A.K. Bhowmick, Synthesis and characterization of novel dendritic (arborescent, hyperbranched) polyisobutylene-polystyrene block copolymers, J Polym Sci A Polym Chem. 43 (2005) 1811-1826.

[0181]

[0043] N.J. Weissman, M.A. Turco, J.A. Ormiston, T. Mann, L.A. Cannon, T.F. McGarry, M.W.I. Webster, J.J. Hall, M.J. Lucca, G.J. Mishkel, C.-J. Wu, L. Mandinov, K.D. Dawkins, Improved strut coverage and less late incomplete apposition with thin-strut TAXUS Liberte vs. TAXUS Express: the importance of stent platform design for drug-eluting stents, Cardiovascular Revascularization Medicine. 12 (2011) 247-257.

[0182]

[0044] Y. Fu, Y. Ding, L. Zhang, Y. Zhang, J. Liu, P. Yu, Poly ethylene glycol (PEG)-Related controllable and sustainable antidiabetic drug delivery systems, Eur J Med Chem. 217 (2021) 113372.

[0045] J. Shi, L. Yu, J. Ding, PEG-based thermosensitive and biodegradable hydrogels, Acta Biomater. 128 (2021) 42-59.

[0183]

[0046] A.B. Kutikov, J. Song, Biodegradable PEG-Based Amphiphilic Block Copolymers for Tissue Engineering Applications, ACS Biomater Sci Eng. 1 (2015) 463-480.

[0184]

[0047] Y. Bilsel, I. Abci, The search for ideal hernia repair; mesh materials and types, International Journal of Surgery. 10 (2012) 317-321.

[0185]

[0048] W. He, F. Shen, Z. Xu, B. Pei, H. Xie, X. Li, The Effect of Mesh Orientation, Defect Location and Size on the Biomechanical Compatibility of Hernia Mesh, IRBM. 44 (2023) 100777.

[0186]

[0049] E.R. Saberski, S.B. Orenstein, YW. Novitsky, Anisotropic evaluation of synthetic surgical meshes, Hernia. 15 (2011) 47-52.

[0187] Example 2. Preparation of drug-eluting surgical meshes using self-regulating manufacturing technology

[0188] Preparation of meshes containing polymer only (no drug model)

[0189] Poly(styrene-Z>-isobutylene-Z>-styrene) (SIBS) was supplied by Kaneka under the trade name SIBStar 073T. According to the datasheet of the product, the polystyrene content of this grade is 30%, while the average molecular weight is below 100,000 Da. First, 3.725 g polymer was dissolved in 47.5 mL chloroform (Sigma-Aldrich, Lot number SHBQ8447) at the boiling point of the solvent (approximately 62 °C). The dissolution lasted an hour under constant reflux and stirring at 300 RPM. The concentration of the solution was 5 wt% with respect to the polymer. Then, the solution was cooled down to room temperature. From this solution, 15 mL was poured into a 20 mL glass vial. To this vial, 0.691 g PEG 4600 was added (Aldrich, Lot number 14316AC). In these experiments, PEG serves as an additive that aids pore formation. Due to the excellent solubility of low MwPEG in chloroform, the dissolution of PEG was possible to carry out using manual shaking only (no refluxing at the boiling point of chloroform was needed). From this solution, 400 pL was taken and dispersed on a 3.5 cm x 3.5 cm glass surface. This step was carried out using a 200 pL automatic pipette (z.e., 400 pL was taken in two consecutive steps). Ensuring that the 400 pL liquid is dispersed uniformly on the 3.5 cm x 3.5 cm glass surface is essential (the thickness of the liquid layer on the surface must not depend on the spatial coordinate); otherwise, considerable variations in the pore size could occur. In the next step, the solvent (chloroform) evaporates. During evaporation, pores are formed; see FIG. 11. In the last step, the mesh was removed from the glass surface. Preparation of drug-loaded SIBS meshes

[0190] The preparation of drug-loaded surgical meshes was carried out according to the procedure described above. The only difference was that 15 mg of model drug was added to the glass vial already containing 15 mL of the polymer solution. As a model drug, curcumin was used. Curcumin was extracted from turmeric; the material was purchased from Walmart (product ID: 525771648). Dissolution of curcumin was carried out at room temperature and required 5 minutes-long manual shaking of the glass vial. After the dissolution of curcumin was completed, a mesh was created exactly as described above. The photo of the drug-loaded mesh is shown in FIG. 12. The presence of the drug does not compromise the viability of this manufacturing method. However, in one week, the color almost completely disappears (FIG. 13). The chemical composition can be characterized using SEM-EDS and XPS.

