DELIVERING NON-PATHOGENIC, INTESTINALLY BENEFICIAL BACTERIA TO A PATIENT HAVING A FEEDING TUBE

Abstract

Devices and methods for delivering non-pathogenic, intestinally beneficial bacteria to a patient having a feeding tube. Examples of non-pathogenic, intestinally beneficial bacteria that could be used include Bifidobacterium species and Lactobacillus species. In one embodiment, the bacteria is contained in a bacteria infusion device that comprises: (a) an internal chamber; (b) an outlet in communication with the internal chamber; and (c) the non-pathogenic, intestinally beneficial bacteria contained in the internal chamber. Another embodiment is a feeding tube comprising a flexible tubing and coating on the outer surface of the flexible tubing. The coating comprises an antimicrobial agent. Also disclosed are methods of administering a non-pathogenic, intestinally beneficial bacteria to a patient.

Claims

1. A bacteria infusion device comprising: an internal chamber; an outlet in communication with the internal chamber; and a non-pathogenic, intestinally beneficial bacteria contained in the internal chamber.

2. The device of claim 1, wherein the bacteria is a Bifidobacterium species.

3. The device of claim 1 or 2, wherein the bacteria is B. breve, B. longum, or B. pseudocatenulatum.

4. The device of any one of claims 1-3, wherein the bacteria is B. longum of subspecies infantis.

5. The device of claim 1, wherein the bacteria is a Lactobacillus species

6. The device of claim 1 or 5, wherein the bacteria is L. plantarum, L. pentosus, L. sahvarius, L. crispatus, L. sakei, L. antri, or L. coleohominis.

7. The device of any one of claims 1-6, wherein the amount of bacteria is 0.1 billion to 100 billion live colony forming units.

8. The device of any one of claims 1-7, further comprising a bacteria-preserving agent mixed with the bacteria.

9. The device of claim 8, wherein the bacteria-preserving agent is trehalose, sorbitol, albumin, polyethylene glycol, polyvinylpyrrolidone, milk fractions, dimethyl sulfoxide, or glycerol.

10. The device of any one of claims 1-9, wherein the bacteria is in a solid form.

11. The device of any one of claims 1-9, wherein the bacteria is in a liquid medium.

12. The device of claim 11, wherein the volume of liquid medium is in the range of 0.3 ml to 5 ml.

13. The device of claim 12, wherein the volume of liquid medium is about 0.5 ml, about 1 ml, about 1.5 ml, about 2 ml, about 2.5 ml, about 3 ml, about 3.5 ml, about 4 ml, about 4.5 ml, or about 5 ml.

14. The device of any one of claims 1-13, wherein the device further comprises a liquid medium which comprises a nutritional ingredient.

15. The device of claim 14, wherein the nutritional ingredient is an oil, a mammalian milk, or an artificial nutritional formulation.

16. The device of claim 15, wherein the oil is a triglyceride oil.

17. The device of claim 16, wherein the oil is a medium chain triglyceride oil.

18. The device of claim 15 wherein the nutritional formulation comprises bacterial supernatant.

19. The device of any one of claims 1-18, wherein the bacteria has surface structures that internalize milk glycans or derivative monomers of milk glycans.

20. The device of any one of claims 1-19, further comprising an outlet fitting for coupling the outlet to a feeding tube.

21. The device of any one of claims 1-20, further comprising an inlet and an inlet fitting for coupling the inlet to an enteral feed source.

22. The device of claim 21, wherein the inlet fitting, outlet fitting, or both are standardized medical connection fittings.

23. The device of claim 22, wherein the medical connection fitting comprises a threaded lock.

24. A feeding tube comprising: a flexible tubing; a feed port on the flexible tubing; and a bacteria infusion device of any one of claims 1-23 coupled to the feed port.

25. The feeding tube of claim 24, wherein the feeding tube is a naso-gastric feeding tube.

26. A feeding tube comprising: a flexible tubing comprising an outer surface; and a coating on the outer surface of the flexible tubing, the coating comprising an antimicrobial agent.

