CA1199580A - Collagen implant material and method for augmenting soft tissue - Google Patents

Collagen implant material and method for augmenting soft tissue

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Publication number
CA1199580A
CA1199580A CA000419184A CA419184A CA1199580A CA 1199580 A CA1199580 A CA 1199580A CA 000419184 A CA000419184 A CA 000419184A CA 419184 A CA419184 A CA 419184A CA 1199580 A CA1199580 A CA 1199580A
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CA
Canada
Prior art keywords
collagen
cross
linked
dispersion
implant material
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
Application number
CA000419184A
Other languages
French (fr)
Inventor
Donald G. Wallace
Susan B. Wade
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Collagen Aesthetics Inc
Original Assignee
Collagen Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Collagen Corp filed Critical Collagen Corp
Application granted granted Critical
Publication of CA1199580A publication Critical patent/CA1199580A/en
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24Collagen
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00365Proteins; Polypeptides; Degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/06Flowable or injectable implant compositions
    • YGENERAL 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
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827Proteins from mammals or birds
    • Y10S530/842Skin; hair; nails; sebaceous glands; cerumen

Abstract

COLLAGEN IMPLANT MATERIAL
AND METHOD FOR AUGMENTING
SOFT TISSUE

Abstract An injectable implant material for soft tis-sue augmentation comprising a dispersion of (a) par-ticles of cross-linked atelopeptide collagen; and (b) reconstituted fibrous atelopeptide collagen in a (c) physiological aqueous carrier. Implants of this material have improved persistence relative to cur-rently used collagen implant materials.

Description

COLLAGEN IMPLANT MATERIAL
AND METHOD FOR
AUGMENTING _ T TISSUE

Description Technical Field The invention is in the field of body treat-ing compositions and methods. More particularly it concerns a collagen implant material of improved vol-ume stability for augmenting soft tissue in mammals.

Background Art Collagen has been used as a pharmaceutical carrier, as a surgical prosthesis (sutures and wound dressings), and as an implant material. In many in-stances the collagen is cross-linked with chemical agents, radiation, or other means to improve its mech-anical properties, decrease its immunogenicity, and/or increase its resistance to resorption.
US Patent No 3949073 describes the use of atelopeptide solutions of collagen as an injectable implant material for augmenting soft tissue. Accor-ding to the patent, the collagen is reconstituted before implantation and forms a ibrous mass of tissue when implanted. The patent suggests adding particles of insoluble collagen microfibrils to control the shrinkage of the fibrous mass formed at the augmenta-tion site. ZYDERM collagen implant is a commercial embodiment of the material described in the patent and is composed of reconstituted atelopeptide collagen in saline that contains a small amount of a local anes-thetic. While this commercial material is remarkablyeffective, it may shrink in volume after implantation * Registered trademark i~ ~

5~3~

due primarily to absorption of its fluid componen-t by the body. Thus~ if volume constancy, sometimes called "persis-tency", is essential, an additional injection or injections of supplemental implant material is required. The present invention provides a collagenous implant material having improved volume stability or "persistence".

Disclosure of the Invention The implant material of this invention is an injectable dispersion of:
(a) particulate cross-linked atelopeptide collagen, and (b) reconstituted atelopeptide collagen fibers, dispersed in (c) an aqueous carrier.
The fibrous collagen constitutes about 5% to 30% by weight of the total collagen in the dispersion and the cross-linked collagen constitutes about 70% to 95% by weight of the total collagen in the dispersion~
This material is used to augment soft tissue by injecting it at the augmentation site. I-t provides an implant having substantially improved persistence relative to the currently used collagen implant material.