[0191] Preparation of meshes containing the model drug Cristal Violet

[0192] Poly(styrene-Z>-isobutylene-Z>-styrene) (SIBS) was supplied by Kaneka under the trade name SIBStar 073T. According to the datasheet of the product, the polystyrene content of this grade is 30%, while the average molecular weight is below 100,000 Da. First, 3.725 g polymer was dissolved in 47.5 mL chloroform (Sigma-Aldrich, Lot number SHBQ8447) at the boiling point of the solvent (approximately 62 °C). The dissolution lasted an hour under constant reflux and stirring at 300 RPM. The concentration of the solution was 5 wt% with respect to the polymer. Then, the solution was cooled down to room temperature. From this solution, 15 mL was mixed with 34.64 mg Crystal Violet (CV), a model drug. The mixture was poured into a 20 mL glass vial. To this vial, 0.691 g PEG 4600 was added (Aldrich, Lot number 14316AC). In these experiments, PEG serves as an additive that aids pore formation. Due to the excellent solubility of low MwPEG in chloroform, the dissolution of PEG was possible to carry out using manual shaking only (no refluxing at the boiling point of chloroform was needed). From this solution, 400 pL was taken and dispersed on a 3.5 cm x 3.5 cm glass surface. This step was carried out using a 200 pL automatic pipette (z.e., 400 pL was taken in two consecutive steps). Ensuring that the 400 pL liquid is dispersed uniformly on the 3.5 cm x 3.5 cm glass surface is essential (the thickness of the liquid layer on the surface must not depend on the spatial coordinate); otherwise, considerable variations in the pore size could occur. In the next step, the solvent (chloroform) evaporates. During evaporation, pores are formed; see FIG. 14. In the last step, the mesh was removed from the glass surface. The drug content of the mesh was 3 wt% with respect to SIBS. The mass of the mesh was 30.724 mg, containing 0.924 mg CV.

[0193] As a model drug, Crystal Violet (4-{Bis[4-(dimethylamino) phenyl]methylidene}-N,N- dimethylcyclohexa-2,5-dien-l-iminium chloride) was used. Crystal Violet (CV) has been used as an antibacterial drug before the development of modem antibiotics. It can also be applied as a dye in the Gram staining process because its molar absorption coefficient is very large, enabling its detection and quantitative analysis even if it is present in the investigated medium in a small concentration. The chemical structure of CV is shown in FIG. 15.

[0194] The ionic form gives the compound a bright blue color. Due to the very nonpolar nature of SIBS, the color of the mesh containing CV faded over time.

[0195] Monitoring of CV Release from an SIBS mesh

[0196] CV release from SIBS was monitored using a Thin Layer Chromatography (TLC) method.

[0197] To create a calibration plot, a dilution sequence spanning the 0.5 - 0.0001 mg / ml concentration range was created. The solvent of the dilution sequence was water.

[0198] Table 1: CV dilution sequence.

[0199] Next, 15 pl of each solution was applied onto the surface of a TLC plate (FIG. 16).

[0200] The intensity of the purple color shown in FIG. 16 correlates positively (although nonlinearly) with the amount of drug present in the sample. Therefore, this dilution sequence can be used for calibration. The computational method of Red-Green -Blue —> Hue- Saturation- Value (RGB— >HSV) data conversion and color intensity (‘Saturation’) data extraction can be performed from regions of the TLC plate. In the next step, the surface integral of each dot (represented by a peak in the three-dimensional visualization) can be calculated. Mathematically, the surface integral can be expressed as follows.