27. The feeding tube of claim 26, wherein the feeding tube is a naso-gastric feeding tube.

28. The feeding tube of claim 26 or 27, wherein the antimicrobial agent is a protein.

29. The feeding tube of any one of claims 26-28, wherein antimicrobial agent is a milk protein.

30. The feeding tube of any one of claims 26-29, wherein the antimicrobial agent is lactoferrin or lysozyme.

31. The feeding tube of any one of claims 26-30, wherein the antimicrobial agent is a naturally-occurring compound.

32. The feeding tube of claim 31, wherein the antimicrobial agent is allicin, catechin, citricidal, cinnamaldehyde, or carvacrol.

33. The feeding tube of claim 26 or 27, wherein the antimicrobial agent is a synthetic compound.

34. The feeding tube of any one of claims 26-33, wherein the antimicrobial agent is covalently immobilized to the outer surface of the flexible tubing.

35. The feeding tube of any one of claims 26-34, further comprising a bacteria infusion device of any one of claims 1-23.

36. A kit comprising: a feeding tube, optionally according to any one of claims 24-35; and a bacteria infusion device of any one of claims 1-23.

37. The kit of claim 36, wherein the bacteria infusion device further comprises an outlet fitting for coupling the outlet to the feeding tube.

38. A method of assembling the kit of claim 36 or 37, wherein the bacteria infusion device has a proximal end and a distal end, the method comprising coupling the distal end to the feeding tube.

39. The method of claim 38, further comprising coupling the proximal end to an enteral feed source.

40. A method of administering a non-pathogenic, intestinally beneficial bacteria to a patient having a feeding tube inserted into the gastrointestinal tract, the method comprising infusing a non-pathogenic, intestinally beneficial bacteria into the patient's gastrointestinal tract.

41. The method of claim 40, wherein the infusion of bacteria is performed through the feeding tube.

42. The method of claim 40 or 41, wherein the bacteria is in a liquid medium.

43. The method of claim 42, wherein the volume of liquid medium is in the range of 0.3 ml to 5 ml.

44. The method of any one of claims 40-43, further comprising, prior to use, storing the bacteria at a temperature that is below 20 C.

45. The method of any one of claims 40-44, further comprising repeating the step of infusing the bacteria into the gastrointestinal tract.

46. The method of claim 45, wherein continued infusion of bacteria is for the duration that enteral feeding is required.

47. The method of claim 45 or 46, wherein the repeated infusion is performed within 12 hours to 72 hours after the initial infusion.

48. The method of any one of claims 40-47, wherein the bacteria is infused simultaneously with infusion of an enteral feed.

49. The method of any one of claims 40-48, wherein the enteral feed comprises an oligosaccharide found in mammalian milk.

50. The method of any one of claims 40-49, further comprising coupling a bacteria infusion device of any one of claims 1-23 to the feeding tube, and wherein the bacteria and/or its supernatant is infused out from the internal chamber through the outlet.

51. The method of claim 50, further comprising coupling an enteral feed source to the bacteria infusion device.

52. The method of claim 51, further comprising infusing the enteral feed source through the bacteria infusion device and into the feeding tube.

53. The method of claim 51 or 52, further comprising detaching the bacteria infusion device after the enteral feed infusion is complete.

54. The method of any one of claims 40-53, wherein the feeding tube comprises: an outer surface; and a coating on the outer surface of the feeding tube, the coating comprising an antibacterial agent.

55. The method of any one of claims 40-54, wherein the patient is a preterm infant.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIGS. 1A and 1B show an example of a bacterial infusion device of the present invention. FIG. 1A shows a cross-section side view; FIG. 1B shows a perspective view.

[0031] FIGS. 2A and 2B show another example of a bacterial infusion device of the present invention. FIG. 2A shows a cross-section side view; FIG. 2B shows a perspective view.

[0032] FIG. 3 shows an example of a feeding tube of the present invention.

[0033] FIG. 4 shows the bacterial infusion device of FIGS. 2A and 2B attached to the feeding tube of FIG. 3.

[0034] FIGS. 5A and 5B show a feeding tube inserted into an infant. FIG. 5A shows a cross-section side view; FIG. 5B shows a front view.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0035] The device and method of the present disclosure may be used to reduce the adventitious microbial growth on NG tubes and protect the intestinal mucosa from damage and invasion by pathogenic bacteria and may be comprised of the following elements: a tube with an antibacterial agent coating. This list of constituent elements is intended to be exemplary only, and it is not intended that this list be used to limit the device and method of the present application to just these elements. Persons having ordinary skill in the art relevant to the present disclosure may understand there to be equivalent elements that may be substituted within the present disclosure without changing the overall invention.

