DE102018007375A1 - Hydroxyapatite pectin-based two-component bone augmentation material - Google Patents

Abstract

An unsintered synthetic high-purity hydroxyapatite (HA) with a particle size <200 nm is stabilized by a pectin, preferably with a low degree of esterification, so that a clinically usable bone building material is produced.

Description

Technical field

Medicine technology / regenerative medicine / bone building

Known state of the art

In addition to bone transplantation, a variety of biological and synthetic bone replacement materials are available for the therapy of bone defects. Calcium phosphates dominate the synthetic materials, especially hydroxyapatite and ß-tricalcium phosphate and their combinations. The conventional hydroxyapatite (HA) is sintered in its production and is not or extremely slowly broken down. It is therefore only a pure bone replacement material. It is not optimally suited for the treatment of bony defects because it is still detected in the body after years.
Therefore, ß-tricalcium phosphate (ßTCP) has been introduced to the clinic as an alternative to hydroxyapatite. This material goes into solution at a physiological pH and, in theory, disappears from the bone defect. The disappearance (dissolution) of the ßTCP takes place via an inflammatory inflammation by macrophages. The calcium and phosphate ions introduced are excreted via the kidney and are therefore not incorporated into the defect. Because of this unphysiological (non-normal) degradation path of the biomaterial, the rate of degradation cannot be predicted with certainty. Therefore, the ßTCP is also not ideal for the treatment of bone defects. Mixing HA with ß-tricalcium phosphate appeared to be a solution to the problem. However, the clinical results of this combination were also unsatisfactory. Sun et al. (1997) even reported an inhibition of osteoblast growth by the addition of β-tricalcium phosphate.
A new approach was the introduction of unsintered nonostructured hydroxyapatite xerogels (Gerber DE0019825419 , Tanner DE 000010338634 ). This material is available under the brand name Nanobone® and is biodegraded (broken down). The breakdown occurs through osteoclasts (bone breakdown cells). Since an osteoclast is “connected” to an osteoblast (bone-forming cell), the breakdown of the biomaterial takes place at the same rate in which new bones are formed (Henkel et al. 2005; Götz et al. 2008).

This solves the problems of conventional calcium phosphates such as hydroxylapatite and ßTCP.
Due to the fixation of the individual HA particles in the nanometer range with silicon oxide, this material (Nanobone®) is available as granules. Due to its powdery consistency, this material is not securely localized and is flushed out when it is used in the oral cavity or in the maxillary sinus and then leads to failure. The stabilization of high-purity nanostructured HA in a saturated aqueous solution, as an alternative to silicon oxide, also does not lead to a secure fixation in the bone defect in the oral cavity. Schneider (2009) shows, however, that unsintered HA with a particle size in the nanometer range leads to a safe ossification of bone defects of critical size if this material can be safely introduced in the bone defect.
The development of a method for the safe stabilization of nanostructured unsintered HA particles is therefore of particular importance.

Invention to solve the problem for which protection claims are sought

These problems are solved with the features listed in the claims 1-7.
The chelate reaction between the pectin and the calcium atoms in the hydroxyapatite during the production of the novel bone building material, for which protection is sought, creates a highly porous HA pectin unit (HAP unit). The porosity is over 80%. The HAP units are characterized by a structure of interconnecting pores ( ). These pores can be varied by the specific choice of the production conditions, such as the ratio of hydroxyapatite to pectin. They are in the nanometer range (nanopores), in the lower micrometer range (micropores) and macropores in the upper micrometer to millimeter range ( ).
Due to capillary suction, the nanopores passively absorb the tissue fluid from the implant site and allow, via van der Waal's forces, the attachment of proteins to the unsintered HA particles (Götz et al. 2008). This creates an osteoinductive property of the novel bone augmentation material that was first demonstrated for Nanobone® (Bienengräber et al. 2008). At the same time, there is a cytotactic stimulus for the osteoclasts. The osteoclasts reach the unsintered HA via the micropores and biodegradate it. The micropores are therefore responsible for the osteoconduction of the innovative biomaterial. By linking the osteoclasts to the osteoblasts

Petrini et al. ( EP 2 593 149 B1 ) also stabilized hydroxyapatite with pectin. However, they let the hydroxyapatite precipitate out of calcium and phosphate directly in the pectin solution.