Modes for Carrying Out the Invention The noncross-linked and cross-linked forms of collagen used in the invention may be derived from collagen collected from any number of mammalian sources. The donor need not be genetically similar to the host into which the material is ultimately implanted. Because of their avail-ability9 bovine or porcine corium will usually be employed.
The first step in making either form is to prepare atelo~
peptide collagen in solution from the corium. The animal skin is softened by soaking it in a mild acid and then scraping it to remove hair, epidermis, and fat. The depilated ,~ i ~$3~S~

skin is then soaked again in mild acid and then com-minuted by grinding, mincing, milling or like physical treatment. The comminution prepares the skin for solubilization.
The divided tissue may be solubilized under nondenaturing conditions by dispersing it in an aque-ous acid medium and digesting it with a proteolytic enzyme other than a collagenase. Dilute acid ~olution at low temperatures will normally be used to avoid denaturation. Mineral acids such as HCl or carboxylic acids such as acetic, malonic or lactic acids may be used at pHs in the range o about 1.5 to 5 and temper-atures of about 5C to 25C. A preferred procedure is to disperse the comminuted tissue in ~Cl to a concen-tration of l to 5 g/l at a pH of about 2 at 20C.After the tissue is dispersed the enzyme is added and the mixture is incubated to permit the enzyme to di-gest the telopeptide and other solubilizable compon-ents of the tissue. Enzymes that attack the telopep-tide portion of the collagen while not denaturing thehelical portion are used. Examples of such enzymes are trypsin, pepsin, chymotrypsin, and papain. Pepsin is preferred because it is relatively easily deacti-vated and removed from the solubilized collagen. The enzyme concentration will usually be in the range of about 0.1% to 10% by weight based on the collagen.
The incubation period will typically vary from about two days to two weeks. The progress of the solubili-zation may be monitored by determining the viscosity o the solut-on. Once the viscosity reaches a sub-stantially constant level, the solubilization is com-plete. At this point, the enzyme is deactivated (denatured) and removed.

~9~5~

The enzyme may be deactivated by raising the pH of the solution to at least about 7 by adding an alkaline material such as sodium hydroxide. Af-ter the enzyme has been denatured the solution is treated to remove denatured enzyme and the portions of the tissue that were digested during the solubilization. Various dialysis, sedimentation, and filtration techniques may be used to effect such removal. For example, U.S.
Patents Nos. 949,073 col 3~ lines 10-22 and 4,140,537 10 col 5, lines 4~3 to col 6, line 34. A preferred procedure is to first lower the pH by adding acid and then clarify the solution by diatomaceous earth sedimentation. The sediment is filtered and the filtrate is concentrated. The concentrate is then fractionated by ion exchange chromatography and further concentrated to produce a substantially pure atelopep-tide collagen solution that may be used to make the cross-linked collagen and the noncross-linked collagen fibers used in the invention.
The fibrous collagen is preferably made by neutralizing the solution with buffer at reduced tem-peraturesO The ionic strength of the neutralized solution is about 0.03 to 0.3 and the pH is about 7.2 to 7.4~ Na2HP04 is a preferred buffer. This increase in pH causes the collagen to reaggregate into atelo-peptide fibrils. These fibrils are separated from the supernatant for combination with the cross-linked gel particles.
The cross-linked particles are made from the solution by first reconstituting the collagen and then cross-linking the reconstituted material. The recon-stitution is preferably carried out by increasing the pH of the solution to about 7.4 to 7~6 by adding buf-fers and base at a reduced temperature and then rais-~, . . .

