WO2018201116A1

WO2018201116A1 - Umbilical cord implantable cover and method of making

Info

Publication number: WO2018201116A1
Application number: PCT/US2018/030066
Authority: WO
Inventors: Christian Beaudry; Grant Dakota SENNER; Merrill B. STROMER
Original assignee: Aluta Biosciences LLC
Current assignee: Aluta Biosciences LLC
Priority date: 2017-04-29
Filing date: 2018-04-28
Publication date: 2018-11-01
Anticipated expiration: 2019-10-29

Abstract

An implantable cover for an implantable article, such as a pacemaker utilizes umbilical cord tissue to form art envelope around at least two opposing sides of the article. A pouch may be formed from the umbilical cord tissue having a single opening for receiving the implantable article. An en velope may be formed by removing the i nterior portion of the umbilical cord to form a tube having two open ends or by forming a cover sheet from the umbilical cord and then folding the cover sheet to form the envelope, A poach may be formed by attaching sides of an envelope, such as either- or both of the sides extending from the fold of the envelope and/or the extended ends of the en velope. The implantable cover derived from the umbilical cord may have some thickness of Wharton's Jelly and/or amniotic membrane. The implantable cover derived from the umbilical cord may be biologically active.

Description

UMBILICAL CORD IMPLANTABLE COVER AND METHOD OF MAKING BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This application relates to covers derived from umbilical cord tissue for use with implantable devices, such as a cardiac pacemaker, implantable cardioverter defibrillator (ICD) or implantable neurostimulator.

Background

[0002] Implantation of medical devices are often associated with inflammation of the surrounding tissue, infections at the site of implant, and fibrotic tissue formation surrounding the implant. Additionally, implantable devices often require replacement and/or repair or alteration and can become enveloped with tissue, including fibrotic tissue making removal of the device and leads difficult. Use of a cover or pouch derived from umbilical cord tissue containing intrinsic anti-inflammatory, anti-bacterial, and anti-fibrotic properties for use with the implantable device may reduce inflammation at the time of implant, reduce infections, reduce the formation of fibrotic tissue, and deliver additional therapeutic benefits.

SUMMARY OF THE INVENTION

[0003] The invention is directed to an umbilical cord cover for use with an implantable article, such as an electronic medical device. An exemplary umbilical cord cover comprises a portion of an umbilical cord having a conduit extending along the length that forms an envelope for receiving an implantable article. An exemplary umbilical cord cover is biologically active. An exemplary umbilical cord cover may have a single opening and be in the form of a pouch for receiving an implantable article. In an exemplary embodiment, a portion of an umbilical cord is used to form an umbilical cord cover and one end is attached together to form a pouch. The attached end of the umbilical cord may be attached by a stitch or suture, by adhesive, or the tissue may be directly attached, wherein tissue in attached directly together by application of pressure over a period of time. The tissue may be welded or laminated together as well. In another embodiment, a separate material, an end-cover is used to seal off one end of the umbilical cord to form a pouch. The end-cover may comprise, consists essentially of or consist of umbilical cord material and may be attached to the umbilical cord by an attachment, as described. In another exemplary embodiment, a sheet of umbilical cord may be prepared by cutting the umbilical cord along the length and splaying the umbilical cord to form a sheet. The sheet may be folded and attached along a portion of the perimeter to form an envelope or a pouch. In another embodiment, two or more sheets of umbilical cord are layered and attached along a portion of the perimeter to form an envelope or a pouch. The inside surface of the umbilical cord may form the inside surface of the umbilical cord cover or the outside surface of the umbilical cord cover. Likewise, the outside surface of the umbilical cord may form the outside surface or inside surface of the umbilical cord cover.

[0004] A biologically active material, such as an implantable cover is defined as a material that is able to elicit cells and tissues responses and that comprises biologically active components including but not limited to proteins, growth factors, cytokines and in some cases cells that may be live active cells. An implantable cover may consist essentially of or consist of a biologically active material derived from umbilical cord tissue. An implantable cover that consists essentially of biologically active material comprises a cover material that is a biologically active, such as umbilical cord tissue and may include non-biologically active attachments, such as a stitch or adhesive and may also include an anti-microbial agent, an antifibrotic agent, a pharmacological agent, anti-inflammatory agents, medicant agents and saline, for example. A biologically active material may be determined to be bioactive through functional-assays demonstrating anti-microbial properties, anti-fibrotic properties, anti-inflammatory properties and other biological and physiological properties including among others modulation of cell migration, cell differentiation, cell proliferation, protein biosynthesis.

[0005] An exemplary biologically active umbilical cord cover is in the form of an envelope and has an inner surface, an outer surface, a first end and a second end that opposes the first end. The envelope may be configured around opposing surfaces of an implantable article and is a one-piece unit. An envelope may be a piece of umbilical cord and be in the form of tube having a continuous wall that extends around the radius of the conduit. An exemplary envelope extends around two opposing sides of an implantable article and is a contiguous piece of material. In another embodiment, an envelope umbilical cord cover is a folded piece of umbilical cord sheet material and the extended or cut ends may be attached to form a conduit for receiving an implantable article. In still another embodiment, an envelope umbilical cord comprises two or more sheets of umbilical cord material that is attached to form a conduit for receiving an implantable article. [0006] An exemplary umbilical cord cover is a pouch that forms an enclosure for receiving an implantable article. The pouch enclosure may be a portion of the length of an umbilical cord that is attached on one end. An umbilical cord tube may have one end of the tube attached by stitched suture, adhesive or a direct attachment. An end-cover may be attached to one end of an umbilical cord tube to form a pouch. In another embodiment, a pouch is formed from a folded piece of umbilical cord sheet material and the perimeter is attached to form a pouch. In still another embodiment, a pouch is formed from two or more layers of umbilical cord sheet material that are attached together along the perimeter to form a pouch. The end-cover material may be umbilical cord sheet material.

