CA1234801A - Collagen membranes for medical use - Google Patents
Collagen membranes for medical useInfo
- Publication number
- CA1234801A CA1234801A CA000496824A CA496824A CA1234801A CA 1234801 A CA1234801 A CA 1234801A CA 000496824 A CA000496824 A CA 000496824A CA 496824 A CA496824 A CA 496824A CA 1234801 A CA1234801 A CA 1234801A
- Authority
- CA
- Canada
- Prior art keywords
- collagen
- cross
- gel
- linked
- approximately
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
- A61F2/06—Blood vessels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/08—Muscles; Tendons; Ligaments
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/10—Hair or skin implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0033—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
- C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
- C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S128/00—Surgery
- Y10S128/08—Collagen
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S602/00—Surgery: splint, brace, or bandage
- Y10S602/90—Method of making bandage structure
Abstract
COLLAGEN MEMBRANES FOR MEDICAL USE
Abstract Collagen membranes with desired properties are prepared by using a variety of gel-forming techniques in combination with methods for converting the gels to solid forms. The properties of these membranes or other solid forms may be further altered by cross-linking the collagen preparation either after formation of the membrane or gel, or most preferably by mixing cross-linked collagen with solubilized collagen in the original mixture used to create the gel.
Abstract Collagen membranes with desired properties are prepared by using a variety of gel-forming techniques in combination with methods for converting the gels to solid forms. The properties of these membranes or other solid forms may be further altered by cross-linking the collagen preparation either after formation of the membrane or gel, or most preferably by mixing cross-linked collagen with solubilized collagen in the original mixture used to create the gel.
Description
~23~80~
COLLAGEN MEMBRANES FOR MEDICAL USE
Technical_Field The invention relates to the field of materials lo use~ul for repair of tissue and relevant to wound healing. ~ore precisely, the invention relates to a collagen membranous material prepared by a novel process, which membranes are biocompatible, noninflamatory, and useful in the repair of tissue as 15 -artificial implants.
Backqround Art Numerous attempts have been made to obtain arti~icial membranes which can be used as substitutes for skin, blood ve6sels, ligaments~ or other connective tissue. Many of these membranes utilize collagen, as collagen is the major component of connective tissue in general. An extensive literature exists with respect to methods for preparing such membranes, either of collagen alone, (see, for example, US Patent, ~,412,947; Japanese Patent 74/039174: and US Patent 4,242,291) or of collagen in combination with other materials (see, e.g., U.S. 4,453,939). Other membranes use combinations~of materials such a~ glycoproteins with fibrinogen and thrombin (EPO Application Publication No. 92200, published 26 October 1983), and a combination of keratin derived and glucosaminoglycan polymers (European Patent Publication 89152, published 21 September 1~83). ~ -:;
..
~234~
The properties and guality of the re6ulting membranes with Le6pect to physical characteristics u6eful in the particular application intended, and their biological characteri6tics, 6uch as biocompatibility, stability, and integration with surrounding tiss~e are determined by the nature of the material, e.g., the nature of the collagen u6ed to form ~he membranes, and on the process used in their formation.
The membranes in the art have had variable 6ùcces6 for their intended u6es, which include cornea replaceménts, artificial 6kin, and wound healing. Many cause inflamation, and have less than optimum properties of flexibility, biological stability, and strength.
The present invention offers a process whereby 1 desirable properties can be obtained in the resulting membrane through the use of nonimmunogenic collagen formed into a membranous material by a spectrum of proces6e6 which offer flexibility in the physical properties of the product, 60 as to permit ~hese properties to be adapted to intended use. The membranous material can be u6ed a6 a two-dimen6ional membrane, including membranes which can be shaped to form tubular vessels, shaped into a three-dimensional implant, or formed into a one-dimensional fiber.
Di6closure of the Invention The invention provides collagen membranes whose ehy6ical propertie6 are de6igned to be suitable for u6es in a variety of medical applications including blood ve66el repair, uteru6 repair, reconstruction of lumen 6ùrface6, tendon replacements, and artificial 6kin. The membranes may also be used a6 6ub6trates for production of desired cell cultures in vitro. The properties of the membrane are determined by appropriate selecSion ~2~
from a 6pectrum o~ preparation processe6 so a6 to obtain those characteristic6 appropriate or a selected u6e.
Similar flexibility i6 available in the propertie6 of the one- and three-dimen6ional construct6 prepared by modification of, or addition6 to, the membrane preparation p~oce~6. The re6ulting fibers are u~eful as replacement material6 for tendon~ or ligaments, and may also be u6ed for 6uturing: the three-dimen6ional blocks or solids provide implant6 for use in tissue repair or wound-gap closure.
Thus, in one aspect, the invention relates to collagenous membranou6 ma~erial~ which are prepared by the general process of obtaining a gel from a 601ution of atelopeptide collagen, optionally mixing the so~ution with a suspen6ion of cro66-linked collagen, and converting the gel into membrane form. In another aspect the invention relates to fiber6 or solids prepared from the gel. In 6till another aspect, the invention relates to the general process itself, and to the specific methods used within the context of this general process to obtain two-dimen6ional membrane6, fibers, and solids of desired properties.
The gel may be obtained from 601ubilized collagen or mixture by three alternative aeproaches. In one approach, the 601ution of collagen is treated with a precipitating buffer which insolublize~ the collagen by rai6ing the pH. In this approach, both collagen and buffer solution6 are preccoled almo6t to freezing, mixed, and then allowed to incubate at a~proximately room temperature to induce gel formation. In a 6econd approach, the above mixture of collagen and buffer is centrifuged, rather than incubated without gravitational pres6ure, and ~he supernatant from the centrifugation is ~ ,~
~L23480~
recovered and allowed to incubate at approximately room temperature. In a third approach, the solution of collagen i6 treat~d with an insolubilizing 601ution at ambient temperature, and the in601ubilizing solution i6 designed to bring the resulting mixture to phy6iological pH and ionic 6t~ength. Thi6 mixture is then allowed to incubate at approximately 37C to create the gel. The third approach may be modified by degassing the mix~ure immediately upon mixing, and placing the dega6sed mixture into a mold before incubation.
The procedure in each of the three case6 recited above may al60 be applied to formation of a gel which includes, in addition to the di6solved collagen, a 6us~en6ion of a cross-linked form. The presence of thi6 additional cross-linked 6ubstrate permits further variation in the propertie6 of the membrane material which ultimately results from the method of the invention.
The procedure set forth above for formation of the gel to include the cro6s-linked collagen in the starting material appears to be critical in the 6ense that formation of the gel from solubilized collagen alone, followed by partial cross-linking, or cros6-linking of the membranes after their formation from the gel, appears to result in a more brittle and unsatisfactory product. Also, if the gel formation procedure from solubilized collagen is modified by the aforementioned addition of cross-linked material, the third method recited is preferred, i.e., the 601ution of collagen (containing, in admixture, the de6ired cro66-linked material) i6 treated with an insolubilizing solution at ambient temperature wherein the in601ubilizing solution-i6 de6igned to bring the mixture to phy6iological pH and ionic strength. The mixture is :1234~0~
allowed to incubate at about 37C to create the gel. In a particularly preferred embodiment, the mixture i~
degas6ed before adding the insolubilizing 601ution.
The conver6ion of the gel to a membrane may also be accomplished by two basic alternative approache6. In one approach, the gel i6 compre6sed under constant eres6ure to form a mat which i5 then dried. Using this method, in addition to obtaining two-dimen6ional membranes, a solid implant may be prepared ,directly by compres6ing the molded gel obtained from the modification of the gel formation process which employ6 degas6ing. A fiber produc~ is obtained if the pre66ure is applied around the circumference of a cylinder formed from the gel. In the 6econd approach, the gel i8 di6rupted, the disrupted gel centrifuged to obtain a precipitate, and the precipitate cast into mold6 and dried. Depending on the dimensions and shape of the mold, either a membrane or 601id can be obtained.
