Biocompatibility testing of a silicone maxillofacial elastomer: Soft tissue study in primates

prosthetic

John F. Wolfaardt, BDS, MDent, PhD,a Peter Cleaton-Jones, BDS, MBBCh, PhD, DA, DTM&H,b John Lownie, BDS, HDipDent, MDent,C and Gail Ackermann, BDS, MDentd Faculty of Dentistry, University of Alberta, Alberta, Canada, and MRC/Dental Research Institute and Faculty of Dentistry, University of Witwatersrand, Johannesburg, South Africa Little information exists on the biocompatibility of maxillofacial prosthetic materia.ls. Cosmesil material is a purpose-designed facial prosthetic elastomer that has an established clinical profile in humans but results of biocompatibility testing have not been published. Cosmesil, acrylic resin (positive control), black surgical gutta-percha (negative control), and Silastic 382 material (Dow Corning, Midland, Mich.) (reference control) were processed as custom-designed implants. The implants were inserted into five chacma baboons for a la-week period in intraosseous, subperiosteal, submucosal, and intramuscular sites. The histologic assessment was based on a modified form of the FDI-IS0 Technical Report 7405 for subcutaneous implants. An evaluation was made of capsule formation and inflammatory response. The statistical analysis involved a three-way ANOVA and a Tukey-Kramer Student range test. The critical level of statistical significance chosen was p < 0.05. The study found that gutta-percha provoked a statistically significatly thicker capsule and a severe inflammatory response. Acrylic resin, Cosmesil material, and Silastic 382 material produced capsule formations and an inflammatory response that did not differ significantly. Cosmesil material is not manufactured as an implant material, but from the present findings it is considered acceptably biocompatible for its intended use where there may be contact with internal tissue spaces that are contiguous to external surfaces. (J PROSTHET DENT 1992;68:331-8.)

B.

locompatibility testing of a biomaterial is an essential step towards the acceptance of the materia1.l It is remarkable how little information exists on the biocompatibility of maxillofacial prosthetic materials that are used to construct facial prostheses. This lack of information is all the more surprising since these materials may have contact with intratissue spaces via compromised tissue surfaces. A wide variety of materials have been developed for constructing facial prostheses. 2-5 Several investigators have described the ideal properties of this group of dental materials, and biocompatibility is always included.6, 7 Silicone elastomers remain the most widely used materials for facial prosthesis construction.8 A review of the available litera-

aProfessor and Chairman, Division of Removable Prosthodontics, Department of Restorative Dentistry, Faculty of Dentistry, University of Alberta. bProfessor and Head, Department of Experimental Odontology, University of the Witwatersrand and Director, MRC/University of the Witwatersrand Dental Research Institute, Johannesburg. cProfessor and Head, Division of Maxillofacial and Oral Surgery, Department of Surgery, University of the Witwatersrand. dSenior Dentist, Department of Oral Pathology, University of the Witwatersrand. 10/l/37848

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ture reveals that little work on the biocompatibility of maxillofacial prosthetic materials has been conducted. Hensten-Pettersen and Hulterstr6mg comment on this fact in a study that they conducted on in vitro cytotoxicity of four room temperature vulcanizing (RTV)-silicone elastomers used for maxillofacial prostheses. Silicone implantation has been routinely carried out in reconstructive genitourinary, orthopedic, neurologic, cardiothoracic, and maxillofacial surgery. lo Complications that have been reported include infection, loosening, breakage, foreign body giant cell reactions, detritic synovitis, and lymphadenopathy.ll Mandibular resorption from silicone chin implants12 and the failure of silicone implants in the head and neck region have also been reported.13a l4 There is no universal agreement on the most appropriate method for biocompatibility testing.15 The U.S. Pharmacopeia, Federation Dentaire Internationale (FDI), American Standards for Testing and Materials, and the British Standards Institution all provide implantation tests for biocompatibility evaluation. Only the FDI standard attempts to correlate a description of the tissue reaction to the implant with what is an acceptable or unacceptable reaction.15 Cosmesil material (Cosmedica, UWIST, Cardiff, Wales) is a more recently introduced, purpose-designed maxillo-

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WOLFAARDT

Table II. Mean type and site

capsule width

in millimeters

ET AL

by implant

Material

Site

Subperiosteal

Acrylic

No. Mean

SD Submucosal

No. Mean

SD Fig.

1. Two-part

mold used to produce

the implants.