[0007] Natural umbilical cord comprises an outer layer of amnion which is the extension of the amniotic membrane covering the placenta and Wharton's Jelly. The umbilical cord further comprises an allantoic duct, two arteries and one vein buried within the Wharton's Jelly. The amniotic membrane is a translucent membrane and has multiple layers; an epithelial layer; a basement membrane layer; a compact layer; a fibroblast layer; and a spongy layer. The amniotic membrane lacks the immunogenic antigens HLA-A, B, or DR, reducing the risk of graft-versus-host reaction. Furthermore, the amniotic membrane is rich in biologically active molecules, including TIMP-1, TIMP-2, IL-lra, EGF, bFGF, TFG-βΙ, IGF-1, PDGF-AA, and PDGF-BB among others. The amniotic membrane contains cells including epithelial cells and mesenchymal stem cells. The amniotic membrane also contains hyaluronic acid and anti-microbial peptides including Pentraxin-3 and S100-A8. The antimicrobial peptides Pentraxin-3 and S100-A8 are known to play an important role against bacterial infection caused by Staphylococcus aureus, Staphylococcus epidermis,

Pseudomonas aeruginosa, Salmonella typhimurium, Streptococcus pneumonia, and

Escherichia coli among others. The Wharton's Jelly contains mesenchymal stem cells, growth factors and a large amounts of extracellular matrix proteins including collagen, hyaluronate and proteoglycans. The amniotic membrane and Wharton's Jelly possess several intrinsic regenerative properties including cellular proliferation, cellular migration, cellular differentiation, modulation of inflammation, reduction of fibrosis, reduction of adhesion among others. Umbilical cord tissue has a wall thickness that is much greater than placental tissue layers, on order of eight times to ten or more times greater. This increased tensile strength provides for a more robust implantable cover. One or more components of the umbilical cord may be removed before, during, or after making an umbilical cord cover. For example, the Wharton's Jelly portion of the umbilical cord may be partially, substantially, or completely removed from the umbilical cord material. Likewise, the smooth musculature may be partially or substantially removed. Portions of the umbilical cord may be removed physically or with chemical agents. Umbilical cord material also comprises growth factors, cytokines, extracellular matrix proteins, hyaluronic acid, proteoglycans, and anti-microbial peptides. These materials are known to provide improved healing and other beneficial therapeutic effects.

[0008] The umbilical cord, implantable envelope, pouch or cover sheet may be soaked in agents to increase or enrich agents. For example, an implantable pouch consisting of umbilical cord tissue may be soaked in an anti-microbial agent, an antifibrotic agent, a pharmacological agent, a solution containing cells, a solution containing growth factors, a solution containing cytokines, a solution containing extracellular matrix proteins and the like.

[0009] An exemplary implantable cover consists essentially of umbilical cord tissue and may include attachments, such as a stitch or adhesive. An exemplary implantable cover may consist of umbilical cord tissue and comprise a conduit formed in the umbilical cord to form a tube or may comprise a folded cover sheet of umbilical cord tissue that forms an envelope and may comprise a direct attachment, wherein the umbilical cord tissue is bonded or attached to itself directly without any additional stitching or adhesive. An implantable cover may consist of umbilical cord tissue when an enlarged cover sheet is utilized having a direct attachment.

[0010] A release layer, or a sheet of material that prevents direct attachment, such as a low surface energy material such as fluoropolymer or polyurethane, may be used to prevent the formation of a direct attachment when pressure is applied to two layered umbilical cord sheets. A release layer may have a release tab that creates a secondary opening in a pouch or envelope.

[001 ] ] An exemplary implantable cover, umbilical cord cover layer or umbilical cover sheet may be bioerodible or biodegradable. A bioerodible material, as used herein, may comprises bioerodible additives to enable the material to breakdown more quickly after being implanted. A bioerodible additive may be a bioresorbable material or biodegradable material. A biodegradable material is susceptible of breakdown into simpler components by biological processes, as by bacterial or other enzymatic action.

[0012] The summary of the invention is provided as a general introduction to some of the embodiments of the invention and is not intended to be limiting. Additional example embodiments including variations and alternative configurations of the invention are provided herein. BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

[0013] The accompanying drawings are included to provide further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention, and together with the description serve to explain the principles of the invention.

[0014] Figure 1 shows a diagram of a fetus coupled to the placenta by the umbilical cord.

[0015] Figure 2 shows a diagram of a fetus coupled to the placenta by the umbilical cord.

[0016] Figure 3 shows a cross-sectional micrograph of an umbilical cord.

[0017] Figure 4 shows a side view of an exemplary umbilical cord that has a length from a placental end to a fetus end and a conduit therethrough.

[0018] Figure 5 shows a placental-end view of an exemplary umbilical cord tube, wherein a portion of the interior of the umbilical cord has been removed to form an implantable tube.