[0036] By way of example, some embodiments of the invention include a method and device for reducing the adventitious microbial growth on NG tubes and protecting the intestinal mucosa from damage and invasion by pathogenic bacteria, particularly in a preterm infant, the device comprising a tube with an outer surface and a coating comprising an antibacterial agent applied to the outer surface. In some embodiments, the antibacterial agent may comprise at least one protein, such as a milk protein, such as lactoferrin or lysozyme. Alternatively or additionally, the antibacterial agent may comprise a natural antibacterial compound, such as allicin, catechin, citricidal, cinnamaldehyde, and carvacrol. The coating may also comprise non-natural antibacterial compounds, such as zinc salts, silver salts, flavanones, and commercial antibiotics. The coating may be applied to the tube using any suitable method and, in some embodiments, the coating's composition may be covalently bonded to the outer surface, where the covalent bond may include a linker moiety positioned between the tube and the protein. In another alternative, the coating may be a whey protein film which may be applied by solvent casting from a whey protein stock which has been enriched in antibacterial proteins, such as lactoferrin and/or lysozyme.

[0037] The tube may be made of any suitable material, such as a material typically used in the enteral feeding of a mammal, such as a human infant that is premature or of low birth weight. For example, the tube may comprise a polyurethane, silicone, polyethylene, polyvinyl chloride, or thermoplastic polymer.

[0038] In another embodiment, the tube may be connected to a bacterial infusion device which comprises a pure bacterial culture in the central volume of the device, where the pure bacterial culture may be present at a level of from about 0.1 billion to 100 billion live colony forming units of the pure bacterial culture. The beneficial bacteria may comprise bacteria that consume milk glycans or their derivative monomers, such as fucose, sialic acid, and N-acetylglucosamine. For example, the pure bacterial culture may comprise a culture from the genus Bifidobacterium or Lactobacillus. The Bifidobacterium species may B. breve, B. longum, or B. pseudocatenulatum and, in some embodiments, comprises B. longum subsp. infantis. The Lactobacillus species may be L. plantarum, L. pentosus, L. salivarius, L. crispatus, L. sakei, L. antri, or L. coleohominis. Cultures for use in this invention may be produced by any suitable culture technique known to be effective for the particular organisms. Exemplary protocols are described in International Patent Application Ser. No. PCT/US15/57226 and Ser. No. PCT/US16/22226, both of which are incorporated by reference herein in their entirety.

[0039] During fermentation of the organism that is activated to use mammalian milk oligosaccharides, the organism may release high amounts of short chain fatty acids, such as acetate, into the supernatant. These short chain fatty acids may have the beneficial effect of suppressing the growth of other potentially pathogenic organisms. As such, the supernatant that is separated from the organism may be stored and used to flush the line following feeding and/or delivery of the bacterial culture. Alternatively, a cell slurry of the bacterial culture plus its supernatant may be frozen and the combination delivered in the infusion device (sealed chamber) that is warmed to 37 C. before use.

[0040] The pure bacterial culture may be present in a formulation that may aid in the preservation of the viability of the pure bacterial culture during storage and delivery. The formulation may comprise, for example, a stabilizing agent, such as trehalose, dimethyl sulfoxide (DMSO), polyethylene glycol (PEG), glycerol, milk fractions, polyvinylpyrrolidone (PVP), sorbitol, or albumin. The formulation may be a dry formulation prepared by, for example, freeze drying. The formulation may also be suspended or dissolved in a liquid such as, but not limited to, an oil, a triglyceride oil, human milk or a fraction thereof, and an artificial nutritional formula prepared for the human in need of the bacteria. Alternatively, the formulation may be semi-solid (e.g., a gel). For stability during storage, it is preferred that the formulation have low water activity (e.g., water activity less than or equal to 0.35). For liquid or semi-solid formulations, in some embodiments, the bacteria-containing formulation may be kept frozen. This may be useful in maintaining the bacteria in a dormant state prior to delivery. Transition from dormant metabolic state to active metabolic state may occur ex vivo or in vivo.

[0041] If the transistion occurs ex vivo for frozen samples, the transition would involve a protocol of warming the frozen samples and holding in the sealed internal chamber at 37 C. to wake up the organisms before injecting or opening the flow into the infant. In the case of the powders or semi-solid low water activity formulations, this would involve adding an aqueous component and holding it at 37 C.

