Title of the Invention

Bioimplant Elements

TECHNICAL FIELD

The present invention concerns bioimplant elements to be used for life support or treatment in case of illness or accidents. That is, it is related to an element which is located at the connection between inside and outside a body to externally provide liquid medicine through a catheter, etc., a bioimplant element which is totally implanted in vivo to provide an injection port for injecting medicine deep inside the body, or a bioimplant element which is to replace or supplement damaged parts of hard structures such as bones.

BACK GROUND ART

Recent progress of research on implant materials has been remarkable. New materials have been developed not only for artificial organs but also for plastic surgery and artificial teeth, etc. Among these materials, hydroxyapatite which is known for its high biological activity and its unique property to integrate with bones has attracted attention. Consequently,

various inventions concerning implant materials which are based on this materials have been published. In Tokkai Hei 3 (1991) - 186272, an element to be used in a bone was disclosed, which is obtained by coating ceramics such as alumina and zirconia _r or pure titanium or titanium alloys with a calcium phosphate material such as hydroxyapatite.

In Tokko Hei 2 (1990) - 13580, a technique was disclosed, in which bioterminals made of sintered hydroxyapatite are used at the connection between inside and outside of a body for externally picking up information in vivo. In addition, in Jikko Hei 3 (1991) - 19884, a technique concerning bioterminals of hydroxyapatite made from animal bones was also published.

In Tokkai Hei 3 (1991) - 32676, a technique concerning compounds of zirconia or alumina and hydroxyapatite was published. It is to increase the strength of hydroxyapatite which had prevented its practical use.

Various methods for obtaining hydroxyapatite were also published. Among them are: the sintering process in Tokko Hei 2 (1990) - 13580; the plasma spray process for metallic implant materials in Tokko Sho 58 (1983) -

50737; the plasma jet process for ceramic core materials in Tokko Sho 59 (1984) - 46911, Tokkai Sho 62 (1987) - 34539, Tokkai Sho 62 (1987) -57548, Tokkai Sho 63 (1988) - 46165 and others; the sputtering process in Tokkai Sho 58 (1983) 109049; the flame jet process in the Proceedings of the Japan Ceramics Society 1988 1st Fall Symposium, Preprint, pp. 401-402; and the glass frit baking process in the Proceedings of the 9th Conference of Biomaterials Society (Preprint, 1987, p.6).

In addition, the electrophoresis process was published in the Japan Ceramics Society, 1988, pp. 417- 418.

The processes to precipitate hydroxyapatite from an artificial body fluid composed of the some ion type and concentration as human blood plasma were published in Tokko Sho 61 (1986) - 10939, Tokko Hei 1 (1989) - 54290 and Tokkai Hei 2 (1990) - 25515.

As described above, various bioimplant elements, specifically, bioimplant elements coated with bioactive apatite and their preparation processes have been published. Nevertheless, there remain many problems resolved, some of which are described in A - F below.

(A) The plasma jet process requires sophisticated and expensive equipment, does not readily produce fine

coating and forms coating of apatite which is different from the apatite in the biological body because the source material hydroxyapatite, is once melted at high temperatures.

(B) The sputtering process requires sophiscated and expensive equipment and forms coating of apatite which is different from the appatite in vivo because the source material, hydroxyapatite, is once melted at high temperatures.

(C) The sintering and glass frit processes require heat treatments at temperatures 850 C or above and therefore can be applied only to base materials with high heat resistance and form coating of apatite which is different from the apatite in vivo because the source material, hydroxyapatite, once receives treatment at high temperatures. Also, terminals made from the sintered material are subjected to severe restrictions on the structure and shape because of the low strength of hydroxyapatite.

(D) The electrophoresis process can be applied only to metallic base materials with good electrical conductivity because it uses the base material itself as electrodes and also forms coating of apatite which is different from the apatite in vivo because it uses

crystal apatite as the source material.

(E) The precipitation process from an artificial body fluid has a weakness that no base material other than CaO/SiO- base glass, which provide a good bonding with hydroxy apatite generated, have been found.

(F) As a method to resolve some of the problems described above, it has been known that epoch-making implant elements can be obtained by coating organic polymers with hydroxyapatite having similar composition to that in living body. However, because the difficulties to obtain sufficient bonding strength between hydroxyapatite and organic polymers have not been resolved, the method could not be implemented in practice.

