FR2564732A1 - BIOMATIERE ARTIFICIAL OSTEOFORMATRICE AND METHOD OF MANUFACTURING THE SAME - Google Patents

Abstract

THE INVENTION CONCERNS AN ARTIFICIAL OSTEOFORMING BIOMATER ALLOWING THE RAPID RESTORATION OF A MISSING BONE PART IN A LIVING BODY. BIOMATIERE CONSISTS OF A MIXTURE OF AN OSTEO-FORMING FACTOR AND OF A FIRST SUPPORT CHOSEN FROM COLLAGEN, ITS DERIVATIVES AND DENATURATION PRODUCTS, THIS MIXTURE CAN BE FIXED TO A SECOND SUPPORT CONSTITUTED OF A CERAMIC MATERIAL, METAL OR A SYNTHETIC RESIN, OR TO BE IMPREGNATED IN THIS SECOND SUPPORT. APPLICATIONS TO ORTHOPEDIC SURGERY AND TO ORTHO-DENTAL SURGERY.

Description

The present invention relates to a biomaterial comprising a factor

  osteoformator for use in a surgical field, such as orthopedic surgery and oral surgery, and a method of

manufacture of this biomaterial.

  So far, for example when

  missing piece of bone in a living body was replaced

  artificial prosthesis, it was practically

  rante to cut a part of a certain region of the bone of the same living body and to transplant that part to the place of the missing part. This autoplastic transplant is optimal in that it offers a

  excellent biocompatibility with the bone to complete.

  But, of course, there is a limit to the amount of bone that can be used for autoplastic transplantation, the surgery being more important because of bone collection and pain.

  caused to the patient being important. For this reason

  when a lack of bone extends over an important area

  aunt, an artificial biomaterial having an affinity for a living body, for example a metal or a ceramic material, is used to fill the gap and for the material to settle at the level of the missing part

of the bone.

  However, the use of such a biomaterial

  Artificial repository, as such, had the disadvantage that the rapid adhesion of the bone to the biomaterial with sufficient strength was made difficult. What is considered to be the main cause of this difficulty is that not enough bone tissue is formed. As a result, it is difficult to quickly get a hard-wearing, hard-living body tissue to

  from a surgical treatment in which one uses

  is a classic artificial biomaterial.

  The present invention aims to eliminate

  the inherent disadvantages of artificial biomaterial-

  the classic described above. In short, this goal is

25647 2

  dyed thanks to a mixture of an osteoforming factor and

  of a first collagen-based support for the fac-

  which is constituted by any osteoforma-

  in the mouse or osteoformator factor derived from Dunn osteosarcoma and human osteoformer factor known so far, in the medical community, as a

  constituting an osteoformator. The factor is worn

  stably by the first support in a living body so as to allow bone formation under

  factor and finally to absorb by the body vi-

  the same first collagen-based support. se-

  In a further developed aspect of the invention, a second support, in addition to the first support, is used to provide mechanical reinforcement in the body.

  living. When the biomaterial of the invention is used

  to replace and fix broken parts and to

  greatly affected, it promotes growth and

  fast restoration of bone by allowing the reconstruction

  bone tissue of sufficient strength.

  The essential element of artificial biomateria

  of the invention is an osteoformative factor, and this factor is a substance whose existence is

  long suspected in living bodies.

  The role of the osteoformer factor is to act

  extracellularly on mesenchymal cells

  undifferentiated and to raise the phenotype of

  cells to turn them into chondrocytes and osteo-

  oblasts to thus form, locally, a bone tissue.

  The Applicant, after years of research, has put

  a method for isolating an osteoformal factor

  (osteoforming factor in mice) from

  Dunn's osteosarcoma, and purified the factor and eli-

  has already mentioned the substance in "BIOMEDICAL RE-

  SEARCH "2 (5) 466-471 in 1981. This substance is a

  basic and hydrophobic polypeptide of molecular weight

  re about 20,000. In addition, the Claimant has r4cem-

  isolated and purified a bio-based osteoform

  similarly from a human osteosarcoma

  transplanted hand in animals by transplantation

from generation to generation.

  The human osteoformer factor also has substantially the same biochemical properties as the osteoformant factor obtainable from the above osteosarcoma, and, therefore, this human osteformatory factor has been used in

  embodiment of the invention in consideration of the

denies.

  In this way, the human osteoformer factor exerts an osteoforming action in the living body, but a certain type of support (or bed) is needed to cause the factor to form bone in a particular region of the living body, and the amount

  of bone formed is regulated by the amount of

  nant and carrying the osteoformer factor. As a result

  quent, to form the osteforming factor in the body

  the first and second supports are

seen, respectively.

