text:
IMMOBILIZATION OF DYES AND ANTIMICROBIAL AGENTS ON A MEDICAL DEVICE
A method for immobilizing dyes and antimicrobial agents on a porous surface is disclosed and described. The surface may be that of a medical device, such as a catheter, a connector, a drug vial spike, a bag spike, a prosthetic device, an endoscope, and surfaces of an infusion pump. The surfaces may also be one or more of those associated with a dialysis treatment, such as peritoneal dialysis or hemodialysis, where it is important that working surface for the dialysis fluid be sterile. These surfaces include connectors for peritoneal dialysis sets or for hemodialysis sets, bag spikes, dialysis catheters, and so forth. A method for determining whether a surface has been sterilized, and a dye useful in so indicating, is also disclosed.
Hai, Ton That (Round Lake, IL, US)
Nordhaus, Mark A. (Antioch, IL, US)
Krongauz, Vadim V. (Bartlett, IL, US)
Lurvey, Kent L. (Grayslake, IL, US)
BAXTER INTERNATIONAL INC. (DEERFIELD, IL, US)
BAXTER HEALTHCARE S.A. (ZURICH, CH)
427/2.28, 546/338, 606/1
A61M25/00; A61B17/00; C07D213/02
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BECKHARDT, LYNDSEY MARIE
K&L Gates LLP-Chicago (Chicago, IL, US)
1. A method of coating a surface, the method comprising: providing a medical device having a porous polymer surface; cleaning the surface of the medical device; providing a plurality of functional groups on the surface; attaching a linking group to the functional group; and attaching a solvatochromic dye or a derivative of the solvatochromic dye to the functional group or to the linking group.
2. The method of claim 1, further comprising attaching an effective amount of an antimicrobial agent to the functional group or to the linking group.
3. The method of claim 1, wherein the functional groups on the surface are provided by reacting the surface with an acid, washing, and drying.
4. The method of claim 1, wherein the linking group is provided by poly(N-succinimidyl acrylate) (PNSA) or a polymer with an aldehyde functional group.
5. The method of claim 1, further comprising masking the polymer surface and directing at least the solvatochromic dye or the derivative of the dye, to a desired location on the porous surface.
6. The method of claim 1, further comprising swabbing the porous polymer surface with a disinfecting solution, whereupon a color or an appearance of the surface changes reversibly.
7. The method of claim 6, further comprising allowing the disinfecting solution to evaporate, whereupon the color or the appearance of the porous polymer surface changes back to the color or the appearance that existed before swabbing.
8. The method of claim 7, wherein the porous polymer surface is a membrane or a coating.
9. The method of claim 1, wherein the porous polymer surface is made from a polymer having an index of refraction from about 1.25 to about 1.6.
10. The method of claim 1, further comprising attaching an effective amount of an alkyl-amino containing compound selected from the group consisting of heparin, proteins, chitosan, Factor VIII or other anti-clotting Factor, polysaccharides, peptides, polymyxins, hyaluronic acid, condroitin sulfate, and derivatives of each of these.
11. A method of coating a surface, comprising: cleaning a porous surface of a medical device made from a polymer; treating the surface with a strong acid to provide a plurality of functional groups on the surface; reacting the functional groups with a linking agent to form attachment sites, the linking agent selected from the group consisting of poly(N-succinimidyl acrylate) (PNSA) and polymers with an aldehyde functional group; and attaching a solvatochromic dye, an antimicrobial agent, or an alkyl-amino containing compound selected from the group consisting of peptides, proteins, Factor VIII or other anti-clotting Factor, polysaccharides, polymyxins, hyaluronic acid, heparin, chitosan, and derivatives of each of these, to the attachment sites.
12. The method of claim 11, wherein the polymer has an index of refraction from about 1.25 to about 1.6.
13. The method of claim 11, further comprising treating the surface to induce amine functional groups.
14. The method of claim 11, wherein the solvatochromatic dye is selected from the group consisting of 4,6-dichloro-2-[2-(6-aminohexyl-4-pyridinio)-vinyl]phenolate and derivatives, Reichardt's dye, its salts and derivatives, and merocyanine dyes and their derivatives.
15. The method of claim 11, further comprising stabilizing the surface by converting unreacted carboxy attachment sites to a salt.
16. The method of claim 11, wherein the surface comprises a membrane or a coating for attachment to the medical device.
17. The method of claim 11, wherein treating a nylon surface with a strong acid results in amino attachment sites, treating a polycarbonate surface with chlorosulfonic acid results in sulfonyl chloride attachment sites, and treating a polyester surface or polycarbonate surface with an acrylic or methacrylic acid results in carboxy attachment sites.
18. A polymeric medical device, comprising: a housing of the polymeric medical device; a porous polymer surface atop the medical device; a plurality of attachment sites on the porous upper polymer surface; optionally, a plurality of functional groups attached to the attachment sites; and at least one of: i. a solvatochromic dye or a derivative of the solvatochromic dye; and ii. an antimicrobial compound, attached to the attachment sites or to the functional groups, wherein the porous polymeric surface is configured to reversibly change from a first appearance to a second appearance when the surface is swabbed with a disinfecting solution.
19. The medical device according to claim 18, wherein the polymer surface is made from a polymer having an index of refraction from about 1.25 to about 1.6.
20. The medical device according to claim 18, wherein the porous upper polymer surface is a discrete membrane cut from a sheet, a foamed article, a thin film, a casting, a molding, or a coating.
21. The medical device according to claim 18, wherein the antimicrobial compound comprises an effective amount of a compound selected from the group consisting of chlorhexidine its salts and derivates, an antimicrobial agent bearing an aminoalkyl group, chloroxyphenol, triclosan and triclocarban and derivatives, and a quaternary ammonium compound.
22. The medical device surface according to claim 18, wherein the housing further comprises an effective amount of an oligodynamic compound or an antimicrobial compound.
23. A medical device, comprising: a medical device having a porous surface made from a polymer; a plurality of attachment sites on the surface of the medical device; optionally, a plurality of functional groups attached to the attachment sites; and an antimicrobial compound, attached to the attachment sites or to the functional groups, wherein the antimicrobial compound is configured to be cidal to, or to resist growth of, microorganisms on the surface of the device.
24. The medical device according to claim 23, wherein the medical device is selected from the group consisting of catheters, drug vial spikes, connectors, vascular access devices, luer access devices, access ports, medication ports, pigtail connectors, prosthetics, endoscopes, bronchoscopes, stethoscopes, and infusion pumps.
25. The medical device according to claim 23, wherein the porous surface is made from a polymer having an index of refraction from about 1.25 to about 1.6 and is configured to change a color or an appearance when the surface is swabbed with a disinfecting solution.
26. The medical device according to claim 23, wherein the porous surface further comprises a solvatochromic dye or a salt or a derivative thereof in an amount from about 0.1% to about 0.5% of the weight of the porous surface.
27. The medical device of claim 23, wherein the polymer is selected from the group consisting of elastomers, acrylic, COC, nylon, methacrylic, elastomer, polycarbonate, polyurethane, polyester, and vinyl-ester.
28. The medical device according to claim 23, wherein the attachment sites comprise one of carboxy groups, amine groups, and amide groups.
29. The medical device according to claim 23, wherein the surface comprises a discrete membrane cut from a sheet, a foamed article, a thin film, a casting, a molding, or a coating.
30. The medical device according to claim 23, wherein the antimicrobial compound comprises an effective amount of compound selected from the group consisting of chlorhexidine, its salts and derivates, an antimicrobial agent bearing an aminoalkyl group, chloroxyphenol, triclosan and triclocarban and derivatives, and a quaternary ammonium compound.
31. The medical device according to claim 23, wherein the surface further comprises an effective amount of an oligodynamic or an antimicrobial material.
32. A medical device, comprising: a medical device having a porous surface made from a polymer; a plurality of attachment sites on the surface of the medical device; optionally, a plurality of functional groups attached to the attachment sites; and an alkyl-amino containing compound selected from the group consisting of peptides, proteins, Factor VIII or other anti-clotting Factor, polysaccharides, polymyxins, hyaluronic acid, heparin, condroitin sulfate, chitosan, and derivatives of each of these, to the attachment sites.
33. The medical device according to claim 32, further comprising an antimicrobial compound, attached to the attachment sites or to the functional groups, wherein the antimicrobial compound is configured to be cidal to, or to resist growth of, microorganisms on the surface of the device.
34. The medical device according to claim 32, further comprising a solvatochromic dye or a derivative of the solvatochromic dye attached to the attachment sites or to the functional groups.
36. A dye, comprising: a compound having a structure and derivatives thereof, wherein R1 is acryloyl, methacryloyl, or hydrogen, R2 is C4 to C10 alkyl, R3 is ethene, R4 and R6 are bromide, chloride, fluoride, iodide, and mixtures thereof, R5 is one of hydrogen or O−, and R7 is the other of hydrogen and O−.
37. The dye according to claim 36, wherein if R1 is acryloyl, the derivatives comprise ammonium hydroxide, alkali and alkaline earth salts, and mixtures thereof, and if R1 is hydrogen, the derivatives comprise a hydrobromide, hydrochloride, hydrofluoride, phosphate, sulfate, and mixtures thereof.
38. The dye according to claim 36, wherein R1 is hydrogen, R2 is n-hexyl, R4 and R6 are chloride, R5 is hydrogen, and R7 is O−.
39. The dye according to claim 36, further comprising a medical access device in which the dye is present in a porous polymer at about 0.1 to about 0.5% as a swabbing indicator.
40. A dye, comprising: a compound having a structure and derivatives thereof, wherein R1 is acryloyl, methacryloyl, hydrogen, halogen, alkoxy, alkyl mercapto, or an aromatic mercaptan, R2 is C4 to C10 alkyl, R3 is ethene, butadiene, or hexatriene, R4 and R6 are bromide, chloride, fluoride, iodide, alkoxy, nitrate, and mixtures thereof, R5 is one of hydrogen or O−, and R7 is the other of hydrogen and O−.
41. The dye according to claim 40, further comprising a medical access device in which the dye is present on a porous surface of the device or in a porous coating in about 0.1% to about 0.5% as a swabbing indicator.
42. The dye according to claim 40, further comprising a medical access device in which the dye is present on the device, in a porous membrane attached to the device, or as part of a porous surface of the device.
43. A process for making a dye, comprising: reacting a t-butyl-oxycarbonyl (BOC) amino aliphatic alcohol with a sulfonyl halide to yield a BOC-amino-aliphatic-sulfonate; reacting the BOC-amino-aliphatic-sulfonate with 4-picoline to form a pyridinium sulfonate; and reacting the pyridinium sulfonate with a substituted salicylaldehyde compound to form a compound with a merocyanine dye functionality, wherein the merocyanine dye has the general structure of wherein R′=t-butyl-oxycarbonyl, n=1, 2, or 3, X=bromide, chloride, fluoride, iodide, alkoxy, nitrate, and mixtures thereof and are both in meta positions, and wherein the O− is in an ortho or para position.
