QUILTED IMPLANTABLE GRAFT

Abstract

Described are embodiments of a multilaminate or multiple layer implantable surgical graft comprising remodelable collagenous sheet material, the graft including one or more interweaving members to stitch together the graft to help prevent the layers from delaminating or separating during handling and the initial stages of remodeling. The interweaving members may comprise lines of suture, thread, individual stitches, strips of material, etc. that are woven through the layers of biomaterial in a desired pattern. In one embodiment, the interweaving members comprise a pharmacologically active substance, such as a drug, growth factors, etc. to elicit a desired biological response in the host tissue. In another embodiment, the graft further comprises a reinforcing material, such as a synthetic mesh, within the layers of remodelable biomaterial and stitched together by one or more interweaving members.

Claims

1-20. (canceled)

21. A method for reinforcing patient tissue at an implant site of a patient, comprising: implanting at the implant site a surgical graft including a plurality of sheets of remodelable collagenous material disposed in a multilayer configuration and affixed together by at least one length of suture interwoven through the plurality of sheets to create a pattern of stitches.

22. The method of claim 21, wherein the patient tissue comprises herniated tissue.

23. The method of claim 22, wherein the remodelable collagenous material comprises submucosal tissue.

24. The method of claim 21, wherein: the sheets of remodelable collagenous material comprise submucosal tissue; the remodelable collagenous material is lyophilized; the remodelable collagenous material includes native fibroblast growth factor-2 retained from a source tissue for the remodelable collagenous material; the stitches are lock stitches: and the pattern of stitches comprises a first set of stitch lines laterally spaced from one another, and a second set of stitch lines laterally spaced from one another, with said first set of stitch lines extending in a first direction and said second set of stitch lines extending in a second direction different from said first direction, and with said first set of stitch lines intersecting said second set of stitch lines.

25. The ethod of claim 24, wherein the patient tissue comprises herniated tissue.

26. The method of claim 21, wherein the sheets of the plurality of sheets are not bonded to adjacent ones except by said at least one length of suture.

27. The method of claim 24, wherein lines of said first set of stitch lines and lines of said second set of stitch lines comprises stitches longitudinally spaced apart from one another by a distance of at least 1 mm within the lines.

28. The method of claim 27, wherein said distance is 1 to 7 mm.

29. A method for reinforcing patient tissue at an implant site of a patient, comprising: implanting a surgical graft at an implant site in the patient so as to reinforce tissue at the implant site, the surgical grail including a. plurality of sheets of remodel able collagenous material disposed in a multilayer configuration and affixed together by at least one non-resorbable suture interwoven through the plurality of sheets to create a pattern of stitches; wherein the at least one note-resorbable suture is effective to: (i) provide reinforcement of a surgical graft during degradation of a remodelable collagenous material and the establishment of remodeled tissue of the patient at the implant site; and (ii) provide continued reinforcement to compliment the remodeled tissue at the implant site.

30. The method of claim 29, wherein the patient tissue includes herniated tissue.

31. The method of claim 29, wherein the sheets of the plurality of sheets are not bonded to adjacent ones except by said at least one non-resorbable suture.

32. The method of claim 29, wherein: the sheets of remodelable collagenous material comprise submucosal tissue; the remodelable collagenous material is lyophilized; the remodelable collagenous material includes native fibroblast growth factor-2 retained from a source tissue for the remodelable collagenous material; the stitches are lock stitches; and the pattern of stitches comprises a first set of stitch lines laterally spaced from one another, and a second set of stitch lines laterally spaced from one another, with said first set of stitch lines extending in a first direction and said second set of stitch lines extending in a second direction different from said first direction, and with said first set of stitch lines intersecting said second set of stitch lines.

33. The method of claim 32, wherein the patient tissue includes herniated tissue.

34. The method of claim 32, wherein the sheets of the plurality of sheets are not bonded to adjacent ones except by said at least one non-resorbable suture.

34. The method of claim 32, wherein lines of said first set of stitch lines and lines of said second set of stitch lines comprises stitches longitudinally spaced apart from one another by a distance of at least 1 mm within the lines.