Intramuscular

No. Mean

SD Table

I.

Processing

of materials

in the stainless

steel

*Only

Cosmesil

Guttapereha

Silastic 382

4 0.69 0.44

3 0.62 0.49

4 1.11 0.45

4 0.58 0.23

5 0.26 0.17

5 0.17 0.05

5 0.90 0.46

5 0.13 0.05

5

5

0.13 0.02

0.27 0.08

2 0.81 0.33

2 0.13 -*

one specimen showed inflammation.

mold Implant material

Processing procedure

Processing time

Sterilization procedure

Cutta-percha

Water bath 65’ C

1 hour in mold

Ethylene oxide cycle

Cosmesil

9 drops crosslinker M, 4 drops catalyst 4D to 5.0 gm base

24 hours in mold

Autoclave

Silastic 382

120’

C for

15 min

2 drops catalyst 6 hours M to 10 gm base in mold

Autoclave 120”

C for

15 min Acrylic resin

3:l Powder/ liquid ratio

6 hours delay, 6 hours

Autoclave 120” C for 15 min

boil

facial elastomer.i6 While a sound clinical profile has been developed over the past 9 years for the use of Cosmesil material in humans, results of biocompatibility testing of the material have not been published. This present study subjects Cosmesil material to soft tissue biocompatibility testing in primates.

MATERIAL Preparation

.AND METHODS of the implant materials

Four materials were tested. Black surgical gutta-percha (Associated Dental Products, Purton, Swindon, England) served as the negative control and clear heat-cured acrylic denture base resin served as the positive control (Stellon-C, DeTrey, Weybridge, Surrey, England). Silastic 382 silicone elastomer material (Dow Corning, Midland, Mich.) was marketed as an implantable silicone elastomer and this material was used as a reference control. Cosmesil silicone elastomer material was the experimental substance. The 332

same lot and batches of each material were used to produce the implants. A two-part stainless steel mold was constructed to produce implants of the desired geometry (Fig. 1). The implants were made as disks 10 mm in diameter and 2 mm in thickness with rounded edges (Fig. 2). The silicone materials were processed in the mold according to the manufacturers’ instructions (Table I). The gutta-percha was immersed in a water bath at 65’ C for 5 minutes and was then introduced to the mold. The heat-cured acrylic resin was mixed in a powder-liquid ratio of 3:l by volume and was then introduced into the mold when in the doughy stage. In all cases the mold was closed until the two sections were in proper contact. The mold was left in this position until processing was complete. All implants were produced in the same mold so that geometry and surface texture would be maintained throughout. The implants were recovered from the mold and the flash was removed with a fine stone rotary instrument. The implants were rinsed in 90% ethyl alcohol for 5 minutes and were then sterilized. Acrylic resin, Cosmesil, and Silastic 382 implants were autoclaved at 120° C for 15 minutes. The gutta-percha implants were subjected to ethylene oxide sterilization using a conventional cycle. The implants were then stored ready for implantation.

The animal

model

The animal model chosen was the adult chacma baboon (Papio ursinus). The animals were housed in squeeze back cages in the Central Animal Service of the University of Witwatersrand where they were fed a standard balanced laboratory diet and were provided with water ad libitum. Before we embarked on the study, the protocol was approved by the University’s Animal Ethics Committee (Clearance 86/76). Subperiosteal, intraosseous, submucosal, and intramuscular implantation sites were chosen, all four being potenAUGUST

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TOP VIEW PROFILE VIEW 2

X 1 m m Radius

L Fig. 2. Geometry

of the implants.

Fig. 3. Sites of implantation, tial sites of contact (Fig. 3).

Surgical

for maxillofacial

prosthetic

materials

procedure

Five baboons were immobilized in their squeeze back cages with intramuscular ketamine 10 (mg/kg Ketalar, Parke-Davis Laboratories, Johannesburg, South Africa). They were then anesthetized with intravenous pentobarbital sodium (Sagatal, MayBaker (SA), Johannesburg, South Africa) and an endotracheal tube was inserted to maintain a patent airway. The submandibular area was shaved, swabbed with aqueous Hibitane chlorhexidine gluconate 4 % wt/vol (ICI Joharmesberg Transvaal Republic of South Africa) and draped with sterile towels. The lower border of the mandible in the premolar and molar regions was exposed bilaterally via a vertical midline skin incision. With a specially THE