44. The process of claim 43, further comprising dissolving the merocyanine dye in acid to form a salt.
45. The process of claim 43, wherein the BOC amino aliphatic alcohol is 6-(BOC-amino)-1-hexanol.
46. The process of claim 43, wherein the BOC amino aliphatic alcohol is a saturated aliphatic alcohol having from 4 to 20 carbon atoms, and having an alcohol function group on one end and a BOC-amino functional group on an opposite end.
47. The process of claim 43, wherein the sulfonyl halide is selected from the group consisting of p-toluenesulfonyl chloride and p-toluenesulfonyl bromide.
48. The process of claim 43, wherein the pyridinium sulfonate comprises 1-(6-BOC-amino)hexyl-4-methyl-pyridinium monotosylate.
49. The process of claim 43, wherein the salicylaldehyde comprises two halogen atoms at 3, 5 positions from a position of an aldehyde functional group on the salicylaldehyde.
50. The process of claim 43, further comprising reacting the compound formed in claim 43 with acrylol chloride or methacryloyl chloride to form a structure, wherein R″ is hydrogen or methyl:
51. The process of claim 50, further comprising hydrolyzing the compound formed in claim 50 with a strong base to form a salt.
52. The process of claim 51, further comprising mixing the compound with a plastic formulation.
53. The process of claim 51, further comprising mixing the compound with a plastic formulation in an amount from about 0.1% to about 0.5% by weight.
54. A process for making a dye, the process comprising: forming a BOC-amino-aliphatic-sulfonate from a primary alcohol and a sulfonyl halide; reacting the BOC-amino-aliphatic-sulfonate with 4-picoline to form a pyridium sulfonate; reacting the pyridinium sulfonate with a substituted salicylaldehye to form a phenolate with a monomerocyanine functionality; and dissolving the phenolate in an acid to form a first salt.
55. The process according to claim 54, further comprising dissolving the salt, reacting the mixture with acryloyl chloride or methacryloyl chloride, and hydrolyzing the solution in a strong base to form a second salt.
56. The process according to claim 54, further comprising mixing the salt with a plastic formulation in an amount from about 0.1% to about 0.5% by weight.
This application is related to another application, entitled MEDICAL FLUID ACCESS DEVICE, Attorney Docket 112713-1206, U.S. patent application Ser. No. ______, which is filed on the same day as the present application, and assigned to the assignee of the present application, the entire contents of which are hereby incorporated by reference. This application is also related to U.S. patent application Ser. No. 11/458,816, filed Jul. 20, 2006, now U.S. Pat. No. ______, entitled Medical Fluid Access Site With Antiseptic Indicator, and U.S. patent application Ser. No. 11/550,643, filed Oct. 18, 2006, of the same title, now U.S. Pat. No. ______, entitled ______, both of which are incorporated by reference in their entirety.
The present disclosure relates generally to methods of immobilizing dyes and antimicrobial agents on a surface, especially a surface of a medical device. In particular, the disclosure relates to methods of treating a polymer surface for better attachment of antimicrobial agents onto the surface, and for the attachment of dyes to the surface. The dyes will change from a first color or appearance to a second color or appearance when they are swabbed with a disinfecting fluid, such as isopropyl alcohol (IPA) or a solution of water and IPA, especially a solution of 70% water/30% IPA.
Polymers are used in many medical devices in the health care industry. These polymers are used to make devices for therapeutic and for diagnostic purposes. For example, connectors for kidney dialysis, such as peritoneal dialysis and hemo-dialysis may be made of polymers. Dialysate fluid containers, access ports, pigtail connectors, spikes, and so forth, are all made from plastics or elastomers. Therapeutic devices such as catheters, drug vial spikes, vascular access devices such as luer access devices, prosthetics, and infusion pumps, are made from polymers. Medical fluid access devices are commonly used in association with medical fluid containers and medical fluid flow systems that are connected to patients or other subjects undergoing diagnostic, therapeutic or other medical procedures. Other diagnostic devices made from polymers, or with significant polymer content meant for contact with tissues of a patient, include stethoscopes, endoscopes, bronchoscopes, and the like. It is important that these devices be sterile when they are to be used in intimate contact with a patient.
Typical of these devices is a vascular access device that allows for the introduction of medication, antibiotics, chemotherapeutic agents, or a myriad of other fluids, to a previously established IV fluid flow system. Alternatively, the access device may be used for withdrawing fluid from the subject for testing or other purposes. The presence of one or more access devices in the IV tubing sets eliminates the need for phlebotomizing the subject repeatedly and allows for immediate administration of medication or other fluids directly into the subject.
Several different types of access devices are well known in the medical field. Although varying in the details of their construction, these devices usually include an access site for introduction or withdrawal of medical fluids through the access device. For instance, such devices can include a housing that defines an access opening for the introduction or withdrawal of medical fluids through the housing, and a resilient valve member or gland that normally closes the access site. Beyond those common features, the design of access sites varies considerably. For example, the valve member may be a solid rubber or latex septum or be made of other elastomeric material that is pierceable by a needle, so that fluid can be injected into or withdrawn from the access device. Alternatively, the valve member may comprise a septum or the like with a preformed but normally closed aperture or slit that is adapted to receive a specially designed blunt cannula therethrough. Other types of access devices are designed for use with connecting apparatus employing standard male luers. Such an access device is commonly referred to as a "luer access device" or "luer-activated device," or "LAD." LADS of various forms or designs are illustrated in U.S. Pat. Nos. 6,682,509, 6,669,681, 6,039,302, 5,782,816, 5,730,418, 5,360,413, and 5,242,432, and U.S. Patent Application Publications Nos. 2003/0208165 and 2003/0141477, all of which are hereby incorporated by reference herein.
Before an access device is actually used to introduce or withdraw liquid from a container or a medical fluid flow system or other structure or system, good medical practice dictates that the access site and surrounding area be contacted, usually by wiping or swabbing, with a disinfectant or sterilizing agent such as isopropyl alcohol or the like to reduce the potential for contaminating the fluid flow path and harming the patient. It will be appreciated that a medical fluid flow system, such as an IV administration set, provides a direct avenue into a patient's vascular system. Without proper aseptic techniques by the physician, nurse or other clinician, microbes, bacteria or other pathogens found on the surface of the access device could be introduced into the IV tubing and thus into the patient when fluid is introduced into or withdrawn through the access device. Accordingly, care is required to assure that proper aseptic techniques are used by the healthcare practitioner. This warning applies to many medical devices, especially those in contact with the patient, and especially so for access devices, which like catheters or infusion pumps, access the patient's bodily orifices, especially those of the vascular system.
As described more fully below, the methods for attaching antimicrobial agents and dyes that indicate that proper aseptic techniques have been used, are believed to represent important advances in the safe and efficient administration of health care to patients.
One embodiment is a method of coating a surface. The method includes steps of providing a medical device having a porous polymer surface, cleaning the surface of the medical device, providing a plurality of functional groups on the surface, attaching a linking group to the functional group, and attaching a solvatochromic dye or a derivative of the solvatochromic dye to the functional group or to the linking group.
Another embodiment is a method of coating a surface. The method includes steps of cleaning a porous surface of a medical device made from a polymer, treating the surface with a strong acid to provide a plurality of functional groups on the surface, reacting the functional groups with a linking agent to form attachment sites, the linking agent selected from the group consisting of poly(N-succinimidyl acrylate) (PNSA) and polymers with an aldehyde functional group, and attaching a solvatochromic dye, an antimicrobial agent, or an alkyl-amino containing compound selected from the group consisting of peptides, proteins, Factor VIII or other anti-clotting Factor, polysaccharides, polymyxins, hyaluronic acid, heparin, chitosan, condroitin sulfate, and derivatives of each of these, to the attachment sites.
Another embodiment is a polymeric medical device. The polymeric medical device includes a housing of the polymeric medical device, a porous polymer surface atop the medical device, a plurality of attachment sites on the porous upper polymer surface, optionally, a plurality of functional groups attached to the attachment sites, and also includes at least one of: i. a solvatochromic dye or a derivative of the solvatochromic dye; and ii. an antimicrobial compound, attached to the attachment sites or to the functional groups, wherein the porous polymeric surface is configured to reversibly change from a first appearance to a second appearance when the surface is swabbed with a disinfecting solution.
Another embodiment is a medical device. The medical device includes a medical device having a porous surface made from a polymer, a plurality of attachment sites on the surface of the medical device, optionally, a plurality of functional groups attached to the attachment sites, and an antimicrobial compound, attached to the attachment sites or to the functional groups, wherein the antimicrobial compound is configured to be cidal to, or to resist growth of, microorganisms on the surface of the device.
Another embodiment is a medical device. The medical device includes a medical device having a porous surface made from a polymer, a plurality of attachment sites on the surface of the medical device, optionally, a plurality of functional groups attached to the attachment sites, and an alkyl-amino containing compound selected from the group consisting of peptides, proteins, Factor VIII or other anti-clotting Factor, polysaccharides, polymyxins, hyaluronic acid, heparin, chitosan, and derivatives of each of these, to the attachment sites.
Another embodiment is a dye. The dye includes a compound having a structure:
and derivatives thereof, wherein R1 is acryloyl, methacryloyl, or hydrogen, R2 is C4 to C10 alkyl, R3 is ethene, R4 and R6 are bromide, chloride, fluoride, iodide, and mixtures thereof, R5 is one of hydrogen or O−, and R7 is the other of hydrogen and O−.
and derivatives thereof, wherein R1 is acryloyl, methacryloyl, hydrogen, halogen, alkoxy, alkyl mercapto, or an aromatic mercaptan, R2 is C4 to C10 alkyl, R3 is ethene, butadiene, or hexatriene, R4 and R6 are bromide, chloride, fluoride, iodide, alkoxy, nitrate, and mixtures thereof, R5 is one of hydrogen or O−, and R7 is the other of hydrogen and O−.
Another embodiment is a process for making a dye. The process includes steps of reacting a t-butyl-oxycarbonyl (BOC) amino aliphatic alcohol with a sulfonyl halide to yield a BOC-amino-aliphatic-sulfonate, reacting the BOC-amino-aliphatic-sulfonate with 4-picoline to form a pyridinium sulfonate, and reacting the pyridinium sulfonate with a substituted salicylaldehyde compound to form a compound with a merocyanine dye functionality, wherein the merocyanine dye has the general structure of
wherein R′=t-butyl-oxycarbonyl, n=1, 2, or 3, X=bromide, chloride, fluoride, iodide, alkoxy, nitrate, and mixtures thereof and are both in meta positions, and wherein the O− is in an ortho or para position.