35. A method for reinforcing patient tissue, comprising: (a) implanting a surgical graft at an implant site to reinforce tissue of a patient, the surgical graft including: a plurality of sheets of remodelable collagenous material arranged in a multilayer configuration and affixed together by at least one non-resorbable suture interwoven through the plurality of sheets to create a pattern of stitches, so that the remodelable collagenous material undergoes remodeling to form remodeled patient tissue at the implant site; wherein the sheets of remodelable collagenous material comprise submucosal tissue; wherein the remodelable collagenous material is lyophilized; wherein the stitches are lock stitches; and wherein the pattern of stitches comprises a first set of stitch lines laterally spaced from one another and a second set of stitch lines laterally spaced from one another, with said first set of stitch lines extending in a first direction and said second set of stitch lines extending in a second direction different from said first direction, and with said first set of stitch lines intersecting said second set of stitch lines; (b) while the sheets of remodelable extracellular matrix material undergo said remodeling to form remodeled patient tissue at the implant site, providing strength to the surgical graft with the at least one non-resorbable suture; and (c) after formation of the remodeled patient tissue, reinforcing the new patient tissue at the implant site with the at least one non-resorbable suture.

37. The method of claim 36, wherein the tissue of the patient includes herniated tissue.

38. The method of claim 36, wherein the sheets of the plurality of sheets are not bonded to adjacent ones except by said at least one non-resorbable suture.

39. The method of claim 38, wherein the tissue of the patient includes herniated tissue.

40. The method of claim 36, wherein lines of said first set of stitch lines and lines of said second set of stitch lines comprises stitches longitudinally spaced apart from one another by a distance of at least 1 mm within the lines.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 is a top view of an embodiment of the present invention comprising a multilaminate graft with a first pattern of stitching;

[0016] FIG. 2 is a top view of a portion of an embodiment of the present invention comprising a multilaminate graft with the first pattern of stitching and a supplemental line of stitching extending around the periphery of the graft;

[0017] FIG. 3 is a top view of a portion of an embodiment of the present invention comprising a multilaminate graft with a second pattern of stitching;

[0018] FIG. 4 is a cross-sectional view of the multilaminate graft of the present invention interwoven with a lock stitch;

[0019] FIG. 5 is a top view of a portion of an embodiment of the present invention comprising a series of discrete stitches distributed about the periphery of the graft;

[0020] FIG. 6 is a cross-sectional view of an embodiment of the present invention comprising an interweaving member that includes a bioactive agent;

[0021] FIG. 7 is a top view of an embodiment of the present invention in which the interweaving members comprise drug-eluting strips of material;

[0022] FIG. 8 is a top view of a portion of an embodiment of the present invention comprising drug-eluting members intertwined with selected ones of the interweaving members; and

[0023] FIG. 9 is a top view of a portion of an embodiment of the present invention comprising a synthetic mesh disposed between layers of the multilaminate graft material.

DETAILED DESCRIPTION

[0024] While the present invention may be embodied in many different forms, for the purpose of promoting an understanding of the principles of the present invention, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended. Any alterations and further modifications in the described embodiments and any further applications of the principles of the present invention as described herein are contemplated as would normally occur to one skilled in the art to which the invention relates.

[0025] As illustrated in the embodiments of FIGS. 1-9, the present invention comprises an implantable surgical graft 10 for repairing or reinforcing tissue, whereby the graft comprises multiple layers 12 of remodelable collagenous sheet material 11 such as sheets derived intact from an animal or human source and processed to retain the ability of the collagen matrix to remodel into site-specific host tissue. While the multiple layers of graft material may be bonded to one another by a process such as lyophilization, vacuum pressing, heat, partial cross-linking, etc., the multilayer graft is further secured together by quilting or stitching the graft using one or more interweaving members 13, such as bioabsorbable suture 14. The pattern 20 of the interweaving members 13 is configured to substantially reduce or prevent delaminating of the graft 10 during handling and/or the early stages of remodeling. Other potential advantages provided by the inclusion of one or more interweaving members will be apparent from the examples discussed later in the text.

[0026] Suitable bioremodelable materials can be provided by collagenous extracellular matrix materials (ECMs) possessing biotropic properties. For example, suitable collagenous materials include ECMs such as submucosa, renal capsule membrane, dermal collagen, dura mater, pericardium, serosa, peritoneum or basement membrane layers, including liver basement membrane. Suitable submucosa materials for these purposes include, for instance, intestinal submucosa including small intestinal submucosa, stomach submucosa, urinary bladder submucosa, and uterine submucosa. Such isolated collagenous material can be processed so as to have remodelable, angiogenic properties and promote cellular invasion and ingrowth. Remodelable materials may be used in this context to provide new patient tissue in bodily regions in which inventive constructs are implanted or engrafted.