  The first support contains and carries the osteoforming factor and enables it to form a bone, while the second support is a shaped body holding on it the first support or the container, having a shape

  required and the necessary mechanical strength.

  The first medium must have the following properties:

  1) when immersed in a living body, the

  port must not cause a reaction to foreign matter, 2) the support must have affinity for the bone, 3) the support can always be provided by an industrially constant source, ready and low-priced, 4) the support must be as it is stably retained without destroying the properties of the factor

  osteoformer and be miscible in any report

  () the support must be able to be finally absorbed into the living body, and (6) the support must be easily

second support.

  The second support must have the following properties: 1) the support must have the properties of the first support mentioned in paragraphs 1 to 4, 2) the properties of the support must remain the same for a prolonged period of time, 3) the support must easily bind physically to the first medium, and

  4) the support must have a high degree of resistance

mechanical.

  Various researches on the material intended to obtain the first support presenting

  these properties led to the discovery that

  gene, its derivatives and denaturing products could

  present the required properties.

  It is well known, in this respect, that

  gene (including its derivatives and denaturing products) which is the basis of the first support, is a protein generally having a low antigenicity, and it is also known that the main part which is

  responsible for the antigenic power of collagen

  kills in the telopeptide portion which constitutes a peripheral end of the molecule. As a result, a solubilized collagen containing substantially no telopeptide, solubilized and purified by subjecting the

  cow skin to enzymatic treatment and treatment.

  well known alkaline solution is preferable for achieving

  the purpose of the invention, but the first support is

  not limited to solubilized collagen. We will make ourselves easily

  It is important to remember that gelatin (including its

  decomposition and derivatives) which is the product of denatu-

  Collagen is also applicable to the

implementation of the invention.

  The required qualities of the second support are as described above, and among the materials

  having the required qualities, ceramics

  special metals and synthetic resins

  are known to be excellent as a material

  res causing no reaction to foreign substances.

  res in the living body and have an affinity

  with the living body and a great resistance

  mechanical. Of the above-mentioned materials, ceramics having excellent affinity for the living body are listed in Table I. According to the first embodiment of the invention (corresponding to Embodiments 1

  and 3 described below), an example is given in the

  which the osteoforming factor is mixed with the first

  first embodiment of the invention (corresponding to embodiments 2 and 4 described hereinafter), an example is given in which the second support is impregnated with

  the mixture above and supported by him.

Table I

  Properties.Resistan-: Density Resistance to) the physical: this to the: Hardness: apparent: chemicals) (flexion: ques, H) (Type of (kg / cm2) ::: 95% liquid) (boiling material (ceramics :: :: mg / cm2 / day)

(:: :)

(:::) ......

  () Ceramic material: 3200: 1000-: 3.6 -: 0.1) Alumina type: 2000: 4.0

(A1203) :( H V):

  ----- ----- ----- ----- --- - ---- ----- -! - ---- ------- I

(: :::;

  (Sapphire (Al 2 O 3): 7000: 2300: 3.97: 0.1)

( (H V)

(.)

(::: :)

  (Zircon oxide 10000: 1250 5.9 0.8 (nium:: (H V): :)

(: :: :)

  (Silicon carbide 5000: 94: 2.2 -: 0.04) (cium (ZrO (HRA) 3.1 rO 2) (-)

  - - - - - - --- - - - - ------ .. -------- -------------

  (Silicon nitride: 5000 87-91 2.9 - 0.42 f (cium (Si3N4) (HRA): 3.3

(: ... ....: -:

  f) (Calcium phosphate: 1400: ---: 3.0 -: Soluble in)

3 (P02)

  ## STR2 ## (## STR2 ## (## STR2 ##) diffulsibly dissolves in (: :: a bae) (: Hydroxyapatite 600-400 - 3.06-: Come Above (Calo (PO4) 6 (OH): 2000: 600 3.13 :)

(::: :)

  (Ceramic glass 1500 - 600 - about Cmmoe above) ("containing 1700 700 3.5 (apatite) ::: :) t ....% Among the ceramic materials indicated in the Table 1, alumina is the most common material and it has no harmful effect on the living body and has a great affinity with it.The materials having affinity and high mechanical resistance are sapphire and Other materials, such as calcium phosphate and hydroxyapatite which are substantially similar to living body bone, have a fairly low mechanical strength, but are characterized by their excellent properties.

  of assimilability and adhesiveness to the body bone Vi

  efore. Therefore, we use among the materials

  ceramics mentioned above those which are

  according to their site of use and the goals

  which they are intended. As for the properties of the ceramic materials, those suitable for their respective applications are dense type or porous type usable. The minimum quantity required

  osteoformative factor in the biomaterial of the invention

  differs according to the degree of purification of the factor

  osteoformator, and for the factors obtained by the

  given in accordance with the literature mentioned in

  Memory, bone formation is possible with a collagen ratio: factor = 100: 0.5 (ratio in

  weight), but to increase and ensure the effect of

  bone ratio, it is desirable to choose a ratio of collagen to osteoformer factor in the range of 100: 1 - 10 (weight ratio), but there is no

  instead of limiting the ratio in this range.