Another embodiment is a process for making a dye. The process includes steps of forming a BOC-amino-aliphatic-sulfonate from a primary alcohol and a sulfonyl halide, reacting the BOC-amino-aliphatic-sulfonate with 4-picoline to form a pyridium sulfonate, reacting the pyridinium sulfonate with a substituted salicylaldehye to form a phenolate with a monomerocyanine functionality, and dissolving the phenolate in an acid to form a first salt.
Additional features and advantages are described herein, and will be apparent from, the following Detailed Description and the figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a perspective view of a medical device; and
FIG. 2 is a cross-sectional view of a medical device.
Synthesis of Solvatochromic Dye Useful as an Antiseptic Indicator
The synthesis of a solvatochromic dye that has been found useful as an antiseptic indicator is herein described. The synthesis was carried out in five distinct steps. A first step reacts 6-t-butyloxycarbonyl-amino-1-hexanol (also known as 6-(BOC-amino)-1-hexanol), compound (1) below, from Sigma Aldrich, St. Louis. Mo., U.S.A., with p-toluenesulfonyl chloride, compound (2) below, to yield 6-(BOC-amino)hexyl-p-toluenesulfonate, compound (3) below.
The second step substituted 4-picoline, compound (4) below, for the p-toluene sulfonate portion, resulting in 1-(6-BOC-aminohexyl)-4-methylpyridinium monotosylate, compound (5) below.
For the third step, 1-(6-BOC-amino)hexyl-4-methylpyridinium was condensed with 3,5-dicholoro-salicylaldehyde, compound 6, in the presence of piperidine, resulting in the formation of 4,6-dichloro-2-[2-(6-BOC-amino)hexyl-4-pyridinio)vinyl]phenolate, compound 7 below.
The fourth step then removed the BOC portion by reacting compound 7 with trifluoroacetic acid to yield 4,6-dichloro-2-[2-((6-amino)hexyl-4-pyridinio)-vinyl]phenolate di(trifluoroacetate) salt, compound 8.
The final step included two parts, the addition of excess acryloyl chloride, compound 9, to form compound 10. This part was followed by hydrolysis of the acryloyl moiety with ammonium hydroxide, which resulted in the dye, compound 11.
DETAILED DESCRIPTION OF INDIVIDUAL STEPS
6-t-butyloxycarbonyl-amino-1-hexanol (also known as (BOC-amino)-1-hexanol), compound (1) above, 34.45 grams (hereinafter abbreviated as "g."), was dissolved in 300 ml chloroform and the solution cooled to about 5° C. in an ice bath while under an argon purge. Triethylamine, 44.2 g. was added and the solution stirred for about 15 minutes. p-Toluene sulfonyl chloride, compound 2, 36.28 g., was added to the solution and the reaction flask was removed from the ice bath and continually stirred for about 4 hours at room temperature. The solution was then concentrated to a clear, slightly yellow oil by rotary evaporation at 30° C. and was azeotroped with 2 sequential extractions with 100 ml chloroform to yield a semi-solid product. The crude product was taken up in 500 ml of a 1:1 mixture of ethyl acetate and hexane, which caused the precipitation of a triethylamine HCl salt, which was removed by filtration. The filter cake was rinsed with 3 sequential rinses of about 75 ml ethyl acetate, which was combined with the filtrate. The filtrate was concentrated to an oil by rotary evaporation at 30° C., yielding about 75 g, and was diluted in 75 ml chloroform. This was purified by flash column chromatography (silica gel) employing a mobile phase solution of hexane: ethyl acetate (5:1 through 1:1). Isolated fractions were then combined and concentrated to yield a white, cloudy oil product, 6-(BOC-amino)hexyl-p-toluenesulfonate, 56.59 g., compound 3 above. The structure was verified with NMR and the mass spectrum (ESI+) peak of 394.2 m/z [M+Na]+ is consistent with the sodium salt adduct.
55.63 g. of compound 3 was diluted in 400 ml isopropyl alcohol and 15.4 g. 4-picoline, compound 4 was added while stirring in an argon purge. The reaction solution was heated to reflux and continued for 21 hours reaction time. The solution was then concentrated to a clear, slightly amber-colored oil, 77.64 g. The crude oil product was then diluted in 75 ml chloroform and purified by flash column photography (silica gel) employing a chloroform:methanol (20:1 through 1:1) mobile phase solution. Three sets of isolated fractions were combined and concentrated by rotary evaporation at 30° C.
The first set was a clear yellow oil, 7.57 g., which was relatively impure. The third set was a pure off-white paste, 11.72 g., of 1-(6-BOC-amino)-hexyl)-4-methyl-pyridinium monotosylate, compound (5). The second set was a relatively pure, clear, slightly yellow oil, 45.11 g., which was further purified as follows. It was diluted in 250 ml chloroform, and upon sitting for a few minutes, clear and colorless floating crystals of p-toluenesulfonic acid formed, which were removed by filtration. The filtrate was extracted with three sequential washes of 100 ml distilled water, and the organic layer was then concentrated by rotary evaporation at 30° C. to a clear, slightly yellow oil, yielding 36.88 g. of compound 5. The structure was verified by NMR (nuclear magnetic resonance), and had a mass spectrum (ESI+) with m/z 293.2 [M]+, which is consistent with the pyridinium portion of the monotosylate salt that is compound 5.
Compound 5, 46.60 g., was then diluted in 500 ml ethanol and 15.0 ml piperidine was added, followed by 19.16 g. 3,5-dicholorosalicylaldehyde, compound 6. The reaction solution was brought to reflux while stirring under a continuous argon purge. After reacting overnight, the solution was concentrated to a dark purple semi-solid by rotary evaporation at 30° C. This was then dissolved in 200 ml ethanol and distilled water was added drop-wise with rapid stirring. After stirring overnight, the solid, which included both fine and agglomerated particles, was collected. The solid was recrystallized a second time in the same manner. After stirring for 2 hours, a fine orange/red precipitate was collected by filtration. When the filter cake was rinsed with 250 ml distilled water, it immediately turned an olive-green color. The solid was dried overnight at room temperature under a high vacuum. The solid was then recrystallized a third time in the same manner. After stirring for two hours, a fine orange/red precipitate was collected by filtration. The filter cake was rinsed with four sequential washes of 250 ml of a 7:1 mixture of distilled water:ethanol. The solid product was dried at 80° C. at a pressure of about 1 mm Hg for 39 hours, yielding a 36.37 g. of a dark purple solid product, compound 7. The structure was verified by NMR and the mass spectrum (ESI+) m/z of 465.2 [M+H]+ was consistent with 4,6-dichloro-2-[2-((6-BOC-amino)hexyl-4-pyridinio)vinyl]phenolate.
10.02 g. of compound 7 was then dissolved in a 1:1 mixture of 100 ml of trifluoroacetic acid and chloroform, and the reaction solution was continuously stirred at room temperature. After 4.5 hours, the reaction was complete and the solution was concentrated to a clear, amber-colored oil. The oil was azeotroped with 3 successive 100 ml aliquots of chloroform, followed by three successive 150 ml aliquots of ethyl acetate, yielding a bright yellow solid product. This product was then taken up in 150 ml ethyl acetate, vigorously shaken, and the fine yellow solid product collected by filtration. The filter cake was rinsed with three successive 25 ml measures of ethyl acetate, and was dried at 50° C. at a pressure of about 1 mm Hg for four hours. The result was 10.73 g. of a bright yellow solid product, 4,6-dichloro-2-[2-((6-amino)hexyl-4-pyridinio)vinyl]phenolate di-(trifluoroacetate) salt, compound 8. The structure was verified by NMR and the mass spectrum (ESI+) m/z of 365.1 [M]+, and 183.1 [M+H]2+, was consistent with the cationic moiety of compound 8.
This product, 7.07 g., was then dissolved in 200 ml of dimethyl formamide, to which was added a 5 ml solution of 2,6-di-tert-butyl 4-methylphenol, 9.27 mg/ml in 71.1 ml DMF. 10 ml triethylamine was then added, causing the solution to become dark purple. The solution was then cooled to about 5° C., while stirring under an argon purge. Acryloyl chloride, compound 9, in an amount of 3.37 ml in 25 ml chloroform was added dropwise to the solution over a period of about 15 minutes, causing the solution to become clear and light brown in color. After complete addition, the reaction solution was evaluated by thin layer chromatography (TLC) using silica gel F254 plates and a chloroform:methanol 2:1 mobile phase. A small amount of acryloyl chloride, about 0.24 ml, was added to the reaction solution and the solution reevaluated later by TLC. The result is believed to be product 10, the chloride salt of 1-acryloyl-4,6-dichloro-2-[2-(1-acrylamidohexyl-4-pyridinio)vinyl]phenolate.
Compound 10 was treated with 15 ml ammonium hydroxide to form the final product. After treatment, 2 L ethyl ether was added to the product with rapid stirring, causing a dark-purple, viscous solid to form. Dark-purple supernatant was decanted from the viscous solid, which was then taken up in 1 L ethyl ether, from which a clear and colorless supernatant was decanted. The solid was mostly dissolved in 100 ml ethanol and 1 L ethyl ether was added to it with rapid stirring. After about 30 minutes, a brownish-purple solid was collected by filtration, and the filter cake was rinsed with ethyl ether. It was then dried under high vacuum for about 2 hours. The product was then purified by flash column chromatography using a 10:1 through 1:1 chloroform:methanol mobile phase solution. Isolated fractions were then combined and concentrated to yield a yellow/orange colored dye. This was then washed with ethyl ether, collected by filtration, and dried under high vacuum overnight, yielding a yellow solid. The solid was dissolved in 150 mL of methanol and 1.5 L of ethyl ether was slowly added with rapid stirring. After 30 minutes, a light green precipitate was collected by filtration and was rinsed with two successive portions of 100 mL ethyl ether. It was dried under high vacuum overnight, yielding 1.085 g. of a light, greenish-yellow solid compound, 11. The structure of compound 11 was verified by NMR and the mass spectrum (ESI+) m/z peak of 419 [M+H]+ was consistent with compound 11.
This product, however, did not enjoy solvatochromic activity. It is believed that this was due to stacking and layering of molecules in a tight formation caused by ionic and hydrophobic interactions between adjacent molecules and portions thereof. The product was therefore made basic to restore its dye activity.