[0042] The device comprising the bacterial culture may have a first end and a second end, each end comprising a locking fitting configured to engage with or be coupled to a NG feeding tube such as described in the first embodiment and an enteral feeding source, such as a luer lock, a threaded lock, a barbed lock, a quick connect fitting, or a Swagelok fitting.

[0043] In some embodiments, the invention may comprise a plurality of tubes, such as two tubes, where a first tube is an enteral feeding tube and a second tube is for infusion of a pure bacterial culture. The first and/or second tube may be coated with the antibacterial agent described above.

DETAILED DESCRIPTION OF THE DRAWINGS

[0044] To assist in understanding the present invention, particular embodiments are described in detail with references to the figures. These particular embodiments are presented as illustrative examples only. Moreover, the constituent elements in these particular embodiments are intended to be exemplary only and not intended to limit the present invention. It will be apparent to persons having ordinary skill in the art that the present invention is not limited to the embodiments set forth below and that the present invention can be adapted for any suitable application, limited only by the appended claims.

[0045] FIGS. 1A and 1B show a syringe-like device 10 having a proximal end 12 and a distal end 14. At its distal end 14, there is an outlet 24. The device 10 has an internal chamber 16 containing 1 mL of a liquid medium 18 of B. infantis bacteria suspended in one gram of medium chain triglyceride oil at a concentration of 10 billion cfu/mL. One end of the internal chamber 16 is sealed with a tightly-fitted piston 20, which is movable within the internal chamber 16 in a proximal-to-distal direction. The piston 20 is connected to a plunger 22 that the user can push to move the piston 20 in a downward direction (with respect to the illustration).

[0046] The internal chamber 16 is in fluid communication with the outlet 24. An end cap (not shown) is fitted over outlet 24 at the distal end 14 to seal the bacterial medium 18 inside the internal chamber 16. At the distal end 14 is a threaded fitting 26 for connecting to a feeding tube. In operation, the user removes the distal cap and connects the outlet 24 to a feeding tube via the fitting 26. The user then pushes the plunger 22 to eject the bacterial medium 18 into the feeding tube.

[0047] This syringe device 10 can be manufactured in any suitable manner. In one example, a sample of Bifidobacterium longum subsp. infantis is prepared and freeze-dried in the presence of a cryoprotectant (trehalose). Once dry, the material is quantified and diluted to about 100 billion cfu/g using pharmaceutical grade lactose. Approximately 100 mg of this material is then suspended in 1 mL of MCT oil. With the piston 20 pushed all the way down to expel any air inside the syringe device 10, the distal outlet 24 is immersed in the liquid suspension of bacteria and drawn into the internal chamber 16 by drawing back on the plunger 22. Any air drawn into the syringe device 10 is gently expelled. The distal outlet 24 is then capped to seal the bacterial medium inside the syringe device 10. The filled syringe device 10 is stored under sealed and refrigerated conditions until use.

[0048] FIGS. 2A and 2B show a dual port, vial-like cassette device 30 having a proximal end 32 and a distal end 34. At its proximal end 32, there is an inlet 40. At its distal end 34, there is an outlet 42. The cassette device 30 has a central diameter of about 1 cm and a length of about 2 cm. The device 30 has an internal chamber 36 containing B. infantis bacteria 38 in powder form. The internal chamber 36 is in fluid communication with the inlet 40 and the outlet 42. Both the inlet 40 and outlet 42 are sealed by removable caps (not shown). At the proximal end 32 of the device 30, there is a threaded inlet fitting 44 for connecting to an enteral feed source. At the distal end 34 of the device 30, there is a threaded outlet fitting 48 for connecting to a feeding tube. The operation of the cassette device 30 is described below in relation to the feeding tube.

[0049] This cassette device 30 can be manufactured in any suitable manner. In one example, a sample of Bifidobacterium longum subsp. infantis is prepared and freeze-dried in the presence of a cryoprotectant (trehalose). One end of an empty cassette device 30 is closed with a luer lock cap, and the unit is filled with the freeze-dried B. infantis material. The top of the cassette device 30 is flushed with nitrogen and sealed with a second luer lock cap over outlet 42. The filled cassette device 30 is stored under sealed and refrigerated conditions until use.

