Free Fatty Acid-Based Composites

Abstract

An improved material, preferably a biomaterial, is provided which is the reaction product of S.sub.8 and a free fatty acid or free fatty acid-containing material, preferably in the presence of metal. The improved material can be made by a method comprising reacting S.sub.8 with a free fatty acid to obtain a FFA/S.sub.8 composite and shaping the FFA/S.sub.8 composite into a solid form. The solid form of said FFA/S.sub.8 is melted to form melted FFA/S.sub.8 and the melted FFA/S.sub.8 is optionally applied as a coating on a surface, used as an adjacent material to a surface or the FFA/S.sub.8 composite itself is shaped thereby forming a device and preferably a medical device.

Claims

1. A material comprising a reaction product of S.sub.8 and a free fatty acid.

2. The material of claim 1 wherein said fatty acid is a free fatty acid from an animal rendering.

3. The material of claim 1 further comprising the reaction product of S.sub.8 and at least one of a triglyceride or a rancid free fatty acid.

4. The material of claim 1 further comprising the reaction product of S.sub.8 and a mixture of free fatty acids.

5. A medical device comprising said reaction product of claim 1.

6. The medical device of claim 5 further comprising a surface.

7. The medical device of claim 6 wherein said surface comprises a material selected from the group consisting of stainless steel, titanium, polyethylene or Teflon.

8. The medical device of claim 5 wherein said reaction product is coated on a surface or is adjacent said surface.

9. A method for forming a material comprising: reacting S.sub.8 with a free fatty acid to obtain a FFA/S.sub.8 composite; and shaping said FFA/S.sub.8 composite into a solid form.

10. The method for forming a device of claim 9 further comprising: melting said solid form to form melted FFA/S.sub.8; and applying said melted FFA/S.sub.8 to a surface thereby forming said device.

11. The method for forming a material of claim 10 wherein said surface comprises a material selected from the group consisting of stainless steel, titanium, polyethylene or Teflon.

12. The method for forming a material of claim 9 wherein said fatty acid is a free fatty acid from an animal rendering.

13. The method for forming a material of claim 9 further comprising the reaction product of S.sub.8 and at least one of a triglyceride or a rancid free fatty acid.

14. The method for forming a material of claim 9 further comprising the reaction product of S.sub.8 and a mixture of free fatty acids.

15. The method for forming a material of claim 9 wherein said reacting is at a temperature of above 159 C.

16. The method for forming a material of claim 9 wherein said solid form is selected from the group consisting of pellets, rods, sheets, and blocks.

17. The method for forming a material of claim 9 further comprising addition of an additive to said material.

18. The method for forming a material of claim 17 wherein said additive is selected from the group consisting of metals, ceramics, cermet, aggregates, lignin-based products, fiberous materials, polymeric based materials, natural or plant-based material, glasses, inert fillers, antimicrobials, antibiotics and sacrificial materials

19. The method for forming a medical device of claim 17 wherein said additive is selected from the group consisting of iron, Zn, ZnO, crystalline ceramics, non-crystalline ceramics, gravel, wood, hemp, carbon fibers, fiberglass, and silicon oxide

Description

BRIEF DESCRIPTION OF FIGURES

[0015] FIG. 1 is a schematic representation of sulfur crosslinking of FFA.

DESCRIPTION

[0016] The present invention is related to an improved FFA, particularly an FFA obtained by animal rendering, wherein the FFA is crosslinked with elemental sulfur, Ss.

[0017] In the instant invention elemental sulfur, Ss, is employed to crosslink unsaturated FFAs, by a mechanism similar to the well-established thiolene reaction, referred to herein as thiolene-like, thereby generating a crosslinked material referred to herein as an FFA/S.sub.8 composite. The FFA/S.sub.8 composite is advantageous as it is relatively free from the hazards of degradation and immune response activation. The FFA/S.sub.8 composites are expected to be inherently antibacterial and antimicrobial and therefore the FFA/S.sub.8 composite are particularly suitable as biomaterials and are likely to provide a transformative advance in human medical device implant technology.

[0018] The mechanical stability and thermal recycling properties also allow for improved coatings or for use in adjacent surfaces in many applications.

[0019] When compared to the gold standard lubricant, such as for joint replacements, the FFA/S.sub.8 composite will likely have lower infection rates due to its innate antimicrobial action and ability to not trigger the FBR. Since fatty acids naturally occur in the body they are far less likely to trigger FBR and therefore the materials are expected to be superior for medical applications.