[0019] Figure 6 shows a fetus-end view the exemplary implantable tube shown in Figure. 4.

[0020] Figure 7 shows a front perspective view of an exemplary umbilical cord tube cover comprising a portion of an umbilical cord that forms an envelope and an attachment on one end to form a pouch.

[0021] Figure 8 shows a side perspective view of an exemplary umbilical cord tube cover comprising a portion of an umbilical cord that forms an envelope and an attachment on one end to form a pouch.

[0022] Figures 9 and 10 show perspective views of an exemplary umbilical cord tube cover comprising a portion of an umbilical cord that forms an envelope and an end-cover attached to one end to form a pouch.

[0023] Figure 1 1 shows a perspective view of an end-cover comprising umbilical cord tissue in a sheet form.

[0024] Figure 12 shows a front perspective view of an exemplary umbilical cord cover comprising a portion of an umbilical cord that forms an envelope and an attachment on one end to form a pouch.

[0025] Figure 13 shows a side perspective view of an exemplary umbilical cord tube cover comprising a portion of an umbilical cord that forms an envelope and an attachment on one end to form a pouch. [0026] Figures 14 and 15 show perspective views of an exemplary umbilical cord tube cover comprising a portion of an umbilical cord that forms an envelope and an end-cover attached to one end to form a pouch.

[0027] Figure 16 shows a perspective view of a portion of an umbilical cord tube with a cut through the umbilical cord tube along the length to form a sheet, as shown in FIG. 16.

[0028] Figure 17 shows a perspective view of an umbilical cord sheet formed from a cut section of umbilical cord.

[0029] Figure 18 shows a perspective view of a section of an umbilical cord having a slit to allow the umbilical cord to be open to produce a cover sheet.

[0030] Figures 19 to 21 show two cover sheets formed from an umbilical cord being attached along a portion of the perimeter to form an enlarged implantable cover sheet.

[0031] Figure 22 shows a perspective view of an umbilical cord sheet folded to form an envelope.

[0032] Figure 23 shows a perspective view of an umbilical cord sheet folded to form an envelope and an attachment around a portion of the perimeter to form a pouch.

[0033] Figure 24 shows a perspective view of two umbilical cord sheets attached around a portion of their perimeters for form a pouch.

[0034] Figure 25 shows a perspective view of two umbilical cord sheets layered one atop the other with a release layer between them and pressure being applied to form a direct attachment.

[0035] Figure 26 shows a perspective view of an implantable pouch having a direct attachment around the perimeter and an opening.

[0036] Figure 27 shows a perspective view of two umbilical cord sheets and a release layer place on one of the sheets having a tab to create a secondary opening when the two layers are attached to form direct attachment around the perimeter.

[0037] Figure 28 shows a perspective view of an exemplary pouch having a secondary opening.

[0038] Figure 29 show a perspective view of the exemplary pouch shown in FIG. 28 with an implantable article inserted into the pouch with leads from the implantable article extending through the secondary opening in the perimeter of the pouch.

[0039] Figure 30 shows a perspective view of an envelope formed from an implantable cover sheet having a release layer inserted into the envelope to allow direct attachment of the two sides to form a pouch.

[0040] Figure 31 shows an exemplary umbilical cord cover. [0041] Figure 32 shows a front view of an exemplary implantable article, a pacemaker.

[0042] Figure 33 shows a front view of the pacemaker shown in FIG. 32 with the umbilical cord cover shown in FIG. 31 partially configured therearound.

[0043] Figure 34 shows a front view of the pacemaker shown in FIG. 32 with the umbilical cord cover shown in FIG. 31 partially configured therearound.

[0044] Figure 35 shows a front view of the umbilical cord cover shown in FIG. 20 configured completely around the pacemaker shown in FIG. 32.

[0045] Figure 36 shows a bar graph of the total proteins for three different samples from an umbilical cord containing different amounts of the Wharton's Jelly.

[0046] Figure 37 shows a graph of protein release from a sample taken from an umbilical cord versus time.

[0047] Figure 38 shows a bar graph of the hyaluronic acid for two different samples from an umbilical cord containing different amounts of the Wharton's Jelly.

[0048] Figure 39 shows a flow diagram of a method to form an implantable cover from umbilical cord cover sheet derived from an umbilical cord.

[0049] Figure 40 shows a flow diagram of a method to form an implantable pouch from an umbilical cord cover sheet derived from an umbilical cord by folding and forming a direct attachment.

[0050] Figure 41 shows a flow diagram of a method to form an implantable cover from umbilical cord cover sheet derived from an umbilical cord.

[0051]

[0052] Figure 42 shows a flow diagram of a method of forming an implantable cover by removing a portion of the interior of a section of an umbilical cord.

[0053] Figure 43 shows a flow diagram of a method of forming an implantable cover by removing a portion of the interior of a section of an umbilical cord and attached an end-cover to one of the open ends to form an implantable pouch.