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manufactured bur turning at 12,000 rpm with an adequate water coolant, recipient cavities slightly larger than the implants were prepared on the inferior aspect of the mandible below the apexes of the mandibular teeth. Five such cavities were prepared in each mandible and randomly selected implants were placed in four of the five cavities. The fifth cavity was left as a sham cavity. The bony responses are still under investigation and will be reported elsewhere. Five subperiosteal implant locations were created by periosteal elevation on the buccal surface of the mandible. Again, implants were randomly selected and placed into four cavities with the fifth remaining as a sham cavity. Implant cavities were placed into the substance of masseter muscles bilaterally, one at its origin, one at the insertion, and unilaterally one in between, thereby providing four implant locations and one sham site. The submandibular incision was closed in layers and fi-

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WOLFAARDT

-

0.8

z E .!d -0

0.6

s cu 2

0.4

0 0

ET AL

0.2

0 Subperiosteal

Submucosal

Intramuscular

Site of Inflammation Fig.

4. Mean

capsule width.

Fig. 6. Thicker capsule with a severe inflammatory response to gutta-percha adjacent to the implant and lymphoid follicles further away from the cavity. (Hematoxylin and eosin stain; original magnification ~76.)

each were created via intraoral incisions 1 cm in length. The pockets were created in the cheek and in the regions of the second premolars and canines, with a sham location prepared in the midline of the lower lip. After an implant had been placed in each pocket, two interrupted sutures were placed in each incision using 3-O chromium-treated catgut suture material. In each animal 16 randomly selected implants and four sham locations were placed. Thus each animal had one implant of each material type and a sham location in all four tissue locations.

Histologic

Fig. 5. Thin tory response (Hematoxylin x195.)

capsule with a mild, diffuse inflammato an intramuscular Cosmesil implant. and eosin stain; original magnification

nal skin closure was achieved by interrupted sutures. The submucosal locations selected for placement of the implants were the cheek and lower lip areas of the mandible. Submucosal pockets large enough to contain one implant

334

methods

Twelve weeks after operation, the baboons were immobilized as before and were then killed with an intravenous overdose of pentobarbital sodium. Blocks of tissue containing the implants were excised and coded. The excised tissue blocks were split down the midline and the implant was gently removed. One side was processed and embedded in wax from which 7 pm sections were cut. Five sections were mounted per glass slide; every fifth slide was stained with hematoxylin and eosin and every sixth was stained with Masson’s trichrome. For the histologic assessment, three examiners (JFW, PCJ, GA) agreed on criteria and examined the sections simultaneously using a Nikon Optiphot microscope (Nippon

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Table III,

OF ELASTOMERS

General Linear Model table for all four implant materials Source

Capsule

Degrees freedom

Type 1 sum of squares

X site

Materials Baboons X materials Site X materials Density of inflammation Model Error Corrected total Baboons Site Baboons X site Materials Baboons X materials Site X materials

34

6.3791

0.1876

11

1.1999

0.1091

45 4 2 7 3 12 6

7.5791 0.2993

34 14 48 4 2 7 3

12 6

0.3732 3.1937 0.7720 0.1751

11414839.6 3193859.1

228132.8

14608698.8 2384747.0 274047.2 960283.0 2137774.6 3822406.7 1835581.3

596186.8 137023.6 137183.3 712591.5 318533.9 305930.2

RESULTS

p Value

1.72

1.17

0.69 7.18 0.49 9.76 0.59 0.27

0.62

1.47

0.22

2.61 0.60 0.60 3.12 1.40 1.34

0.08 0.56 0.75 0.06 0.27 0.30

335730.6

0.01 0.82 0.002 0.81 0.94

IV. Tukey-Kramer Student range (HSD) test for variable capsulewidth

Table

Material comparison

Gutta-perchaAcrylic Gutta-perchaCosmesil Gutta-perchaSilastic 382 Acrylic-Guttapercha Acrylic-Cosmesil Acrylic-Silastic 382 Cosmesil-Guttapercha Cosmesil-Acrylic Cosmesil-Silastic