Brief Description of the Drawinqs Figures 1-2 are electron micrographs at 30,000 x magnification of the prepared membranes G-2, and G-3.
Modes of CarrYinq out the Invention A. Preparation of CIS
The proces6 of the invention 6tart6 with a collagen in ~olution, either alone, or in admixture with cro6s-linked fibrillar collagen. The collagen may be solubilized and purified from mammalian connective tis6ue~ and has been prepared from bovine skin, porcine 6kin, and mammalian bone, along with a number of other source6. Purification proce66es are well known in the art. See, for example, U.S. 3,949,073, U.S. 4,066,083, and GB 1,565,340. Collagen can be readily soluhilized ~3~301 in concentrations useful in the invention by disrupting the fiber6 in acid, as ifi well known in the art, and is dissolved at pH values between 1-4. Indeed, collagen in solution (CIS) ifi commercially available, conveniently, under the trademark Zygen~ from Collagen Corporation, Palo Alto, California.
Native collagen exists in a fibrillar form which results from the triple helical structure of the peptide chains. The helical ~tructure is generated by virtue of,repeating triplet sequences composed of glycine linked to two amino acidfi, commonly proline and hydroxyproline in the amino acid ~equence. The regions of these triplet repeating units aggregate themselves into triple helical 6tructures. In addition, all collagen chains contain regions at each end which do not have the triplet glycine sequence and are thus not helical. These regions are thought to be responsible for the immunogenicity associated with mo6t collagen preparations, and are called telopeptides. The immunogenicity of a collagen preparation can, in large part, can be mitigated by removal of these telopeptides to produce ~atelopeptide collagen". The removal is accomplished by dige6tion with proteolytic enzymes 6uch as tryp6in or pepsin. The nonhelical telopeptide 25 region6 are al60 required to form the cros6-lin~6 which are responsible for 6tability of the fibrillar struc~ure in the native material. Ateloee~tide collagen must be cro6s-linked artificially, if it is desired to obtain this characterifiti~.
The collagen in solution which form~ the 6tarting material for the process of the invention i6 an atelopeptide collagen, preferably a dilute commerically available product such as Zygen~ CIS. Concentrations of collagen in the range of 1-10 mg/ml are suitable ~234801 for u8e in the invention. This range i6, of course, sugge6tive of suitable concentrations and not meant to represent an absolute limitation; any upper and lower limit is arbitrary in this context.
B. PreParation of Cross-Linked Collaaen ~ g used herein, ~cross-lin~ed collagen" refers to an atelopeptide purified reconstituted collagen preparation which has been artificially cro6s-linked by chemical o,r radiation treatment or by other appropriatë `~
mean6 to obtain 6ufficient cross-link6 that the visco6ity of the pre~aration is 700-3000 centerpoise when measured at 22C and a shear rat~ of 5000 sec ~gain, precise limits are arbitrary and this is illustrative of a useful range.
To prepare the cro6s-linked form, solubili~ed collagen i6 first precipitated by neutralizing at room temperature or a preparation of precipitated or reconstituted collagen, such as Zyderm~ collagen implant i8 used, and then cross-linked using standard procedure6, including reactivity with chemical cross-linking reagents, 6uch as formaldehyde, glutaraldehyde, glyoxal, and 60 forth, or with ionizing radiation such as gamma ray radiation. Heat and W
radiation can also be u6ed, but are less efficient. The cross-linked material i6 then collected by centrifugation and washed with a suitable aqueous solution, such a6 physiological saline, and the concentration adjusted to a workable level in su6pension of 1-10 mg/ml.
In more detail, the cro66-linking agent is a polyfunctional, and more u6ually bifunctional, compound which is used in concentration to produce a viscous, covalently cros6-linked collagen before quenching with ~23~80~
an agent which form6 an innocuous, water-soluble adduct with the cro66-linking agent. The concentration of the collagen in the suspen~ion during the reaction, the concentration of cro6s-linking agent, and the dura~ion of the cross-linking reaction are significant, but de~endent on the nature of the cros~-linking agent. The collagen concentration is typically in the range of 0.1-10 mg/ml, more usually 1-5 mg/ml. Aldehyde6 are preferred a6 cros6-linking agent~, and 6uitable aldehydes include formaldehyde, glutaraldehyde, acid aldehyde, glyoxal pyruvic aldehyde, and aldehyde starch, but preferably glutaraldehyde. Amines are prefer~ed quenching agents, in particular, glycine. The concentration of glutaraldehyde, if this is the 6elected cros6-linker, i6 typically about 0.001%-0.05% by weight/volume, and thè cross-linking reaction takès place over about one-half hour to one week. The reaction is carried out at about 10C-35C before adding the quenching agent in at least stochiometric proportion6 with the cro66-linking agent, although an excess is preferred. One exemplary cros6-linking protocol includes a collagen concentration o 3 mg/ml and 0.01% by weight glutaraldehyde for abou~ 16 hour~ at 22C. The cro6s-linked product is washed to remove unreacted cross-linker, polymers ~ormed by the cro6s-linker, and the unreacted ~uenching agent, if quenching is employed. A workable buffer is a sodium phosphate~sodium chloride buffer solution of approximately pH 7.
The washed product may be concentrated by filtration or centrifugation to a ~uitable 2rotein concentration range, which is typically about 20-50 mg/ml, preferably about 25-40 mg/ml. The washed product should have an aldehyde content of less than about 20 ~~~ 1239~8~
ppm and a visco~ity in the range of about 700-~ooo cp at 22OC measured by an oscilla~ing disc vi&aosimater, which mea~ures dynamic, not steady flow, viscosity (Nametre Company, Model 7.006PBD).
C. Formation of the Gel The process of the invention for forming collagen membranes or related membranous material~, comprise6, basically, two steps: the formation of a gel from a collagen in solu~ion, and the conversion of the gel to the membrane or other desired form.
Each of these proce6ses may be performed in a spectrum of tem~erature, gravitational, and ionic 6trength condition~, and the intermediate solutions may or may not be dega6sed, and the re6ulting ~roduct will have properties which vary accordingly. The temperature at which gel formation takes place may be between approximately 4C and approximately 37C: the ionic ~trength may vary between about 0.05 to about physiological ionic strength, and the gravitational field conditions may vary from 1 x g to about 13000 x g.
The exemplary proce~se6 set forth below typify the extreme6 of these va~iables, and it is understood that intermediate cases may also be useful, depending on the nature of the membrane desired. Degas6ing and molding prior to formation of the gel appears to result in a tougher product, which can be further manipulated to form a fiber, membrane or solid.
Three general approaches may be used, as i6 outlined above. In the first, CIS is cooled and mixed wi~th precooled buffer at an ionic strength well below physiological, preferably about 0.05, and the mixture incubated at low temperature. In the second, the CIS iB
mixed with buffer at physiological ionic strength and ~;3~801 temperature conditions and incubated at phy6iological temperature. In a third approach, the CIS i6 treated with buffer a& in the first method, but subjected to gravitational pressure before incubating at room temperature.
The gel may optionally contain an arbitrary amount of previou61y cross-linked collagen material which i8 itself prepared from solubilized collagen. The relative amounts of cross-linked and noncross-linked collagen ma~erials appear to determine the pLo~ertie6 of the resulting membranes, as well as do the conditions for formation of the gel and membrane stages. The formation of the gel and the conve~sion to membranes utilize6 the 6ame set of options, whether or not the cross-linked material is included in the original composition.
In forming the gel, as the intermediate material to the final membranous product to include the cro6s-linked fibrillar collagen, the gelling procedure is conducted as outlined above, except that, in addition to the collagen in solution, a portion of the ~u6pension containing the cros6-linked form at the above-mentioned suspension concentration levels i6 mixed with the 601ubilized collagen. The ratio of the two components, ba6ed on the relative weight6 of the collagen contained in each, is quite broad, depending on the nature of ~he final product desired. For softer and more Elexible compositions, a greater proportion of collagen in so`lution is used for tougher membranes as final products, a greater concentration of the cross-linked fo~m i~ used. For example, if the membrane final product i~ to be used as an artificial tendon to hold 6utures or to form a tubular ve6sel held together by ~23~80~
such ~uture6, a cross-linked collagen percentage of about 40-80%, preferably around 50%, is preferred.