  We give, below, a description of forms

embodiment of the invention.

Example 1

  After cleaning and purifying the skin layer of a young cow's skin, it is cut into small pieces with a chopper. A solution of hydrochloric acid is added to the dermal layer thus chopped so as to modify the solution in

  bringing its pH to 3. We add to the solution thus

  dify pepsin at a rate of 2% of the dry weight and the solution thus obtained is treated at 20 C for OS 48 hours. The solution is filtered and caustic soda is added to the filtered solution to bring its pH to 10 in order to deactivate the pepsin. The pH of the solution is then brought to 7, and the deposits formed are collected from the solution and washed well with water.

  then they are dissolved again in an acid solution.

  Hydrochloric acid pH 3. The solution is filtered and added more caustic soda to the solution which is modified by bringing its pH to 7. The deposits formed from the modified solution are collected and washed with water. and then dissolved again in a hydrochloric acid solution of pH 3 to obtain a

  purified collagen has a concentration of 3.0 mg / ml.

  An osteoformer factor is then dissolved

  purified by the process described in the literature.

  above-mentioned amount in normal 0.01 hydrochloric acid to prepare a solution with a concentration of 1.0 mg / ml. 0.2 ml of the solution is poured into a

  test tube, 1.0 ml of the solution of col-

  lagene and mix well. The mixture is lyophilized and then sterilized with gaseous ethylene oxide

to obtain a biomaterial.

  The biomaterial is transplanted into the

  of a mouse and, after three weeks,

  derives the grafted biomaterial to find that

  has been replaced by 20 mg wet weight of

bone tissue.

Example 2

  We dive a square body made of hydro-

  xyapatite and having 5 mm side, but all four

  missing corners and a thickness of 2 mm, and a

  40%, or a record made of ceramic material

  alumina type in 1.2 ml of the mixed solution.

  of the collagen and osteoformer factor described in Example 1 and treated in a vacuum to allow the mixed solution to penetrate well into the ceramic body, then the body is subjected to lyophilization and

  gas sterilization to form a grafted biomaterial

  iron. The biomaterial thus obtained is grafted into the mus-

  dorsal key of a mouse and, after three weeks,

  we remove the grafted material to see the growth

  bone tissue on the surface of the second

  Harbor. In this case, the result obtained using hydroxyapatite was substantially the same as

  obtained by using the ceramic material of the aluminum type

mine.

Example 3

  The gel is dissolved in purified water.

  tine (viscosity: 4.4 mPa.s; gel strength: 253 degrees Bloom; pH: 5.8; moisture: 11.0%), obtained by subjecting a cow bone in the form of a material to normal treatment to lime, to obtain a

  gelatin solution with a concentration of 50 mg / ml.

  0.2 ml of the chlorinated solution is mixed well

  The osteoformer factor hydrate described in Example 1 with 1.0 ml of the gelatin solution was allowed to stand in a refrigerator for about 16 hours for the mixed solution to form a gel. The gelled material is immersed in 100 ml of a buffer solution.

  phosphoric acid (pH 7.2) containing 0.1% aldehyde

  glutatic hyde at 5 C for 16 hours and is

  puts in linkage processing. We then remove the

  gelled and washed with purified water, then subjected to lyophilization and sterilization

  gas to obtain a biomaterial to graft.

  Biomaterial is grafted into the back muscle

  of a mouse to obtain substantially the results of

as in Example 1.

Example 4

  The body consisting of hydroxyapatite or ceramic material of the alumina type used in Example 2 is immersed in 1.2 ml of mixed factor solution.

  osteoformator and gelatin obtained from the same

  than in Example 3 and treated under vacuum for

  that the mixed solution penetrates well into the body by

  ceramics, then let stand under refrigeration

  about 16 hours for the gelatin to

  held in the ceramic body forms a gel. The gelled material containing the ceramic body is treated in the same manner as in Example 3 with a phosphoric acid buffer solution containing glutaraldehyde, washed with water and subjected to lyophilization and freeze-drying. gas sterilization to obtain a biomaterial

  to graft. The biomaterial thus obtained provides the same

  my results than that of Example 2.

  As can be seen from the forms of

  tion of the invention described above, it has been

  only in osteogenic artificial biomateria

  trainer of the invention, the biological function of the

  The osteoformer factor is very small, as

  specificity of species. Judging from the embodiments, the invention is very effective in the clinical sphere of orthopedic surgery and

  oral and maxillary surgery.