Simultaneous lower confidence limit 0.3196

-0.8944 -0.2232 -0.2416

Difference between means

Simultaneous upper confidence limit

0.6070

0.8944*

0.6512

0.9432*

0.6620

0.9810*

-0.6070 0.0442 0.0550

-0.3196” 0.3116 0.3516

-0.6512

-0.3592*

-0.3116 -0.2903

-0.0442 0.0108

0.2232 0.3118

-0.9810

-0.6620

382

The meancapsulewidth in millimeters waslisted by implant type (Table II), and this thickness wascontrasted in bar chart form (Fig. 4). The shamoperation siteshealedby primary intention without inflammation cluded in the statistical analysis. Recause eration sites will be the subject of a later not included in the statistical analysis.

and were not inthe osseous opreport, they are

At all sites the fibrous tissuecapsulewasthickest around the gutta-percha implants, and the thickness for all implants was greatest in the subperiosteal site. The three-way analysis of variance

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0.0748 0.7830 0.0533 1.0646 0.0643 0.0292

1.5659

Kogaku KK, Tokyo, Japan) with a multiteaching head (MTH-5). All observationswere madein a blinded manner, the specimen coding being broken only at the end of assessment.Capsule width was measured using a calibrated graticule with a linear scale(linear ocular graticule, 150 divisions; Reichert, Vienna, Austria) in a Univar researchmicroscope (Reichert). Density of inflammation was determined using an 0.22 x 0.11 mm graticule at a magnification of 100power over the densestconcentration of inflammatory cells seenaround each implant. The Statistical Analysis System 18 (1985 version) was used and, because of 11 missing values, the resulting unbalanced designwas analyzed with the General Linear Models17procedure using a fixed effects model, including main effects and a two-factor interaction. In none of the analyseswere any statistically significant interaction effects found. A Tukey-Kramer Student range test wasalso applied. The critical level of statistical significancechosen wasp < 0.05.

THE

Mean squares

width

Model Error Corrected total Baboons Site Baboons

of

OF PROSTHETIC

DENTISTRY

Silastic 382.Guttapercha Silastic 382Acrylic Silastic 382Cosmesil

-0.3516 -0.3118

-0.3430* 0.2416

-0.0108

Note: This test controls the type 1 experiment error. confidence interval = 0.95; Width rate: (Y level = 0.05; MSE = 0.0670758; critical value of Student range = 3.791. *Significant at p < 0.05.

df = 40;

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Fig. 7. Moderate, localized area of inflammation in the fibrous capsule adjacent to a gutta-percha implant. (Hematoxylin and eosin stain; original magnification ~122.)

Table V. Tukey-Kramer variable implant site Implant comparison

site

SubperiostealSubmucosal SubperiostealIntramuscular SubmucosalSubperiosteal SubmucosalIntramuscular Intramuscularsubperiosteal Intramuscularsubmucosal

Student

Simultaneous lower confidence limit

range (HSD)

Difference between means

test for

Simultaneous upper confidence limit

0.1535

0.3781

0.6027*

0.2304

0.4777

0.7249*

-0.6027

-0.1250

-0.3781

0.0996

-0.7249

-0.4777

-0.3242

-0.0996

-0.1535* 0.3242 -0.2304* 0.1250

Note: This test controls the type 1 experiment error. Width rate: a level = 0.05; confidence interval = 0.95; MSE = 0.0670758; critical value of Student range = 3.791. *Significant at p < 0.05.

df = 40;

(ANOVA) using the General Linear Models procedure (Table III) showed highly significant differences in capsule width for material (F = 9.76, p = 0.002) and implant site (F = 7.18, p = O.Ol), but no statistical significance between animal variation (F = 0.69, p = 0.62). No statistically significant diirerences in inflammation density were found for 336

ET AL

Fig. 8. The inflammatory response consisted mostly of lymphocytes and histiocytes as shown below this guttapercha implant. (Hematoxylin and eosin stain; original magnification X300.)

material (F = 3.12, p = 0.06), implant site (F = 0.06, p = 0.56), orbetween-animalvariation (F = 2.61,~ = 0.08). No statistically significant interactions were found. The Tukey-Kramer Student range test (p < 0.05) was then used to compare the capsule widths between each of the implant materials (Table IV). Gutta-percha produced a significantly thicker capsule than each of the other three implants. Acrylic resin, Cosmesil, and Silastic 382 capsule widths did not differ significantly from each other. Subperiosteal capsule thickness was significantly greater than that of the other two sites, which in turn did not differ significantly from each other (Table V). All the implants were surrounded by a fibrous tissue capsule, which in most cases was cellular and mature (Fig. 5). The number of baboons from which an implant was recovered was listed for each of the material-location combinations tested (Table VI). The type, pattern, and amount of inflammation varied, but there was a tendency for mild to moderate inflammation around the acrylic resin, Cosmesil, and Silastic 382 implants, and moderate to severe inflammation around the gutta-percha implants (Figs. 5 to 7). The inflammation was usually diffuse through the entire capsule and in most it consisted of a mixture of lymphocytes, histiocytes, and eosinophils (Fig. S), indicating that the response was probably allergic and probably cellmediated. Only in the subperiosteal site was inflammation frequent within the implant cavity. Giant cells were rare and necrosis was not noted with any of the materials. The AUGUST

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Table

VI.