[0054] Corresponding reference characters indicate corresponding parts throughout the several views of the figures. The figures represent an illustration of some of the

embodiments of the present invention and are not to be construed as limiting the scope of the invention in any manner. Further, the figures are not necessarily to scale, some features may be exaggerated to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention. DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

[0055] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Also, use of "a" or "an" are employed to describe elements and components described herein. This is done merely for convenience and to give a general sense of the scope of the invention. This description should be read to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

[0056] Certain exemplary embodiments of the present invention are described herein and are illustrated in the accompanying figures. The embodiments described are only for purposes of illustrating the present invention and should not be interpreted as limiting the scope of the invention. Other embodiments of the invention, and certain modifications, combinations and improvements of the described embodiments, will occur to those skilled in the art and all such alternate embodiments, combinations, modifications, improvements are within the scope of the present invention.

[0057] Referring to FIGS. 1 and 2 a fetus 34 is coupled to the placenta 32 by the umbilical cord 20. The umbilical cord has a placenta end 22 that connects the umbilical cord to the placenta and a fetus end 34 that connects the umbilical cord to the fetus. The fetus and placenta are within the amniotic sack 30 comprising amnion tissue 31.

[0058] As shown in FIG. 3, an umbilical cord 20 comprises a cord lining comprising amnion 82, Wharton's Jelly, allantoic duct, umbilical vein, and two umbilical arteries.

Referring to FIGS. 4, 5 and 6, an exemplary umbilical cord 20 has a length 23 from a placenta end 22 to the fetus end 24 and has a conduit 21 therethrough. The umbilical cord may have an interior portion removed to form an umbilical tube cover 18 that has an inside surface 29 and an outside surface 27. Figure 4 shows a placental end 22 of an exemplary umbilical tube cover 18. The inner diameter 25 of the umbilical cord conduit 21 is shown as well as the wall thickness 28 of the umbilical cord. Figure 5 shows a fetus end 24 of an exemplary umbilical tube cover 18. The outer diameter 26 of the umbilical cord is shown.

[0059] Referring to FIGS. 7 and 8, an exemplary umbilical cord cover 15 comprises a portion of an umbilical cord 20 having an interior portion removed to make an umbilical tube cover 18 that forms an envelope 17 and an attachment 56 on one end to form a pouch 50. The attached end 54 of the umbilical tube cover comprises a stitch closes the open end of the conduit 21 by securing the cover wall 52 together. The cover opening 51 allows an implantable article to be placed therein. The inside surface 29 of the umbilical tube cover is the inside surface of the umbilical cord cover and the outside surface 27 of the umbilical cord is the outside surface of the umbilical cord cover.

[0060] Referring to FIGS. 9, 10 and 1 1 , an exemplary umbilical cord cover 15 comprises a portion of an umbilical cord 20 having a portion of the interior remove that forms an envelope 17 and an end cover 40 that is attached to the umbilical tube cover to form pouch 50. The end-cover is attached to the umbilical cord 20 by an attachment 56 to form an attached end 54, or closed end of the pouch. The end-cover is a sheet of umbilical cord 42 comprising umbilical cord tissue 43. The end-cover prepared by cutting open a section of an umbilical cord to form a sheet of material. The cover opening 51 allows an implantable article to be placed therein. The inside surface 29 of the umbilical cord is the inside surface of the umbilical cord cover and the outside surface 27 of the umbilical cord is the outside surface of the umbilical cord cover.

[0061] Referring now to FIGS. 12 and 13, an exemplary umbilical cord cover 15 comprises a portion of an umbilical cord 20 having an interior portion removed to form a tube that has been inverted such that the inside surface 29 of the umbilical cord forms the outside surface 55 of the umbilical tube cover 18 and the outside surface 27 of the umbilical cord is configured on the inside surface 59 of the umbilical tube cover or cord cover 15. The attached end 54 of the cover is attached by an attachment 56, a stitch 57.

[0062] Referring now to FIGS. 14 and 15, an exemplary umbilical cord cover 15 comprises a portion of an umbilical cord 20 having an interior portion removed to form a tube that has been inverted such that the inside surface 29 of the umbilical cord forms the outside surface 55 of the umbilical cord cover and the outside surface 27 of the umbilical cord is configured on the inside surface 59 of the umbilical cord cover 15. The attached end 54, or closed end, of the cover comprises an end-cover 40 attached to the umbilical cord by an attachment 56, a stitch 57. The end-cover may be a piece of umbilical cord and may be configured with the inside surface of the umbilical cord facing into the cover or forming an outside surface of the cover.

[0063] Referring to FIGS. 16 and 17, an umbilical cord 20, with an interior portion removed to from an umbilical tube cover 18, is cut along the length to form an umbilical cord sheet 42, as shown in FIG. 17. The cut along the length of the umbilical cord tube creates a first cut edge 76 and a second cut edge 78. When the umbilical cord is opened and flattened out it forms the umbilical cord sheet 42 shown in FIG. 17 having a length 45 from a first end 44 to a second end 46 and a width 48 from a first side 47 to a second side 49. The sides are the first and second cut edges as shown in FIG. 16. The umbilical cord tissue 43 may comprise amniotic membrane, Wharton's jelly, and/or smooth musculature. Layers of the umbilical cord tissue may be removed as required for the application of use.

[0064] Figure 18 shows a perspective view of a section of an umbilical cord 20 having a slit to allow the umbilical cord to be open to produce a cover sheet. The slit umbilical cord may be opened or flattened out to form a cover sheet. The slit cord may have additional material removed to form a substantially flat sheet, such as some of the Wharton's Jelly, veins and/or artery. The cover sheet may be rolled or placed under pressure to enlarge the sheet dimension size of the cover sheet.