  In Examples 2 and 4, the forms of

  in which the second medium is

  and supported by the mixed solution of the first

  port and osteoformer factor have been described as an example, but instead of impregnating and supporting the mixed solution, the mixture can be

  simply attached to the second support. The fixed state is

  it in which the mixture is attached to the surface of the second support, while the state impregnated and supported

  is the one in which the mixture is fixed not only

  on the surface, but also at each corner of the interior of the second support and, consequently, the

  difference between the two is simply a difference

  about the importance of bone formation.

  It goes without saying that the invention is not limited

  to the embodiments described and that it is capable of various variants without departing from its scope.

Claims (18)

  1. An artificial osteoformative biomaterial, characterized in that it comprises a mixture of osteoforming factor and a first support for said factor, said support being chosen between the   collagen, its derivatives and denaturing products.   2. Artificial osteoformative biomaterial   characterized in that it comprises a mixture of   an osteoformator and a first support for said factor, said support being chosen between collagen,   its derivatives and denaturing products, and a se-   cond support for said mixture, said support consisting of a body shaped ceramic material, metal or synthetic resin, said mixture being fixed   second support, or impregnated and supported by him.   3. Artificial osteotyping biomaterial according to claim 1 or 2, characterized in that   said osteoforming factor is an osteoforming factor   isolated and purified from Dunn osteosarcoma or isolated and purified human osteoform   from a human osteosarcoma.   4. Artificial osteotyping biomaterial according to claim 1 or 2, characterized in that   said mixture of the first carrier and the osteogenic factor   trainer consists of a mixed solution of respective liquids containing said carrier and said osteoformer factor. - 5. Artificial osteoforming biomaterial according to claim 4, characterized in that said first support is in the form of a solution, in hydrochloric acid, of collagen or gelatin and the osteoforming factor is in the form of a solution,   in hydrochloric acid, said osteoformal factor human   6. Artificial osteotyping biomaterial according to claim 1, characterized in that said mixture of the first support and the osteoformer factor   is a freeze-dried mixture derived from a mixed liquid   by respective liquids containing said first support and said factor.   7. Artificial osteoforming biomaterial according to claim 1, characterized in that said mixture of the first carrier and the osteoformer factor is a gelled substance derived from a mixed liquid consisting of respective liquids containing said support and said factor.   8. Artificial osteoforming biomaterial according to claim 2, characterized in that said second support is a shaped body of hydroxyapatite   and ceramic material of the alumina type.   9. Artificial osteotyping biomaterial according to claim 8, characterized in that said mixture of the first support and the osteoform factor   is impregnated in and supported by said second support.   10. Artificial osteotyping biomaterial according to claim 9, characterized in that said   mixed liquid impregnated in and supported by said   The carrier is formed into a gel and lyophilized.   11. A method of manufacturing an artificial osteoforming biomaterial, characterized in that it comprises the steps of mixing a liquid   containing a first support for an osteofor factor   meter with a liquid containing the osteofor factor   said first medium being selected from   collagen, its derivatives and denaturing products.   12. The method of claim 11, wherein   characterized in that it comprises the steps of causing a mixed liquid containing a first support for an osteoformer factor and a liquid containing said osteoforming factor to be fixed at   or impregnated and supported by a second support   formed of a body shaped of a ceramic material,   a metal or a synthetic resin, said first   port being chosen between collagone, drvs - and its denaturing products.   13. A method of manufacturing an artificial osteoforming biomaterial according to claim 12, characterized in that said first support is in the form of a solution in hydrochloric acid of collagen or an aqueous solution of gelatin and said liquid containing the osteoformator factor is an isolated human osteoformer factor solution   and purified from human osteosarcoma.   14. A method of manufacturing an artificial osteoforming biomaterial according to claim 12 or 13, characterized in that said second support is hydroxyapatite or a ceramic material. alumina type.   15. A method of manufacturing an artificial osteoforming biomaterial according to claim 11 or 13, characterized in that it further comprises the lyophilization step of a mixed liquid containing   said first support and said osteoformer factor.   16. A method of manufacturing an artificial osteoforming biomaterial according to claim 11 or 13, characterized in that it further comprises a   gel forming step of said mixed liquid   holding said first support and said osteofor factor sumer.   17. A method of manufacturing an artificial osteoforming biomaterial according to claim 12 or 13, characterized in that it further consists in gelling and lyophilizing a mixed liquid containing the   first support impregnated in and supported by said cond support.   18. A method of manufacturing an osteoforming artificial biomaterial according to any one of   claims 15 to 17, characterized in that   finally includes a step of sterilization by means of of ethylene oxide gas.