[0027] As prepared and used, the submucosa material and any other ECM used, may optionally retain growth factors or other bioactive components native to the source tissue. For example, the submucosa or other ECM may include one or more growth factors such as basic fibroblast growth factor (FGF-2), transforming growth factor beta (TGF-beta), epidermal growth factor (EGF), and/or platelet derived growth factor (PDGF). As well, submucosa or other ECM used in the invention may include other biological materials such as heparin, heparin sulfate, hyaluronic acid, fibronectin and the like. Thus, generally speaking, the submucosa or other ECM material may include a bioactive component that induces, directly or indirectly, a cellular response such as a change in cell morphology, proliferation, growth, protein or gene expression. A preferred ECM material is porcine small intestinal submucosa (SIS), sold commercially by Cook Medical Inc. (Bloomington, Ind.) under the trade name of Surgisis® Biodesign™, a material that has been shown to remodel effectively into site-specific host tissue in a number of clinical applications.

[0028] Further, in addition or as an alternative to the inclusion of such native bioactive components, non-native bioactive components such as those synthetically produced by recombinant technology or other methods, may be incorporated into the submucosa tissue or other ECM material. These non-native bioactive components may be naturally-derived or recombinantly produced proteins that correspond to those natively occurring in the ECM tissue, but perhaps of a different species (e.g. human proteins applied to collagenous ECMs from other animals, such as pigs). The non-native bioactive components may also be drug substances. Illustrative drug substances that may be incorporated into and/or onto the devices include, for example, antibiotics, thrombus-promoting substances such as blood clotting factors, e.g. thrombin, fibrinogen, and the like. These substances may be applied to the graft as a premanufactured step, immediately prior to the procedure (e.g. by soaking the material in a solution containing a suitable antibiotic such as cefazolin), or during or after deployment of the device in the patient.

[0029] Submucosa or other ECM tissue used in the invention is preferably highly purified, for example, as described in U.S. Pat. No. 6,206,931 to Cook et al. Thus, preferred ECM material will exhibit an endotoxin level of less than about 12 endotoxin units (EU) per gram, more preferably less than about 5 EU per gram, and most preferably less than about 1 EU per gram. As additional preferences, the submucosa or other ECM material may have a bioburden of less than about 1 colony forming units (CFU) per gram, more preferably less than about 0.5 CFU per gram. Fungus levels are desirably similarly low, for example less than about 1 CFU per gram, more preferably less than about 0.5 CFU per gram. Nucleic acid levels are preferably less than about 5 μg/mg, more preferably less than about 2 μg/mg, and virus levels are preferably less than about 50 plaque forming units (PFU) per gram, more preferably less than about 5 PFU per gram. These and additional properties of submucosa or other ECM tissue taught in U.S. Pat. No. 6,206,931, or in International Publication No. WO 2008067085 (Jun. 5, 2008) may be characteristic of the submucosa or other ECM tissue used in the present invention.

[0030] Submucosa-containing or other ECM materials of the present invention can be derived from any suitable organ or other tissue source, usually sources containing connective tissues. The ECM materials processed for use in the invention will typically include abundant collagen, most commonly being constituted at least about 80% by weight collagen on a dry weight basis. Such naturally-derived ECM materials will for the most part include collagen fibers that are non-randomly oriented, for instance occurring as generally uniaxial or multi-axial but regularly oriented fibers. When processed to retain native bioactive factors, the ECM material can retain these factors interspersed as solids between, upon and/or within the collagen fibers. Particularly desirable naturally-derived ECM materials for use in the invention will include significant amounts of such interspersed, non-collagenous solids that are readily ascertainable under light microscopic examination with appropriate staining. Such non-collagenous solids can constitute a significant percentage of the dry weight of the ECM material in certain inventive embodiments, for example at least about 1%, at least about 3%, and at least about 5% by weight in various embodiments of the invention.