The present invention is the result of the concentrated efforts by its inventor to resolve the various problems described above, more specifically, the problem in (F) . It is intended to provide bioimplant elements of organic polymer base which have excellent biological compatibility, sufficient strength and design flexibility.

DISCLOSURE OF INVENTION

The bioimplant element pertaining to the present invention features hydroxyapatite coating formed on the surface of the base material in a practically saturated or supersaturated water solution of hydroxyapatite, more preferably in an artificial body fluid with the same ion type and concentration as the human blood plasma, where the base material is selected from polymers containing esters in the principal or/and side chains or polymers containing hydroxyl group in the side chains or/and at the end of the chain.

More specific characteristics of the said bioimplant element include the following.

a. The desirable thickness of hydroxyapatite is in the range of 3 - IOOIUI

b. The effective organic polymer containing esters in the principal chain can be selected from among allyl resi _r oxybenzoyl polyester, polyacrylate, polybutylene terephthalate, polycarbonate or polyethylene terephthalate.

c. The effective organic polymer containing esters in the side chains can be selected from among AAS resin (acrylic ester-acrylonirile-stylrene copolymer) , cellulosic plastics such as cellulose acetate,

cellulose butyrate and ethylene cellulose, ethylene- acrylic ester copolymer, acrylic ester-butadien-styrene copolymer, methacrylic resin, or vinyl acetate resin.

d. The desirable organic polymer containing hydroxyl group in the side chains or/and at the end of the chain can be selected from epoxy resin, phenol resin, or polyvinyl alcohol.

e. Nonspecular surface of the base material is particularly effective.

f. A part of phosphate group or hydroxyl group in hydroxyapatite has been substituted by carbonic group.

g. It is desirable that more than 80% of CaO/SiO_ base glass powder has grain diameters in the range of 100 - 600 urn .

In the present invention, an organic polymer for the base material of the bioimplant element must be selected from polymers containing esters in the principal chain or/and the side chains or polymers containing hydroxyl group in the side chains or/and at the end of the chain in order to obtain sufficient bonding strength with hydroxyapatite for practical use.

The organic polymer containing esters in the principal chain can be selected from among allyl resin, oxybenzoyl polyester, polyacrylate, polybutylene terephthalate, polycarbonate or polyethylene terephthalate. However, other polymers may be used satisfactorily for the purpose of the present invention as long as sufficient esters are contained in the principal chain.

The organic polymer containing esters in the side chains can be selected from among AAS resin (acrylic ester-acrylonitrile-styrene copolymer) , cellulosic plastics such as cellulose acetate, cellulose butyrate and ethylene cellulose, ethylene-vinylacetate-vinyl chloride copolymer, ethylene-vinyl chloride copolymer, methacrylic resin, or vinyl acetate resin. However, other polymers may be used satisfactorily for the purpose the present invention as long as sufficient esters are contained in the side chains.

The organic polymer containing hydroxyl group in the side chains or/and at the end of the chain can be selected from epoxy resin, phenol resin or polyvinyl alcohol, however, other organic polymers may be satisfactorily used for the purpose of the present invention as long as sufficient hydroxyl group is contained in the side chains or/and at the end of the

chain .

In the case of polyvinyl alcohol, it must be in the partially bridged form so that it is insoluble in water. Otherwise its function as a bioimplant element cannot be achieved.

The desirable thickness of hydroxyapatite coating is in the range of 3-100z-m. When the thickness of coating is below 3,um it may possibly be eroded and eliminated while implanted in a living body. When it exceeds 100 zzm, strains caused by the differences in expansion coefficients between the base material and hydroxyapatite against temperature and humidity changes tend to be excessive and as a consequence the hydroxyapatite coating becomes more susceptible to cracking and subsequent separation which develops from such cracks. In addition, for example, the increased time to formation of such thick coating of hydroxyapatite inflates the manufacturing costs, making the thickner coating unpracticable.

The preferable hydroxyapatite is that with a part of its phosphate or hydroxyl group substituted by carbonic group, because in such form it is closer to hydroxyapatite in a living body and has better biological compatibility.

The Ca0/Si0 base glass powder refers to the glass powder which contains CaO and i0 ₂ in the following ranges.

