DE19805673C2 - Process and kit for making bone replacement and augmentation material - Google Patents

Description

The invention relates to a method for producing an Application site to one. Bone replacement and augmentation mate rial hardening material mixture and an associated kit for the production.

The biocompatible manufactured according to the invention Bone replacement material can be used as a filling material Bone defects in periodontology and for bone augmentation tion used in dental implantology. It is also used as a material for filling bone defects in used in surgery.  

The material you are looking for must be biologically compatible. H. in vivo no immunogenic or continued inflammatory response induce. Its physical structure must be infiltration of cells and there must be a resorption time in vivo that are suitable for this function. In addition, a such material be good initial mechanical stability sit. It would also be desirable that such a material in the application and modeling of the Be is easy to use.

For such a material there is surgery, in which Periodontology and dental implantology a big one Desire. The previous techniques and materials have been removed which is complicated to use, or the material has - ge long-term - not the desired properties.

For bone regeneration in periodontology and bone new formation in dental implantology is in addition to the Use of membranes (GTR and GBR) or autologous bones Bone replacement material as a placeholder for new bone formation applied.

The membranes that prevent epithelial migration into the defect are without the additional use of bones or bone replacement materials often unable to ur originally created space up to complete bone rain to keep generation or new formation free, since the membranes do not have sufficient mechanical stability. Besides, that is Application of the membrane is a very complex technique and with a relatively high complication rate such as membrane exposure and Suture dehiscence afflicted.

A basic distinction is made between four different types of implantation materials for filling up bone defects (Kohal, R.-J., ZM 87 , No. 10, 1997, pp. 56-61). Autologous (autogenous) materials come from the same organism, homologous (allogeneic) materials are obtained from other individuals of the same species, heterologous (xenogeneic) materials come from individuals of a different species (for example: bovine bone). Alloplastic materials are synthetically manufactured materials (hydroxyapatite, bio glasses).

Autologous bone is the optimal material for filling Bone defects and for augmentation. An immunolo reaction is impossible. The car also has lied bones a certain osteogenetic potential. The Ver However, the use of autologous bone often reaches the limit the sufficient availability and is also problematic of a second intervention for the removal.

The allogeneic bone comes from individuals of the same species, but different genetic makeup. The alloge Bones are classified as demineralized or mineralized freeze-dried bones are offered. When using this Er is a transmission of infectious diseases not excluded. Furthermore, this can be genetically foreign Material may trigger local immune reactions.

Xenogenic materials are obtained, for example, from cattle bones (BioOss®, Biomaterialien Geistlich) or corals (Interpore 200 ®, Interpore International). These are calcium phosphate preparations because the bovine bone or coral are completely freed from all organic components. Disadvantages of these preparations are the lack of bone inductance and a very slow absorption (1 to 5 years).

The bone replacement materials are often used as shaped bodies provided, which can then be deformed by heat or ground and machined. This Ma materials enable precise prosthetic replicas conditions, however, unless an exact Form is required, the handling is far more complex than mo peelable materials. Such as shaped bodies or granules available bone substitute materials are, for example, be known from DE 196 14 421 A1, DE 42 19 321 A1, DE 41 20 325 A1 or DE 35 17 456 C2.  

Hydroxyla are found as alloplastic bone replacement materials patit and tricalcium phosphate application. Is hydroxyapatite not and tricalcium phosphate is only very slowly absorbable. Due to the insufficient biodegradability, one becomes full constant integration in the newly formed bones not he enough.

From US 54 25 769 A is already at the application site a bone replacement and augmentation material Known material that is previously soft to process and model is cash. It is a material made from collagenfa serum in a calcium sulfate matrix. The handling of this mate rials is not easy. In particular, it is not a good thing to mo dellieren. Because of the fibers, the material is initially, in liquid state, not really flowable. Once the out the direction of the fibers is disturbed, the arbitrary malleable speed, d. H. Modelability disturbed. At the end of the day Calcium sulfate tends to crumble. On the other Calcium sulphate is also important in terms of its absorption not optimal, especially since the absorbability cannot be influenced.