[0020] In the thiol-ene reaction, a thiol (R.sup.1SH) reacts with unsaturated, preferably alkene, bonds by the following reaction:

R.sup.1SH+HR.sup.2CCR.sup.3H.fwdarw.R.sup.1SCR.sup.2HCR.sup.3H.sub.2. Reaction 1

[0021] Because the electronegativity of sulfur is nearly identical to that of carbon, the thiol-ene-like reaction represents a non-oxidative crosslinking process. Of particular importance is the fact that S.sub.8 is inherently antibacterial and antimicrobial, therefore any Ss crosslinked FFA-based biomaterials will preclude the possibility of patients becoming infected by implanted materials thereby mitigating a leading cause of postoperative infection and implant failure.

[0022] By extension of Reaction 1, S.sub.8, can react with unsaturated, preferably alkene, bonds by the following reaction:

HR.sup.2CCR.sup.3H+S.sub.8+HR.sup.4CCR.sup.5H.fwdarw.H.sub.2CR.sup.2HR.sup.3CS.sub.xCR.sup.4HCR.sup.5H.sub.2 Reaction 2

wherein S.sub.x represents a link comprising x sulfur atoms wherein x is 1-8 and preferable 2-3. R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are those groups necessary to form an FFA-based biomaterial of, preferably, different FFA molecules. Groups R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may represent those atoms necessary to represent internal disubstituted alkenes, alkenes integral to a substrate with the alkenes external to the substrate, monosubstituted alkenes, disubstituted alkenes, or trisubstituted alkenes. The reaction to form an FFA/S.sub.8 composite is illustrated schematically in FIG. 1.

[0023] As an alternate to Reaction 2 the sulfur can crosslink two identical alkene molecules or the sulfur can loop back onto the same alkene molecule to make a sulfur ring.

[0024] The reaction of sulfur with polyisoprene is illustrated schematically in Reaction 3.

##STR00001##

[0025] This fatty acid chains crosslinked by elemental sulfur in a thiol-ene-like reaction provides a mechanically robust material. Furthermore, the materials are thermally recyclable without loss of mechanical stability. A particular feature is the ability to self-heal wherein deviations in the material can be removed by thermal treatment. Without limit thereto, the materials can be thermally self-healed at temperatures of 100-120 C. when used as an adjacent material or a coating with the understanding that the temperature will vary based on the presence of additives to the material.

[0026] FFA/S.sub.8 composites will function as inherently antibacterial/antimicrobial biomaterials thereby enabling their use with implantable human medical devices that are far less likely to lead to infections. The combined biocidel and biocompatible properties of these composites will be entirely unique to the combination of S.sub.8 and FFA, given the biocidel activity of the former and the biocompatibility of the latter. Although some existing technologies employ crosslinked FFAs loaded with various drugs, the duration of protection is limited, and the nature of the crosslinks present can cause inflammation, leading to an adverse immune reaction. The synergy between biocompatible FFAs and antimicrobial sulfur afforded by the materials will leapfrog all existing technologies and offer numerous opportunities for biomaterial and human medical device patents.

[0027] A feature of the invention is the inclusion of additives which are particularly advantageous when incorporated during the melt-phase to make a composite. Particularly preferred additives are metals, ceramics, cermets, aggregates, lignin-based products, fiberous materials, polymeric based materials, natural or plant-based materials, glasses, inert fillers, antimicrobials, antibiotics and sacrificial materials which can be removed to create porosity. Particularly preferred additives comprise iron, Zn, ZnO, crystalline ceramics, non-crystalline ceramics, gravel, wood, hemp, carbon fibers, fiberglass, and silicon oxide.

[0028] Metals are a particularly suitable additive. In the absence of metal salts, the FFA and S.sub.8 remain phase-separated and do not mix to a sufficient extent to afford any chemical reactivity. While not limited to theory, it is hypothesized that the COOH group on the FFA is too polar in comparison to the nonpolar nature of S.sub.8 thereby inhibiting reaction. When metal salts are added, the COOH groups of the FFAs are hypothesized to bind the metals thereby decreasing the polarity sufficiently to allow them to mix to a sufficient extent to allow reaction with S.sub.8. The reaction of oleic acid with sulfur, in the presence of a metal represented as ZnO is illustrated schematically in Reaction 4.

##STR00002##

[0029] The material can be utilized as a coating wherein the material, with or without additives, is bound to a surface thereby forming a composite. Alternatively, the material can be formed as a distinct formed body wherein the body is used adjacent a surface. An adjacent surface is one wherein the material is in physical contact with the adjacent surface but not bound thereto. A coating is particularly advantageous if the properties imparted by the FFA/S.sub.8 are intended to be integral to the coated material. FFA/S.sub.8 is particularly advantageous for use with an adjacent surface if the properties of the material are intended to facilitate or alter the movement of the adjacent surface relative to, and independent of, the FFA/S.sub.8.