CaO 20 - 60 mol%

Si0 ₂ 40 - 80 mol%

and more than 70 mol% CaO and Si0 ₂ combined and more than 80% of powder having grain diameters in the range of 100 - 600izm. The composition of Ca0/Si0„ base glass is published in Tokkai Hei 2 (1990) - 25515.

The preferred grain diameter of the glass powder is in the range of 100 - 600um. If it is below 100 xim, it is too small for sufficient amount of saturated or supersaturated water solution .of hydroxyapatite to be supplied between glass grains and the base material and the growth of the hydroxyapatite coating does not occur or is too slow to be practicable. If, on the other hand, it exceeds 600um, sufficient nuclei for growth are not formed on the surface of the base material and therefore the growth is too slow or the surface becomes nonuniform, making it unpracticable. In addition, it is desirable that more than 80% of the glass powder has grain diameters in the range of 100 - 600 xtm. If it is below 80%, the increase in grains having diameters not in the range of 100 - 600 m retards the growth of

hydroxyapatite or totally prevents its growth.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1. Configuration of the bioimplant element used in embodiments of the present invention.

Fig. 2. Schematic of first process of hydroxyapatite coating in the present invention.

Fig. 3. Schematic of second process of hydroxyapatite coating in the present invention.

Fig. 4. An implant device assembled using the bioimplant element of the present invention.

Fig. 5. Illustration of the bioimplant element in Fig. 4 implanted in a living body.

Legend

1 top adapter

2 bottom adapter

3 flange

4, 4a vessel

5 glass powder

6 Solution (1)

7 Solution (2)

8, 8a, 8b vents

11 implant element

EMBODIMENTS

The CaO/SiO- base glass used in the present invention was prepared from the compound of glass materials shown in the left column below. The composition of the glass obtained is shown in the right column.

Compound of Glass materials

CaCo ₃ 28.431 g

MgO 2.289 g β - Ca ₂ P ₂ 0 ₇ 14.517 g

CaF ₂ 0.249 g

Si0 ₂ 17.015 g

Composition of Glass mol% CaO 49.87

Si0 ₂ 35.46

P ₂ 0 ₅ 7.153

MgO 7.111

CaF, 0.399

The uniformly mixed fine powder obtained from the compound of glass materials shown above using a mortar was melted for 2 hours at 145°C in a platinum crucible. It was rapidly quenched on a steel plate and then

milled in a ballmill. This was then shifted to prepare several glass powders classified in Table 1. These 4 glass samples were used in the evaluation.

TABLE

Glass Glass Glass Glass A B C D

Proportion of powder with grain diameter 50% 75% 82% 95% within 100 - 600 urn

The practically saturated or supersaturated water solutions of hydroxyapatite with the compositions shown below were prepared and their pH at 36.5°C were adjusted to be 7.4 by controlling the contents of hydrochloric acid.

Compositions in 1 Water Solutions

Solution (1) Solution (2)

NaCl 7.996 g 11.994 g

NaHC0 ₃ 0.350 g 0.535 g

KC1 0.244 g 0.336 g

K ₂ HP0 ₄ 3H ₂ 0 0.228 g 0.342 g

MgCl ₂ 6H ₂ 0 0.305 g 0.458 g

CaCl ₂ 0.278 g 0.417 g

Na ₂ S0 ₄ 0.071 g 0.107 g

INHC1 Approx. 45 ml Approx. 68 ml

Tri (hydroxylmethyl) aminomethane ...... 6.057 g 8.086 g

The bioimplant elements in the present invention is explained using Figure 1, which shows the configuration of the implant element called a skin button, and Figures 2 and 3, which are schematics of the process of hydroxyapatite coating on the surface of the implant element. In Figure 1, 11 is the implant element made of polyethersulfon (ICI Co. brand name: PES4100G) ,

1 is the top adapter, 2 is the bottom adapter which is connected to the flange 3 of the top adapter 1 and connects the vents 8 and 8a via the vent 8b. In Figures

2 and 3, 4 and 4a are the vessel, 5 is the glass powder described above, 6 is Solution(l) , and 7 is Solution (2).

Implant a part of the implant element 11 shown in Figure 1 in the glass powder 5 of Glass D and immersed it in Solution (1) 6. After leaving it in the thermostatic chamber at 36.5 for 1 week, take out the implant element 11 and immerse it in Solution (2)

7. After leaving it in the thermostatic chamber at 36.5°C for 1 week, take out the implant element 11 and clean it with distilled water and dry it at 60°C. Through this procedure, hydroxyapatites coating (not shown in the figure) of the present invention similar to bones is formed on the surface of the implant element 11 which is in contact with the glass powder 5, as shown in Figure 1.