The invention is therefore based on the problem of a biological compatible material for bone augmentation and To provide restoration of bone defects that the infiltration of cells enables a good initial me has mechanical stability, simple, easy to use de can be applied and is easy to model.

To solve this problem, the invention is in a Ver drive the mixing of Füllpar articles made from collages or a biodegradable art fabric with a matrix-forming bio embedding the particles logically degradable mass made of fibrin glue or methyl cellulose or polymerizable organic materials, namely light curable or 2-component plastics of a flowable gene, soft processable mixture provided, the Mi then cures at the application site.  

This makes a biologically compatible bone replacement and Augmentation material provided as a composite consists of 2 parts. The first portion is a liquid ma trix-forming mass, which after mixing with the particles should harden. After curing, the mass has a shape stability, is biologically well tolerated and becomes absorbed by the surrounding tissue for a certain time. The second part of the composite consists of filling particles, each according to the degree of addition in the material the desired consi lend strength and improve shape stability. This one part is also absorbable.

A bone defect is filled in or closed with the material augmenting area built. After a certain time all of the material is absorbed, making room for newly formed bone that occupies the appropriate space.

By suitable selection of the particle size and the particle density The consistency during application can be in the matrix and optimized the mechanical stability after curing become. These values may vary depending on the application you want can be easily determined experimentally. The volume fraction of the Particles in the total mixture can be between 10 and Make up 70 vol .-%, preferably between 20 and 50 vol .-%. The particles are preferably smaller than 0.5 mm around the To ensure fluidity of the mixture during processing Afford. A mean diameter is more preferred Particles between 0.1 and 0.3 mm are provided.

Since the material produced with the method according to the invention al after the mixing process and before curing a liquid to pasty consistency, the viscosity of which is determined by the men The proportion of solid particles can be controlled, the material easily applied and modeled.

The solid, but bioabsorbable particles that the Composite greater strength and moldable consistency should be made out of collages. Collagen is the main protein of the bone. Purified collagen,  whose antigenic components (telopeptides) have been removed, has good biocompatibility. It will depend on the Her Notification procedure after 4 weeks at the earliest after 6 Months absorbed. Because of its microstructure, it is too well suited for the intake and protracted delivery of effective substances such as antibiotics or bone growth factors.

Alternatively, the filler particles could also consist of a different, most biologically compatible material or a biodegradable plastic. For example, the use of Polyglactin 910 (Vicryl®) would be possible for this purpose. Polyglactin is a copolymer consisting of glycolide and lactide. The material has so far proven itself in a wide variety of implant forms, for plates, screws, stents, nets, foils and sutures. The hydrolytic degradation of the substance begins after about 2 to 4 weeks. It is split into the body's own breakdown products (lactic acid) without leaving any residue. Foreign body contamination and immunological or infectious side effects must therefore be excluded.

The matrix-forming mass should be viscous at the time of application be liquid and harden later at the application site. As for this mass of suitable material comes for example fibrinkle About in question within the inventive method can be produced by mixing two components and which then cures to form a fibrin network. To the fibrin network shows sufficient tear when hardened stability and volume stability. It is biocompatible and through fibrinolysis completely degradable. It poses a bad thing ten breeding ground for bacteria, so that the application of Fi Brinkleber does not increase the risk of wound infection. The fibrin stars form guide rails for the sprouting of vascular material granulation tissue rich in fibroblasts.

Alternatively, a biodegradable could consist of 2 components polymerizable plastic can be used.

The use of 2 components is not mandatory, insofar as one too early curing of the curable mass reliably prevented  can be. For example, plastics would be considered here bar, which are stored in the dark and harden under the influence of light Another biologically compatible material for the matrix-forming mass could be methyl cellulose.

In a development of the invention it is provided that the materi al the particle and the material of the matrix-forming mass so be selected so that one of the two materials is clear biodegrades faster than the other.

Due to different absorption rates of matrix and particles form voids in the material, so that on the one hand osteoblasts in the material for new bone immigration, on the other hand during these bones the modeled form of the bone replacement measure terials is still preserved.

