AU614700B2 - Creación de Inventos y Patentes con Inteligencia Artificial

AU614700B2 – Collagen compositions for bone repair containing autogenic marrow
– Google Patents

AU614700B2 – Collagen compositions for bone repair containing autogenic marrow
– Google Patents
Collagen compositions for bone repair containing autogenic marrow

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Publication number
AU614700B2

AU614700B2
AU68801/87A
AU6880187A
AU614700B2
AU 614700 B2
AU614700 B2
AU 614700B2
AU 68801/87 A
AU68801/87 A
AU 68801/87A
AU 6880187 A
AU6880187 A
AU 6880187A
AU 614700 B2
AU614700 B2
AU 614700B2
Authority
AU
Australia
Prior art keywords
collagen
bone
marrow
composition
repair
Prior art date
1986-02-14
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.)

Ceased

Application number
AU68801/87A
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AU6880187A
(en

Inventor
Karl A. Piez
Schlomo Weintraub
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.)

Ramot at Tel Aviv University Ltd

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.)
1986-02-14
Filing date
1987-02-13
Publication date
1991-09-05

1987-02-13
Application filed by Collagen Corp
filed
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Collagen Corp

1987-08-20
Publication of AU6880187A
publication
Critical
patent/AU6880187A/en

1991-09-05
Application granted
granted
Critical

1991-09-05
Publication of AU614700B2
publication
Critical
patent/AU614700B2/en

2007-02-13
Anticipated expiration
legal-status
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Status
Ceased
legal-status
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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

A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix

A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel

A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder

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

A61F2/28—Bones

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES

A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution

A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells

A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

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

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses

A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body

A61L27/3645—Connective tissue

A61L27/365—Bones

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

Abstract

composition which combines autogenic bone marrow with a suspension of purified atelopeptide reconstituted collagen is used to repair bone defects in mammals.