Total 22 samples consisting of 11 embodiments and 11 references were prepared through the procedure described above. Two elements were prepared for each sample condition and one was used for breaking test and the other was implanted in a grown dog to evaluate biological compatibility. The following three characteristics, A - C, were evaluated.

A. Measurements of Hydroxyapatite Coating

A part of the flange of the said implant element was cut off and a slit was made on undamaged part of the coating with a knife. Then the thickness of hydroxyapatite at the cut by a scanning electron microscope tilting the sample by 50 to the direction of electron beam. The results obtained after calibrating for this angle are presented in the following tables.

B. Bonding Strength between Base Material and

Hydroxyapatite Coating

A part of the flange of the said implant element was cut off and a cellophane tape (adhesive tape ) was put on undamaged part of coating. The bonding strength was evaluated by observing whether separation of the hydroxyapatite coating occurs when the tape was peeled off.

C. Biological Compatibility

The implant device shown in Figure 4 was assembled using the said implant element which was not used in the breaking test. The device sterilized with ethylene oxide gas was implanted in the breast of a grown dog, as shown Figure 5. The biological compatibility was evaluated observing the conditions after 1 day, 3 days, 1 week, 2 weeks, 3 weeks and 1 month. To facilitate the sensitive evaluation of the biological compatibility, the implant device was partially implanted in the body. The evaluation was made by observing the conditions at the interface between the skin surface and the implant device. In Figures 4 and 5, the upper type 12 is connected to the vent 8 of the implant element 11 and the lower tube 13 is connected to the vent 8a by the tightening thread 14. At the end of the upper tube 12, a uer adapter 17 and an intermittent infusion plug 18 are attached and fixed with a clamp 19. The bottom adapter 2 including the flange 3 the implant element 11

is implanted under the skin, namely is inside the body and the end of the lower tube 13 is connected to the inserted catheter 16 via the connector 15 and extended to the prescribed organ (not shown) in the body.

In the following, the results of the evaluation are explained for Embodiments 1 - 3, Embodiment 4 and Embodiment 5 - 10 in comparison with the reference samples.

Embodiments 1 - 3 :

In Embodiments 1 - 3, it is shown that the implant elements base on the present invention can be bonded to hydroxyapatite coating with more than adequate strength for practical use and have excellent biological compatibility. The embodiments were prepared varying the base material and the glass, as presented in Table 2 along with the results of evaluation. The base materials used in the reference samples are polystyrene, polypropylene, Teflon, ABS resin, polyvinyl chloride resin, polyurethane resin and nylon. The specifications of References 1 - 10 and the results of evaluation are presented in Table 3.

Polymethyl methacrylate base material in Reference 1 was the same as that in Table 7 of Embodiment 2 in Tokkai Hei 2 (1990) - 25515, but Ca0/Si0 ₂ base glass

sheets with the same composition as the glass powder were immersed in Solution (1) at intervals of 0.5 mm.

Polyethylene base material in Reference 2 was prepared in the same conditions as those in Table 7 of Embodiment 2 in Tokkai Hei 2 (1990) - 25515. Ca0/Si0 ₂ base glass sheets were immersed in Solution (1) at intervals of 0.5mm along with the base material.

Polyethylene base material in Reference 3 was prepared in the same conditions as those in Table 7 of Embodiment 2 in Tokkai Hei 2(1990) - 25515, which was immersed in Solution (1) along with the same Ca0/Si0 ₂ base glass powder as that used in Embodiment 1. The surfaces of all base materials were made rough using #150 sand paper.

TABLE 2

The bioimplant elements in Embodiment 2 were prepared in the following procedure. The injection molded bioimplant elements made of Denkastyrol MW in the same shape as those in Embodiment 1 were dipped twice in the solution described below, cooled at -5 C and gelled by crystallizing- polyvinyl alcohol. The samples were then annealed in silicone oil to be coated with a transparent hydro gel containing less than 20% water. The bioimplant elements thus prepared were then coated with hydroxyapatite in the same procedure as in Embodiment 1.