[0050] FIG. 3 shows a feeding tube 50 having a proximal end 52, a distal end 54, and a flexible tubing 56. At the proximal end 52 of the feeding tube 50 is a feeding port 58 that ordinarily connects to an enteral feeding source. Attached by a tether is a removable cap 64 for capping feed port 58. Feeding tube 50 may have any suitable length. In some embodiments, the length of the feeding tube is in the range of 30-140 cm.

[0051] The outer surface of the flexible tubing 56 of the feeding tube 50 has a coating of lactoferrin as an antimicrobial agent. The lactoferrin is immobilized onto the outer surface by covalent bonding. The lactoferrin could be covalently bonded to the outer surface of the flexible tubing 56 using the method described in U.S. Pat. No. 3,574,062, the entire disclosure of which is incorporated herein by reference. This method could be implemented on a commercially-available polyurethane NG tube that is diazotized by reacting with the diazonium salt of an amino acid (e.g. hippuric acid). An intermediate protein layer is created by coupling bovine serum albumin to the diazo-hippurate by reacting with N,N-dicyclohexyl carbodiimide. The antibacterial protein is then coupled to the bovine serum albumin layer by reacting with N,N-dicyclohexyl carbodiimide.

[0052] The feeding tube 50 can be manufactured in any suitable manner. In one example, a commercially-available 20 inch polyurethane pediatric NG feeding tube is obtained. The distal end of the NG tube is sealed tightly with a clamp or a plug to prevent any liquid from entering the tube. The distal 16 inches of the NG tube is then coated with lactoferrin in the manner described above. After thorough rinsing and drying of the feeding tube 50, it is re-cut just above the site of the clamp or plug.

[0053] FIG. 4 shows the feeding tube 50 combined with the cassette device 30. The feeding tube 50 may be provided with the cassette device 30 attached. Or alternatively, the feeding tube 50 and cassette device 30 may be provided separately, e.g., in a kit.

[0054] In operation, the cassette device 30 is taken out from cold storage and warmed to room temperature. The outlet 42 on the cassette device 30 is uncapped and the outlet fitting 48 is connected to the feed port 58 of the feeding tube 50. Next, the inlet 40 on the cassette device 30 is uncapped and the inlet fitting 44 is connected to the enteral feed source. The enteral feed infusion is then started. The enteral feed enters the internal chamber 36 of device 30 through the inlet 40 and mixes with the bacteria powder 38. With this mixing, the bacteria powder 38 is suspended in the liquid enteral feed. With the bacteria mixed therein, the enteral feed continues to travel out through the outlet 42 of the cassette device 30 and into the feeding tube. After the bacterial powder 38 is depleted, the cassette device 30 may be disconnected from the feeding tube and the enteral feed source. Repeated administration of the bacteria (e.g., once daily) could be performed by attaching a new cassette device 30 to the feeding tube 50.

[0055] FIGS. 5A and 5B show an NG feeding tube inserted into an infant. The feeding tube is inserted through the infant's nose until the distal end is placed into the stomach. The syringe-like device 10 of FIGS. 1A and 1B could be connected to the proximal end of the NG feeding tube. The B. infantis bacteria carried in the device 10 is ejected into the feeding tube by pushing the plunger 22. Alternatively, the cassette device 30 of FIGS. 2A and 2B could be connected to the proximal end of the NG feeding tube. An enteral feed line could be connected to the proximal end of cassette device 30 and the enteral feeding could be infused through the cassette device 30 into the feeding tube.

EXAMPLES

Example 1: Preparation of a Feeding Tube Coated With Lactoferrin

[0056] A commercial brand of a 20 inch polyurethane pediatric nasogastric feeding tube with a single or dual port connector is obtained. The distal end of the NG tube is first sealed tightly with a clamp or a plug to prevent any liquid from entering the tube. The distal 16 inches of the NG tube is then diazotized with a diazonium salt of an amino acid by, for example, the method disclosed by U.S. Pat. No. 3,574,062, the entire disclosure of which is incorporated herein by reference, and then reacted with purified lactoferrin or devitalized forms thereof to produce a coating of lactoferrin on the outside surface of the polyurethane tube. After thorough rinsing and drying of the tube, it is re-cut just above the site of the clamp or plug. This or an equivalent tube may be used in any of the kits or methods of this invention.