All composition6 of membrane6 formed wherein tha original mixture for gel formation contain6 both a suspen6ion of cross-linked collagen and collagen in solution are expre6sed as a percentage by weight of cross-linked collagen to total collagen content. Thu~, when a membrane is de6cribed a6 having 10% cro6s-linked collagen, the original components were supplied such lo that lO~,of the total weight of collagen was contained in a cro6s-linked collagen 6u~pen6ion and 90% was supplied a6 ~oluble collagen in 601ution. The composition6 of the invention may contain up to 9o%
cro66-linked collagen.
D. Con~er6ion to the Membrane The conver6ion of the gel to a membrane may be effected in two basically different ways: either by compre6sing the gel to 6~ueeze out liquid to form a more cohesive "mat", followed ~y drying at roughly atmospheric pressure, for example, in air; or by di6rupting the gel matrix, centrifuging the di6ruptate to recover a precipitated collagen, homogenizing the precipitate into a pa6te, and ca6ting the paata with a mold.
The nature of the propertie6 of the re~ulting membrane depend6 greatly on which of the6e two conversion proceg6es i6 used; the product of the compres6ion proce66 is flexible, tran61ucent, and 6mooth, and form6 a filmlike material with relatively high tensile 6trength. The product of disrupting the gel followed by precipitation of the disruptate, is relatively brittle and semitran~parent, ha6 a rough 6urface, and i6 relati~ely thick.
-12- ~23~01 Either membrane, however, can be characterized a6 a random fibrillar network wherein the fibrils are approximately of the diàmetër 70-300 nanometer6, and approximately 0.5-5~ in length.
The inclusion of cro6s-linked collagen doe6 not change the6e propertie6, except to toughen the product.
The cro6s-linked material i6 embedded in the fibrillar network described.
For the compre66ion process, the gel i8 6queezed in a suitable pi6ton type device, such as, for example, the apparatu6 pre6ently u6ed to obtain cakes of tofu. Compre66ion i6 conducted at approximately room temperature by using the collagen gel in 6itu in the medium in which it wa6 prepared. The compre~6ion is applied u6ing 1.1 - 3 atmo~phere6 pressure, and continued until the volume is approximately les6 than 5%
of the original gel. The re6ulting flat collagen fiber mat i6 then dried in air or other appropriate atmospbere at a low temperature (le66 than about 37C) to obtain the de6ired membrane. It is also de6irable to wa6h the remaining 6alt6 from the membrane. The wa6hing can be effected by washing with water, and redrying, again at atmospheric pres6ure, at low temperature.
The proce66 which utilize6 di6ruption of the gel typically i6 conducted by mechanically disrupting the matrix, such as with a spatula, followed by centrifugation at approximately 8000-16000 x g, preferably about 13000 x g for about 20-30 minute6 to obtain the precipitate. The force of centrifugation i6, of course, variable and no definite boundary limitations can be 6et. The precipitate i6 then homogenized sufficiently to form a pa6telike material, at room temperature, and the paste is cast into a mold an~
allowed to 6et in at atmo6pheric pre6sure at low ~L23~
temperature (below about 37C). The dried material i6 then de6alted, if desired, by washing in water, and redrying.
Cro6s-linking of the collagen in the re6ulting membranou6 material i6 optional, but can effected by treating the membranous material with glutaraldehyde to obtain the desired cro~s-links; however, as set forth above, this approach may re6ult in a more brittle product. Procedure6 for thi6 cro66-linking are known in the art. Briefly, in typical procedu~e6, the material i6 treated with a 601ution containing 0.05-1%
glutaraldehyde for 1-16 hours, and then quenched by addition of a glycine 601ution to a concentration of about 0.1-0.4M glycine. The cross-linking 601ution is then removed by washing.
E.
The resulting materials may be employed in the soft ti6sue repair constructions ordinarily utilizing artificial membranes, such a6 burned skin reelacement6, tendon reconstruction, or wound repair. They may also be shaped into variou6 form6 and used in connection with hard ti66ue repair. The ca~t or compre6sed membranes may be reformed into three dimensional object6 for implantation in replacing 6ections of bone by rolling into cylinders, or by 6tacking and cutting to shape.
The membrane6 may al60 be u6ed in their two dimensional configuration by succe66ively packing the membranes into a defect, such as a cranial or peridontal cavity. In general, onlay-type repair may be done by fitacking the~e membrane6 into the cavity.
Three dimensional implants are also obtainable directly from ~he gel by compre66ion into an appropriate mold. In this method of construction, it is pre~erred that the mixture containing the CIS and precipitatinq 1~:34~
buffer be dega66ed and molded pLior to compres~ion.
(Degas6ing may be used in the related proces6es which result in membrane~ and fibers, also). The dense collagen fiber network which is formed by compre6sion of the degassed, molded collagen gel i6 dried, desalted by wa6hing, remolded before redrying, and, if desired, aged at elevated temperature to encourage residual cro6s-linking. In addition, fibers can be formed preferably di~ectly from the gel before compression or disruption. The gel is wrapped in a porou6, absorbent material and squeezed or rolled into the de6ired diameter fiber. The disrupted gel may also be used, but in this event fiber6 mu6t be formed by ca6ting and 6tretching, and the proce6s i6 more cumber60me, leading to a less desirable product.
ExamPles The ~ollowing examples are intended to illustrate, but not to limit the invention. The first three examples represent alternative methods of forming the gel, com~ined with the compres6ion method for forming a membrane; examples 4-6 represent similar gel forming methods, ollowed by membrane formation u6ing the disruptate, all 6tarting with CIS alone. Examples 7 2S and 8 illustrate formation of cross-link~ in the re6ulting membranes whether the membrane6 are formed by compression or by disruption and precipitate recovery.
Example 9 shows the use of dega6sed and molded mixtures in gel formation where the gel is u6ed directly in forming a three dimensional implant. Example 10 shows thè formation of a gel which includes a portion of cro66-linked collagen, and Example 11 illustrates the conver6ion of this gel into a membrane. Example 12 .. . ... . .. .. ... . ....
~3~0~
illustrate6 additional embodiments of membranou6 material which include6 cros6-linked collagen.
ExamPle 1 90 ml Zygen~ (2 mg/ml bovine atelopeptide collagen, in HCl, pHl-4) CIS wa6 cooled to 4C, and mixed with 10 ml of precooled buffer containing 0.2 M
Na2HPO4/0.09 M NaOH. The solution was mixed at 4C, and incubated at room temperature for about 16-20 hour6, i.e., overnight, for convenience. The re~ulting collagen gel wa6 then ~laced in a pres6 and compre66ed u6ing con6tant pres6ure of about 1.5 atmo6phere6 to a flat collagen fiber network. The re6ulting network was dried in air at room temperature, wa6hed with water, and redried in air. The re6ulting collagen membrane was designated G-l.
Example 2 90 ml of Zygen~ CIS at ambient temperature ~!
was mixed with 10 ml of room temperature ~uf~er containing 0.2 M Na2HPO~1.3 M NaCl/0.09 ~ NaOH, and the mixture incubated at 37C overnight. The resulting matrix was converted to a membrane a~ 6et forth in Example 1. The resulting membrane, G-2, is a 6mooth flexible translucent material. An electron microg~aph of the fiber structure is 6hown in Figure 1.
ExamPle 3 90 ml o Zygen~ CIS wa6 cooled to 4C, and mlxed rapidly with 10 ml cold (4C) ~uffer containing 0.~ M Na2HPO4~0.09 M NaOH, and tran6ferred immediately to centrifuge bottles. The mixture wa~
centrifuqed at 8000 x g for 2 hour6 at about 20C, and the fiupernatant recovered from the bottles. The -16- 123~
6upernate wa6 incubated at 20C for ~vernight, re6ulting in the gel. The gel was converted into the membrane in a manner exactly 6imilar to tha~ set forth Example 1, and designated G-3. An electron micrograph of the fiber structure ig shown in Figure 2.