OF ELASTOMERS

Details

of tissue responses

by implant

material

and site Implant

material

Acrylic P

Site M

Cosmcsil I

P

Site M

Gutta-percha

Site

I

P

M

2

2

4

3

2

1

Silastic I

P

382

Site

M

I

3

2

Number* Response Capsule

fibrous

tissue

Cellular/mature Acellular/hyaline Immature Inflammation-amount

None Mild Moderate Severe

1 3 2

2

2

1

1

3

1

Inflammation-type

Focal Diffuse

3

3

1

1

1

1

2

2

3

1

3

3

2 3

3

1 3

2

Inflammation--pattern

LymphocytesJhistiocytes Lymphocytes/histiocytes/ eosinophils Lymphocytes/neutrophils Inflammation in implant cavity Giant cells present P, Subperiosteal; M, submucos’~; *Number of animals from which

1

The FDI-IS0 standard subcutaneous implant t&l7 was selected as the basis from which to develop the present study, since it was the only standard that offered a correlation between tissue reaction and product acceptability. The standard was deviated from in terms of implant construction and design. William@ draws attention to the importance of implant geometry and surface texture. It was considered unacceptable to use the poly(tetrafluoroethylene) tube technique of the FDI-IS0 standard. Moreover, the standard was designed for use in guinea pigs and the implant sizes were too small for use in large primates. The standard also allows for subcutaneous testing only. Williams15 considers that intramuscular testing is more valid in longer term testing and employs 5 mm diameter, 2 mm thick disks for implantation in rats. Therefore 10 mm OF PROSTHETIC

Table VII. Mean density square millimeter

1

DENTISTRY

of inflammatory

cells per

Material

Site

Subperiosteal

Submucosal

DISCUSSION

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I, intramuscular. implant was recovered.

variation in the degree of inflammation between the same implant material may be attributable to individual baboon sensitivity. Fisher’s exact probability test was used to examine for significant differences in type, pattern, and amount of inflammation using 2 X 2 tables for combinations of material and for implant site. No statistically significant differences were found. The mean density of cells per square millimeter is listed in Table VII and shown in Fig. 9. There was no clear pattern with respect to both implant material and implant site.

THE

2

1

Intramuscular

Acrylic

Guttapercha

Cosmesil

Silastic 382

No. Mean SD

173

978

878

714

171

933

669

554

No. Mean SD

463

340

1198

653

551

367

442

519

No. Mean SD

446

711

421

440

3

4

5

4

5

5

4

5

5

5

2 1198 58

2 186 263

diameter, 2 mm thick disks were used for implantation into large primates. This design geometry was believed to be satisfactory, since the implants were placed in intraosseous, subperiosteal, submucosal, and intramuscular sites. In accordance with the FDI-IS0 standard, it was decided to kill the animals at 12 weeks. Because of the complexity and cost of working with a primate animal model, the 2-week observation period was eliminated. The FDI-IS0 technique of 337

WOLFAARDT

0 a

ET AL

tomer material were found to provoke capsule formation and an inflammatory response that was not significantly different statistically. In terms of the screening process offered by the modified application of the FDI-IS0 standard for subcutaneous implant tests applied in the present study, Cosmesil material was found to have acceptable biocompatibility. Cosmesil material is not manufactured as an implantable material and carries a manufacturer’s warning to that effect. In the light of the current study, Cosmesil elastomer material was considered to be acceptably biocompatible for its intended purpose and for contact with internal tissue spaces where these occur in contiguity with external applications.

Gutta Percha Silastic 382

We thank Mrs. Hazel Ball, Mrs. Pat Tremaine, and Lori Auld for their expert word processing and Miss Marguerite de Beer for histologic preparation.

Subperiosteal

Submucosal

Intramuscular

Site of Inflammation Fig.