Example 2: Use of the Antimicrobial-Coated Feeding Tube

[0057] The feeding tube of Example 1 is gently placed through the nose or mouth of an infant and into the stomach using standard practices. In babies with feeding problems, the tip of the tube may be placed past the stomach into the small intestine, providing slower, continuous feedings. The tube is then connected to a supply source of an enteral feed and can be used to provide feedings and medications into the stomach of the baby for many days without significant build-up of bacteria on the feeding tube. The enteral feed may contain mammalian milk oligosaccharides as disclosed in U.S. Pat. No. 8,197,872, International Patent Application Publication No. WO 2012/009315, and International Patent Application Ser. No. PCT/US15/57226, the entire disclosures of which are incorporated by reference herein. Equivalent devices may be used in similar methods according to this invention.

Example 3: Use of Bacteria Infusion Device with Conventional Feeding Tube

[0058] A plastic luer lock device is prepared or obtained from a commercial vendor. The unit has male and female luer lock fittings at either end and a central diameter of about 1 cm and a length of about 2 cm. A sample of Bifidobacterium longum subsp infantis is prepared and freeze-dried in the presence of a cryoprotectant (trehalose). Once dry, the material is quantified and diluted to about 100 billion cfu/g using pharmaceutical grade lactose. Approximately 100 mg of this material is then suspended in 1 mL of MCT oil. One end of the luer lock device is closed with a luer lock cap, and the unit is filled with 1 mL of the MCT oil containing 10 billion cfu of B. infantis. The top of the unit is flushed with nitrogen and sealed with a second luer lock cap. The filled unit is stored under sealed and refrigerated conditions until use. Once a standard feeding tube is inserted into a subject, the filled unit can be removed from storage, warmed to body temperature and connected to the feeding tube between the feeding tube and the source of enteral feeds. The enteral feed may contain mammalian milk oligosaccharides as disclosed in U.S. Pat. No. 8,197,872, International Patent Application Publication No. WO 2012/009315, and International Patent Application Ser. No. PCT/US15/57226, the entire disclosures of which are incorporated by reference herein. Once the enteral feed pump is started, the MCT oil containing the beneficial bacteria is transferred into the stomach of the subject. Equivalent devices may be used in similar methods according to this invention.

Example 4: Use of the Bacteria Infusion Device and an Antimicrobial Coated Feeding Tube

[0059] The bacteria-containing tube of Example 3 is locked into the lactoferrin-coated feeding tube of Example 1 before or after the insertion of the feeding tube into the infant in need of enteral feeding. The bacteria-containing tube is then connected to a supply source of an enteral feed. The enteral feed may contain mammalian milk oligosaccharides as disclosed in U.S. Pat. No. 8,197,872, International Patent Application Publication No. WO 2012/009315, and International Patent Application Ser. No. PCT/US15/57226, the entire disclosures of which are incorporated by reference herein. The first feeding will provide the infant with a first daily dose of B. infantis along with 1 g of MCT oil. After the first feed, the bacteria-containing tube can be removed and subsequent enteral feeds for that day can be provided directly to the infant via the NG tube. Daily additions of the B. infantis can be made with the insertion of a new bacteria-containing tube to the NG tube, and this process can be maintained for as long as the infant is taking enteral feeds. Equivalent devices may be used in similar methods according to this invention.

Example 5: Feeding Tube Laminated With Whey Protein Film

[0060] Another example of an antimicrobial coating that could be used is a whey protein film, such as those described in H. Jooyandeh, Whey Protein Films and Coatings: A Review, Pakistan Journal of Nutrition 10(3): 296-301 (2011), the entire disclosure of which is incorporated by reference herein. The whey protein film may have an antimicrobially-effective amount of lactoferrin and/or lysozyme. The whey protein film could be applied by solvent casting or as a laminate sheet around a feeding tube to provide the antimicrobial coating on feeding tubes according to this invention.

[0061] The above-described embodiments and examples of the invention are presented for purposes of illustration and not of limitation. While these embodiments of the invention have been described with reference to numerous specific details, one of ordinary skill in the art will recognize that the invention can be embodied in other specific forms without departing from the spirit of the invention. Thus, one of ordinary skill in the art would understand that the invention is not to be limited by the foregoing illustrative details, but rather is to be defined by the appended claims.