Example 4 sO ml Zygen~ CIS and 10 ml in~olubilizing buffer were mixea at 4C, and incubated to form a gel exactly as 6et forth in Example 1. The gel matrix was broken with a 6patula, tranaferred to a centrifuge bottle, and centrifuged at 13,000 x g for ~0 minutes.
The re~ulting precipitate wa~ recovered and homogenized into a pa6te form. The paste was ca~t into a mold and dried in air at 37C, then washed with water and redried in air at 37C to give the membrane P-l.
ExamPle 5 Zygen~ CIS was treated with buffer to form a gel exactly as de6cribed in Example 2, and the gel then converted to a membrane u6ing the procedure exactly a6 6et forth in Example 4. The re6ulting membrane waa designated P-2.
ExamPle 6 Zygen~ CIS waa used to form a gel uaing the procedure a6 6et forth in Example 3, and the reaulting gel converted to a membrane as 6et forth in Example 4.
The re6ulting membrane wa6 de6ignated P-3.
ExamPle 7 90 ml Zygen~ CIS at ambient temperature was mixed with 10 ml buffer which contained 0.2 U
Na2HP04/1.3 M NaCl/O.O9 M NaOH, and the mixture :
, .
~2348~1 incubated at 37OC overnight. The re~ulting gel wa6 compre6sed a6 6et forth in Example 4, dried, and de6alted by washing. The washed membrane was then cro6s-linked by treating with 0.1% glutaraldehyde di6solved in water at 20C, and the cros6-linked membrane wa6hed and dried at low temperature to obtain membrane XG-2.
Example 8 A gel was formed from 90 ml Zygen~ CIS as described in Example 7, and the resulting gel broken with a spatula, tran6ferred to a centrifuge bot~le, and centrifuged at 13000 x g for 30 minute6. The precipitate wa6 recovered and homogenized to a pa6te~
The pa6te was cast into a mold and dried in air at 37C, and the re6ulting membrane wa6hed with water. The washed membrane was then treated with a 0.1% solution of glutaraldehyde, as set forth in Example 7, and the cro6~-linked membrane wa6hed and dried in to yield membrane XP-2.
Example 9 The procedure for gel formation a6 6et forth in Example 2 wa6 modified by dega66ing and molding the pre-gel mixture. Before incubation, the mixture wa6 degas6ed by reduced ~res6ure and ~laced in a mold.
After incubation at 37 for 16-20 hour6, the molded gelatin was compressed at about 1.5 atm to obtain a dense fiber network, which was dried in air at 37 or les6. The dried solid wa6 de6alted by wa6hing, remolded, dried, and aged at an elevated temperature of about 40C-100C to increa6e re6idual cross-linking, to give the product de~ignated ~preformed G-2~.
123~8~
Example 10 A. Preparation of Cro66-Linked Collaqen Fibrous collagen was recon6tituted from collagen in 601ution (a 3 mg/ml 601ution of atelopeptide bovine collagen in dilute aqueous HCl, pH 1-4) by adding 0.02 M di60dium pho~hate to the solution at 18-20C to obtain a pH of 7.4, and allowing fibers to form for 1--2 hours. To 16~ ml of the resulting fibrous collagen suspension, 1.62 ml of 1% aqueous glutaraldehyde at pH 3 -10 was added. The glutaraldehyde ~olution was added gradually with stirring to obtain a final concentration of 0.01% glutaraldehyde, and the mixture was allowed to react for 16 hours at room temperature before quenching by the addition of 3 M glycine to 0.2 M. After a 1 hour quench time, the cro6s-linked collagen was washed 3 times with approximately 100 ml of a buffer which contain~ 0.02 M disodium pho6pha~e, 0.13 M NaCl, pH 7.4, with centrifuging at 17,000 x g for 5-7 minutes between each wash. The dynamic visco6ity of the collagen was measured by an o~cillating disc device (Nametre Company, Model 7.006PBD) mea6ured at a shear rate of about 5,000 6ec , and found to be approximately 700 cp at 22C.
After the final wa6h and centrifugation, the collagen wa6 re6uspended in the above buffer to obtain a protein concentration of about 30 mg/ml.
B. Preparation of the Gel Ten ml of the 6u6pen6ion of l~A wa6 mixed with 30 ml Zygen~ CIS and the thoroughly mixed component6 were degassed under a vacuum. To the degassed mixture was added 10 ml of room temperature buffer containing 0.2 M Na2P04/1.3 M ~aCl/O.O9 M NaOH, and the mixture was incubated at 37C overnight. The re6ulting gel contain6 55.5% cro66-linked collagen by weight.
~Z34~30~
Example 11 The gel of Example 10 wa~ placed in a press and compres6ed u6ing constant pressure of about 1.5 atmo6phere6 to obtain a flat collagen fiber network.
The re6ulting network was dried in air at room temperature, wa6hed with water, and redried in air. The resulting collagen membrane was designated GX-2.
Example lZ
The cross-linked collagen preparation prepared a~ in ~A of Examele lo i6 u6ed in a ratio of 1:8 to colla~en in 601ution (prepared as in Example 1) and 6ubjected to the proce~6 o~ Exam~le 1 to obtain a membrane de6ignated GX-l or of Example 3 to obtain a membrane designated GX-3. Similarly, PX-l, PX-2, and PX-3 are prepared a6 6et forth in Example6 4, s, and 6, but u6ing a 1:8 mixture of cros6-linked to CIS collagen as the ~tarting material.
Variation6 in the percentage of cro6s-linked collagen in the product are al60 obtained by ~arying the proportion6 of the su6een~ion of Exam~le lOA to the CIS.
1, ~, . ;
~,:
COLLAGEN MEMBRANES FOR MEDICAL USE
Technical_Field The invention relates to the field of materials lo use~ul for repair of tissue and relevant to wound healing. ~ore precisely, the invention relates to a collagen membranous material prepared by a novel process, which membranes are biocompatible, noninflamatory, and useful in the repair of tissue as 15 -artificial implants.
Backqround Art Numerous attempts have been made to obtain arti~icial membranes which can be used as substitutes for skin, blood ve6sels, ligaments~ or other connective tissue. Many of these membranes utilize collagen, as collagen is the major component of connective tissue in general. An extensive literature exists with respect to methods for preparing such membranes, either of collagen alone, (see, for example, US Patent, ~,412,947; Japanese Patent 74/039174: and US Patent 4,242,291) or of collagen in combination with other materials (see, e.g., U.S. 4,453,939). Other membranes use combinations~of materials such a~ glycoproteins with fibrinogen and thrombin (EPO Application Publication No. 92200, published 26 October 1983), and a combination of keratin derived and glucosaminoglycan polymers (European Patent Publication 89152, published 21 September 1~83). ~ -:;
..
~234~
The properties and guality of the re6ulting membranes with Le6pect to physical characteristics u6eful in the particular application intended, and their biological characteri6tics, 6uch as biocompatibility, stability, and integration with surrounding tiss~e are determined by the nature of the material, e.g., the nature of the collagen u6ed to form ~he membranes, and on the process used in their formation.
The membranes in the art have had variable 6ùcces6 for their intended u6es, which include cornea replaceménts, artificial 6kin, and wound healing. Many cause inflamation, and have less than optimum properties of flexibility, biological stability, and strength.
The present invention offers a process whereby 1 desirable properties can be obtained in the resulting membrane through the use of nonimmunogenic collagen formed into a membranous material by a spectrum of proces6e6 which offer flexibility in the physical properties of the product, 60 as to permit ~hese properties to be adapted to intended use. The membranous material can be u6ed a6 a two-dimen6ional membrane, including membranes which can be shaped to form tubular vessels, shaped into a three-dimensional implant, or formed into a one-dimensional fiber.