The product was then made basic by dissolving 0.8 g. of compound 11 in 20 ml methanol, to which was added 2.00 ml of 1 M NaOH, causing the product to dissolve and form a dark purple color. After stirring for 10 minutes, the solution was concentrated by rotary evaporation at 30° C. to a dark solid. This was redissolved in 20 ml methanol and re-concentrated. It was then azeotroped in three successive aliquots of 25 ml chloroform. The resultant product was then recrystallized by dissolving in 5 ml methanol and adding 100 ml ethyl ether dropwise, while stirring. After about 30 minutes, a fine dark, purple colored solid product precipitated out of solution. This was collected by filtration, washed with ethyl ether, and dried under high vacuum for 11 hours. The result, 0.81 g. of a fine, dark brownish purple solid, was obtained. Other bases may also be used, including at least the hydroxyl compounds of alkali metals, alkaline earths, and ammonium, i.e., potassium hydroxide, calcium hydroxide, ammonium hydroxide, and virtually any other strong hydroxide basic compound.
The result, 4,6-dichloro-2-[2-(1-acrylamidohexyl-4-pyridinio)vinyl]-phenolate, was dissolved in radical polymerizable acrylated resin, discussed elsewhere in this application, in concentrations ranging from 0.1% to 0.5%. The resin was then cured by UV irradiation of 320-350 nm at doses ranging from 0.8 J/cm2 to 1.8 J/cm2. The result was a solvatochromic film with a bluish-purplish color. When wiped with isopropyl alcohol, the film turned pink, and then returned to a blue color after drying.
While the above description is accurate, it is clear that many modifications may be made to the process and to the end products achieved. For instance, while sodium hydroxide was used to achieve a solvatochromic dye, other bases may also be used for the same purpose, at least the monovalent ones, such as potassium or sodium. Divalent bases, such as calcium or magnesium hydroxide, are also appropriate and work well. It is believed that the more important aspect of making the dye basic is the separation of the molecular layers, rather than the particular cation and base used, e.g., NaOH, NH4OH, KOH, Mg(OH)2, Ca(OH)2, Ba(OH)2, and so forth, especially bases made with the alkali and alkaline earth metals.
Without being bound to any particular theory, the solvatochromic activity is believed to be due at least in part, to the portion of the molecule between the phenolate ring and the pyridine ring. Accordingly, it has been found that substitution of a hydrogen atom for the acrylamido group does not adversely affect the solvatochromic activity of the dye. The structure of the this molecule, 4,6-dichloro-2-[2-(6-aminohexyl-4-pyridinio)vinyl]phenolate compound 12, is shown below, and is compound 8 discussed above, after neutralization and removal of the trifluoroacetate counterions. In one sense, compound 12 below is compound 11 with a hydrogen substituting for the acryl group.
Compound 12 is more easily handled as a salt, which may be the HCl, HBr, HF, phosphate, sulfate, and many others, so long as the species is not carboxylated. In order to make this substance, the compound #8 above is neutralized with a mixture of HCl/dioxane (available from Aldrich) or HCl dissolved in other compatible organic solvent, such as chloroform.
The same compound, with a methacrylamido group, equally activating or electron-withdrawing, is also suitable and may be achieved using methacryloyl chloride in the step for the conversion of compound 8 above. Other substitutes, R1, on the amine group nitrogen atom include at least the halogens, chloride, bromide, fluoride, iodide, and alkyl mercapto. Alkyl mercapto groups, such as ethyl mercapto, and non-bending aromatic bridge groups, such as aromatic mercaptan, are also suitable. It is also possible that at least short chain alkoxy derivatives, such as C3 through C6, especially C3 and C6, are suitable. A hexyl group between the amine group and the pyridine ring worked well. Other short chain aliphatic molecules may also be used in these solvatochromic dyes, such as isohexyl, pentyl, isopentyl, butyl, isobutyl, and decyl and many others, up to C20, i.e., C4 to C20 aliphatic. It is also believed that aliphatic species are required. Other molecules that will perform well as a solvatochromic dye include substitution of ethene group between the pyridine ring and the benzene ring by conjugated double bonds of butadiene, —C═C—C═C— or hexatriene, —C′C—C═C—C═C—. Other embodiments may include substitutions on the benzene ring, as shown below in structure 13. Either or both of the chlorides at R4, R6, may be replaced by iodide, bromide, or fluoride. The O− group in the 1-position could instead be placed in the 5-position between the chlorides. It is possible that nitrate, —NO2, alkoxy, such as methoxy, ethoxy, may also yield a solvatochromic dye. Note that a number of substations on the benzene ring are readily available. For example, several salicylaldehyde compounds with halogen atoms in the 3, 5 positions are readily available from manufactures, such as Sigma-Aldrich, St. Louis, Mo., USA. When the salicylaldehyde molecule reacts with its aldehyde functionality to the pyridine ring on structure 5, the 3, 5 positions on the salicylaldehyde molecule become the 4, 6 positions on the phenol/phenolate product formed. Of course, R1 may be amine or acrylamido, R2 is C4 to C20 aliphatic, R3 is ethene, butadiene, or hexatriene, R4 and R6 are as discussed above, and R5 may be one of hydrogen and O− and R7 may be the other of hydrogen and O−.
It is possible to incorporate the dye into a coating, preferably a permeable coating, that may be applied to luer access device (LAD) housings. LAD housings are typically made from polycarbonate (PC), but they may also be made from elastomers and other plastics, such as acrylic (such as PMMA), acrylonitrile butadiene styrene (ABS), methyl acrylonitrile butadiene styrene (MABS), polypropylene (PP), cyclic olefin copolymer (COC), polyurethane (PU), polyvinyl chloride (PVC), nylon, and polyester including poly(ethylene terephthalate) (PET). There are many coatings that will firmly adhere to the above mentioned plastics, including epoxies, polyesters, and acrylics. An example of a medical device, a vascular access device, is seen in FIG. 1. Luer access device 10 includes a housing 12, male luer connector threads 14, a rim 16, and a septum 18. Rim 16 is porous and includes a swab-access dye, shown as a dotted surface 16a. Rim 16 and rim surface 16a have been treated so that antimicrobial compounds and dyes will attach to surface 16a.
Other embodiments are described in related application, MEDICAL FLUID ACCESS DEVICE, Attorney Docket 112713-1206, U.S. patent application Ser. No. ______, which is filed on the same day as the present application, and is assigned to the assignee of the present application, the entire contents of which are hereby incorporated by reference. Surface 16a is porous or permeable and the polymer from which the surface is made preferably has an index of refraction from about 1.25 to about 1.6. The permeable surface is typically opaque and may incorporate a small amount of dye. The amount of the dye, such as from about 0.1% to about 1%, is effective in adding a color to the surface, or rendering the surface a translucent with a tint or hint of color.
The surface is porous, so that a disinfecting or antiseptic swabbing solution, such as IPA or a 70% IPA/30% water solution, will permeate the surface. The disinfecting solution may also contain an antimicrobial compound, such as chlorhexidine. If the index of refraction of the swabbing solution, about 1.34, matches or is close to the index of refraction of the polymer from which the porous surface is made, the surface will become transparent, if there is no dye. If a dye is present, the surface will change color as the dye changes state from a first pH to a second, different pH, the pH of the swabbing solution. Solutions or swabbing compounds other than IPA and water may be used, although theses are the most common. For example, ethanol has a refractive index of 1.36. Additions to the swabbing solution, such as chlorhexidine, will also vary the refractive index, thus allowing users to tailor the swabbing solution to insure a visually distinct appearance change, whether from opaque to transparent or from one color to another.
FIG. 2 depicts a medical device 20 with housing 22 and a porous surface layer 24. The pores are shown as narrow channels 25 in the surface layer 24. The porous surface layer may include effective amounts of the dye 26, about 0.1 to about 1.0% by weight, and may also include small amounts of antimicrobial or oligodynamic compounds 28. There are many ways to make compounds porous, e.g., by purchasing membranes with known pore size and density, by applying solvents in the well-known TIPS (thermal inversion phase separation) process, or by inducing surface crazing or cracking into the surface. Polycarbonate membranes with tailored pore sizes may be purchased from Osmonics Corp., Minnetonka, Minn., U.S.A., and polyethylene membranes may be purchased from DSM Solutech, Eindhoven, The Netherlands. Pore sizes may vary from 1 μm down, preferably 0.2 μm down. This small pore size, and smaller, is sufficient to allow permeability to antimicrobial swabbing solutions, but large enough to prevent access by many microorganisms, which tend to be larger than 0.2 μm diameter. Many of these techniques are described in the above-mentioned related patent applications, all of which were previously incorporated by reference.
Immobilization of Dyes and Microbial Agents on Polymer Surfaces
This section describes the experimental work that was done to prepare such surfaces for direct attachment of the dye molecules. The substances used to prepare the surfaces function by reacting the surfaces and adding functional groups that will bind the dye to the surface. Examples of dyes include Reichardt's dye and the solvatochromic dye described above. As also described above, the dye changes color to alert a medical professional that the surface, such as a luer access device (LAD) surface, has been swabbed and is momentarily clean. This technique is also effective in binding microbial agents to the surface. Examples include chlorhexidine compounds and derivatives, such as chlorhexidine gluconate, and other antimicrobial agents bearing aminoalkyl groups. Examples also include chloroxyphenol, triclosan, triclocarban, and their derivatives, and quaternary ammonium compounds. Many other antimicrobial or oligodynamic substances may also be attached. These compounds are cidal to, or at least to inhibit the growth of, harmful bacteria or other microorganisms on the surfaces to which they are applied, which is beneficial to the patient.
Materials known to have properties of resistance to such microorganisms are described and disclosed in U.S. Pat. No. 4,847,088, U.S. Pat. No. 6,663,877, and U.S. Pat. No. 6,776,824, all of which are hereby incorporated by reference in their entirety as though they were copied directly into this patent. For instance, quaternary ammonium compounds (frequently with organic or silicate side chains) are well-known for such properties, as are boric acid and many carboxylic acids, such as citric acid, benzoic acid, and maleic acid. Pyridinium and phosphonium salts may also be used. Besides organic compounds, certain non-organic materials and compounds are also known for their resistance to germs and organisms. Antimicrobial compounds are used in low concentrations, typically about from about 0.1% to 1% when incorporated into the material itself, e.g., a housing of a luer access device or other vascular access device. Antimicrobial compounds may also be used on many other medical devices, such as catheters, dialysis connects, such as those used in peritoneal dialysis, hemodialysis, or other types of dialysis treatment. They may also be applied to drug vial spikes, prosthetic devices, stethoscopes, endoscopes and similar diagnostic and therapeutic devices, and to infusion pumps and associated hardware and tubing. The use of antimicrobial compounds on these devices, among others, can help to prevent infection and to lessen the effect of infection.