[0031] The submucosa-containing or other ECM material used in the present invention may also exhibit an angiogenic character and thus be effective to induce angiogenesis in a host engrafted with the material. In this regard, angiogenesis is the process through which the body makes new blood vessels to generate increased blood supply to tissues. Thus, angiogenic materials, when contacted with host tissues, promote or encourage the formation of new blood vessels into the materials. Methods for measuring in vivo angiogenesis in response to biomaterial implantation have recently been developed. For example, one such method uses a subcutaneous implant model to determine the angiogenic character of a material. See, C. Heeschen et al., Nature Medicine 7 (2001), No. 7, 833-839. When combined with a fluorescence microangiography technique, this model can provide both quantitative and qualitative measures of angiogenesis into biomaterials. C. Johnson et al., Circulation Research 94 (2004), No. 2, 262-268.

[0032] ECM materials may be essentially free of additional, non-native crosslinking, or may contain additional crosslinking. Such additional crosslinking may be achieved by photo-crosslinking techniques, by chemical crosslinkers, or by protein crosslinking induced by dehydration or other means. However, because certain crosslinking techniques, certain crosslinking agents, and/or certain degrees of crosslinking can destroy the remodelable properties of a remodelable material, where preservation of remodelable properties is desired, any crosslinking of the remodelable ECM material can be performed to an extent or in a fashion that allows the material to retain at least a portion of its remodelable properties.

[0033] Now referring to the specific illustrative embodiments, FIG. 1 depicts an embodiment of the present invention comprising a multilaminate graft portion 10 similar to the Surgisis® Biodesign™ Complex Hernia Graft, (a 20×20 cm eight-layer, lyophilized graft construct) and a stitching pattern 20 comprising a series of parallel suture lines 19 (spaced about 2.5 cm apart) extending diagonally across the graft 10 in a first direction, and a second series of parallel suture line extending across the graft in a second direction such that a ‘diamond’ pattern is created. In the illustrative embodiment, the suture lines 19 are spaced between every other row of apertures 29 that are formed in the graft 10 (typically to allow passage of fluid therethrough) so that each ‘diamond’ includes a four-perforation cluster therein. In addition to diamond shapes, in certain embodiments, other stitched shapes will be constructed which fully or partially surround one or more perforations occurring in the material. These shapes include circles, ovals, rectangles and various other shapes having curvilinear and/or rectilinear features. The graft 10 may be optionally textured during the lyophilization process, for example, to improve its handling characteristics. Illustratively, a texturing process can include forcibly contacting a hydrated ECM material with another object or material (e.g., a synthetic grate or mesh) while drying the ECM material.

[0034] When an inventive construct includes a stitching pattern, this pattern can occupy a variety of shapes and configurations. In some forms, a useful pattern will include one or more stitched lines. Optionally, a pattern that includes a plurality of stitched lines will have lines that intersect one another. In certain embodiments, a pattern that includes a plurality of stitched lines will include a first line that coextends with an adjacent line in a concentric or parallel fashion, or in a combination of the two. As well, when an otherwise perforated material is used in the manufacture of a stitched construct, the stitching and perforations can be arranged in a variety of manners relative to one another. Perforations can include slit and non-slit openings.

[0035] In the illustrative interweaving member 13 of FIG. 1, the suture 14 material that stitches together the layers of the graft, may comprise either a synthetic or natural (e.g., collagenous) material. A bioresorbable polymeric suture material, such as 4-0 TRISORB® suture (Samyang Corporation, Seoul, Korea) or other vicryl suture (made from a polyglycolic acid block copolymer), advantageously permits the suture to degrade and be completely resorbed by the body as the graft remodels. However, a non-resorbable synthetic interweaving material, such as a suture made of cross-linked collagen could be used, particularly if there is a desire or need to enhance the strength of the remodelable graft and/or provide continued reinforcement to compliment the remodeled tissue. These types of sutures can be provided in various widths and diameters as will be recognized by those skilled in the art.