Di6closure of the Invention The invention provides collagen membranes whose ehy6ical propertie6 are de6igned to be suitable for u6es in a variety of medical applications including blood ve66el repair, uteru6 repair, reconstruction of lumen 6ùrface6, tendon replacements, and artificial 6kin. The membranes may also be used a6 6ub6trates for production of desired cell cultures in vitro. The properties of the membrane are determined by appropriate selecSion ~2~
from a 6pectrum o~ preparation processe6 so a6 to obtain those characteristic6 appropriate or a selected u6e.
Similar flexibility i6 available in the propertie6 of the one- and three-dimen6ional construct6 prepared by modification of, or addition6 to, the membrane preparation p~oce~6. The re6ulting fibers are u~eful as replacement material6 for tendon~ or ligaments, and may also be u6ed for 6uturing: the three-dimen6ional blocks or solids provide implant6 for use in tissue repair or wound-gap closure.
Thus, in one aspect, the invention relates to collagenous membranou6 ma~erial~ which are prepared by the general process of obtaining a gel from a 601ution of atelopeptide collagen, optionally mixing the so~ution with a suspen6ion of cro66-linked collagen, and converting the gel into membrane form. In another aspect the invention relates to fiber6 or solids prepared from the gel. In 6till another aspect, the invention relates to the general process itself, and to the specific methods used within the context of this general process to obtain two-dimen6ional membrane6, fibers, and solids of desired properties.
The gel may be obtained from 601ubilized collagen or mixture by three alternative aeproaches. In one approach, the 601ution of collagen is treated with a precipitating buffer which insolublize~ the collagen by rai6ing the pH. In this approach, both collagen and buffer solution6 are preccoled almo6t to freezing, mixed, and then allowed to incubate at a~proximately room temperature to induce gel formation. In a 6econd approach, the above mixture of collagen and buffer is centrifuged, rather than incubated without gravitational pres6ure, and ~he supernatant from the centrifugation is ~ ,~
~L23480~
recovered and allowed to incubate at approximately room temperature. In a third approach, the solution of collagen i6 treat~d with an insolubilizing 601ution at ambient temperature, and the in601ubilizing solution i6 designed to bring the resulting mixture to phy6iological pH and ionic 6t~ength. Thi6 mixture is then allowed to incubate at approximately 37C to create the gel. The third approach may be modified by degassing the mix~ure immediately upon mixing, and placing the dega6sed mixture into a mold before incubation.
The procedure in each of the three case6 recited above may al60 be applied to formation of a gel which includes, in addition to the di6solved collagen, a 6us~en6ion of a cross-linked form. The presence of thi6 additional cross-linked 6ubstrate permits further variation in the propertie6 of the membrane material which ultimately results from the method of the invention.
The procedure set forth above for formation of the gel to include the cro6s-linked collagen in the starting material appears to be critical in the 6ense that formation of the gel from solubilized collagen alone, followed by partial cross-linking, or cros6-linking of the membranes after their formation from the gel, appears to result in a more brittle and unsatisfactory product. Also, if the gel formation procedure from solubilized collagen is modified by the aforementioned addition of cross-linked material, the third method recited is preferred, i.e., the 601ution of collagen (containing, in admixture, the de6ired cro66-linked material) i6 treated with an insolubilizing solution at ambient temperature wherein the in601ubilizing solution-i6 de6igned to bring the mixture to phy6iological pH and ionic strength. The mixture is :1234~0~
allowed to incubate at about 37C to create the gel. In a particularly preferred embodiment, the mixture i~
degas6ed before adding the insolubilizing 601ution.
The conver6ion of the gel to a membrane may also be accomplished by two basic alternative approache6. In one approach, the gel i6 compre6sed under constant eres6ure to form a mat which i5 then dried. Using this method, in addition to obtaining two-dimen6ional membranes, a solid implant may be prepared ,directly by compres6ing the molded gel obtained from the modification of the gel formation process which employ6 degas6ing. A fiber produc~ is obtained if the pre66ure is applied around the circumference of a cylinder formed from the gel. In the 6econd approach, the gel i8 di6rupted, the disrupted gel centrifuged to obtain a precipitate, and the precipitate cast into mold6 and dried. Depending on the dimensions and shape of the mold, either a membrane or 601id can be obtained.
Brief Description of the Drawinqs Figures 1-2 are electron micrographs at 30,000 x magnification of the prepared membranes G-2, and G-3.
Modes of CarrYinq out the Invention A. Preparation of CIS
The proces6 of the invention 6tart6 with a collagen in ~olution, either alone, or in admixture with cro6s-linked fibrillar collagen. The collagen may be solubilized and purified from mammalian connective tis6ue~ and has been prepared from bovine skin, porcine 6kin, and mammalian bone, along with a number of other source6. Purification proce66es are well known in the art. See, for example, U.S. 3,949,073, U.S. 4,066,083, and GB 1,565,340. Collagen can be readily soluhilized ~3~301 in concentrations useful in the invention by disrupting the fiber6 in acid, as ifi well known in the art, and is dissolved at pH values between 1-4. Indeed, collagen in solution (CIS) ifi commercially available, conveniently, under the trademark Zygen~ from Collagen Corporation, Palo Alto, California.
Native collagen exists in a fibrillar form which results from the triple helical structure of the peptide chains. The helical ~tructure is generated by virtue of,repeating triplet sequences composed of glycine linked to two amino acidfi, commonly proline and hydroxyproline in the amino acid ~equence. The regions of these triplet repeating units aggregate themselves into triple helical 6tructures. In addition, all collagen chains contain regions at each end which do not have the triplet glycine sequence and are thus not helical. These regions are thought to be responsible for the immunogenicity associated with mo6t collagen preparations, and are called telopeptides. The immunogenicity of a collagen preparation can, in large part, can be mitigated by removal of these telopeptides to produce ~atelopeptide collagen". The removal is accomplished by dige6tion with proteolytic enzymes 6uch as tryp6in or pepsin. The nonhelical telopeptide 25 region6 are al60 required to form the cros6-lin~6 which are responsible for 6tability of the fibrillar struc~ure in the native material. Ateloee~tide collagen must be cro6s-linked artificially, if it is desired to obtain this characterifiti~.
The collagen in solution which form~ the 6tarting material for the process of the invention i6 an atelopeptide collagen, preferably a dilute commerically available product such as Zygen~ CIS. Concentrations of collagen in the range of 1-10 mg/ml are suitable ~234801 for u8e in the invention. This range i6, of course, sugge6tive of suitable concentrations and not meant to represent an absolute limitation; any upper and lower limit is arbitrary in this context.
B. PreParation of Cross-Linked Collaaen ~ g used herein, ~cross-lin~ed collagen" refers to an atelopeptide purified reconstituted collagen preparation which has been artificially cro6s-linked by chemical o,r radiation treatment or by other appropriatë `~
mean6 to obtain 6ufficient cross-link6 that the visco6ity of the pre~aration is 700-3000 centerpoise when measured at 22C and a shear rat~ of 5000 sec ~gain, precise limits are arbitrary and this is illustrative of a useful range.
To prepare the cro6s-linked form, solubili~ed collagen i6 first precipitated by neutralizing at room temperature or a preparation of precipitated or reconstituted collagen, such as Zyderm~ collagen implant i8 used, and then cross-linked using standard procedure6, including reactivity with chemical cross-linking reagents, 6uch as formaldehyde, glutaraldehyde, glyoxal, and 60 forth, or with ionizing radiation such as gamma ray radiation. Heat and W
radiation can also be u6ed, but are less efficient. The cross-linked material i6 then collected by centrifugation and washed with a suitable aqueous solution, such a6 physiological saline, and the concentration adjusted to a workable level in su6pension of 1-10 mg/ml.