99.5 mol% saponified polyvinyl alcohol manufactured by Kurashiki Rayon was desolved in a mixed solvent of 30% water and 70% dimethylformamid. The polyvinyl alcohol solution with 10% concentration was thus prepared.

TABLE

The downgrowth shown in Tables 2 and 3 refers to the phenomenon that the skin sinks around the interface with the implant element when their biological compatibility is poor. The biological compatibility is judged to be better when there is less downgrowth. It is believed that, when the biological compatibility is good, the resistance of the organism against external infectants does not decrease and that therefore the infection does not readily develop.

Considering the results collectively, it is regarded as an epoch-making success that no infection occurred for the implant elements in these embodiments of the present invention even after disinfection was discontinued.

Brand names and manufactures of organic polymers used in Embodiments 1 - 3 and References 1 - 10 are listed below.

Brand Name Manufacturer

PBT1401 Toyo Rayon

Polyethylene

Terephthalate Toyo Rayon

*Dankastyrol MW Denki Kagaku Kogyo

*Delpet 60N Asahi Kasei

*Neozex 45150 Mitsui Sekiyu Kagaku

*Dialex HF-77 Mitsubishi Monsanto *Noble EBG Mitsui Toatsu PTFE Tetrafluoropolyethylene (scientific name)

*Styrac 101 Asahi Kasei

SR - 1158 Riken Vinyl Kogyo (Medical use grades)

EG65D *Thermedics Co..

*Diamid 1901 *Huhls Co..

(* indicates transliteration)

Embodiment 4:

In Embodiment 4, it is demonstrated that it is desirable for more than 80% of the glass powder to have grain diameters in the range of 100 - 600 urn.

Polyethersulfon was used for the base material and, except for changing the glass powder samples A - C, the conditions were the same as those in Embodiment 1. The results of evaluation are presented in Table 4.

TABLE 4

The results in Table 4 demonstrate that more than 80% of glass powder must have grain diameters in the range of 100 - 600 urn .

Embodiments 5 - 10:

Embodiments 5 - 10 were prepared by changing only the duration of immersion of the implant elements in Solution (2) to obtain different thicknesses of hydroxyapatite coating. Other conditions were the same as those in Embodiment 1. The specifications of the embodiments and the results of evaluation are present in Table 5.

TABLE 5

It was observed that, after 3 weeks, hydroxyapatite coating had disappeared from the sample in Embodiment 5, and that, after 1 month, it had partially disappeared from the sample in Embodiment 10.

Embodiment 11:

In Embodiment 11, the implant base material made of polyethylene terephthalate (manufactured by Tokyo Rayon in the shape of a circular cylinder with a radius 8mm and a height 15mm was coated with 14mm thick hydroxyapatite in a manner similar to that in Embodiment 1. This element was implanted in a thighbone of a rabbit. It was removed after 10 weeks and the bonding conditions between the implant element and the bone were examined. It was observed that living tissue was totally united with the implant element. This material,

2 with its bonding strength exceeding 800kg/cm and elongation to rupture over 100%, is far superior to other material such as bioglass and sintered hydroxyapatite, and can provide light weight implant elements with excellent biological compatibility.

The implant elements of the present invention were described above using various embodiments. It has been well known that hydroxyapatite exhibits excellent biological compatibility. Nevertheless, because of its

low strength, its use for implant elements in the form of the sintered hydroxyapatite has been limited to the parts not subjected to large loads. While metallic base materials or processes of coating ceramics have been developed to overcome this difficulty, they have not been used for general purpoose implant elements because the materials are expensive or have poor moldability. Naturally it is ideal to coat organic polymers, which have much better moldability and are less expensive than other materials, with hydroxyapatite. However, this has not been practicable because the bonding strength with hydroxyapatite has not been sufficient.

In the embodiments, it was demonstrated that "bioimplant elements made of organic polymer materials coated with hydroxyapatite" having sufficient bonding strength for practical use and excellent performance were obtained successfully.

INDUSTRIAL APPLICABILITY

As described above, the present invention creates bioimplant elements with bone-like hydroxyapatite coating on the surface of organic polymer base materials containing esters in the principal chain or/and the side chains or hydroxyl group in the side chains or/and at the end of the chain using practically saturated or supersaturated water solution of hydroxyapaties. The bioimplant elements thus obtained have excellent

biological compatibility, sufficient strength and design flexibility, and its significant contributions to medical field are expected.