Metals, especially heavy metals, and ionic compounds and salts of these metals, are known to be useful as antimicrobials even in very low concentrations or amounts. These substances are said to have an oligodynamic effect and are considered oligodynamic. The metals include silver, gold, zinc, copper, cerium, gallium, platinum, palladium, rhodium, iridium, ruthenium, osmium, bismuth, and others. Other metals with lower atomic weights also have an inhibiting or cidal effect on microorganisms in very low concentrations. These metals include aluminum, calcium, sodium, lithium, magnesium, potassium, and manganese, among others. For present purposes, all these metals are considered oligodynamic metals, and their compounds and ionic substances are oligodynamic substances. The metals and their compounds and ions, e.g., zinc oxide, silver acetate, silver nitrate, silver chloride, silver iodide, and many others, may inhibit the growth of microorganisms, such as bacteria, viruses, or fungi, or they may have cidal effects on microorganisms, such as bacteria, viruses, or fungi, in higher concentrations. Because many of these compounds and salts are soluble, they may easily be placed into a solution or a coating, which may then be used to coat a vascular access device, such as a luer access device. Silver has long been known to be an effective antimicrobial metal, and is now available in nanoparticle sizes, from companies such as Northern Nanotechnologies, Toronto, Ontario, Canada, and Purest Collids, Inc., Westampton, N.J., U.S.A. Other oligodynamic metals and compounds are also available from these companies.
Other materials, such as sulfanilamide and cephalosporins, are well-known for their resistance properties, including chlorhexidine and its derivatives, ethanol, benzyl alcohol, lysostaphin, benzoic acid analogs, lysine enzyme and metal salt, bacitracin, methicillin, cephalosporin, polymyxin, cefachlor, Cefadroxil, cefamandole nafate, cefazolin, cefime, cefinetazole, cefonioid, cefoperazone, ceforanide, cefotanme, cefotaxime, cefotetan, cefoxitin, cefpodoxime proxetil, ceftaxidime, ceftizomxime, ceftrixzone, cefriaxone moxolactam, cefuroxime, cephalexin, cephalosporin C, cephalosporin C sodium salt, cephalothin, cephalothin sodium salt, cephapirin, cephradine, cefuroximeaxetil, dihydracephaloghin, moxalactam, or loracarbef mafate. Microban, "Additive B," 5-chloro-2-(2,4 dichloro-phenoxy)phenol is another such material.
The following portion discusses a number of processes found to be effective in providing functional groups for the attachment of the above-mentioned solvatochromic dyes and antimicrobial agents. Functional groups may include an activated carboxy group, an activated amine group, or an activated amide group. The desired dye or agent may then be directly attached, or an intermediate group may be used attach the desired substance.
Nylon Surfaces
In one example, a Whatman nylon-6,6 membrane, pore size 0.2 μm, 47 mm, Whatman Cat. No. 7402-004, was obtained from Whatman Inc., Florham Park, N.J., USA. Other membranes are also available from Whatman, including other nylons or polyamides, polytetrafluoroethylene (PTFE or Teflon®), polyester, polycarbonate, cellulose and polypropylene. The membranes were first washed thoroughly, successively with dichloromethane, acetone, methanol and water. The membranes were then washed several times with water to achieve a neutral pH. They were finally washed in methanol and dried under high vacuum. The membranes were then treated with 3M HCl at 45° C. for four hours to yield specimen NM-1. Without being bound by any particular theory, it is believed that this resulted in the creation of a number of amino groups on the membrane surface. The free amine concentration of the untreated nylon was calculated as 6.37×10−7 moles/cm2, while the free amine concentration after acid treatment was calculated as 13.28×10−7 moles/cm2. The concentration was calculated using the method of Lin et al., described in Biotech Bioeng., vol. 83 (2), 168-173 (2003). Thus, the treatment appeared to double the concentration of free amine on the surface and available for binding.
The NM-1 membrane was then contacted with poly(N-succinimidyl acrylate) (PNSA) dissolved in dimethylformamide (DMF) by placing the membrane in a flask with the dissolved PNSA. It is expected that treatments with other polymers containing aldehyde groups, such as polyacrylaldehyde or polyacrolein, would also be effective. Triethanolamine was then added to the flask, which was rotary shaken while under a continuous argon purge for about 6 hours. The treated nylon membrane was then thoroughly washed with DMF to produce N-succinimidyl carboxylate groups on the surface of the nylon, forming NM-2. The di(trifluoroacetate) salt of 4,6-dichloro-2-[2-(6-amino-hexyl-4-pyridinio)-vinyl]phenolate was dissolved in DMF and was converted by neutralization of the trifluoroacetate counter ions with triethylamine. The previously-treated membrane was added to the reaction flask and was rotary-shaken overnight. The resulting membrane, NM-3, with the salt of 4,6-dichloro-2-[2-(6-amino-hexyl-4-pyridinio)-vinyl]phenolate on its surface, was then thoroughly washed with DMF. The surface of the membrane was a light purple when dry. The same surface turned dark purple when swabbed with isopropyl alcohol, and turned a salmon color when swabbed with a mixture of isopropyl alcohol containing about 30% water.
It is believed that the NM-3 membrane had excess N-succinimidyl carboxylate on its surface. It is also believed that this excess would hydrolyze and protonate the dye at the phenolate position, rendering the dye colorless. A number of NM-3 membranes were treated with different amines to stabilize the carboxy groups and also to discover what colors or other properties would result from the use of different amines. A series of membranes, NM-4 to NM-9 were treated with different amines, resulting in membranes with more stable surfaces but with only slightly different colors. The particular amine was dissolved in methanol, the membrane was added to the reaction flask, and the flask was rotary shaken overnight. The resulting membrane was then washed with acetone and dried under vacuum. Table 1 below summarizes the different used amines and the resulting properties. These results suggest that a number of amino and ammonium compounds may be used to provide attachment sites, including primary amines, ammonium hydroxide, amine (NH2)-terminated compounds and polymers, morpholine, and an aromatic primary amine.
The membranes had pores on the order of 0.2 μm, resulted in rapid color changes when swabbed, and returned to the dry color within a minute or two. As noted, it is believed that the NM-3 membrane had an excess of carboxylate groups on its surface. Therefore, an antimicrobial agent, chlorhexidine, was applied. Chlorhexidine was dissolved in methanol, the membrane was added to the reaction flask, and the flask was rotary shaken overnight. The membrane was thoroughly washed with acetone and dried under vacuum. It is believed that this membrane, NM-10, now contained both antimicrobial agent and dye. The membrane was tested. Its dry color was a moderate purple, turning to a dark purple in isopropyl alcohol (IPA) and to a moderate orange/red in 70% IPA.
Amine Treatment of Nylon Membranes
Nylon Amine Color,
Membrane- dose, reagent Soln Color, IPA + 30%
Number Amine used mmol. soln, ml pH Color, dry IPA water
NM-4 2-methoxyethylamine 15 7.50 ml 11.5 Very, very Light Light
DMF light pink brown/ brown/
NM-5 Hexylamine 15 7.50 ml 12 Very, very Light Light
DMF light brown/ brown/
brown/pink pink pink
NM-6 Benzylamine 15 7.50 ml 11.5 Very light Light Light
DMF pink brown/ brown/
NM-7 Morpholine* 15 7.50 ml 10 Moderate Dark Salmon
DMF purple purple
NM-8 Ammonium hyroxide excess 20 ml ND** Moderate Dark Salmon
NH4OH purple purple
NM-9 3-aminopropyl- 3.51 10 ml 10 Light Moderate Moderate
terminated poly- toluene purple purple salmon
dimethylsiloxane
*NM-7 had an additional 0.1 ml triethylamine added, with a final pH of 11- to 11.5.
**The pH of the NM-8 solution was not determined.
Polycarbonate Surfaces
A second series of plastic surfaces was also tested. DE1-1D Makrofol® polycarbonate films, 0.005 inch thick, clear-gloss/gloss, were obtained from Bayer Polymers Division, Bayer Films Americas, Berlin, Conn., USA. The films were cut into 1 cm squares and were treated with 4 ml of a solution of 0.25 M chlorosulfonic acid in ethyl ether. The square and the solution were placed in a screw-cap vial and cooled to about 5° C. and rotary shaken for 1 hour. The resulting chlorosulfonated film was thoroughly washed with ethyl ether to yield membrane PC-1. It is believed that the amino end groups on the 4,6-dichloro-2-[2-(6-amino-hexyl-4-pyridinio)-vinyl]phenolate dye would react with the chlorosulfonyl groups which had been attached to the polycarbonate surface. A solution of the dye was prepared by dissolving 10 mmol in ethanol and treating with 0.22 mmol triethylamine. The resulting dye solution had a pH of 9.7. The PC-1 film was then added to a rotary flask containing the dye and was rotary shaken overnight and then washed thoroughly with methanol to yield film PC-2. The dry film had a moderately pinkish/purple color. When wetted with 70% IPA, it turned to a peach color.
Other films treated in the same manner, but with a four-hour chlorosulfonic acid treatment, had no color change activity. It is believed that the chlorosulfonyl moiety is a temporary transition product that converts to a more stable entity over time, and thus is not available for attachment of the dye. Other experiments included varying the time for dye attachment from 1 day to 5 days. The films treated for longer periods of time also had more intensely-colored surfaces. Due to the solubility of PC in other solvent, only ethyl ether was used for this experiment. The color change in the polycarbonate film, with very low porosity, was much slower than the color change in membranes, which have a high and regulated porosity. Treatment of polycarbonate surfaces with methacrylic acid or acrylic acid is expected to add carboxyl function groups to the surface.
Polyester Surfaces
Polyester surfaces were also obtained and tested, e.g., Millipore polyethyleneterephthalate (PET) membranes were obtained, Cat. No. T6PN1426, from Millipore Corp., Billerica, Mass., USA. These membranes were 47 mm in diameter, 0.013 mm thick, with pores having a nominal diameter of 1.0 μm. The membranes were cut into 3 cm×3 cm squares and added to a solution of water and acetone in a screw-cap bottle. 7.5 mmol of methacrylic acid, followed by 0.090 mmol of benzoyl peroxide in 2 ml acetone, were added to the solution. The bottle was rotary shaken at 85 C for 4 hours. The resulting membrane was thoroughly washed several times with hot water, followed by acetone, and then dried under vacuum to yield membrane PET-1. Without being bound to any particular theory, it is believed that this treatment results in substitution of a benzene ring hydrogen in the terephthalate moiety by the acrylic functionality. The membranes were tested, and treatment by acrylic acid resulted in weight gains of 50-53 percent. It is also believed that the subsequent treatment with benzoyl peroxide results in attachment of carboxyl groups to the polyester or PET surface. At least some of the attachments may be of a polymeric rather than monomeric nature, i.e., the attachments may be at least short chains with multiple carboxyl terminations. The terminal amine groups of the 4,6-dichloro-2-[2-(6-amino-hexyl-4-pyridinio)vinyl]phenolate dye, or of an antimicrobial agent, can then attach to the carboxyl groups, with the elimination of water.