In more detail, the cro66-linking agent is a polyfunctional, and more u6ually bifunctional, compound which is used in concentration to produce a viscous, covalently cros6-linked collagen before quenching with ~23~80~
an agent which form6 an innocuous, water-soluble adduct with the cro66-linking agent. The concentration of the collagen in the suspen~ion during the reaction, the concentration of cro6s-linking agent, and the dura~ion of the cross-linking reaction are significant, but de~endent on the nature of the cros~-linking agent. The collagen concentration is typically in the range of 0.1-10 mg/ml, more usually 1-5 mg/ml. Aldehyde6 are preferred a6 cros6-linking agent~, and 6uitable aldehydes include formaldehyde, glutaraldehyde, acid aldehyde, glyoxal pyruvic aldehyde, and aldehyde starch, but preferably glutaraldehyde. Amines are prefer~ed quenching agents, in particular, glycine. The concentration of glutaraldehyde, if this is the 6elected cros6-linker, i6 typically about 0.001%-0.05% by weight/volume, and thè cross-linking reaction takès place over about one-half hour to one week. The reaction is carried out at about 10C-35C before adding the quenching agent in at least stochiometric proportion6 with the cro66-linking agent, although an excess is preferred. One exemplary cros6-linking protocol includes a collagen concentration o 3 mg/ml and 0.01% by weight glutaraldehyde for abou~ 16 hour~ at 22C. The cro6s-linked product is washed to remove unreacted cross-linker, polymers ~ormed by the cro6s-linker, and the unreacted ~uenching agent, if quenching is employed. A workable buffer is a sodium phosphate~sodium chloride buffer solution of approximately pH 7.
The washed product may be concentrated by filtration or centrifugation to a ~uitable 2rotein concentration range, which is typically about 20-50 mg/ml, preferably about 25-40 mg/ml. The washed product should have an aldehyde content of less than about 20 ~~~ 1239~8~
ppm and a visco~ity in the range of about 700-~ooo cp at 22OC measured by an oscilla~ing disc vi&aosimater, which mea~ures dynamic, not steady flow, viscosity (Nametre Company, Model 7.006PBD).
C. Formation of the Gel The process of the invention for forming collagen membranes or related membranous material~, comprise6, basically, two steps: the formation of a gel from a collagen in solu~ion, and the conversion of the gel to the membrane or other desired form.
Each of these proce6ses may be performed in a spectrum of tem~erature, gravitational, and ionic 6trength condition~, and the intermediate solutions may or may not be dega6sed, and the re6ulting ~roduct will have properties which vary accordingly. The temperature at which gel formation takes place may be between approximately 4C and approximately 37C: the ionic ~trength may vary between about 0.05 to about physiological ionic strength, and the gravitational field conditions may vary from 1 x g to about 13000 x g.
The exemplary proce~se6 set forth below typify the extreme6 of these va~iables, and it is understood that intermediate cases may also be useful, depending on the nature of the membrane desired. Degas6ing and molding prior to formation of the gel appears to result in a tougher product, which can be further manipulated to form a fiber, membrane or solid.
Three general approaches may be used, as i6 outlined above. In the first, CIS is cooled and mixed wi~th precooled buffer at an ionic strength well below physiological, preferably about 0.05, and the mixture incubated at low temperature. In the second, the CIS iB
mixed with buffer at physiological ionic strength and ~;3~801 temperature conditions and incubated at phy6iological temperature. In a third approach, the CIS i6 treated with buffer a& in the first method, but subjected to gravitational pressure before incubating at room temperature.
The gel may optionally contain an arbitrary amount of previou61y cross-linked collagen material which i8 itself prepared from solubilized collagen. The relative amounts of cross-linked and noncross-linked collagen ma~erials appear to determine the pLo~ertie6 of the resulting membranes, as well as do the conditions for formation of the gel and membrane stages. The formation of the gel and the conve~sion to membranes utilize6 the 6ame set of options, whether or not the cross-linked material is included in the original composition.
In forming the gel, as the intermediate material to the final membranous product to include the cro6s-linked fibrillar collagen, the gelling procedure is conducted as outlined above, except that, in addition to the collagen in solution, a portion of the ~u6pension containing the cros6-linked form at the above-mentioned suspension concentration levels i6 mixed with the 601ubilized collagen. The ratio of the two components, ba6ed on the relative weight6 of the collagen contained in each, is quite broad, depending on the nature of ~he final product desired. For softer and more Elexible compositions, a greater proportion of collagen in so`lution is used for tougher membranes as final products, a greater concentration of the cross-linked fo~m i~ used. For example, if the membrane final product i~ to be used as an artificial tendon to hold 6utures or to form a tubular ve6sel held together by ~23~80~
such ~uture6, a cross-linked collagen percentage of about 40-80%, preferably around 50%, is preferred.
All composition6 of membrane6 formed wherein tha original mixture for gel formation contain6 both a suspen6ion of cross-linked collagen and collagen in solution are expre6sed as a percentage by weight of cross-linked collagen to total collagen content. Thu~, when a membrane is de6cribed a6 having 10% cro6s-linked collagen, the original components were supplied such lo that lO~,of the total weight of collagen was contained in a cro6s-linked collagen 6u~pen6ion and 90% was supplied a6 ~oluble collagen in 601ution. The composition6 of the invention may contain up to 9o%
cro66-linked collagen.
D. Con~er6ion to the Membrane The conver6ion of the gel to a membrane may be effected in two basically different ways: either by compre6sing the gel to 6~ueeze out liquid to form a more cohesive "mat", followed ~y drying at roughly atmospheric pressure, for example, in air; or by di6rupting the gel matrix, centrifuging the di6ruptate to recover a precipitated collagen, homogenizing the precipitate into a pa6te, and ca6ting the paata with a mold.
The nature of the propertie6 of the re~ulting membrane depend6 greatly on which of the6e two conversion proceg6es i6 used; the product of the compres6ion proce66 is flexible, tran61ucent, and 6mooth, and form6 a filmlike material with relatively high tensile 6trength. The product of disrupting the gel followed by precipitation of the disruptate, is relatively brittle and semitran~parent, ha6 a rough 6urface, and i6 relati~ely thick.
-12- ~23~01 Either membrane, however, can be characterized a6 a random fibrillar network wherein the fibrils are approximately of the diàmetër 70-300 nanometer6, and approximately 0.5-5~ in length.
The inclusion of cro6s-linked collagen doe6 not change the6e propertie6, except to toughen the product.
The cro6s-linked material i6 embedded in the fibrillar network described.
For the compre66ion process, the gel i8 6queezed in a suitable pi6ton type device, such as, for example, the apparatu6 pre6ently u6ed to obtain cakes of tofu. Compre66ion i6 conducted at approximately room temperature by using the collagen gel in 6itu in the medium in which it wa6 prepared. The compre~6ion is applied u6ing 1.1 - 3 atmo~phere6 pressure, and continued until the volume is approximately les6 than 5%
of the original gel. The re6ulting flat collagen fiber mat i6 then dried in air or other appropriate atmospbere at a low temperature (le66 than about 37C) to obtain the de6ired membrane. It is also de6irable to wa6h the remaining 6alt6 from the membrane. The wa6hing can be effected by washing with water, and redrying, again at atmospheric pres6ure, at low temperature.
The proce66 which utilize6 di6ruption of the gel typically i6 conducted by mechanically disrupting the matrix, such as with a spatula, followed by centrifugation at approximately 8000-16000 x g, preferably about 13000 x g for about 20-30 minute6 to obtain the precipitate. The force of centrifugation i6, of course, variable and no definite boundary limitations can be 6et. The precipitate i6 then homogenized sufficiently to form a pa6telike material, at room temperature, and the paste is cast into a mold an~
allowed to 6et in at atmo6pheric pre6sure at low ~L23~
temperature (below about 37C). The dried material i6 then de6alted, if desired, by washing in water, and redrying.
Cro6s-linking of the collagen in the re6ulting membranou6 material i6 optional, but can effected by treating the membranous material with glutaraldehyde to obtain the desired cro~s-links; however, as set forth above, this approach may re6ult in a more brittle product. Procedure6 for thi6 cro66-linking are known in the art. Briefly, in typical procedu~e6, the material i6 treated with a 601ution containing 0.05-1%
glutaraldehyde for 1-16 hours, and then quenched by addition of a glycine 601ution to a concentration of about 0.1-0.4M glycine. The cross-linking 601ution is then removed by washing.