51~1~

ing the -temperature to a suitable temperature ie 26C
to 38C. The collagen reaggregates spontaneously under such eonditions. AEter the reeonstituted eolla-gen is formed it is eross-linked by exposing it to a cross-linking agent that forms covalent bonds between collagen chains. Radiation~induced eross-linking or ehemieal indueed cross-linking may be used. Either nonparticulate radiation (ultraviolet, gamma, X~ray) or particulate racliation (~-particles, protons, ~-particles, e:Leetrons) may be used. Chemieal eross-linking agents that may be used include those that are eommonly used to cross-link proteins for medical use such as formaldehyde, glutaraldehyde, aeetaldehyde, glyoxal pyruvie aldehyde, dialdehyde s-tareh, quinones, hydroquinones, dimethylol acetone, and divinyl sul-fone. Glutaraldehyde is a preferred cross-linking agent.
The condi-tions of cross-linking, particu-larly the concentration of cross-linking agent the temperature, and the duration of the reac-tion, will affect the degree to which the collagen is cross-linked. The degree of eross-linking is commonly ex-pressed indirectly in terms of physical measurements such as molecular weight changes, gela-tion character-istics, swell.ing properties or tensile properties suchas Young's modulus. The eonditions and agent are preferably such as to give a cross-linked material having a Young's modulus in the range of about 1,000 to 10,000 dynes/cm2 before it is eoneentrated by cen-trifuging and about 5,000 to 50,000 dynes/em2 aftereentrifuging as described below. When glutaraldehyde is employed, reaction with about 0.004 to 4 mg of glutaraldehyde per g of collagen gel at 15C to 30C
for about 1/2 to 20 hr will provide suitable cross-~6~

linking. The glutaraldehyde will normally be added tothe gel as a dilute aqueous solution. After the de-sired reaction period the cross-linked gel is washed to remove any cross-linking agent and is then concen-trated by filtration or centrifugation to about lO tolO0 mg protein/ml. The concentrated gel is then sub-~ected to mild shear stress to comminute it into uni-form particles about 50 to about 200 microns in equiv-alent spherical diameter. A high speed grater or kni~e mill may be used to comminute the gel.
The fibrous collagen and cross-linked col-lagen particles are dispersed in an appropriate aque-ous parenteral carrier. The dispersion is placed in a syringe or other injection apparatus. The fibrous collagen will usually constitute about 5% to 30~ by weight of the total collagen in the dispersion, pre-ferably 15% to 25% by weight and the cross-linked gel will usually constitute about 70% to 98~ by weight of the total collagen in the dispersion, preferably 75%
to 85% by weight. A particularly preferred dispersion contains the fibrous collagen and cross-linked colla-gen in a 20:80 weight ratio. Minor amounts of addi-tives such as local anesthetics may be included in the implant composition. The aqueous carrier should be a medium that is physiologically acceptable to the host. Thus, its ionic strength and pH should be phys-iological (ie pH 6.8 to 7.5, ionic strength 0.1 to 0.2). Saline is a preferred carrier. The total col-lagen concentration in the dispersion will usually be in the range of about 15 to about 80 mg/ml, preferably 40 to 60 mg/ml.
The above described collagen implant mater-ial may be injected intradermally to augment soft tissue, to repair or correct congenital anomalies, 35~3 acquired defects or cosmetic defects. E'xamples of such conditions are conyenital anomalies such as hemi-facial microsomia, malar and zygomatic hypoplasia, unilateral mammary hypoplasia, pectus excavatum, pec-toralis agenesis (Poland's anomaly). and velopharyn-geal incompetence secondary to cleft palate repair or submucous cleft palate (as a retropharyngeal implant);
acquired defects (post traumatic, post surgical, post infectious) such as depressed scars, subcutaneous atrophy (eg, secondary to discoid lupis erythema-tosis), enophthalmos in the enucleated eye (also superior sulcus syndrome), acne pitting of the face, linear scleroderma with subcutaneous atrophy, saddle-nose deformity, Romberg's disease and unilateral vocal cord paralysis: and cosmetic defects such as glabellar frown lines, deep nasolabial creases, circum-oral geographical wrinkles, sunken cheeks and mammary hypo-plasiaO
The following examples illustrate the implant materials, the method by which they are used, and the merits of implants made of these materials.
These examples are not intended to limit the invention in any manner.