To achieve this, for example, in the event that the matrix-forming mass consists of fibrin glue, the Fi brine glue, preferably a fibrinolysis inhibitor, d. H. an anti fibrinolytic such. B. aprotinin, are added. The fi Brinolytic degradation of the solidified fibrin glue is shown here through delayed. By concentrating the Fi used Brinolysis inhibitors can achieve the optimal degradation rate can be set.

In a further development of the invention, the material of the parti kel or the matrix-forming mass before processing additional substances with pharmacological and / or bone ductive effect are added, such as. B. antibiotics or bone morphogenetic proteins (BMP), also known as bone morphogenetic proteins. By doing If the particles consist of collagen, it is advantageous adherent, these effective substances, such as antibiotics or kno growth factors to add to the collagen as it is due to its microstructure for receiving and protracted delivery of Active substances are well suited.

The method of the invention can also be used in Kombina tion with known membrane techniques, such as controlled tissue regeneration  (guided tissue regeneration (GTR)) or the ge guided bone regeneration (GBR) be used.

Furthermore, to achieve the object according to the invention, a kit is provided for producing a flowable, softly processable material mixture that hardens at the application site for a bone substitute and augmentation material, which comprises:

• - Filling particles from collagen or a biodegradable plastic
• - A polymerizable organic material, namely light curable or 2-component plastic, fibrin glue or methyl cellulose for embedding the particles of colla gene or a biodegradable plastic as well
• - An application unit for applying the material mix at the application site, consisting of:
• - An applicator for feeding the finished mixed material than to the application site
• - A mixing device upstream of the applicator for Mixing the particles with the matrix-forming mass,
• - Means for feeding the particles and the matrix-forming Bulk in the form of one or more components to the mix contraption.

Here, the application unit consists of an applicator for feeding the finished mixed material to the application sort, a mixing device upstream of the applicator for mixing the particles with the matrix-forming mass, and Means for supplying the particles and the matrix-forming mas se to the mixing device.

An advantage of the method according to the invention is that that the bone replacement and augmentation material in simple wise  can be prepared by mixing certain components. The kit according to the invention increases the manageability of the process rens in addition and enables the Ver drive under reproducible conditions with sufficient Si safety also in individual practices, for example dental Practices can be applied. For this, the application unit from a double syringe provided with a mixing tip stand. The components for the matrix-forming mass and the Particles can be placed in the syringe and stored. If the matrix-forming mass consists of a 2-component system exists, it is possible, for example, that a component for the matrix-forming mass in one syringe of the double syringe and the other component with the already mixed parts hold in the other syringe. During the spraying gangs mix when flowing through a Mixing cannula, so that after application of the curing process puts.

The advantages of the invention will become clearer from the drawing with FIGS. 1 to 3. It shows examples in dental periodontology and implantology without the application of the invention being restricted to this.

In the drawing shows

FIG. 1 shows the use according to the method Augmen obtained tationsmaterials in periodontal therapy;

Fig. 2 shows the use of the augmentation material in dental implantology

Fig. 3 shows an application unit for performing the method

Fig. 1 shows in longitudinal section under Figure A a bone cal 1 next to an incisor. The situation is shown after removal of the granulation tissue and the pocket epithelium and after the root planing. As shown under B, the defect heals without further measures in the sense of a repair without new bone formation. An epithelial attachment is formed ( 2 ). If, however, the defect is filled out as shown under C with the augmentation material ( 3 ) obtained by the procedure and the mucoperiosteal flap is fixed above it, as can be seen under E, there is a real regeneration of desmodont and bone ( 5 ). The course of regeneration according to the GTR method known in the prior art with the aid of a membrane ( 4 ) is shown comparatively in Figure D, this method also being intended to lead to a regeneration as shown under E.

Fig. 2 shows the use of the augmentation material in dental implantology. Figure A shows the case where several threads are exposed after an implant has been inserted due to insufficient bone availability ( 1 ). Filling the bone defect with the augmentation material ( 2 ) obtainable by the method and wound closure lead to the situation shown under B. This induces new bone formation in the augmentation area at position ( 3 ).