Description

III
2 Form 10 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPEES4Aj-O1lNO
(ORIGINAL)
Application Number: Lodged: 60/87 Class Int. Class Complete Specification Lodged: Accepted: Published: Priority: *..ReAted Art:
S
S
S.
S
56
S.
S.*
Name of Applicant: ooo Address of Applicant: S S
S.*
Actual Inventor:
S
5S Address for Service:
S
S
COLLAGEN CORPORATION and RAMOT UNIVERSITY 2500 Faber Place, Palo Alto, California 94303 United States of America, and 32 University Street, Ramat Aviv, 63192 Israel.
KARL A. PIEZ and SHLOMO WEINTRAUB EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
.G mplete Specification for the invention entitled: COLLAGEN COMPOSITIONS FOR BONE REPAIR CONTAINING AUTOGENEIC MARROW The following statement is a full description of this invention, including the best method of performing it known to us r t -1-A COLLAGEN COMPOSITIONS FOR BONE REPAIR CONTAINING AUTOGENEIC MARROW Technical Field The invention relates to the repair of defects in human bone. More particularly, it relates to the use of especially efficacious compositions for filling these defects. The compositions comprise purified fibrillar reconstituted collagen with a preparation of autogeneic bone marrow.
Background Art The use of autogeneic bone particles and/or 20 bone marrow is widespread and well known in the art.
See, for example, Salama, et al, J Bone Joint Surg (Br) (1973) 55: 402-417. Bone marrow has also been combined with biodegradable ceramic for periodontal e.g defect repair (Levin, et al. J Biomed Mater Res (1975) 9: 183-195). The marrow or cancellous bone appears quite effective in mediating repair.
The use of collagen preparations for the repair of bone defects has also been extensively reported. The use of Collagenfleece®, in particular, which is a 30 freeze-dried, pepsin-treated preparation from pig skin, sterilized by gamma irradiation (as described in US 4,066,083) has been reported by Krekeler. et al, j Oral Surg (1981) 10:suppl. 1: 151; Joos, et al, Biomaterials (1980) 1: 23-26: Zetzmann, et al, -2- Schweiz Mschr Sabnhelik (1982) 92: 119; and Springorum.
et al, Z Orthorp (1977) 115: 686. Other collagen preparations were used by Jaffee, et al, Arch Oral Biol (1978) 23: 415; ibid (1982) 27: 999, and by Cucin, et al, NY State J Med (1979) 1856. The use of atelopeptide fibrillar bovine collagen as a composition for conductive bone repair was disclosed in U.S. Serial No. 752,447, filed 5 July 1985, assigned to the same assignee, and incorporated herein by reference. In addition, collagen has been used in conjunction with a factor extractable from bone which mediates inductive bone repair as disclosed by Jeffries in U.S. 4,394,370 and in U.S. Serial No. 664,158, filed 24 October 1984, assigned to the same assignee and incorporated herein by 15 reference.
S. While it seems clear that bone marrow derived from the same individual, or, at worst, from an individual closely related, is helpful in repairing bone .injuries or defects, it is a problem to keep the bone 20 marrow in any but very small defects. Thus, bone marrow is not widely used as such. The material of choice is cancellous bone, which consists of a porous bone containing bone marrow. The problems with cancellous bone are that a second operation may be required to obtain it and it may be in short supply.
Disclosure of the Invention The invention provides a composition for repair of bone defects that permits the advantages inherent in 30 a natural tissue such as bone marrow to be utilized 0* while overcoming the problems of handling. It has been found that suitable collagen preparations are capable of adding sufficient body to keep the mixture in a defect rS ooooo *see 0 0000 0 0 00 0 0 0@* *0* 0 0* 0 .0 0 o 00° 0o 0 *000 0 -3and provide a biocompatible environment to induce bone repair by the cells in bone marrow.
Accordingly, in one aspect, the invention is directed to a method to mediate the repair of bone defects which utilizes a composition containing, in addition to autogeneic bone marrow, an extender which comprises reconstituted fibrillar atelopeptide collagen. Additional materials such as binders may optionally be added. In another aspect, the invention relates to compositions which are useful in this method, and to processes for preparing these compositions.
Modes of Carrying Out the Invention A. The Autogeneic Marrow Component 15 The compositions for use in the method of the invention are comprised of an autogeneic tissue-derived component and a collagen component. The autogeneic component is derived from either the same individual who bears the defect to be repaired or from an individual 20 sufficiently closely related genetically that the materials derived from this individual are not immunogenic in the recipient. It is recognized that, except for the same individual or an identical twin, the degree of genetic relatedness represents a continuum, 25 and that methods for predicting in advance whether or not sufficient close relationship is present to prevent immunogenicity are not entirely precise. However, current practice does operate within these parameters and attempts to evaluate genetic matching for surgical 30 transplantation procedures, with varying degrees of success. In general, as used herein, «autogeneic» refers to material either derived from the same person (or his twin) or from an individual judged by standard and commonly practiced techniques and criteria to be -4sufficiently closely related to provide a workable source of such material.
The methods of obtaining this evaluation of «autogeneic» character and/or excising bone marrow from such individuals are standard in the art and do not for, part of the invention. The bone marrow would generally be used directly in the form obtained.
B. The Collagen The collagen portion of the preparation is a nonimmunogenic form of a reconstituted fibrillar preparation, such as, for example, commercially available preparations used for soft tissue repair.
These preparations include Zyderm® collagen implant 15 (ZCI), which is available from Collagen Corporation, Palo Alto, CA, in concentrations of 35 mg/ml and mg/ml. In general, these suitable collagen preparations are prepared from animal skins, although any source of predominantly type I collagen can be used. The 20 preparation will include treatment with a suitable proteolytic enzyme to remove the telopeptide portions extending beyond the triple helical segments, which telopeptide portions are responsible for the native cross-linking between helices and for at least a portion
S.
of the immunogenicity of the preparation.
In a suitable procedure, a mammalian skin preparation, preferably bovine skin, is depilated and ground or minced to form a finely divided preparation which is solubilized under nondenaturing conditions by 30 dispersing it in an aqueous medium and digesting with a proteolytic enzyme other than a collagenase, preferably an enzyme that is active at low pH. Dilute acid solutions of, for example, HC1 or of carboxylic acids, such as acetic, malonic, or lactic acids, are used at ii low temperature with a pH normally in the range of 1.5-5, depending on the enzyme used. A preferred procedure is to disperse the comminuted tissue in HC1 to a concentration of 1-5 g/l at a pH of about 2 at 20 0
C.
After the tissue is dispersed, the enzyme is added and the mixture is incubated to permit the enzyme to digest the telopeptide and other solubilizable components of the tissue. Suitable enzymes for the digestion of the telopeptides which do not attack the triple helical portion of the collagen include pepsin, papain and trypsin, preferably pepsin, with an enzyme concentration in the range of 10% by weight based on the collagen content of the tissue. The incubation period can last from about 1 day to 2 weeks and the process of solubilization may be monitored by determining the viscosity of the solution. Once the viscosity reaches a *substantially constant level, the solubilization is complete, and the enzyme is deactivated and removed.