Materials and Methods Preparation of Atelopeptide Bovine Collagen Solution Bovine hide was softened and depilated by treatment with acetic acid. The hide was then comminuted and dispersed in HCl, pH 2, at 8-11 g/l.
Pepsin was added to the dispersion at 0.1~ by weight based on total protein and the mixture was allowed to incubate for about 100-300 hr at 15C to 20~C. ~aOH
was then added to raise the pH of the incubation 5&~0 medium to about 7 and thereby terminate the dlgestion. The denatured enzyme was removed from the reaction mlxture by sedlmentatlon at reduced pH. The solution was then purifled and concentrated by filtratlon and chromatography to form a 3 mg/ml solu-tlon of atelopeptide bovlne collagen ln dilute aqueous HCl, pH 2. This solution is herelnafter referred to as CIS.

Preparatlon of Flbrous Collagen Flbrous collagen was reconstituted from CIS
by adding 0.02 M ~a2HPO4, to the CIS at 18C to 1n-crease its pH to 7.4. The precipitated flbrous cclla-gen was separated from the supernatant, concentrated, and homogenized with NaCl and Na2HPO4 to a physio-logical pH and lonic strength. The concentratlon of collagen in the resulting dlspersion was 35 mg/ml.

Preparation of Cross-linked Gel Particles CIS was mixed at 0C wlth a buffer composed of 1.3M NaCl and 0.2M Na2HPO4 and the pH of the mix-ture was ra1sed to 7.4-7.6 with 0.lN NaOH. The tem-perature of the mlxture was then raised to 34C and held there for two hours during which tlme the solu-tion gelled.
The gel was added to a 0.4% by weight solu-tion of glutaraldehyde in physiological phosphatebuffer, pH 7.4 (280 mg glutaraldehyde per g of colla-gen ln the gel) and allowed to react for one hour.
The resulting cross-linked gel was washed repeatedly wlth the phosphate buffer to remove the aldehyde. The gel was then centrifuged until a proteln concentration of approximately 30 mg/ml (determined by quantltative nlnhydrin assay) was reached. A sample of the gel was 5~3~

removed and its Young's modulus was determined by the methods descrlbed in Mechanical Properties of Polymers and Composites, Vol. 1, Dekker, New York 1974, pp 1-50 and Gordon, et al, ~ature 217: 735 (1968).
Comminution of the centrifuged collagen was carrled out by one of several methods dependlng upon the toughness of the gel. Low strength materlals could be fragmented or shredded by extruding bac~ and forth between two syringes joined by a #12 gauge bore tube. Stronger gels requlred mincing into strips before applylng the double syrlnge method. Once the cross-linked preparatlons were homogenlze~, fibrous collagen could be mixed with them and further homo-genlzed by passage between syringes.

Preparation of Implant Materials The fibrous collagen dispersion was mlxed with the cross-linked collagen gel particles in var-ious proportions and the mixtures were placed in ster-ile syringes. Control materials of only the disper-sion and only the gel were also placed ln sterlle syringes.

Implantation Sprague Dawley female rats weighlng 125~20g were used as hosts.
Each rat was implanted ln two sites, flbrous collagen alone as control ln the left dorsal cra~ial region, and glutaraldehyde cross-llnked collagen wlth or wlthout admixed fibrous collagen in the rlght dor-sal cranial regions. Injectlons were through ~18 gauge needles into the subcutaneumO Injectlon of the cross-llnked collagen alone was dlfficult. Weighed quantlties (usually about 0O5 g) were delivered.

s~

Explantatlon of palred experlmental and con-trol samples was carrled out at intervals ranglng from 5 to 50 days. Host tlssue was carefully dlssected from collagen lmplants, and the wet welghts were re-corded. The percent welght recovery (persistence) wasthen calculated from the weight implanted. Welghed speclmens were then embedded, sectioned, and stained for histological examlnatlon. Stains used included hematoxylln and eosin, trlchrome, and von Kossa.

Results The table below presents the results of the implantation of the implant materlals of the invention and the control implant materials.