[0030] A particular feature of the material is the natural hydrophobicity. A hydrophobic coating, or hydrophobic adjacent surface, can be utilized in many environments. Another particular feature is the ability to alter the hydrophobicity by additives as discussed above.

EXAMPLES

[0031] All NMR spectra were recorded on a Bruker Avance spectrometer operating at 300 MHz for protons. Thermogravimetric analysis (TGA) was recorded on a TA SDT Q600 instrument over the range 20 to 800 C., with a heating rate of 5 C. min.sup.1 under a flow of N.sub.2 (100 mL min.sup.1). Differential Scanning calorimetry (DSC) was acquired using a Mettler Toledo DSC 3 STARE System over the range of 60 to 130 C., with a heating rate of 10 C. min.sup.1 under a flow of N.sub.2 (200 mL min.sup.1). Each DSC measurement was carried out over three heat-cool cycles to confirm consistent results following the first heat-cool cycle. The data reported were taken from the third cycle of the experiment. Dynamic Mechanical Analysis (DMA) was performed using a Mettler Toledo DMA 1 STARE System in dual cantilever mode. DMA samples were cast from silicone resin molds (Smooth-On Oomoo 30 tin-cure). The sample dimensions were 1.5850 mm. Clamping force was 1 cN.Math.m and the temperature was varied from 60 to 60 C. with a heating rate of 5 C. min.sup.1. The measurement mode was set to displacement control with a displacement amplitude of 5 pm and a frequency of 1 Hz. Fourier transform infrared spectra were obtained using a Shimadzu IRAffinity-1S instrument operating over the range of 400-4000 cm.sup.1 at ambient temperature using an ATR attachment. Oleic acid (Fisher), zinc oxide (Sigma Aldrich), elemental sulfur (99.5+%, Alfa Aesar) were used without further purification.

Example A

Preparation of Homogenous FFA/S.SUB.8

[0032] A single pure, free fatty acid (FFA) would be obtained in pure form from commercial sources. The FFA would be thoroughly mixed with Ss, and the mixture would be heated to higher than 159 C. to open the S.sub.8 ring and initiate the thiolene-like crosslinking reactions to form the FFA/S.sub.8 composites. Because each reaction will use a single FFA in pure form, as opposed to mixtures of multiple FFAs, the composite formed is referred to herein as a homogenous FFA/S.sub.8 composite. The molten reaction mixtures would be poured into molds, such as silicon molds, to cast rectangular bars with dimensions appropriate for dynamic mechanical analysis (DMA). Small aliquots of the molten reaction mixtures would be collected and allowed to cool to provide samples suitable for thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The TGA experiments would reveal the upper limit of thermal stability for each FFA/S.sub.8 composite. The DSC experiments would reveal the temperatures at which glass transitions (T.sub.g) and melting (T.sub.m) occur. A glass transition occurs when a material changes from crystalline to amorphous. T.sub.g values would be optimized. Optimization insures maximum material flexibility, for use in applications such as membranes or coatings of flexible devices. Alternatively, optimization could be directed to maximum rigidity for applications providing for structural support. Composite Tm values would be optimized to facilitate re-melting and re-molding, while retaining firm structure at target application temperatures. DMA experiments would reveal the mechanical strength of each composite under multiple stress/strain modes under ASTM testing protocols designed to assess long-term durability. Data from TGA, DSC, and DMA experiments would be analyzed as functions of FFA identity and FFA:S.sub.8 ratio, to elucidate structureproperty relationships. The FFA identity and FFA:S.sub.8 ratio would be modulated to achieve optimum thermal stability, T.sub.g and T.sub.m values, and mechanical strength for each composite.

Example B

Testing of Homogenous FFA/S.SUB.8

[0033] Ultimately, the FFA/S.sub.8 composite materials would be sold in a solid form preferably selected from pellets, rods, sheets, and blocks, which are typical feedstocks for biomedical device manufacturing and would be particularly well-suited for 3D printing. The homogenous FFA/S.sub.8 composites developed under Example A would be designed such that the composite can be re-melted and reshaped to achieve a targeted shape and dimensions. The FFA/S.sub.8 composites would be tested to determine the recyclability which is a determination of how closely the properties of the re-melted/re-formed material agree with the properties of the initially-formed material. Consistency (<1% change) in T.sub.g, T.sub.m, and DMA values across 10 heating/casting cycles would serve as evidence that a given FFA/S.sub.8 composite exhibits good recyclability and would allow customers to reshape that product to their design specifications.