[0065] Figures 19 to 21 show two cover sheets 42, 42 formed from an umbilical cord being attached along a portion of the perimeter to form an enlarged implantable cover sheet 41. In FIG. 19, the attachment 56 is a stitch 47 along the perimeter. In FIG. 20, the attachment 56 is an adhesive 58. In FIG. 21, the attachment 56 is a direct attachment 69, wherein the two cover sheets bond directly together through application of pressure over a period of time wherein the umbilical cord tissue may dry and form a direct bond. The sheets will bond and attach with application of pressure.

[0066] Referring now to FIGS. 22 and 23, an umbilical cord sheet 42 is folded to form an envelope and then a portion of the perimeter is attached to form a pouch 50. The umbilical cord sheet is folded about a fold 60 with the first and second cut edges, 76, 78 aligned on the extended ends 62 of the folded sheet material. The inside surface 29 of the umbilical cord 20 is facing out on the pouch 50, or forms the outside surface. Again, some layers of the umbilical cord may be removed prior to or after forming the umbilical cord cover 15. A portion of the perimeter of the folded sheet are attached together by an attachment 56, an adhesive 58, leaving an opening 51 for receiving an implantable article.

[0067] As shown in FIG. 24, two umbilical cord sheets 42, 42' are attached around a portion of their perimeter to form a pouch 50. The umbilical cord cover 15 has the outside surface 27 of the umbilical cord tissue 43 forming the outside surface of the 55 of the umbilical cord cover 15.

[0068] As shown in FIG. 25, two umbilical cord sheets 42, 42' are layered one atop the other with a release layer 67 between them. Pressure is applied, as indicated by the large bold arrows to form a direct attachment 69 or bond. The pressure is applied at least around the perimeter to cause the two umbilical cord sheets to bond together as they dry in contact with each other under pressure. The release sheet can be removed after the direct bond is formed and prevents the middle portion of the two umbilical cord sheets from bonding, thereby forming a pouch.

[0069] As shown in FIG. 26, an exemplary implantable pouch 50 has a direct attachment around the perimeter and a cover opening 51 to receive an implantable article. The pouch consists of umbilical cord tissue 43.

[0070] Referring to FIGS. 27, 28 and 29, a first umbilical cord sheet 42 has a release layer 67 with a release tab 68 configured thereon. A second umbilical cord sheet 42' may then be place over the first sheet and release layer and pressure may be applied to form a direct attachment around the perimeter, where the release layer and release tab do not interfere with direct contact between the two umbilical cord sheets. After the direct attachment is formed, the release layer is removed to form an implantable pouch 50 having a cover opening 51 for receiving an implantable article 120, and a secondary opening 66 for extending a lead 65 therethrough. The secondary opening may be configured in any location around the perimeter of the pouch including proximal with the cover opening 51. The secondary opening may extend down from the cover opening along one of the sides. An implantable article, such as an electronic device is configured within the pouch 50 with a lead 65 extending through the secondary opening in FIG. 29.

[0071] As shown in FIG. 30, an envelope 17 is formed from an implantable cover sheet 42 and a release layer 67 is inserted into the envelope to allow direct attachment of the two envelope sides 1 10 and 1 12, to form a pouch.

[0072] Referring now to FIS. 31 to 35, an exemplary umbilical cord cover 15 is configured for placement at least partially over and implantable article 120, such as an electronic device 122. The pacemaker 124 has an irregular shape that is covered, at least in part, by umbilical cord cover 15. The opening 51 of the cover is extended over the implantable article. As shown in FIG.33 and 34, the umbilical cord cover is partially extended over the implantable article and in FIG. 35 the implantable cover 15 substantially covers the implantable article 120.

[0073] Referring to FIG. 36, total proteins in different degree of Wharton's Jelly (WJ) contained umbilical cord (UC) membrane were measured using collagenase type I digested membrane solution by Nanodrop 8000. WJ - means WJ fully removed UC membrane, WJ + means 2mm of WJ remained UC membrane, and WJ ++ means 3mm of WJ remained UC membrane. Total protein was increased as more WJ contained UC membrane, exact value of total protein is presented in the FIG. 36 (n=3). [0074] Referring to FIG. 37, to measure cumulative protein release profile in UC membrane (WJ ++), released protein amount from 1cm x 2cm UC membrane in 250 uL saline was measured on schedule time by Nanodrop 8000. All data was normalized on 1cm x 1 cm membrane size. Initial burst was showing on first day, and then protein was released slowly over 5 days. Released total protein amount was 673.5 ±146.9 μ^ΐατι x 1cm.

[0075] Referring to FIG. 38, to measure hyaluronic acid (HA) amount in different degree of Wharton's Jelly(WJ) contained umbilical cord membrane, digested UC membrane solution by collagenase type I was used for enzyme-linked immunosorbent assay (ELISA). In experimental groups, WJ - means WJ fully removed UC membrane, and WJ ++ means 3mm of WJ remained UC membrane. WJ - and ++ UC membrane contained 9.88 ± 0.13 and 21.47 ± 0.5 μg/lcm x 1cm, respectively. HA existed in greater level in higher WJ containing UC membrane.

[0076] Figure 39 shows a flow diagram of a method to form an implantable cover, in the form of an envelope or pouch, form a folded umbilical cord cover sheet.