Persls-Materlal Blocompatlbllity tence (%) 1. Flbrous Collagen Modest cell invasion, 36t6 Alone (35 mg/pro- vascularizatlon, gen-teln/ml) erally acceptable
2. Cross-linked More extensive cell 108+19 Collagen (57 mg invasion and vascu-proteln/ml) larlzation, acceptable
3. Cross-linked Similar to 2, but 89~2 Collagen plus fewer cells, accep-Fibrous Collagen table (80:20, w/w; total mg proteln/ml:53) As lndicated by the above results, the lm-plant materlal made from the combination of noncross-llnked fibrous collagen and cross-llnked collagen has substantlally better perslstence than the implan~
contalnlng only noncross-linked flbrous collagen.
While the perslstence of the cross-llnked collagen lmplant was even better, the 1njectabil1ty of th1s materlal is poor. The injectabllity of the implant made from the comblnatlon noncross-linked and cross-llnked collagen was acceptable.
Hlstologlcally all three materlals were blocompatable, The lmplant contalning cross-linked collagen were invaded by more cells and vascularlzed more rapldly than flbrous collagen alone. New col-lagen synthesls appeared to be occurring in the cross-linked collagen; presumably this explalns the lncrease in welght of such explants. At early time polnts some cell types associated wlth an inflammatory response appeared in cross-linked samples. At later tlmes the cells were prlmarlly fibroblasts, whlch are indlcatlve of a beneElcent colonization.
Modlflcations of the above descrlbed embodl-ments of the lnventlon that are obvious to those of sklll in the blochemlcal, medical, and/or surglcal arts are lntended to be withln the scope of the fcl-lowing claims.

Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. An injectable implant material for soft tissue augmentation comprising a dispersion of:
(a) particulate cross-linked atelopeptide collagen;
and (b) reconstituted fibrous atelopeptide collagen;
dispersed in (c) an aqueous carrier, and wherein said fibrous collagen constitutes about 5% to 30%
by weight of the total collagen in the dispersion and the cross-linked collagen constitutes about 70% to 95% by weight of the total collagen in the dispersion.
2. The implant material of claim 1 wherein said carrier has a substantially physiological pH and ionic strength.
3. The implant material of claim 1 wherein the total collagen in the dispersion is in the range of about 15 to about 80 mg/ml.
4. The implant material of claim 1 wherein the cross-linked collagen constitutes about 75% to 85% by weight of the total collagen in the dispersion and the fibrous collagen constitutes about 15% to about 25% by weight of the total collagen in the dispersion.
5. The implant material of claim 4 wherein the particle size of the cross-linked collagen is in the range of about 50 to about 200 microns and the cross-linked collagen has a Young's modulus of about 5,000 to about 50,000 dynes/cm2.
6. The implant material of claim 5 wherein the cross-linked collagen is cross-linked with glutaraldehyde.
7. The implant material of claim 1 wherein the carrier has a substantially physiological pH and ionic strength; the total collagen in the dispersion is in the range of 40 to 60 mg/ml; the cross-linked collagen constitutes 75%
to 85% by weight of the total collagen in the dispersion and the fibrous collagen constitutes 15% to 25% by weight of the total collagen in the dispersion, and the cross-linked collagen has a particle size in the range of about 50 to about 200 microns and a Young t S modulus of about 5,000 to 50,000 dynes/cm2.
8. The implant material of claim 1 or 7 wherein the dispersion includes (d) a local anesthetic.
CA000419184A 1982-01-11 1983-01-10 Collagen implant material and method for augmenting soft tissue Expired CA1199580A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/338,661 US4424208A (en) 1982-01-11 1982-01-11 Collagen implant material and method for augmenting soft tissue
US338,661 1982-01-11

Publications (1)

Publication Number Publication Date
CA1199580A true CA1199580A (en) 1986-01-21

Family

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Family Applications (1)

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CA000419184A Expired CA1199580A (en) 1982-01-11 1983-01-10 Collagen implant material and method for augmenting soft tissue

Country Status (5)

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US (1) US4424208A (en)
EP (1) EP0083868B1 (en)
JP (1) JPS6054288B2 (en)
CA (1) CA1199580A (en)
DE (1) DE3270910D1 (en)

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