o. After denaturation of the enzyme, the solution 20 is treated to remove the denatured enzyme and the digested portions of the tissue by various techniques, and combinations thereof including, for example, dialysis, precipitation, and filtration. The soluble components including the collagen are segregated from sedimented or filtered solids and concentrated, optionally fractionated on ion exchange chromatography, and further concentrated to produce a substantially pure atelopeptide collagen solution. Typical concentration levels of the collagen in the solution are 1-10 mg/ml.
30 The collagen in solution is reconstituted to a fibrillar form by neutralizing the solution at reduced temperatures, preferably about 10-250 preferably under hypotonic conditions relative to physiological ionic strength. The neutralizing solution may be added r ii_ a a a.
a.
*r S *5 *r a *40
S
a *5 00 a
S
a directly or, preferably, by dialysis of the solubilized collagen against it. Ionic strengths of about 0.03-0.1, preferably 0.06, are used, and the pH is raised by adding an appropriate base or buffer such as disodium phosphate or sodium hydroxide to a level at which the collagen in solution reaggregates into fibrils. Fibril formation occurs under these conditions at a pH in the range of about 5-10, and the final pH is preferably in the range of of 7-8. The duration of the fibril formation step is normally in the range 1/2-18 hours.
Optionally, the reconstituted atelopeptide collagen gel suspension may be cross-linked with a cross-linking agent such as, for example, various aldehydes such as formaldehyde, acetaldehyde, glyoxalpyruvic aldehyde, and dialdehyde starch, preferably glutaraldehyde. During the cross-linking reaction, the collagen concentration is kept at about 0.1-10 mg/ml, preferably 1-5 mg/ml. Following cross-linking, the reaction may be quenched with compounds which have functional groups that react with the functional groups of the cross-linking agent to form water soluble adducts. In particular, compounds containing free amino groups, such as, for example, glycine, are usable in this respect. Optionally, the 25 excess crosslinking agent may be removed by washing.
The foregoing general preparation procedures are typical of those used to prepare suitable collagen for the composition of the invention. However, the specific procedure used is not significant so long as 30 the resulting preparation is substantially free of the telopeptide portions, has been reconstituted, is fibrillar, and is basically pure collagen uncontaminated with materials coexisting with the collagen in its -7native environment. These characteristics are required for biocompatibility.
The collagen suspension that results is typically a suspension in aqueous solution at a concentration of 10-100 mg/mil, preferably about 35 or mg/ml. A favorable suspension medium is isotonic saline, but other buffer solutions or aqueous solutions which permit the collagen suspension to be stabilized are also acceptable.
C. The Mixture The compositions of the invention are formed by simple mixing of the suspensions of the bone marrow with the suspension of the fibrillar collagen. The suspensions are mixed in a volume ratio of 5-50 marrow in admixture with the collagen suspension.
The preferred ratios depend on a number of *factors, including the nature of the defect, the size of the defect, the metabolism of the subject, and judgment 20 of the practitioner repairing the defect. In general, the compositions of the invention comprise a wide range of ratios of bone marrow to the collagen carrier.
S*r The compositions of the invention are implanted into a bone defect using standard surgical procedures for cancellous bone preparations. Such procedures are well known to orthopedic, reconstructive and dental surgery practitioners and are applied using the generally understood practices of the these professions. In addition, if the collagen used is 30 injectable, as is ZCI. the mixture will also be injectable. Therefore, in the case of bone defects which are not surgically opened, the mixture may be transcutaneously injected.
-8- Defects which are suitable subjects for implantation by the compositions of the invention include bone fractures, bone structures requiring supplementation, such as alveolar ridge augmentation, periodontal defects, congenital bone defects and surgical bone loss. Any defect which is a suitable substrate for filling with an autogeneic cancellous bone is a suitable substrate for the composition of the invention, except that the increased availability of materials in the composition of the invention may make possible the treatment of defects which were too large and require too much material to permit filling with autogeneic cancellous bone.
In summary, the compositions contain a S 15 suspension of bone marrow in admixture with a suspension 06. *of an atelopeptide pure reconstituted fibrillar collagen. The bone marrow must be autogeneic as defined above; that is, it must be derived from the same individual or from an individual sufficiently closely 20 related that the marrow is nonimmunogenic in the recipient. The collagen portion, on the other hand, may be derived from any source. The removal of the telopeptides diminishes the immunogenicity sufficiently that even xenogeneic sources may be used. The reconstituted fibrillar nature of the collagen preparation permits conduction of the bone growth which is induced by the bone marrow in the composition.
Examples 30 The following example is intended to illustrate but not to limit the invention. In this illustration, various compositions falling within the description of the invention are used to repair an artificial bone defect in rats, and compared with the results of -9corresponding implants using either collagen or bone marrow alone.
Rats were provided with bone defects by removal of a 6 mm segment of the femur. The bone was fixed with a plate and pins in a standard manner. Defects were filled with either bone marrow alone, or bone marrow in combination with collagen. The results were compared for either no treatment or for treatment with collagen alone. The implants were examined by radiology, giving the results after various intervals up to 12 weeks in Table 1.
The observations were graded on a scale of 0 to 4, where 0 represented no change and 4 represented complete filling of the defect with a medullary canal.
As seen in Table 1, the combination of bone marrow prepared from the individual subject rats with ZCI (a mg/ml suspension of atelopeptide fibrillar reconstituted collagen) was compared with the effect of this collagen *oalone, of marrow alone and of cancellous bone.
S. 20 As shown in Table 1, ZCI alone was relatively ineffective in repair of the defect. Over a long time period (12 weeks), the combinations of bone marrow with collagen were superior to marrow alone, although marrow •o alone was reasonably effective.
It can be imagined that in larger defects, marrow alone would be less effective. Cancellous bone, the standard material now used, was somewhat less effective than ZCI plus marrow.
666 69 6 6 6 66 9 w 0 6, 666 66 6 3 Week 0 0 6 9 a U, 0 Table 1 Union* 6 Week 9 Week 12 Week zCI Control ZCi marrow Marrow alone Cancellous Bone o (14) o (18) o (14) 0.86+1.51 (14) 0.604-1.06 (15) 0.21+0.80 (14) 0 2.07 1.26 (13) 1.43+1.72 (14) 1.71+1.64 (14) 0.54+1.33 (13) 0.21±0.80 (14) 3.00 0.58 (13) 1.38+1.85 (13) 2.23+1.59 (13) 0.83±1.59 (12) 0.21±0.81 (14) 3.83±0.39 (12) 2.27+1.79 (11) 3.00+1.54 (12) *Scale 0-4, estimated from x-rays Number of rats is shown in parentheses