Fig. 3 shows an application unit for performing the method with a 2-component system. The ready-to-use application unit consists of a syringe 1 which contains a component of a matrix-forming mass, a syringe 2 which contains a second component for the matrix-binding mass and the particles, and a mixing cannula 4 in which all components are brought together. The syringes 1 and 2 are held together in a holder 3 .

The application unit works as already described above, is easy to handle and enables a sufficiently intense Mixing of the components at the time of application so that the bone substitute or augmentation material in situ Application site forms.

Of course, others are also within the scope of the invention Bone defect treatments possible. An application of the with the Process available material would come e.g. B. in splinter breaks in consideration or in casualty surgery to cement others Defects.  

Example of the use of a mixture of collagen particles and fibrin glue as bone substitute material for filling up a periodontal bone defect (subsequently submitted)

Material and method

On a 68-year-old patient, tooth 21 , which had a combined profound marginal and apical periodontitis, was treated with a material combination of fibrin glue as a liquid matrix with collagen filling particles. The patient was informed about the experimental nature of the procedure and agreed to try to save the tooth. The initial examination consisted in the production of an X-ray image using the parallel technique, elevation of pocket depth and gingival recession at 6 measuring points and the degree of loosening of teeth 21 and 221 . The patient received oral hygiene instructions and professional teeth cleaning and preparation. In addition, tooth 21 was trepanned two days before the procedure. After root canal preparation, a calxyl insert was made. Due to the strong loosening, composite splinting of the VMK crowns from 11 to 23 was carried out.

Materials were Tissucol®-Kit 0.5 from Immuno GmbH and the Bio-Gide® membrane used by Geistlich Kbiomaterialien. to next, two Bio-Gide® membranes were prepared by un the sterile cautery into small pieces with an edge length of approx. 1 mm were cut. The fibrin glue components Rissucol solution and thrombin solution were prepared according to the manufacturer's instructions and Store in a water bath at 37 ° C. It became the thrombin solution L (4I.E. throbin / ml) used which has a longer processing time time allows.

After an internal gingivectomy incision, a mucoperiosteal flap was created educated. All granulation tissue was removed from the bone removed defective, and the root surface carefully with Ultra sound and hand instruments cleaned and smoothed. Before on The root surface was brought in the bone substitute material conditioned with citric acid and rinsed with saline.  

The tissue solution was initially added to the collagen particles, then added the thrombin solution and mixed intensively. To when mixed, the material got a pasty consistency. It was easy to apply to the defect with a spatula and mo dellieren. A slight excess was modeled. To extensive solidification of the collagen-fibrin mixture was on Mucoperiosteal flaps made a periosteal slit to ensure tension-free reduction of the flap. Inter the flap was fixed with vertical mattress sutures. There was antibiotic coverage for 10 days with doxy cyclin. The patient was directed to the operating area to avoid oral hygiene, instead use CHX- Rinse solution. He was also on the wound area in which he Apply CHX gel once a day for a few days in the practice.

Results

In the initial examination, the labial recession was 22 3 mm on tooth 22 and 2 2 mm on tooth 21. Labial tooth 21 had a probing depth of 9 mm, distal like tooth 22 mesial 4 mm. The probing depth on the other surfaces was 3 mm. Tooth 21 showed a degree III loosening with strong vertical mobility, tooth 22 a degree II loosening.

Intraoperatively, tooth 21 showed a defect that extended to the root with a lateral extension to the mesi al and distal. Only the palatal part of the root was attached to the bone.

The surgical intervention went smoothly. One day postoperatively There was a fracture due to the composite splint the poor adhesion of the composite to the veneering ceramic.

5 days postoperatively, there was a suture dehiscence between 21 and and 22 because the patient had an interden contrary to the instruction valley cleaning. Despite exposing the kno infection, there was no infection, but inter dental to a secondary wound closure after 3 weeks.  