A solution of the dye was prepared as follows for the PET membranes. 0.25 mmol of the di(trifluoroacetate) salt was dissolved in 10 ml of DMF, to which was added 0.51 mmol of triethylamine. 0.30 mmol of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2 dihydroquinoline) coupling agent was added. The PET-1 membrane was added to this reaction solution and was rotary shaken overnight. The resulting membrane was thoroughly washed with methanol. This membrane had a light orange/red color. It is believed that the residual carboxyl groups may protonate the phenolate moiety of the dye, rendering it colorless. Therefore, the membrane was surface-treated with a 5% sodium bicarbonate solution to convert any remaining carboxy groups to the sodium salt. The membrane was then washed with water, followed by methanol, and dried under vacuum to yield the PET-2 membrane. The dry film was orange/red. When wetted with 70% IPA, the membrane became a light salmon color, and changed to a salmon color when tested with IPA alone. In further experiments, it was found that increasing the treatment time of the membrane by the dye solution caused a more intense coloration of the membrane.
The results of these tests demonstrate that several substrates are suitable for the attachment of solvatochromic dyes, or may be treated so that the dyes easily attach. In addition to the particular materials tested, urethane membranes and foams may be used, perhaps without any treatment because of the NHCOO functional groups inherent in urethanes. These results demonstrate that discrete, small rings or membranes, such as those cut from a sheet, may be used. Other polymeric surfaces useful in embodiments include thin films, cast films, molded or shaped parts, or even thin coatings intended for placement on another object, for example, a vascular access device, such as a luer access device.
As discussed above, acrylic membranes or coatings may be used, at least for Reichardt's dye without treatment. The presence of polyester-like RCOO groups in acrylic polymers renders them suitable from the start for attachment of amine-containing dyes or antimicrobials, as well as other dyes. Urethane membranes or foams may be used as is, or they may be treated to make them even more suitable for dye or antimicrobial attachment. Polyimides may suitable if they are flame- or plasma treated, or if foamed polyimides are used. Melamines, maleic anhydride derivatives, blends and co-polymers may also be useful, as may blends, co-polymers and composites of any of these materials. Silicones are less amenable to treatment, however, foamed silicones may be used. For example, treating silicone with 5-10 M NaOH for several hours forms Si—OH (silanol) groups, which can then be used to form carboxy or other functional group attachment sites.
Solvatochromic Dyes
The dyes described above, Reichardt's dye, 4,6-dichloro-2-[2-(6-acrylamido-hexyl-4-pyridinio)vinyl]phenolate, and 4,6-dichloro-2-[2-(6-amino-hexyl-4-pyridinio)vinyl]phenolate, are only a few of many examples of useful solvatochromic dyes that may be used in these applications. There are many other solvatochromic dyes that could be used. As noted above, the principal requirements are the ability to reversibly change color when swabbed, e.g., with IPA. Without being bound to any particular theory, it is believed that the conjugation between the pyridine ring and the benzene ring, with the intermediary double bond, whether one, two, or three, that accounts for the solvatochromic activity in the new structures. Since these structural features are present in merocyanine dyes, it is believed that a number of these dyes would also be effective as indicators for swabbing, whether incorporated into a coating, as the acrylics described above, or used as part of a surface treatment. Of course, merocyanine dyes typically have a phenoxide ring, rather than a substituted benzene ring. The phenoxide ring functions as the aromatic donor and the pyridine or pyridinium ring functions as the acceptor. Of course, in the new structures, the benzene ring is the donor and the pyridine ring is the acceptor. Thus, it is believed that merocyanine dyes, structure 14 below, with conjugated pyridinium-phenoxide rings (having resonance with a pyridine-benzene structure)
are also suitable. Examples include 1-methyl-4-(4′-hydroxybutyl)pyridinium betaine and Brooker's merocyanine dye, 4′-hydroxy-1-methylstilbaxolium betaine.
Other solvatochromic dyes may also be used, such as an abundance of previously-known dyes, and for which the small change from their normal environment to a slightly acidic environment, such as the 6-7 pH range of IPA, will produce a color change. The table below lists a number of these dyes and their colors before and after. Note that the "before" environment of the coating or LAD housing material may be altered, such as by making it basic, by simple adjustments during the formation of the coating, the method of treating the surface, or the species used for attaching the dye. A few examples of solvatochromic dyes are presented in Table 2 below.
First state Second
Dye pH Color state, pH Color
Bromocresol purple 6.8 blue 5.2 yellow
Bromothymol blue 7.6 blue 6.0 yellow
Phenol red 6.8 yellow 8.2 red
Cresol red 7.2 red 8.8 Red/purple
Methyl red 4.2 pink 6.2 yellow
Reichardt's Dye Unk green 6-7 dark blue
Morin hydrate 6.8 red 8.0 yellow
Disperse orange 25 5.0 yellow 6.8 pink
Nile red Unk Blue/purple 6-7 bright pink
These and many other solvatochromic and merocyanine dyes many be used in applications according to this application. Other solvatochromic dyes include, but are not limited to, pyrene, 4-dicyanmethylene-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; 6-propionyl-2-(dimethylamino)naphthalene; 9-(diethylamino)-5H-benzo[a]phenoxazin-5-one; phenol blue; stilbazolium dyes; coumarin dyes; ketocyanine dyes, Reichardt's dyes; thymol blue, congo red, methyl orange, bromocresol green, methyl red, bromocresol purple, bromothymol blue, cresol red, phenolphthalein, seminaphthofluorescein (SNAFL) dyes, seminaphtharhodafluor (SNARF) dyes, 8-hydroxypyrene-1,3,6-trisulfonic acid, fluorescein and its derivatives, oregon green, and a variety of dyes mostly used as laser dyes including rhodamine dyes, styryl dyes, cyanine dyes, and a large variety of other dyes. Still other solvatochromic dyes may include indigo, 4-dicyanmethylene-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (DCM); 6-propionyl-2-(dimethylamino)naphthalene (PRODAN); 9-(diethylamino)-5H-benzo[a]phenox-azin-5-one (Nile Red); 4-(dicyanovinyl)julolidine (DCVJ); phenol blue; stilbazolium dyes; coumarin dyes; ketocyanine dyes; N,N-dimethyl-4-nitroaniline (NDMNA) and N-methyl-2-nitroaniline (NM2NA); Nile blue; 1-anilinonaphthalene-8-sulfonic acid (1,8-ANS), and dapoxylbutylsulfonamide (DBS) and other dapoxyl analogs. Other suitable dyes that may be used in the present disclosure include, but are not limited to, 4-[2-N-substituted-(1,4-hydropyridin-4-ylidine)ethylidene]cyclohexa-2,5-di-en-1-one, red pyrazolone dyes, azomethine dyes, indoaniline dyes, and mixtures thereof.
Other merocyanine dyes include, but are not limited to, Merocyanine dyes (e.g., mono-, di-, and tri-merocyanines) are one example of a type of solvatochromic dye that may be employed in the present disclosure. Merocyanine dyes, such as merocyanine 540, fall within the donor—simple acceptor chromogen classification of Griffiths as discussed in "Colour and Constitution of Organic Molecules" Academic Press, London (1976). More specifically, merocyanine dyes have a basic nucleus and acidic nucleus separated by a conjugated chain having an even number of methine carbons. Such dyes possess a carbonyl group that acts as an electron acceptor moiety. The electron acceptor is conjugated to an electron donating group, such as a hydroxyl or amino group. The merocyanine dyes may be cyclic or acyclic (e.g., vinylalogous amides of cyclic merocyanine dyes). For example, cyclic merocyanine dyes generally have the following structure 15, in association with structure 14 above:
wherein, n is an integer, including 0. As indicated above by the general structures 14 and 15, merocyanine dyes typically have a charge separated (i.e., "zwitterionic") resonance form. Zwitterionic dyes are those that contain both positive and negative charges and are net neutral, but highly charged. Without intending to be limited by theory, it is believed that the zwitterionic form contributes significantly to the ground state of the dye. The color produced by such dyes thus depends on the molecular polarity difference between the ground and excited state of the dye. One particular example of a merocyanine dye that has a ground state more polar than the excited state is set forth above as structures 14 and 15.
The charge-separated left hand canonical 14 is a major contributor to the ground state, whereas the right hand canonical 15 is a major contributor to the first excited state. Still other examples of suitable merocyanine dyes are set forth below in the following structures 19-29, wherein, "R" is a group, such as methyl, alkyl, aryl, phenyl, etc. See Structures 19-29 below.
In addition to dyes and antimicrobial compounds, the preparations discussed herein may be used to attach to desired surfaces other compounds or substances containing amino alkyl groups. Examples of these types of compounds include poly(ethylene glycol) (PEG)-containing amino alkyl groups, peptides including antimicrobial peptides, proteins, Factor VIII, polysaccharides such as heparin, chitosan, hyaluronic acid derivatives containing amino alkyl groups, and condroitin sulfate derivates containing amino alkyl groups. One example of a protein is albumin, and an example of a peptide is polymyxin. The one thing these compounds have in common is an amino alkyl group, such as the amino alkyl group discussed above in the new dye, 4,6-dichloro-2-[2-(6-aminohexyl-4-pyridinio)vinyl]phenolate.
Per the discussion above for surface preparation, the same preparation used to attach dyes and antimicrobial compounds containing alkyl amino groups will be suitable for these additional compounds. The amino alkyl groups will bind to the N-succinimidyl carboxylate groups. One technique for treating these groups is to clean the surface, followed by treatment with acid at elevated temperature, and then contacting the surface with poly(N-succinimidyl)acrylate (PNSA). It is believed that this induces carboxylate groups on the nylon surface, suitable for binding to aminoalkyl groups. Other methods are also described. For polycarbonate surfaces, treating with chlorosulfonic acid followed by washing is believed to induce chlorosulfonyl groups. These are suitable for binding by aminoalkyl groups. The treatment above of the PET surfaces is believed to result in attachment of carboxyl groups to the surface, making the also suitable for attachment of aminoalkyl groups.
Thus, polymeric surfaces as described above may also be used for attachment of peptides, proteins, Factor VIII or other anti-clotting Factors, polysaccharides, polymyxins, hyaluronic acid, heparin, chitosan, condroitin sulfate, and derivatives of each of these.
It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.
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text:
School of Games, Film and Animation
Search School of Games, Film and Animation
Two-Year FastTrack
Gamer camp
Film futures
Search School of Games, Film and Animation Search all of BCU
School of Games, Film and Animation Home Page
Shaun Magher
Course Director MA Feature Film Development
shaun.magher@bcu.ac.uk
Shaun is a graduate of the National Film and Television School and has worked in the film and animation industry for over 30 years. He has worked with a number of studios such as Manga, Maddogs, Aardman, Slave, Hibbert Ralph Animation, Moving Picture Company and Passion Pictures in a variety of roles such as Director, Creative Director, Animation Director and Supervising Animator. His work includes feature films, television series, commercials, station idents, promos and music videos.