Claims (8)

1. A method to mediate the repair of bone defects which comprises placing into said defect a composition containing reconstituted fibrillar atelopeptide collagen and autogeneic bone marrow.

2. The method of claim 1 wherein the collagen is supplied as an aqueous suspension containing 10-100 mg/ml and is 50%-95% of said composition by volume.

3. The method of claim 1 wherein the collagen is of xenogeneic origin.

4. The method of claim 3 wherein the collagen is of bovine origin. eoA S

5. The method of claim 1 wherein the S* composition is injected into the defect. 3

6. A composition for use in the repair of bone defects which comprises, as active ingradiants an aqueous suspension containing 10-100 mg/ml of reconstituted fibrillar atelopeptide purified 4 collagen, and autogeneic bone marrow.

7. The composition of claim 6 wherein the S collagen suspension comprises 50%-95% by volume of the 30 composition.

8. The composition of claim 6 which is an injectable suspension. DATED THIS 12th day of February, 1987. COLLAGEN CORPORATION and RAMOT UNIVERSITY 4-1 PATENT ATTORNEYS, ~50 QUEEN STREET, MELBOURNE. VIC. 3000.

AU68801/87A
1986-02-14
1987-02-13
Collagen compositions for bone repair containing autogenic marrow

Ceased

AU614700B2
(en)

Applications Claiming Priority (2)

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Priority Date
Filing Date
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US829809

1986-02-14

US06/829,809

US4774227A
(en)

1986-02-14
1986-02-14
Collagen compositions for bone repair containing autogeneic marrow

Publications (2)

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Publication Date

AU6880187A

AU6880187A
(en)

1987-08-20

AU614700B2
true

AU614700B2
(en)

1991-09-05

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Priority Date
Filing Date

AU68801/87A
Ceased

AU614700B2
(en)

1986-02-14
1987-02-13
Collagen compositions for bone repair containing autogenic marrow

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US
(1)

US4774227A
(en)

EP
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EP0233770B1
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JP
(2)

JPS63260568A
(en)

AT
(1)

ATE52416T1
(en)

AU
(1)

AU614700B2
(en)

CA
(1)

CA1279010C
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DE
(1)

DE3762569D1
(en)

ES
(1)

ES2015950B3
(en)

GR
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GR3000691T3
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Also Published As

Publication number
Publication date

JPS6437956A
(en)

1989-02-08

JPS63260568A
(en)

1988-10-27

JPH0434907B2
(en)

1992-06-09

CA1279010C
(en)

1991-01-15

US4774227A
(en)

1988-09-27

EP0233770B1
(en)

1990-05-09

AU6880187A
(en)

1987-08-20

EP0233770A2
(en)

1987-08-26

GR3000691T3
(en)

1991-09-27

ES2015950B3
(en)

1990-09-16

ATE52416T1
(en)

1990-05-15

DE3762569D1
(en)

1990-06-13

EP0233770A3
(en)

1987-12-02

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