E.
The resulting materials may be employed in the soft ti6sue repair constructions ordinarily utilizing artificial membranes, such a6 burned skin reelacement6, tendon reconstruction, or wound repair. They may also be shaped into variou6 form6 and used in connection with hard ti66ue repair. The ca~t or compre6sed membranes may be reformed into three dimensional object6 for implantation in replacing 6ections of bone by rolling into cylinders, or by 6tacking and cutting to shape.
The membrane6 may al60 be u6ed in their two dimensional configuration by succe66ively packing the membranes into a defect, such as a cranial or peridontal cavity. In general, onlay-type repair may be done by fitacking the~e membrane6 into the cavity.
Three dimensional implants are also obtainable directly from ~he gel by compre66ion into an appropriate mold. In this method of construction, it is pre~erred that the mixture containing the CIS and precipitatinq 1~:34~
buffer be dega66ed and molded pLior to compres~ion.
(Degas6ing may be used in the related proces6es which result in membrane~ and fibers, also). The dense collagen fiber network which is formed by compre6sion of the degassed, molded collagen gel i6 dried, desalted by wa6hing, remolded before redrying, and, if desired, aged at elevated temperature to encourage residual cro6s-linking. In addition, fibers can be formed preferably di~ectly from the gel before compression or disruption. The gel is wrapped in a porou6, absorbent material and squeezed or rolled into the de6ired diameter fiber. The disrupted gel may also be used, but in this event fiber6 mu6t be formed by ca6ting and 6tretching, and the proce6s i6 more cumber60me, leading to a less desirable product.
ExamPles The ~ollowing examples are intended to illustrate, but not to limit the invention. The first three examples represent alternative methods of forming the gel, com~ined with the compres6ion method for forming a membrane; examples 4-6 represent similar gel forming methods, ollowed by membrane formation u6ing the disruptate, all 6tarting with CIS alone. Examples 7 2S and 8 illustrate formation of cross-link~ in the re6ulting membranes whether the membrane6 are formed by compression or by disruption and precipitate recovery.
Example 9 shows the use of dega6sed and molded mixtures in gel formation where the gel is u6ed directly in forming a three dimensional implant. Example 10 shows thè formation of a gel which includes a portion of cro66-linked collagen, and Example 11 illustrates the conver6ion of this gel into a membrane. Example 12 .. . ... . .. .. ... . ....
~3~0~
illustrate6 additional embodiments of membranou6 material which include6 cros6-linked collagen.
ExamPle 1 90 ml Zygen~ (2 mg/ml bovine atelopeptide collagen, in HCl, pHl-4) CIS wa6 cooled to 4C, and mixed with 10 ml of precooled buffer containing 0.2 M
Na2HPO4/0.09 M NaOH. The solution was mixed at 4C, and incubated at room temperature for about 16-20 hour6, i.e., overnight, for convenience. The re~ulting collagen gel wa6 then ~laced in a pres6 and compre66ed u6ing con6tant pres6ure of about 1.5 atmo6phere6 to a flat collagen fiber network. The re6ulting network was dried in air at room temperature, wa6hed with water, and redried in air. The re6ulting collagen membrane was designated G-l.
Example 2 90 ml of Zygen~ CIS at ambient temperature ~!
was mixed with 10 ml of room temperature ~uf~er containing 0.2 M Na2HPO~1.3 M NaCl/0.09 ~ NaOH, and the mixture incubated at 37C overnight. The resulting matrix was converted to a membrane a~ 6et forth in Example 1. The resulting membrane, G-2, is a 6mooth flexible translucent material. An electron microg~aph of the fiber structure is 6hown in Figure 1.
ExamPle 3 90 ml o Zygen~ CIS wa6 cooled to 4C, and mlxed rapidly with 10 ml cold (4C) ~uffer containing 0.~ M Na2HPO4~0.09 M NaOH, and tran6ferred immediately to centrifuge bottles. The mixture wa~
centrifuqed at 8000 x g for 2 hour6 at about 20C, and the fiupernatant recovered from the bottles. The -16- 123~
6upernate wa6 incubated at 20C for ~vernight, re6ulting in the gel. The gel was converted into the membrane in a manner exactly 6imilar to tha~ set forth Example 1, and designated G-3. An electron micrograph of the fiber structure ig shown in Figure 2.
Example 4 sO ml Zygen~ CIS and 10 ml in~olubilizing buffer were mixea at 4C, and incubated to form a gel exactly as 6et forth in Example 1. The gel matrix was broken with a 6patula, tranaferred to a centrifuge bottle, and centrifuged at 13,000 x g for ~0 minutes.
The re~ulting precipitate wa~ recovered and homogenized into a pa6te form. The paste was ca~t into a mold and dried in air at 37C, then washed with water and redried in air at 37C to give the membrane P-l.
ExamPle 5 Zygen~ CIS was treated with buffer to form a gel exactly as de6cribed in Example 2, and the gel then converted to a membrane u6ing the procedure exactly a6 6et forth in Example 4. The re6ulting membrane waa designated P-2.
ExamPle 6 Zygen~ CIS waa used to form a gel uaing the procedure a6 6et forth in Example 3, and the reaulting gel converted to a membrane as 6et forth in Example 4.
The re6ulting membrane wa6 de6ignated P-3.
ExamPle 7 90 ml Zygen~ CIS at ambient temperature was mixed with 10 ml buffer which contained 0.2 U
Na2HP04/1.3 M NaCl/O.O9 M NaOH, and the mixture :
, .
~2348~1 incubated at 37OC overnight. The re~ulting gel wa6 compre6sed a6 6et forth in Example 4, dried, and de6alted by washing. The washed membrane was then cro6s-linked by treating with 0.1% glutaraldehyde di6solved in water at 20C, and the cros6-linked membrane wa6hed and dried at low temperature to obtain membrane XG-2.
Example 8 A gel was formed from 90 ml Zygen~ CIS as described in Example 7, and the resulting gel broken with a spatula, tran6ferred to a centrifuge bot~le, and centrifuged at 13000 x g for 30 minute6. The precipitate wa6 recovered and homogenized to a pa6te~
The pa6te was cast into a mold and dried in air at 37C, and the re6ulting membrane wa6hed with water. The washed membrane was then treated with a 0.1% solution of glutaraldehyde, as set forth in Example 7, and the cro6~-linked membrane wa6hed and dried in to yield membrane XP-2.
Example 9 The procedure for gel formation a6 6et forth in Example 2 wa6 modified by dega66ing and molding the pre-gel mixture. Before incubation, the mixture wa6 degas6ed by reduced ~res6ure and ~laced in a mold.
After incubation at 37 for 16-20 hour6, the molded gelatin was compressed at about 1.5 atm to obtain a dense fiber network, which was dried in air at 37 or les6. The dried solid wa6 de6alted by wa6hing, remolded, dried, and aged at an elevated temperature of about 40C-100C to increa6e re6idual cross-linking, to give the product de~ignated ~preformed G-2~.
123~8~
Example 10 A. Preparation of Cro66-Linked Collaqen Fibrous collagen was recon6tituted from collagen in 601ution (a 3 mg/ml 601ution of atelopeptide bovine collagen in dilute aqueous HCl, pH 1-4) by adding 0.02 M di60dium pho~hate to the solution at 18-20C to obtain a pH of 7.4, and allowing fibers to form for 1--2 hours. To 16~ ml of the resulting fibrous collagen suspension, 1.62 ml of 1% aqueous glutaraldehyde at pH 3 -10 was added. The glutaraldehyde ~olution was added gradually with stirring to obtain a final concentration of 0.01% glutaraldehyde, and the mixture was allowed to react for 16 hours at room temperature before quenching by the addition of 3 M glycine to 0.2 M. After a 1 hour quench time, the cro6s-linked collagen was washed 3 times with approximately 100 ml of a buffer which contain~ 0.02 M disodium pho6pha~e, 0.13 M NaCl, pH 7.4, with centrifuging at 17,000 x g for 5-7 minutes between each wash. The dynamic visco6ity of the collagen was measured by an o~cillating disc device (Nametre Company, Model 7.006PBD) mea6ured at a shear rate of about 5,000 6ec , and found to be approximately 700 cp at 22C.