In the control examination after 4 months, the probe depth was between 3 mm labially on the 21 and 1 mm on the 22nd palatal, there was no change in the probe depth, since no material had been applied here. Due to the suture dehiscence, the recession on 21 labial and interdental between 21 and 22 had increased by 1 mm, so that the effective labial attachment gain was 5 mm on 21. The loosening of tooth 21 had decreased from grade III to grade II.

discussion

This first trial application of a material mixture of fibrin glue and collagen particles should show whether this material combination can be used as a bone replacement material. With tooth 21 , which was not considered to be worth preserving, an attachment gain of 5 mm was achieved with the help of this material in the labial area. The severely loosened tooth has consolidated so much that it now has a good prognosis. Early suture dehiscence on the fifth postoperative day prevented an even better result. However, it has led to the important finding that exposure does not result in infection or loss of this material.

Crucial advantages of such a material combination from egg a liquid matrix that hardens after application and in it embedded particles made of a solid material are part of the egg the ease of application and modeling of the Mate rials, secondly the material composite, which in addition to the important mechanical stability of the augmented area leads to that does not lose the material even after exposure what is the case with bone substitute materials in granular form would be. Furthermore, the dense surface of the material fulfills as and its firm attachment to the root surface of a bar barrier function, which is effective in ingrowth of epithelial cells prevented so that the additional use of a membrane is not appears to be necessary. During the mucoperio flap adheres poorly or not at all to a membrane as a base, but is easy to move, and therefore only a very careful one  Seam technique a permanent, safe wound closure guaranteed, there was good adhesion between the mucope rio flaps and augmentation material.

For routine clinical use it is possible to use the Mate rial in an application system in the form of a dop pelspritze with a mixing device so that the material with this application system directly in and on the bone defect can be filled and only a slight remodeling is required.

Claims (13)

1. A method for producing a material mixture that hardens at the application site to form a bone substitute and augmentation material, characterized in that the method comprises mixing filler particles made of collagen or a biodegradable plastic with a biodegradable mass of fibrin glue or methyl cellulose or polymer embedding the particles sizable organic materials, namely light-curable or two-component plastics, to form a flowable, softly processable mixture, and that the mixture is then cured at the application site. 2. The method according to claim 1, characterized in that the volume fraction of the Particles in the total mixture 10 to 70%, preferably between 20 and 50% is. 3. The method according to claim 1 or 2, characterized in that the particles egg have an average diameter of less than 0.5 mm, preferably between 0.1 and 0.3 mm. 4. The method according to any one of claims 1 to 3, characterized in that the Particles consist of purified collagen freed from telopeptides.   5. The method according to any one of claims 1 to 4, characterized in that the matrix-forming mass from at least two liquid-storable components Mixing is available. 6. The method according to any one of claims 1 to 5, characterized in that the Material of the particles and the material of the matrix-forming mass selected in this way be that one of the two materials biodegrades significantly faster is than the other. 7. The method according to claim 6, characterized in that the matrix-forming Mass consists of fibrin glue, preferably with a fibrinolysis inhibitor will. 8. The method according to any one of claims 1 to 7, characterized in that the Additional material of the particles or the matrix-forming mass before processing che substances with pharmacological and / or bone inductive effect beige will give. 9. The method according to claim 8, characterized in that antibiotics or kno Chen morphogenetic proteins (BMP) are added. 10. The method according to any one of claims 1 to 9, characterized in that it in combination with membrane techniques, especially controlled tissue regeneration tion (guided tissue regeneration = GTR) or controlled bone regeneration (guided bone regeneration = GBR) is used. 11. Kit for producing a flowable, softly processable material mixture that hardens at the application site to a bone replacement and augmentation material, which comprises:
Filling particles made of collagen or a biodegradable plastic
a polymerizable organic material, namely light-curable or 2-component plastic, fibrin glue or methyl cellulose for embedding the particles of collagen or a biodegradable plastic and
an application unit for applying the material mixture at the application site, consisting of:
an applicator for feeding the finished mixed material to the application site
a mixing device upstream of the applicator for mixing the particles with the matrix-forming mass,
Means for supplying the particles and the matrix form the mass in the form of one or more components to the mixing device. 12. Kit according to claim 11, characterized in that the application unit there is a double syringe with a mixing tip. 13. Kit according to claim 12, characterized in that the starting materials, d. H. the filling particles and the components for the matrix-forming mass in the fuel zen available.