[0077] Figure 40 shows a flow diagram of a method to form an implantable pouch from an umbilical cord cover sheet derived from an umbilical cord by folding and forming a direct attachment. Note that two or more umbilical cover sheets may be attached to form an enlarged cover sheet before it is folded and bonded to form the pouch as described in this method diagram.

[0078] Figure 41 shows a flow diagram of a method to form an implantable cover, in the form of an envelope or pouch, form a two layered and attached umbilical cord cover sheets.

[0079] Figure 42 shows a flow diagram of a method of forming an implantable cover by removing a portion of the interior of a section of an umbilical cord.

[0080] Figure 43 shows a flow diagram of a method of forming an implantable cover by removing a portion of the interior of a section of an umbilical cord and attached an end-cover to one of the open ends to form an implantable pouch.

[0081] It will be apparent to those skilled in the art that various modifications, combinations and variations can be made in the present invention without departing from the spirit or scope of the invention. Specific embodiments, features and elements described herein may be modified, and/or combined in any suitable manner. Thus, it is intended that the present invention cover the modifications, combinations and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

What is claimed is:

1. An implantable cover comprising:

a) an outer surface;

b) an inner surface; and

c) an envelope having:

i) a first end having an opening; and

ii) a second end that is opposing said first end;

wherein said implantable cover comprises umbilical cord tissue.

2. The implantable cover of claim 1 , wherein the umbilical cord tissue is biologically active.

3. The implantable cover of claim 2, wherein the biologically active umbilical cord tissue demonstrates bioactivity through functional-assays or in vivo testing.

4. The implantable cover of claim 3, wherein the biologically active umbilical cord tissue demonstrates at least one of anti-microbial, anti-fibrotic, anti-inflammatory, modulation of cell migration, cell differentiation, cell proliferation, protein biosynthesis.

5. The implantable cover of claim 1 , wherein the envelope is an umbilical cord tube.

6. The implantable cover of claim 1 , wherein the envelope is formed from an umbilical cord cover sheet.

7. The implantable cover of claim 6, further comprising an attachment around a perimeter of the folded umbilical cord cover sheet to form a pouch.

8. The implantable cover of claim 6, wherein the envelope is formed from a folded

umbilical cord cover sheet.

9. The implantable cover of claim 8, further comprising an attachment around a perimeter of the folded umbilical cord cover sheet to form a pouch.

10. The implantable cover of claim 6, wherein the envelope is formed from two umbilical cord cover sheets that are attached along a portion of a perimeter of the two umbilical cord cover sheets by an attachment.

1 1. The implantable cover of claim 10, wherein said attachment extends around a perimeter of the folded umbilical cord cover sheet to form a pouch.

12. The implantable cover of claim 1, wherein the envelope is formed from an enlarged

umbilical cord cover sheet, wherein two umbilical cord sheets are attached by an attachment to produce said enlarged umbilical cord cover sheet.

13. The implantable cover of claim 12, further comprising an attachment around a perimeter of the folded umbilical cord cover sheet to form a pouch.

14. The implantable cover of claim 1, further comprising an attachment on the second end of the envelope that forms a pouch.

15. The implantable cover of claim 1 , wherein the implantable cover consists essentially of an umbilical cord tissue.

16. The implantable cover of claim 1, wherein the implantable cover consists of umbilical cord tissue.

17. The implantable cover of claim 1 , wherein the implantable cover consists essentially of an umbilical cord amniotic membrane and Wharton's Jelly.

18. The implantable cover of claim 1, wherein the implantable cover consists essentially of an umbilical cord amniotic membrane.

19. The implantable cover of claim 1 , wherein the implantable cover consists of an umbilical cord amniotic membrane and Wharton's Jelly

20. The implantable cover of claim 1 , wherein the implantable cover consists of an umbilical cord amniotic membrane.

21. The implantable cover of claim 1 , wherein the implantable cover consists essentially of an umbilical cord tissue free of a vein or artery.

22. The implantable cover of claim 1 , wherein the implantable cover consists essentially of an umbilical cord tissue free of red blood cells.

23. The implantable cover of claims 8 to 1 1 , wherein the attachment comprises a stitch.

24. The implantable cover of claims 8 to 1 1, wherein the attachment comprises an adhesive.

25. The implantable cover of claims 8 to 1 1, wherein the attachment comprises umbilical cord tissue that is attached by a direct attachment of umbilical cord tissue.

26. The implantable cover of claim 1 , wherein an end cover is configured on the second end.

27. The implantable cover of claim 1 , wherein an end cover is configured on the second end of an umbilical cord tube to form a pouch.

28. The implantable cover of claim 1 , wherein outer surface of the implantable cover is an outer surface of umbilical cord tissue.

29. The implantable cover of claim 1 , wherein the outer surface of the implantable cover is an inner surface of umbilical cord tissue.

30. The implantable cover of claim 29, wherein the cover consists essentially of an umbilical cord that is inverted.

31. The implantable cover of claim 1 , wherein an umbilical cord cover sheet is folded about a fold with two extended ends extending from said fold and wherein the implantable cover comprises an attachment along a portion of the perimeter.

32. The implantable cover of claim 31, further comprising an attachment along the second of the implantable cover to form a pouch.

33. The implantable cover of claim 1, wherein the implantable cover comprises two umbilical cord sheets that are attached along a first and a second side to form said cover.