[0201] In Eq. 1, S(x,y) is the surface function containing the saturation parameters of the pixels, and x, y are the spatial coordinates. Plotting these surface integrals against the concentration yields the calibration diagram; see FIG. 17. Since the last two samples in the dilution series (PP_2025_02_25_I and PP_2025_02_25_J in Table I) did not provide a visible color (see FIG. 16), they were omitted. Since the points outline a nonlinear tendency, calculating the regression requires an iterative computational method. For this purpose, the Levenberg- Marquardt algorithm was used. The regression function was Eq. 2.

[0202] In this equation, the dependent variable (y) represents the calculated surface integral (see Eq. 1), while x is the independent variable (concentration of crystal violet in this particular case). The remaining letters (a, b, and c) denote the regression parameters.

[0203] The best possible fit (R2= 0.9769) was achieved by using a=-6.912, Z>=15.93, and c=0.1037.

[0204] The mesh was placed into 50 ml PBS buffer, which served as the release medium. As shown in FIG. 18, CV was immediately released.

[0205] This step was followed by a 24-hour waiting period during which the release medium was not stirred. After 24 hours, a second 15 pL sample was taken and analyzed immediately. The same sampling procedure was repeated 48 hours (third sample) and 72 hours (fourth sample) after the start of the release study. Thus, 4 samples were collected and analyzed in total. The saturation surface integrals were converted to concentrations. The release profiles are visualized in FIG. 19A-19B.

[0206] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

[0207] The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.

Claims

WHAT IS CLAIMED IS:

1. A method of forming a porous polymer film utilizing reaction-diffusion phenomena, the method comprising: dissolving a thermoplastic elastomeric polymer (TPE) in a first solvent to form a polymer solution; contacting a layer of the polymer solution with a layer of a precipitator medium; and allowing diffusion to occur between the polymer solution and the precipitator medium, thereby inducing precipitation of a porous polymer film comprising the TPE.

2. The method of claim 1, wherein the layer of the precipitator medium has a first volume and the layer of the polymer solution has a second volume; and wherein the ratio of the first volume to the second volume is from 2.5: 1 to 100: 1, such as from 2.5: 1 to 50: 1, from 2.5: 1 to 25: 1, from 5: 1 to 100: 1, from 5: 1 to 50: 1, or from 5: 1 to 25: 1.

3. The method of any one of claims 1-2, wherein the layer of the polymer solution has a thickness of from 0.1 mm to 10 mm, such as from 0.5 mm to 5 mm; wherein the layer of a resulting mat has a thickness of from 0.01 mm to 1 mm, such as from 0.05 mm to 0.5 mm; or a combination thereof.

4. The method of any one of claims 1-3, wherein layer of the precipitator medium has a thickness of from 0.5 mm to 25 mm, such as from 1 mm to 25 mm; wherein the precipitator medium has a volume of at least 5 or at least 10 times greater than a volume of the polymer solution; or a combination thereof.

5. The method of any one of claims 1-4, wherein the first solvent comprises a non-polar solvent or a polar aprotic solvent.

6. The method of any one of claims 1-5, wherein the first solvent comprises a Ci-6 haloalkane, such as a Ci-4 haloalkane.

7. The method of any one of claims 1-6, wherein the first solvent comprises 1, 1,2,2- tetrachloroethane, chloroform, carbon tetrachloride, dichloromethane, or a combination thereof.

8. The method of any one of claims 1-7, wherein the first solvent has a higher density than the precipitator medium.

9. The method of any one of claims 1-8, wherein the precipitator medium comprises a polar, protic solvent.

10. The method of claim 9, wherein the precipitator medium comprises an alcohol, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or t-butyl alcohol.

11. The method of any one of claims 1-8, wherein the precipitator medium comprises acetonitrile, acetone, or a combination thereof.

12. The method of any one of claims 1-11, wherein the first solvent has a density of greater than 1.1 g / mL and the precipitator medium has a density of less than 1.0 g / mL.

13. The method of any one of claims 1-12, wherein the layer of the polymer solution is contacted with a layer of the precipitator medium on a static plate.