Screen writing
Character concept – development and creation
Performance animation
BA (Hons) Animation, St Martin's School of Art.
PGCert in Animation, National Film and Television School.
Founder of Stoke Your Fires animation festival
Media Work
1989 - 1992 Big Pig Studios
1992 - 1994 Creative Director at Manga Studios
1994 - 2000 Creative Director at Slave Studios
1996 - 2004 Studio Director at Maddogs
2004 - 2006 Supervising Animator at Aardman Animation
2006 - 2017 Studio Director at SMA Studios
Links and Social Media
4 Cardigan Street
Birmingham B4 7BD

redpajama_set_name: RedPajamaCommonCrawl


The children have already amazed me with their fantastic behaviour, independence and love of learning. I would like to take this opportunity to say thank you for your support, they all have their book bags every day, PE Kits are on pegs and they look fantastic in their school uniform.
Our topic for this half term is "Bears". We will be exploring this through books and will be ensuring that we cover all areas of the curriculum. After half term our topic will be toys and then leading into Christmas. The focus for this will be physical development and we will be doing lots of designing and making.
Reading at home - In Willow class, the expectation is that the children read to an adult each night. I realise that this is not always possible, but 10-15 minutes will make all the difference! If you could write a comment or simply initial their reading diary after reading, that would be really helpful.
Bear words – This is a new form of learning keywords that we have adopted. The idea is that as well as reading the words, children can use those words to read and write simple sentences. The bear words build on each other and very soon your child will have built up a bank of words that they can read and write. The children will work at their own pace on these words and will practise once a week on a 1:1 in school. Please support us by using them at home.
Mathletics – The children have login details for the Mathletics website (www.mathletics.com) in the front of their reading diary. Mathletics has a variety of numeracy activities that your child can experience. Later in the year homework will be set each week for you to help your child complete.
PE will take place every Monday in Willow class. Please ensure that your child has the appropriate kit in school every day and has also removed any jewellery on this day.
These are the rewards that the children can receive in their class and in school.
Certificates – Each week, 2-3 children are awarded with a certificate in the whole-school 'Aim High' assembly from each class. This award can be presented for a particularly good piece of work, exemplaryattitude or general good behaviour.
Sunshine and Rain cloud– Children who work hard and follow the school rules are rewarded by their name moving from the cloud to the sunshine. If they are struggling with the school rules they will move from the cloud to the raincloud.
This year we will have support from Mrs Greenhalgh most mornings and Mrs Smith every afternoon.
Finally, thank you again for your continued support and please pop in or telephone if you have anything you'd like to talk about.


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The first thing we do...
"The first thing we do, let's kill all the lawyers" - Act IV, Scene II, Henry VI, William Shakespeare.
And the saga continues.
To recap: after a grotesque evaluation of an honours thesis in which portions of text had been invented by the examiners while at the same time turning a blind eye to entire tracts, the effects were felt over the years. A stand-offish attitude which prevented a proper analysis of the issue built a wall around the culprits and the kept the accuser - myself - firmly on the outside. When some form of communication was attempted earlier this year, Griffith University's vice chancellor Ian O'Connor had the police take me away from his campus.
Getting bundled into a police van is one thing, but such action as an eventual result of academic achievement is quite another (by the way, no complaint against the attending officers - their manners were far superior to those of this vice chancellor).
Then there is the case of the destroyed records. A request under the freedom of Information Act to learn the names of the three examiners yielded one; and he died last year. The other two, still alive and well, have been erased from history. Interesting. Good work, Mr. O'Connor.
The university's law firm is Minter Ellison which, so their website tells us, has a "a pre-eminent reputation" in Queensland. It must have taken some effort to get there; no doubt choosing your clients carefully along the way as their interests - whatever they may be - are vigorously defended would be one factor.
A query to that citadel of cooperation referred to what kind of action would lead to being taken to court for defamation. Not being the sort of customer who could mark their glory book I was not deemed worthy of a reply. Instead a note from Griffith's pro vice chancellor told me to engage my own legal advisor to answer that question. Clearly, Minter Ellison know how to write letters, they're just being selective about whom they send them to.
Phantasising about a thesis, using Queensland Police to whisk away some pesky ex-student and destroying evidence along the way paints the kind of ethics forming Minter Ellison's definition of a 'good client'.
Shady characters huddling together for their own criminal ends and using the trappings of success thus gained to bludgeon critics is nothing new here. Our honourable system of the law drapes them in gilded ermine where the cloak itself becomes a signal for the rest to stay well away. Being rather immune to the heavy symbolism of rich wigs - perhaps put it down to my republican heritage - I tend to see past the curly hair, however flea-ridden it may be; there is enough vermin to contend with.
One does not have to be a Jack Cade nor one of his cronies to get the itch from their bites.
at September 26, 2008 No comments: Links to this post
Griffithgate: let's ask the experts
Astute readers of this blog may recall the outcome from my application under the Freedom of Information Act to know the names of the three examiners responsible for the bizarre marks of my honours thesis (see Griffithgate: One dead, two to go).
Not only were the results ambiguous, they further hinted at attempts by Griffith University to throw a veil over the affair. Since it is not within my nature to block the traffic protesting nor aim a blow to the vice-chancellor's head (I leave that to my more hot-blooded compatriots) one looks for other avenues.
Some time ago I was threatened with possible court action for defamation and bullying which did not eventuate. Nor was there such a response when I repeated what led to the threat in the first place (see An update... and then there was silence).
Being a mere layman as far as the law is concerned (my sense of ethics may allow me to comment on what is just, but the law and justice are like sports and fitness - the relation does not necessarily work both ways) I thought it would be a good idea to engage the experts.
Minter Ellison is a prominent law firm with offices in Brisbane. Griffith University happens to be one their clients. In a letter I briefly described the situation and asked whether under the conditions something like defamation was indeed inapplicable. Three weeks have passed and no response.
One would imagine given its association with the university the law firm would have something to say on the topic. Yet either my letter invited no consideration whatsoever or some communication did indeed eventuate between the two. In the latter case the advice, it is reasonable to assume, would fall on the side of the client.
Associations are a tricky business. They can be of mutual benefit but can also turn into a noose around both necks if one of them should be strung up. Lawyers may not always see it that way, but public life offers us certain examples in which erstwhile marriages dissolve into a form of amnesia with the previous link erased from the memory banks of one party should the other enter a state of opprobrium (and of course the media have a field day).
How far Minter Ellison would be prepared to go is anyone's guess, but comparing the status of Griffith with that of myself is not an altogether irrelevant exercise. While a few things come to mind via the keywords 'Griffith', 'vice-chancellor' and 'criminal' it is too early for the group with 'Minter Ellison' added to it. Then again, perhaps not.
In the same context letters were sent to Anna Bligh, state premier of Queensland, and Julia Gillard, federal minister for education, informing them about my ride in a police van from Griffith campus and the destruction of the two examiners' records. While the matter has been referred to the state's education minister, his federal counterpart has remained silent so far. Naturally it is not for me to prescribe the scope of a politician's interest.
In the meantime the general public is fed sweet bread in the form of ads run by Griffith [1] self-applauding its academic rigour on one hand and of the grand vision as presented by the state government - "strong, green, smart, healthy and fair" [2] on the other.
Further references:
1. Courier Mail, "The Griffith Honours College...", 30 Aug 08.
2. Courier Mail, "The ringmaster reflects", 13 Sep 08.
The fate of society
What determines the path of a society can be analysed under the auspices of a general formality. It starts with a prerequisite: being able to sustain one's presence.
The effort required to pursue the challenges of the moment needs a commensurate supply of resources. That can be transferred from one scale to another, provided we keep referring to principles.
For example, if a society decides to go urban the inherent activities must produce a sufficient amount of skills, materials and finance to support cities. Moving to the lower end of the scale, the cognitive dynamics can be analysed in a similar light.
The mental picture that represents an urban lifestyle requires a level of comprehension sufficient to address the administrative and organisational issues that relate to a relatively complex environment - and that includes an adequate degree of foresight.
Since most societies are hardly an island, interactions with the outside generates a flow of information whose contents are not necessarily in synch with the recipient. How the differences are dealt with depends on the overall quality of understanding on either side. The result becomes a function of the interacting dynamics at whatever level of efficacy.
That brief summary already hints at the contingencies needed for a well-functioning human activity system at any scale. On an individual level ideas make for potential options but need their host's situatedness in the real to turn them into effective outcomes. Groups may have ideals too, but unless the former are able to organise themselves so they will shape their environment in a realisable manner, those ideals will come to nothing. Worse still, they force their bearers into scenarios that are not sustainable and may well prove the group's downfall.
Societies at large follow the calls of their culture, but somewhere along the way their environment (geography, resources and other humans) needs to come to the party.
No path through history is ever a smooth one. Discrepancies between the inner imagery and the real impose qualifications often diametrically opposite to an intent. What overcomes such adversities is the vigour of a people and the ability to adjust one's imagination to what is.
The vigour comes from the will to look, and the readiness to adjust comes from the capacity to see.
Even a cursory glance around the world will show the extent to which either is manifest.
Ideology, that mental straightjacket par excellence, projects its own chimera onto the psyche of a people. Sometimes the spectres happen to be in line with reality, often they interfere with its dynamics. Submission to ideology's tenets impoverishes the will and makes for brittle sycophancy.
But reality, reality could not care less.


When the fund accepts a structured settlement contribution such as personal injury compensation.
Superannuation funds are also required to report the value of existing superannuation income streams at 30 June 2017.
While reporting of these events to the ATO does not formally start until 1 July 2018 for SMSFs, event based reporting still needs to be completed if these events occur from 1 July 2017 – that is, you have a reprieve from the compliance but not the actual reporting.
If we are managing your SMSF's accounting and compliance, we will track most of these events for you electronically where you have enabled us to access feeds from your SMSF's bank accounts. If we see any transactions that could meet the reporting criteria, we will be in touch with you to confirm the nature of these events.
Where electronic feeds are not available – if your bank does not support them or where you have opted not to enable the feeds, you will need to let us know about these events at the time they occur.
In addition to the new events based reporting regime, SMSFs are also obliged to report any of the following changes to the ATO within 28 days.


~~~ Reflections ~~~ Open subject thread.
There always seems to be old BMWs by the canal, there was a C reg 6 series there yesterday.
ive posted boats and cars..sooooooo....logical next step?
are videos admissible evidence?... hope so!


This guy is almost the biggest bird I've made. I started him last week when the boy was at theater rehearsal. I had an audience - some of the younger actors who were not rehearsing at the time gathered around and watched as I began to build him. There were lots of questions about how the felting works, and was that really going to be an owl?
Owl faces are really fun, the eyes are so detailed. And I loved making the tufts!