In the process for which the claim for protection is sought with this application, sterile aqua destilata is added to a dry powder mixture of HA and pectin. A dough-like bone build-up material is created, which is then sterile added to the bone defect. The separately manufactured hydroxylapatite particles have a length of <200nm. The pectin used preferably has a low degree of esterification and is preferably apple pectin. However, other types of pectin, such as citrus pectin etc., are also possible, but alternatively, agar is also possible. The mixing ratio is in the ratio of 50 vol% HA to 50 vol% pectin to 95 vol% HA to 5 vol% pectin, preferably from 80 vol% HA to 20 vol% pectin to 90 vol% HA to 10 vol% pectin.
The mixing ratio of HAP powder to water is 4 parts to 1 part, preferably 1 part to 1 part.
The combination with other additives is possible depending on the clinical application.

The pectin is bioinert ( ) and only serves to stabilize the unsintered HA with its particle size of <200 nm. Ultimately, this results in a clinically easy-to-process bone building material that remains stable in the defect.
When adjusting the size of the HAP units, care must be taken that the fibrillogenesis is not disturbed. Since this leads to an additional stabilization of the
introduced new biomaterial leads in the bone defect. Heinemann ( EP 2600911 ) writes that fibrillogenesis does not occur when the collagen template length is less than 500 nm. Therefore the length of the HAP units is greater than 500nm.

Industrial applicability

The invention is of interest to companies that manufacture bone substitute materials and bone cements. This invention is also of interest to companies that produce implants, such as artificial hip joints or dental implants.
It is easy to implement: the manufacturing process has been described above.

• Bee diggers V, Lenz S, Kirchhoff M, Henkel K-O A novel osteoinductive bone grafting substitute? CMF.Impl.Dir. 2008: 36-39
• Tanner T DE 000010338634
• Tanner T DE0019825419
• Götz W, Gerber T, Michel B, Lossdörfer S, Henkel K-O, Heinemann F Immunohistochemical characterization of nanocrystalline hydroxyapatite silica gel (Nanobone®) osteogenesis: a study on biopsies from human jaws Clin.Oral Impl.JRes. 2008; 19: 1016-1026
• Heinemann S EP 2600911
• Henkel K-O, Gerber T, Dörfling P, Gundlach KKH, Bienengräber V Repair of bone defects by applying biomaterices with and without autologous osteoblasts Journal of Cranio-Maxillofacial Surgery 2005; 33: 45-49
• Petrini et al. EP 2 593 149 B1
• Clerk S In vivo long-term testing of the bone augmentation materials NanoBone® and Ostim® in the reossification of mandibular defects Med Diss A Rostock 2009
• Sun JS, Tsuang YH, Liao CJ, Liu HC, Hang YS, Lin FH. The effects of calcium phosphate particles on the growth of osteoblasts. J Biomed Mater Res 1997; 37 (3): 324-334

QUOTES INCLUDE IN THE DESCRIPTION

This list of documents listed by the applicant has been generated automatically and is only included for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• DE 0019825419 [0001, 0007]
• DE 000010338634 [0001, 0007]
• EP 2593149 B1 [0004, 0007]
• EP 2600911 [0006, 0007]

Claims (10)

The invention is characterized by the following features An unsintered synthetic high-purity hydroxyapatite (HA) with a particle size <200 nm is stabilized by a pectin, preferably with a low degree of esterification, so that a clinically usable bone building material is produced. The hydroxyapatite is combined with the pectin by a chelation reaction. In the course of the production, a powder mixture of hydroxyapatite (HA) and pectin (P) in a ratio of 50% by volume to 50% by volume to 95% by volume to 5% by volume, preferably from 80% by volume HA to 20% by volume Pe to 90% by volume HA to 10% by volume pectin . Water, preferably sterile and distilled, is then added to this dry HA pectin powder. The mixing ratio of HAP powder to water is 4 parts to 1 part, preferably 1 part to 1 part. A porridge-like “paste” is created, which is then introduced into the defect. The invention shows a high proportion of interconnecting pores. These pores have a structure. The nanopores are in the nanometer range, the micropores in the micrometer range and the macropores in the millimeter range. Apple pectin is preferably used. However, other pectins are also possible. Alternatively, agar can be used instead of pectin. The unsintered hydroxylapatite pectin units stimulate the bone structure at the rate at which the bone is broken down. It is not growth-inhibiting. The addition of proteins to the surface of the hydroxyapatite-pectin units also makes the bone-building material osteoinductive. The new bone augmentation material is delivered as a combination of HAP powder and sterile aqua. It is mixed extra corporally and then sterile with a dough-like consistency into the defect. The novel bone augmentation material described in the above claims is used for the reconstruction of bone defects and for the attachment of endoprostheses, e.g. artificial hip joints, used. It is also possible to glue fractures or pieces of bone that are not mechanically stressed.

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