After the final wa6h and centrifugation, the collagen wa6 re6uspended in the above buffer to obtain a protein concentration of about 30 mg/ml.
B. Preparation of the Gel Ten ml of the 6u6pen6ion of l~A wa6 mixed with 30 ml Zygen~ CIS and the thoroughly mixed component6 were degassed under a vacuum. To the degassed mixture was added 10 ml of room temperature buffer containing 0.2 M Na2P04/1.3 M ~aCl/O.O9 M NaOH, and the mixture was incubated at 37C overnight. The re6ulting gel contain6 55.5% cro66-linked collagen by weight.
~Z34~30~
Example 11 The gel of Example 10 wa~ placed in a press and compres6ed u6ing constant pressure of about 1.5 atmo6phere6 to obtain a flat collagen fiber network.
The re6ulting network was dried in air at room temperature, wa6hed with water, and redried in air. The resulting collagen membrane was designated GX-2.
Example lZ
The cross-linked collagen preparation prepared a~ in ~A of Examele lo i6 u6ed in a ratio of 1:8 to colla~en in 601ution (prepared as in Example 1) and 6ubjected to the proce~6 o~ Exam~le 1 to obtain a membrane de6ignated GX-l or of Example 3 to obtain a membrane designated GX-3. Similarly, PX-l, PX-2, and PX-3 are prepared a6 6et forth in Example6 4, s, and 6, but u6ing a 1:8 mixture of cros6-linked to CIS collagen as the ~tarting material.
Variation6 in the percentage of cro6s-linked collagen in the product are al60 obtained by ~arying the proportion6 of the su6een~ion of Exam~le lOA to the CIS.
1, ~, . ;
~,:
Claims (16)
1. A process for preparing a collagen membranous material which comprises compressing a collagen gel matrix, which matrix optionally includes up to 90% by weight of cross-linked collagen, with constant pressure to form a fiber network, and drying said network.
2. The process of claim 1 which further includes the step of cross-linking the material with glutaraldehyde.
3. The process of claim 1 wherein the gel is formed from collagen in solution mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight.
4. The process of claim 1 wherein the gel is formed by:
cooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of ue to 90% by weight, to approximately 4°C, treating the cooled solution with a buffer solution precooled to approximately 4°C, to obtain a mixture with a pH of approximately 7 and an ionic strength of approximately 0.05, and incubating the mixture at about 20°C for about 16-20 hours.
cooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of ue to 90% by weight, to approximately 4°C, treating the cooled solution with a buffer solution precooled to approximately 4°C, to obtain a mixture with a pH of approximately 7 and an ionic strength of approximately 0.05, and incubating the mixture at about 20°C for about 16-20 hours.
5. The process of claim 1 wherein the gel is formed by:
mixing at ambient temperature collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, with sufficient salt/buffer solution to obtain a mixture with a pH of approximately 7 and approximately physiological ionic strength, and incubating the mixture at about 37°C for 16-20 hours.
mixing at ambient temperature collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, with sufficient salt/buffer solution to obtain a mixture with a pH of approximately 7 and approximately physiological ionic strength, and incubating the mixture at about 37°C for 16-20 hours.
6. The process of claim 1 wherein the gel is formed by:
precooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, to about 4°C, mixing the cooled collagen in solution with a buffer solution, precooled to about 4°C to obtain a mixture with a pH of approximately 7 and ionic strength of about 0.05, and centrifuging the mixture at about 8000 x g-13000 x g for 1-2 hours at about 20°C, immediately after mixing to obtain a supernatant, recovering the supernatant, and incubating the supernatant at about 20°C for 16-20 hours.
precooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, to about 4°C, mixing the cooled collagen in solution with a buffer solution, precooled to about 4°C to obtain a mixture with a pH of approximately 7 and ionic strength of about 0.05, and centrifuging the mixture at about 8000 x g-13000 x g for 1-2 hours at about 20°C, immediately after mixing to obtain a supernatant, recovering the supernatant, and incubating the supernatant at about 20°C for 16-20 hours.
7. A process for preparing a collagen membranous material which process comprises:
disrupting a collagen gel matrix, centrifuging the disrupted matrix at about 13000 x g for about one half-hour, homogenizing the resulting precipitate into a paste, casting the paste, and drying the cast paste at a temperature less than 37°C.
disrupting a collagen gel matrix, centrifuging the disrupted matrix at about 13000 x g for about one half-hour, homogenizing the resulting precipitate into a paste, casting the paste, and drying the cast paste at a temperature less than 37°C.
8. The process of claim 7 which further includes cross-linking the membrane with glutaraldehyde
9. The process of claim 7 wherein the gel is formed from collagen in solution mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight.
10. The process of claim 7 wherein the gel is formed by:
cooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, to approximately 4°C, treating the cooled solution with a buffer solution precooled to approximately 4°C, to obtain a mixture with a pH of approximately 7 and an ionic strength of approximately 0.05, and incubating the mixture at about 20°C for about 16-20 hours.
cooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, to approximately 4°C, treating the cooled solution with a buffer solution precooled to approximately 4°C, to obtain a mixture with a pH of approximately 7 and an ionic strength of approximately 0.05, and incubating the mixture at about 20°C for about 16-20 hours.
11. The process of claim 7 wherein the gel is formed by:
mixing at ambient temperature collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, with sufficient salt/buffer solution to obtain a mixture with a pH of approximately 7 and approximately physiological ionic strength, and incubating the mixture at about 37°C for 16-20 hours.
mixing at ambient temperature collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, with sufficient salt/buffer solution to obtain a mixture with a pH of approximately 7 and approximately physiological ionic strength, and incubating the mixture at about 37°C for 16-20 hours.
12. The process of claim 7 wherein the gel is formed by:
precooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, to about 4°C, mixing the cooled collagen in solution with a buffer solution, precooled to about 4°C to obtain a mixture with a pH of approximately 7 and ionic strength of about 0.05, and centrifuging the mixture at about 8000 x g-13000 x g for 1-2 hours at about 20°C, immediately after mixing to obtain a supernatant, recovering the supernatant, and incubating the supernatant at about 20°C for 16-20 hours.
precooling collagen in solution, optionally mixed with a suspension of cross-linked collagen to obtain a percentage of cross-linked collagen of up to 90% by weight, to about 4°C, mixing the cooled collagen in solution with a buffer solution, precooled to about 4°C to obtain a mixture with a pH of approximately 7 and ionic strength of about 0.05, and centrifuging the mixture at about 8000 x g-13000 x g for 1-2 hours at about 20°C, immediately after mixing to obtain a supernatant, recovering the supernatant, and incubating the supernatant at about 20°C for 16-20 hours.
13. A membranous collagen material prepared by the process of claim 1.
14. A membranous collagen material prepared by the process of claim 3.
15. A membranous collagen material prepared by the process of claim 7.
16. A membranous collagen material prepared by the process of claim 9.
Applications Claiming Priority (2)
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US06/685,350 US4600533A (en) | 1984-12-24 | 1984-12-24 | Collagen membranes for medical use |
US685,350 | 1984-12-24 |
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CA1234801A true CA1234801A (en) | 1988-04-05 |
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CA000496824A Expired CA1234801A (en) | 1984-12-24 | 1985-12-04 | Collagen membranes for medical use |
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EP (2) | EP0376931B1 (en) |
JP (2) | JPS61210040A (en) |
AT (2) | ATE63936T1 (en) |
AU (1) | AU588560B2 (en) |
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EP0376931A1 (en) | 1990-07-04 |
US4655980A (en) | 1987-04-07 |
DE3587857T2 (en) | 1995-01-26 |
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