9. Mean density

of inflammatory

cells (cells/mm2).

grading inflammation was used and, in addition, it was concluded that many other parameters including inflammation density and capsule thickness require quantification. Black surgical gutta-percha was selected as a control irritant, and it is clear from the thickness of capsule formation and the inflammatory cell response that this material is not suitable for implantation. Of interest is that subperiosteal capsule thickness was significantly thicker for all materials but that the other two sites did not differ significantly from one another. Acrylic resin, Cosmesil material, and Silastic 382 material were not found to be significantly different in terms of capsule formation. In our opinion, the fibrous tissue capsule seen around specimens must be expected around all synthetic materials such as those investigated. It was thus concluded that the amount of inflammation present is of greater importance in determining the acceptability of a material. The finding that a mild to moderate inflammatory response occurred around acrylic resin, Cosmesil, and Silastic 382 materials would indicate that Cosmesil material is of similar biocompatibility to the two other materials.

CONCLUSIONS The FDI-IS0 technique of grading inflammation, together with other parameters such as capsule thickness and inflammation density, were used to evaluate the materials. The results of the study indicated that inflammatory response and not capsule thickness is the indicator of greater significance in evaluating biocompatibility. Guttapercha functioned well as a control irritant. Acrylic resin, Cosmesil silicone elastomer material, and Silastic 382 elas-

338

REFERENCES 1. Jones D. The future of biomaterials. Can Dent Assoc J 1988;54:163-73. 2. Conroy BF. The historyoffacialprostheses. ClinPlast Surg 1983;10:689707. 3. Gonzalez JB. Polyurethane for facial prostheses. J PROSTHET DENT 1978;39:179-87. 4. Lewis DH, Castleberry DJ. An assessment of recent advances in external maxillofacial materials. J PROSTHET DENT 1980;43:426-32. 5. Moore DJ, Glaser ZR, Linebaugh MG. Evaluation of polymeric materials for maxillofacial prosthetics. J PROSTHET DENT 1977;38:319-26. 6. Rahn AO, Boucher LJ. Maxillofacial prosthetics-principles and concepts. 1st ed. Philadelphia: WB Saunders, 1970:1-5. 7. Schaff NG. Materials in maxillofacial prosthetics. Dent Clin North Am 1975;19:347-56. 8. Beumer J, Zlotow I. Restoration of facial defects. In: Beumer J, Curtis TA, Firtell DN, eds. Maxillofacial rehabilitation. Chapter 8. St. Louis: CV Mosby, 1979:31?-71. 9. Hensten-Pettersen A, HulterstrBm A. Assessment of in vitro cytotoxicity of four RTV-silicone elastomers used for maxillofacial prostheses. Acta Odontol Stand 1980;38:163-7. 10. Williams DF. Biocompatibility of clinical implant materials. Vol. II. Boca Raton: CRC Press, 1981:89-92. 11. Dolwick MF, Aufdemorte TB. Silicone-induced foreign body reaction and lymphadenopathy after temporomandibular joint arthroplasty. Oral Surg Oral Med Oral Pathol 1985;59:449-52. 12. Peled IJ, Wexler MR, Ticher S, Lax EE. Mandibular resorption from silicone chin implants in children. J Oral Maxillofac Surg 1986;44:346-8. 13. Saer MR. Complications in treatment of a mandibular defect with a Silastic implant. J Oral Surg 1978;36:616-7. 14. Ridley MT, Jones RS. Failure of Silastic chin implant four years postoperatively. J Oral Surg 1978;36:616-7. 15. Williams DF. Techniques of biocompatibility testing. Vol. 1. Boca Raton: CRC Press, 1986:84. 16. Wolfaardt JF, Chandler HD, Smith BA. Mechanical properties of a new facial prosthetic material. J PROSTHET DENT 1985;53:228-34. 17. Statistical Analysis System. Version 5 ed. Cary, NC: SAS Institute Inc., 1985. 18. Biological evaluation of dental material-subcutaneous implant tests. Technical Report 7405. London: Federation Dentaire InternationaleInternational Organization for Standardization. 198435-6. Reprint requests to: DR. JOHN F. WOLFAARDT 4036 DENTISTRY/PHARMACY FACULTY OF DENTISTRY UNIVERSITE’ OF ALBERTA EDMONTON, ALBERTA T6G 2N8 CANADA

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