[0036] As depicted, the suture 14 or other interweaving member 13 is sewn into the graft 10 using a commercial sewing machine adapted for the type of stitching material selected. Applicants have successfully used a model number DDL-9000A-DS sewing machine manufactured by JUKI Corporation (Tokyo, Japan) with TRISORB® suture to create a series of stitches 17 through an eight-layer, lyophilized SIS sheet graft 10. A preferred lateral spacing of parallel suture lines 19 in the illustrative embodiment would be 2-4 cm apart with 3 cm being most preferred. A preferred longitudinal spacing 18 between stitches in a line or row of stitches is at least about 1 mm. In general, the longitudinal spacing between stitches will be in the range of 1-7 mm with a preferred longitudinal spacing of about 3 mm. If more closely spaced, there is a concern that the suture line 19 could weaken the material 11, essentially creating a perforation line that could cause the graft 10 to tear therealong in instances where such tearing is undesirable. If too widely spaced, the suture 14 could unravel along edges when the graft 10 is cut for resizing, increasing the risk of edge delamination.

[0037] The exemplary interweaving member 13 comprises a series of lock stitches 17, depicted in FIG. 4, in which a first suture 30 is captured from below by a second suture 31 that has penetrated the multiple layers 12 of the graft 10 with the assistance of the sewing needle (not shown) or other suitable device. The lock stitch 17 is simple to create with standard sewing techniques and advantageously resists unraveling; however, other types of stitching including alternatively-arranged lock stitching may be effective to create the quilting pattern. As will be understood by those skilled in the art, with lock stitches, a variety of manipulations can be made to the stitching material(s), the materials being stitched and/or the manner of stitching to vary the final configuration of the stitches. In the illustrative embodiment, the location of the ‘lock’ between the first suture 30 and second suture 31 can be moved relative to the multiple layers 12, for example, more toward an interior region of the multilayer structure. In some forms, the stitches will be sufficiently taut to form dimples or other indentations in the graft's surface at locations where the lock is pulled into the interior of the graft.

[0038] FIG. 2 depicts an embodiment similar to that of FIG. 1 with the addition of a suture line 19 coextending along the periphery 25 of the graft 10 to further limit the possibility of the multiple layers 12 delaminating therealong during handling and implantation. It is within the spirit of the invention for the quilting pattern 20 to comprise only the peripheral suture line 19 without the additional sutures lines comprising the diamond pattern. Alternatively, as depicted in FIG. 3, the interweaving member 13 may comprise a ‘spiral’ pattern 20 that extends from the first, inner region 23 of the graft outward to the second, outer region 24 of the graft 10 (or visa versa), resulting in quilting pattern across the entire face of the graft 10 using only a single suture line 19. As an alternative (or supplement) to the one or more suture lines 19, the interweaving member 13 may also comprise a series of discrete fixation points 16, such as the illustrative suture knots of FIG. 5. The knots 16 can be distributed along the periphery 25 of the graft or across the entirety thereof to affix and/or reinforce the multiple layers 12 of the graft 10. The knots can be created individually (as shown) or a chain of knots 16 may be created from a single length of suture with the interconnecting suture 14 being left intact between adjacent knots or clipped away at the knot after the chain is created such that they appear as they would have if created individually. In general, the suture density (or other interweaving member density) can vary across different regions of an inventive construct. Illustratively, there can be a relatively greater amount of suture material occurring in a first region (e.g., periphery) of a graft relative to a second region (e.g., center) of the graft.

[0039] In addition to fulfilling a fixation function, the interweaving member 13 of the present invention may also serve as substrate from which pharmacologically active substance may be delivered. As depicted in FIG. 6, once the graft 10 has been implanted in the patient, such as by attaching it to an area in the body in need of repair using a series of anchoring sutures 28, the pharmacologically active substance 26 is delivered from the interweaving member 13 into the tissue 27 layer that is in contact with the graft. The bioactive agent or drug 26 can be coated onto or applied to the outer surface illustrative suture 14 or other interweaving member, loaded into the polymer or other material during manufacture, or soaked in the agent and taken up through absorption. The dosage and amount of drug or agent applied and delivered is determined by several factors, including the potency thereof, the size/diameter of the suture 14 or interweaving member 13, and the density and distribution pattern of the interweaving member 13 across the graft. Examples of agents appropriate for elution in this matter include compounds selected from a group comprising pharmaceuticals having antimicrobial, analgesic, anti-inflammatory, anti-adhesion, or anti-tumorigeneic properties, and substances that stimulate remodeling, such as growth factors.