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Hall inductee Stoner was winner in baseball at Behrend, PSU
Mike Copper @etncopper
Clarence Stoner coached Nittany Lions to more than 200 wins in less than a decade
Clarence Stoner also goes by "Stoney" in his Florida retirement community.
The former Penn State Behrend baseball coach considers that better than "Shorty," the unwanted nickname an uncle dubbed him as a youth.
Each, though, remains preferable to his birth name.
"Clarence," Stoner said. "That just sounds too much like fingernails on a blackboard."
Stoner didn't have an issue with the latest title he can be addressed.
The former Gulf Coast League MVP, who combined to manage the Behrend and Penn State University baseball programs for 22 seasons, was one of the 12 individuals voted into this year's Metropolitan Erie Chapter of the Pennsylvania Sports Hall of Fame.
It's the second time Stoner, 74, has been so honored. He joined Behrend's athletic hall of fame in 1992, and was part of the second class enshrined in school history.
Stoner said he was surprised by his latest hall inclusion because he spent the bulk of his career either coaching or teaching at Penn State, where he retired as an assistant professor in 2010.
"I wasn't sure with their criteria if I fit their bill," he said. "I guess that's what made this (announcement) particularly nice."
Stoner's tenure at Behrend covered its transition from a two-year to four-year school. He was a two-time NAIA District 18 Coach of the Year with the Lions, who went 156-122.
That was enough for Penn State to woo Stoner back to its main campus. He was hired to coach the same Nittany Lions' baseball team where he once played, and he coached them from 1982 until he stepped down after the 1990 season.
Penn State's record over that span was 216-171-1.
Stoner took over the Nittany Lions from Charles Medlar, the same coach he played for in college. Penn State's current baseball complex is named after Medlar and Anthony Lubrano, a 1982 graduate.
Stoner turned to baseball as a kid when, as his original nickname implies, he realized he was too small to play football. His prowess as a first baseman for State College High School and Penn State led the New York Yankees to draft him in 1966.
When Stoner didn't sign with them, he went back into the draft pool. He did sign with the Kansas City Athletics when they chose him in 1967.
The Athletics, who moved to Oakland a year later, assigned Stoner to their rookie affiliate in the Gulf Coast League. He was voted the league's MVP in 1967, largely due to his .341 batting average over 43 games.
Stoner, though, hit .221 over a full season of Class A ball with Leesburg during the 1968 Florida State League. That reality, along with being recently married, led him to end his brief professional playing career and find a new way to keep active in the sport.
Coaching Behrend's baseball team provided that opportunity.
Stoner said he's unsure if he'll attend his induction ceremony in 2021, even if the coronavirus pandemic is under control by then. He and his wife, Ann, currently reside in The Villages, a massive retirement community in central Florida, and they no longer care to travel much.
If not, Stoner still wanted all of his former players, both at Behrend and Penn State, to know that he wouldn't have been chosen for this year's hall of fame class without them.
"This COVID-19 situation has given me plenty of time to reflect back on all of the people in your life who helped you get to where you are today," he said. "Everybody should try to do that."
Mike Copper can be contacted at mcopper@timesnews.com. Follow him on Twitter @ETNcopper.


Hilda Caroline Smith, 82, of Summit Avenue in Hagerstown, died Friday, Oct. 17, 2003, at Washington County Hospital.
She was a 1938 graduate of Smithsburg High School and a 1940 graduate of Columbia College.
She was employed by Bohman-Warne Inc. in Hagerstown, retiring in 1984 after 44 years of service.
She was a member of Christ Reformed Church of Christ in Cavetown.
Private services and burial will be in Cavetown Cemetery. The Rev. Carol D. Hallman will officiate.
ZEPHYRHILLS, Fla. - William Roger Mortimer, 69, of Zephyrhills, died Saturday, Oct. 18, 2003, at City Hospital in Martinsburg, W.Va.
Born March 18, 1934, in Brookville, Pa., he was the son of the late Ralph and Lottie Wingard Mortimer.
He was a member of the U.S. Navy Reserve.
He is survived by his wife, Marlene Stermer Mortimer; one daughter, Bonnie Farmer of Florida; three sons, David Mortimer of Seattle, John Mortimer of Middleway, W.Va., and Clay Mortimer of Millport, N.Y.; one sister, Marion Scott of Florida; two brothers, Charles Mortimer and Richard Mortimer, both of Florida; 10 grandchildren; two great-grandchildren; and nieces and nephews.
He was preceded in death by two brothers, Frank Mortimer and Delmar Mortimer.
Arrangements are by Brown Funeral Home, Martinsburg.
BERKELEY SPRINGS, W.Va. - Junior Clyde Jackson, 72, of Berkeley Springs, died Sunday, Oct. 19, 2003, at War Memorial Hospital.
Born March 23, 1931, in Brosious, W.Va., he was the son of the late William Clyde Jackson and Mary E. Wills Jackson-Young.
He attended Morgan County schools.
He was a self-employed carpenter for more than 17 years.
He was a member of Berkeley Springs Presbyterian Church.
He is survived by his wife, Phyllis I. Beddow Jackson, whom he married Dec. 10, 1951; three sons, William C. Jackson of Hancock, and Edward L. Jackson and Robert A. Jackson, both of Berkeley Springs; four sisters, Frances Moss and Julia Young, both of Berkeley Springs, Mary L. Ward of Hancock and Loretta Hendershot of Cumberland, Md.; one brother, Bobbie Young of Berkeley Springs; six grandchildren; and nieces and nephews.
He was preceded in death by one infant brother.
Services will be Wednesday at 11 a.m. at Helsley-Johnson Funeral Home, Berkeley Springs. The Rev. Robert S. Osborne will officiate. Burial will be in Alpine United Methodist Church Cemetery, Berkeley Springs.
The family will receive friends Tuesday from 2 to 4 p.m. and 7 to 9 p.m. at the funeral home.
In lieu of flowers, memorial contributions may be made to American Heart Association, West Virginia Region, Ohio-West Virginia Affiliate, 1319 Quarrier St., Charleston, WV 25301.
QUINCY, Pa. - Janet I. Myers Daugherty, 90, a resident of Quincy United Methodist Home, and formerly of 9639 Garnes Road in Mercersburg, Pa., died Saturday, Oct. 18, 2003, at the home.
Born Oct. 29, 1912, in Antrim Township, Pa., she was the daughter of the late Calvin C. and Carrie M. Swailes Myers.
Her husband, William C. Daugherty, died Oct. 9, 1996. They were married Dec. 24, 1935.
She was a homemaker and helped on the family farm.
She was a member of the former Trinity United Brethren Church in State Line, Pa.
She is survived by two daughters, Thelma M. Decker and Lois I. Fetterhoff, both of Greencastle, Pa.; one son, Ralph E. Daugherty of Mercersburg; one sister, Hazel N. Brinkley, a guest at Morning Glory Retirement Home in State Line; two brothers, Harold E. Myers and Donald C. Myers, both of Greencastle; three grandchildren; and two great-grandchildren.
She was preceded in death by three brothers, Daniel Myers, John Myers and Linford Myers; and two grandchildren.
Services will be Tuesday at 11 a.m. at Harold M. Zimmerman and Son Funeral Home, Greencastle. Pastor Michael Wentz will officiate. Burial will be in Parklawns Memorial Gardens, Chambersburg.
The family will receive friends today from 7 to 9 p.m. at the funeral home.
CHAMBERSBURG, Pa. - Gene T. "Aucky" Aughinbaugh, 74, of 21 Acorn Circle, died Friday, Oct. 17, 2003, at his home.
Born Feb. 19, 1929, in Chambersburg, he was the son of the late Charles E. and Helen E. Trayer Aughinbaugh.
He owned and managed the former Aucky's Camping Center in Fayetteville, Pa., retiring in 1984.
He served in the U.S. Army during the Korean War, and later served in the U.S. Air Force Reserve.
He was a member of Calvary United Methodist Church in Chambersburg.
He was a member of Charles W. McCleary Disabled American Veterans Post 78, where he had served as commander and treasurer; played with the Chambersburg Fifty and Over Slow Pitch League, playing until last year; and was a member of Burt J. Asper American Legion Post 46, Gen. James Chambers A.F.&A.M. Lodge 801 and George Washington Royal Arch Chapter 176, all in Chambersburg, as well as other organizations.


Three-year study shows abnormally high radiation levels in 101 of 172 elementary schools, 125 out of 814 kindergartens examined.
An unusually high percentage of elementary schools and kindergartens in Israel are unknowingly exposing their students to unacceptable radiation levels, according to the NGO Malraz.
Malraz, the Council for the Prevention of Noise and Air Pollution in Israel, conducted a study over the past three years that found abnormally high radiation levels in 101 of 172 elementary schools tested and 125 out of 814 kindergartens examined, according to data from the organization. Particularly disturbing is that for the cases in which deviations from the norm occurred, relatively simple means to minimize or eliminate the radiation damage exist, but the parent committees – which would have the most sway among school and authorities testing for radiation – lack awareness on the subject, according to Malraz.
The radiation measured by Malraz was divided into two types, the first being Radio Frequency (RF) Radiation – non-ionizing electromagnetic radiation, transmitted mainly through broadcasting and communications, in a frequency range of 100 kHz to 300 Mhz. This type of signal includes frequencies from televisions, radios, cellular communications, microwaves and satellite radars.
The second type of radiation, Extremely Low Frequency (ELF), includes frequencies coming from energy supply sources, such as highvoltage and low-voltage cable lines.
This group can include transformer stations and electrical cabinets in multi-story residential and public buildings, as well as domestic electrical equipment like ovens, hair dryers and washing machines, the organization said.
Looking at the three separate years, in 2009, 50 of 67 elementary schools and 69 of 342 kindergartens had abnormally high radiation levels. In 2010, 29 of 56 elementary schools and 21 of 226 kindergartens had disturbing levels, and in 2011, 8 of 18 elementary schools and 11 of 101 kindergartens exceeded the norm, according to Malraz. Through October 2012, 14 of 31 elementary schools and 24 of 145 kindergartens deviated unacceptably from the norm, the Malraz data said.
Despite repeated requests for comment, the Education Ministry did not provide a respond to The Jerusalem Post by press time.
Guidelines have been written by the Environmental Protection Ministry on the subject, the spokeswoman said.
The ministry takes all of the preventative measures it is able to in terms of maintaining infrastructure in schools, such as wireless networks, and has advised that schools to use local computer networks instead of wireless, according to the spokeswoman. The ministry has sent professional bodies to handle this issue and to monitor radiation, she added.
All electronic products emit radiation, and the Education Ministry criticized Malraz for not specifying which installations were most problematic.
It is necessary to address these issues with all relevant authorities, such as local governments and the Israel Electric Corporation, the spokeswoman said.