34. The implantable cover of claim 33, further comprising an attachment along the second of the implantable cover to form a pouch.

35. The implantable cover of claim 1 , wherein the umbilical cord tissue is comprised of an amniotic membrane and Wharton's Jelly.

36. The implantable cover of claim 35, wherein the Wharton's Jelly has a thickness of at least lOOum.

37. The implantable cover of claim 35, wherein the Wharton's Jelly has a thickness of no more than 50um.

38. The implantable cover of claim 35, wherein there is an amniotic membrane on the outside surface of the implantable cover.

39. The implantable cover of claim 35, wherein there is an amniotic membrane on the inside surface of the implantable cover.

40. The implantable cover of claim 35, wherein Wharton's Jelly is on the outside surface of the implantable cover.

41. The implantable cover of claim 35, wherein Wharton's Jelly is on the inside surface of the implantable cover.

42. The implantable cover of claim 1 , wherein the Wharton's Jelly is completely removed from the umbilical cord tissue.

43. The implantable cover of claim 1, wherein the umbilical cord tissue comprises of

epithelial cells, mesenchymal stem cells, growth factors, cytokines, extracellular matrix proteins, hyaluronic acid, proteoglycans, and anti-microbial peptides.

44. The implantable cover of claim 1 , where the umbilical cord tissue is resorbable

45. The implantable cover of claim 1 , wherein the umbilical cord tissue comprises an antiinflammatory agent.

46. The implantable cover of claim 1 , wherein the umbilical cord tissue comprises an antimicrobial agent.

47. The implantable cover of claim 1 , wherein the umbilical cord tissue comprises an antimicrobial agent.

48. The implantable cover of claim 1 , wherein the umbilical cord cover is comprised of a pharmaceutical excipient, carrier, or combination thereof.

49. The implantable cover of claim 1 , wherein the umbilical cord tissue releases growth factors, cytokines, extracellular matrix proteins, hyaluronic acid, proteoglycans, antimicrobial peptides, lipids, particles.

50. The implantable cover of claim 1 , wherein the umbilical cord tissue comprises additional cells that are added to the umbilical cord tissue.

51. The implantable cover of claim 1 , wherein the umbilical cord tissue is molded around the implantable device to create an envelope.

52. The implantable cover of claim 1 , wherein the umbilical cord tissue comprises of

53. The implantable cover of claim 1, wherein the umbilical cord tissue is resorbable.

54. The implantable cover of claim 1 where the umbilical cord tissue is biodegradable.

55. The implantable cover of claim 1, where the umbilical cord tissue is bioerodible.

56. A method of forming an implantable cover comprising the steps of:

a) providing an umbilical cord;

b) preparing an implantable cover from said umbilical cord;

wherein the implantable cover comprises:

an outer surface;

an inner surface; and

an envelope having:

a first end having an opening; and

a second end that is opposing said first end;

wherein said implantable cover comprises umbilical cord tissue.

57. The method of forming an implantable cover of claim 56, wherein the umbilical cord tissue is biologically active.

58. The method of forming an implantable cover of claim 57, wherein the biologically active umbilical cord tissue demonstrates bioactivity through a functional-assays or in vivo testing.

59. The method of forming an implantable cover of claim 58, wherein the biologically active umbilical cord tissue demonstrates at least one of anti-microbial, anti-fibrotic, antiinflammatory, modulation of cell migration, cell differentiation, cell proliferation, protein biosynthesis.

60. The method of forming an implantable cover of claim 56, wherein the umbilical cord comprises an umbilical vein and two umbilical arteries, and wherein the step of preparing an implantable cover from said umbilical cord comprises the step of removing umbilical vein and the umbilical arteries.

61. The method of forming an implantable cover of claim 56, wherein the umbilical cord comprises an allantoic duct, and wherein the step of preparing an implantable cover from said umbilical cord comprises the step of removing allantoic duct.

62. The method of forming an implantable cover of claims 56 to 58, wherein a portion of an interior of the umbilical cord is removed along the length of the umbilical cord to produce an implantable umbilical tube.

63. The method of forming an implantable cover of claim 62, wherein Wharton's Jelly is removed from the interior of the umbilical cord.

64. The method of forming an implantable cover of claim 62, wherein the portion of the interior of the umbilical cord is removed with a water jet.

65. The method of forming an implantable cover of claim 62, wherein the portion of the interior of the umbilical cord is removed with a laser.

66. The method of forming an implantable cover of claim 62, wherein the portion of the interior of the umbilical cord is removed with a cutting implement.

67. The method of forming an implantable cover of claim 62, further comprising the step of forming a cover sheet from the umbilical tube by slitting the umbilical tube.

68. The method of forming an implantable cover of claim 67, further comprising the step of attaching two implantable cover sheets with an attachment to form an enlarged cover sheet.

69. The method of forming an implantable cover of claim 56, wherein the step of preparing an implantable cover from said umbilical cord comprises the step of slitting the umbilical cord along a length of the umbilical cord and opening the umbilical cord about the slit to form a sheet of umbilical cord tissue comprising Wharton's Jelly and amniotic membrane.

70. The method of forming an implantable cover of claim 69, further comprising the step of removing at least a portion of the Wharton's Jelly from the sheet of umbilical cord tissue to form an implantable cover sheet having a first surface a second surface opposing said first surface, a thickness and a perimeter.