[0034] Homogenous FFA/S.sub.8 composites that exhibit good thermal recyclability would be subjected to a comprehensive battery of ASTM testing methods. Because these composites would be well-suited for a diverse array of applications; such as stents, human implantable medical devices, marine construction, etc.; composites would undergo UV, abrasion, salt spray, scratch resistance, impact, tensile strength, compressive strength, flexural strength, compression, vibration, as well as temperature and humidity cycling preferably using ASTM testing methods.

Example C

Preparation of Heterogenous FFA/S.SUB.8

[0035] Examples A and B involve individual FFAs purchased in pure form, primarily for the purposes of testing and optimization. Commercial rendering processes generate mixtures of multiple FFAs as well as mixtures of FFAs and triglycerides and other biomolecules. Ideally, FFA/S.sub.8 composites could be prepared directly from the rendering process from FFA streams without requiring separation and isolation of individual FFA components. The thiolene-like reaction will proceed with any alkene present in any unsaturated FFA or triglyceride, so FFA/triglyceride mixtures obtained directly from rendering processes would still afford composite materials upon reaction with Ss. In addition, the thiolene reaction and the rancidification process both proceed via radical mechanisms, so even FFA/triglyceride mixtures that have developed unacceptably high levels of rancidity for use in any other application will still react with S.sub.8 to afford the same kinds of composite materials suitable for use in biomaterial applications.

[0036] Representative samples of FFA, FFA/triglyceride, and rancid FFA/triglyceride mixtures, as generated during a conventional rendering process, would be requested to serve as practical substrates for the S.sub.8 crosslinking reactions. Because these reactions would utilize mixtures of FFAs and triglycerides, these products would be referred to herein as heterogenous FFA/S.sub.8 composites. Heterogenous FFA/S.sub.8 composites would be analyzed by TGA, DSC, and DMA to determine thermal stability, T.sub.g and T.sub.m values, and mechanical strength. Data from these experiments would be analyzed as functions of composition such as; relative amounts of FFA, triglyceride, and rancid material; and FFA:Ss ratio, to elucidate structureproperty relationships. Elucidating these relationships would be more complex than in Example A, due to the fact that there are multiple different substrates reacting with S.sub.8. It would therefore allow for an understanding of how the individual FFAs affect FFA/S.sub.8 composite properties thereby leading to an understanding of how multiple FFA mixtures affect those properties.

Example D

General Synthesis of ZOS.SUB.x

[0037] Elemental sulfur was weighed directly into a reaction vessel equipped with a magnetic stir bar and then appropriate amounts of oleic acid and zinc oxide were added as listed below. The vessel was slowly heated to 180 C. in a silicone oil bath. The reaction mixture was manually stirred for the first 60 min, over which time the sulfur melted and homogenized with the other components. After a period of 24 h, the reaction was removed from the oil bath and allowed to cool to room temperature. Reagent masses and results of elemental combustion microanalysis are provided below. Heating elemental sulfur with organics can result in the formation of H.sub.2S gas. H.sub.2S is toxic, foul-smelling, and corrosive and its generation should be suppressed or it should be trapped as it is formed.

Example E

Synthesis of ZOS.SUB.99

[0038] The general synthesis above was used to synthesize ZOS.sub.99 (99 wt % sulfur) where 36.73 g of elemental sulfur, 0.08 g zinc oxide, and 0.32 mL oleic acid were used in the reaction. Elemental analysis calculated: C: 0.19, H: 0.03, S: 99.69%. Found: C: 0.56, H: 0.0, S: 99.44%.

Example F

Synthesis of ZOS.SUB.96

[0039] The general synthesis above was used to synthesize ZOS.sub.96 (96 wt % sulfur) where 11.74 g of elemental sulfur, 0.14 g zinc oxide, and 0.54 mL oleic acid were used in the reaction. Elemental analysis calculated: C: 2.27, H: 0.36, S: 96.34%. Found: C: 2.69, H: 0.19, S: 96.47%.

Example G

Synthesis of ZOS.SUB.79

[0040] The general synthesis above was used to synthesize ZOS.sub.79 (79 wt % sulfur) where 5.56 g of elemental sulfur, 0.14 g zinc oxide, and 0.54 mL oleic acid were used in the reaction. Elemental analysis calculated: C: 13.17, H: 2.09, S: 78.83%. Found: C: 18.27, H: 2.42, S: 78.83%.

REFERENCES

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[0056] The invention has been described with reference to the preferred embodiments without limit thereto. One of skill in the art will realize additional embodiments and improvements which are not specifically stated herein but which are within the scope of the claims as set forth herein.