14. The method of any one of claims 1-12, wherein the layer of the polymer solution is contacted with the layer of a precipitator medium on a conveyor belt.

15. The method of claim 14, wherein the method comprises a continuous process.

16. The method of any one of claims 14-15, wherein the layer of the polymer solution and the layer of the precipitator medium are continuously distributed on the conveyor belt, and the porous polymer film is continuously formed and removed from the conveyor belt.

17. The method of any one of claims 1-16, wherein the porous polymer film comprises a population of pores having an average pore size of from 50 pm to 5 mm, such as from 100 pm to 5 mm, from 100 pm to 2 mm, from 200 pm to 5 mm, or 200 pm to 2 mm.

18. The method of claim 17, wherein the population of pores is monodisperse.

19. The method of any one of claims 1-18, wherein the porous polymer film has a thickness of from 0.01 mm to 2.5 mm, such as from 0.1 mm to 2.5 mm, from 0.01 mm to 1.0 mm, from 0.1 mm to 1.0 mm, from 0.01 mm to 0.5 mm, from 0.05 mm to 0.5 mm, or from 0.1 mm to 0.5 mm.

20. The method of any one of claims 1-19, wherein the TPE comprises a polyisobutylene- based TPE.

21. The method of any one of claims 1-20, wherein the TPE comprises triblock copolymer having at least one elastomeric polyisobutylene block.

22. The method of any one of claims 1-21, wherein the TPE comprises polystyrene- polyisobutylene-polystyrene (SIBS).

23. The method of any one of claims 1-21, wherein the TPE comprises poly(alloocimene-b- isobutylene-b-alloocimene).

24. The method of any one of claims 1-23, wherein the TPE has a structure selected from the group consisting of linear, star, arborescent, comb, brush, centipede, hyperbranched, and dendritic.

25. The method of any one of claims 1-24, wherein the TPE is present in the polymer solution at a concentration of from 1% by weight to 25% by weight, based on the total weight of the polymer solution, such as from 2.5% by weight to 25% by weight, from 2.5% by weight to 20% by weight, from 2.5% by weight to 15% by weight, or from 2.5% by weight to 10% by weight.

26. The method of any one of claims 1-25, wherein the polymer solution further comprises an additive27. The method of claim 26, wherein the additive comprises a polymeric additive, such as a hydrophilic polymer.

28. The method of claim 27, wherein the hydrophilic polymer comprises a polyalkylene oxide, such as polyethylene glycol or a copolymer thereof.

29. The method of any one of claims 26-28, wherein the additive comprises an inorganic additive, such as a metal oxide (e.g., zinc oxide).

30. The method of any one of claims 26-29, wherein the additive comprises an active agent.

31. The method of claim 30, wherein the active agent comprises a therapeutic agent, a prophylactic agent, or a diagnostic agent.

32. The method of any one of claims 30-31, wherein the active agent is selected from the group consisting of proteins or peptides, nucleic acids, lipids, sugars or polysaccharides, small molecules, or combinations thereof.

33. The method of any one of claims 30-32, wherein the active agent is present in an amount of from between 0.5% and 70% weight / weight, between 1% and 50% weight / weight, or between 5% and 30% weight / weight in the polymer solution.

34. The method of any one of claims 1-33, further comprising altering the composition of the first solvent, the precipitator medium, or a combination thereof to alter the average pore size of pores present in the porous polymer film.

35. The method of any one of claims 1-34, further comprising altering the concentration of the TPE present in the polymer solution to alter the average pore size of pores present in the porous polymer film.

36. The method of any one of claims 1-35, wherein the layer of the precipitator medium has a first volume and the layer of the polymer solution has a second volume; and wherein the method further comprises altering the ratio of the first volume to the second volume to alter the average pore size of pores present in the porous polymer film.

37. The method of any one of claims 1-36, wherein the method leverages the pattern-forming capabilities and self-regulating nature of parallel reaction and diffusion.

38. A porous polymer film prepared by the method of any of claims 1-37.

39. The method of claim 38, wherein the porous polymer film is a surgical mesh.

Images