[0040] FIG. 7 depicts a graft embodiment of the present invention in which the spacing of the interweaving members 13 is increased along the outer region 24 or periphery 25 of the graft member to increase the available amount of pharmacological agent thereabout. Alternatively, spacing of the interweaving members 13 may be increased in the center portion 23 relative to the outer portion 24, or the agent may be selectively incorporated into the interweaving members 13 within one portion of the graft member 10 while those in another portion do not include the agent. Another strategy for producing increased drug delivery from one portion of the graft 10 relative to another would be to increase the diameter or size of the interweaving members 13 in selective areas so that they can hold more of the active agent than a standard or smaller-sized counterpart.

[0041] An alternative strategy of delivering a drug or agent 26 into adjacent tissue is depicted by the graft 10 embodiment shown in FIG. 8 in which the interweaving member 13 comprises a first portion 32 that is interwoven through the multiple layers 12 of the graft and second portion 33 comprising the pharmacologically active substance that is affixed to the graft by the first portion of the interweaving member. The second portion 33, which may comprise a strip 15 or other elongate member, may be placed over the outer surface 21 of the graft 10 along selected areas of the intended suture line and sewn into place during the interweaving process (such as with a sewing machine), or the second portion may be interwoven with the first portion 32 after the latter has been woven into the graft, particularly if the first interweaving member includes sufficient spacing with the graft to permit the second member comprising the drug to be inserted therebetween. The drug-containing member may be attached to one or both outer surfaces 21,22 of the graft in identical or varying patterns and may include one type or group of agents on one outer surface 21 of the graft 10 and a different agent or group of agents incorporated thereinto on the opposite side 22 of the graft. The use of a separate strip 15 comprising the agent 26 advantageously allows for the drug-containing portion 33 to be optimized for delivering the agent (i.e., dosage, release rate, location on the graft, etc.), while the first interweaving member portion 32 is optimized for providing the interweaving function (e.g., compatibility with a sewing machine). The second portion 33 or strip 15 may be formed from a porous degradable or bioabsorbable polymer, a biological material, or any biocompatible substrate suitable for carrying and delivering an agent to achieve a predictable and effective biological response. Besides affixing the illustrative strips 15 or members to one or both outer surfaces of the graft, they may be sewn between layers of the biomaterial, particularly if it would be advantageous to control or delay release of the bioactive substance, such as to a later point in the remodeling process.

[0042] FIG. 9 depicts a graft 10 embodiment in which the interweaving member 13 affixing the layers 12 of the graft together provides the function of preventing premature delamination thereof when a synthetic mesh 34 is inserted within the layers of biomaterial. In the illustrative embodiment, a medical-grade polypropylene mesh fabric commercially available from ATEX Technologies, Inc. (Pinebluff, N.C.), is sandwiched between a first group of sheets 35 and a second group of sheets 36 (or two individual sheet for a two-layer graft) and the graft is laminated with the synthetic mesh inside. The interweaving members thus provide further fixation to help prevent delamination. Alternatively, the mesh could be inserted between multilayer constructs 35,36 that have been previously lyophilized or otherwise laminated together, such that the stitching from the interweaving member provides the dual function of holding the graft together and preventing delamination. A variety of medical mesh materials including some that are already commercially available can be utilized in the regard as will be recognized by those skilled in the art.

[0043] The constructs described herein have broad application. In some aspects, inventive products will find use as precursor materials for the later formation of a variety of other medical products, or components thereof. Medical grafts and materials that are already commercially available can be modified in accordance with the present invention as well. In certain embodiments, inventive products are useful in procedures to replace, augment, support, repair, and/or otherwise suitably treat diseased or otherwise damaged or defective patient tissue. Some of the illustrative constructs described herein will be useful, for example, in treating herniated tissue although inventive constructs and materials can be developed and used in many other medical contexts. In this regard, when used as a medical graft, inventive constructs can be utilized in any procedure where the application of the graft to a bodily structure provides benefit to the patient. Illustratively, graft materials of the invention can be processed into various shapes and configurations, for example, into a variety of differently shaped urethral slings, surgical bolster or reinforcement materials (e.g., for use in tissue resection and similar procedures), wound products and other grafts and graft-like materials.

[0044] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Further, any theory, mechanism of operation, proof, or finding stated herein is meant to further enhance understanding of the present invention, and is not intended to limit the present invention in any way to such theory, mechanism of operation, proof, or finding. While the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only selected embodiments have been shown and described and that all equivalents, changes, and modifications that come within the spirit of the inventions as defined herein or by the following claims are desired to be protected.