71. The method of forming an implantable cover of claim 70, wherein the two implantable cover sheets are attached along an overlap of the two implantable cover sheets to form an enlarged cover sheet.

72. The method of forming an implantable cover of claim 70, wherein the implantable cover sheet is folded to form an envelope having a folded side, two opposing sides and an extended end.

73. The method of forming an implantable cover of claim 72, wherein at least two of the two opposing sides and the extended end are attached by an attachment to form a pouch.

74. The method of forming an implantable cover of claim 73, wherein the attachment

comprises a stitch.

75. The method of forming an implantable cover of claim 73, wherein the attachment

comprises an adhesive.

76. The method of forming an implantable cover of claim 73, wherein the attachment

consists of a direct attachment.

77. The method of forming an implantable cover of claim 76, further comprising the step of placing a release layer within the implantable envelope and applying pressure to the implantable envelope to directly attach at least two sides to form an implantable pouch.

78. The method of forming an implantable cover of claim 77, wherein the release layer comprises a tab that leaves an opening in an attached side.

79. The method of forming an implantable cover of claim 73, wherein the attachment

comprises a direct attachment.

80. The method of forming an implantable cover of claim 79, further comprising the step of placing a release layer within the implantable envelope and applying pressure to the implantable envelope to directly attach at least two side to form an implantable pouch.

81. The method of forming an implantable cover of claim 80, wherein the release layer comprises a tab that leaves an opening in an attached side.

82. The method of forming an implantable cover of claim 79, wherein the opening extends from the opening of the pouch.

83. The method of forming an implantable cover of claim 70, wherein two implantable cover sheets are layered and attached by an attachment to form a pouch.

84. The method of forming an implantable cover of claim 70, wherein two implantable cover sheets are layered and attached by an attachment to form an envelope.

85. The method of forming an implantable cover of claim 84, wherein the attachment

comprises a stitch.

86. The method of forming an implantable cover of claim 84, wherein the attachment

comprises an adhesive.

87. The method of forming an implantable cover of claim 84, wherein the attachment

consists of a direct attachment.

88. The method of forming an implantable cover of claim 84, wherein the attachment

comprises a direct attachment.

89. The method of forming an implantable cover of claim 88, further comprising the step of placing a release layer within the implantable envelope and applying pressure to the implantable envelope to directly attach at least two side to form an implantable pouch.

90. The method of forming an implantable cover of claim 89, wherein the release layer comprises a tab that leaves an opening in along an attached side.

91. The method of forming an implantable cover of claim 84, wherein the opening extends from the opening to the pouch.

92. The method of forming an implantable cover of claim 56, wherein the implantable cover has a thickness from the inside surface to the outside surface of more than 1 OOum.

93. The method of forming an implantable cover of claim 56, wherein the implantable cover has a thickness from the inside surface to the outside surface of more than 500um.

94. The method of forming an implantable cover of claim 56, wherein the implantable cover has a thickness from the inside surface to the outside surface of more than 1 OOOum.

95. The method of forming an implantable cover of claim 56, wherein the implantable cover has a thickness from the inside surface to the outside surface of more than 1500um.

96. The method of forming an implantable cover of claim 56, wherein the implantable cover consists essentially of an umbilical cord tissue.

97. The method of forming an implantable cover of claim 56, wherein the implantable cover consists of umbilical cord tissue.

98. The method of forming an implantable cover of claim 56, wherein the implantable cover consists essentially of an umbilical cord amniotic membrane and Wharton's Jelly.

99. The method of forming an implantable cover of claim 56, wherein the implantable cover consists essentially of an umbilical cord amniotic membrane.

100. The method of forming an implantable cover of claim 56, wherein the implantable cover consists of an umbilical cord amniotic membrane and Wharton's Jelly.

101. The method of forming an implantable cover of claim 56, wherein the implantable cover consists of an umbilical cord amniotic membrane.

102. The method of forming an implantable cover of claim 56, wherein the implantable cover consists essentially of an umbilical cord tissue free of a vein or artery.

103. The method of forming an implantable cover of claim 56, wherein the implantable cover consists essentially of an umbilical cord tissue free of red blood cells.

104. The method of forming an implantable cover of claim 56, wherein the implantable cover sheet comprises Wharton's Jelly having a thickness of at least lOOum.

105. The method of forming an implantable cover of claim 56, wherein the implantable cover sheet comprises Wharton's Jelly having a thickness of at least 500um.

106. The method of forming an implantable cover of claim 56, further comprising the step of adding an anti-microbial agent to the implantable cover.

107. The method of forming an implantable cover of claim 56, further comprising the step of adding an anti-fibrotic agent to the implantable cover.

108. The method of forming an implantable cover of claim 56, further comprising the step of adding addition cells to the implantable cover.

109. The method of forming an implantable cover of claim 56, wherein the umbilical cord tissue comprises of epithelial cells, mesenchymal stem cells, growth factors, cytokines, extracellular matrix proteins, hyaluronic acid, proteoglycans, and anti-microbial peptides.

1 10. The method of forming an implantable cover of claim 56, wherein the umbilical cord tissue is resorbable.

1 1 1. The method of forming an implantable cover of claim 56, where the umbilical cord tissue is biodegradable.

1 12. The method of forming an implantable cover of claim 56, where the umbilical cord tissue is bioerodible.