J. BIOMED. MATER. RES.

VOL. 10, PP. 857-865 (1976)

In vivo Tissue Reactivity of Radiation-Cured Silicone Rubber Implants* GEORGE H. GIE’FORD, JIt., Children’s Hospital Medical Centw, Boston, Massachusetts, EDWARD W. MERRILL, Massachusetts Institute of Technology, Cambridge, Massachusetts, and MICHAEL S. MORGAN, Department of Environment and Health, University of Washington at Seattle, Seattle, Washington

Summary Silicone rubber implants are clinically used in large numbers and elicit a mild tissue reaction. An occasional patient develops an accentuated reaction, an observation which has stimulated clinicians to try to understand this process more fully. The chemistry of medical silicone implants, including quantitative composition, is reviewed. This in vitro laboratory study show less tissue reaction from radiation-cured pure silicone polymer, as compared with radiation-cured silicone with SiOz filler. A proposed system for fabrication and curing of a silicone implant, with the qualities of strength and diminished tissue reactivity, is discussed.

CLINICAL BACKGROUND Silicone rubbers have been prized among prosthetic devices because they elicit a relatively mild tissue reaction. In 1964, Braleyl estimated that 40,000 persons had had silicone rubber ventricular caval shunts placed for treatment of hydrocephalus. In the same year, Cronin and Gerow2 reported the use of a new “natural feel” mammary prosthesis for augmentation mammoplasty. Since that time, the number of silicone prostheses placed for tissue augmentation has skyrocketed. The initial impression that the silicone rubbers are relatively nonreactive compared to other prosthetic materials

* Presented a t the Seventh Annual International Biomaterials Symposium on Materials for Reconstructive Surgery, Clemson University, Clemson, South Carolina, April 26-30, 1975. 857 1976 by John Wiley & Sons, Inc.

858

GIFFORI), MERRILL, ANT) MOItGAN

seems to have stood the test of time.1*3z4However, there is not a complete lack of reaction (as stated by Azaato) ; 3 indeed, clinical experience with silicone rods used to form tendon sheaths, and laboratory evaluation of this phenomenon by Conway et al.,5indicate that we are using this very tissue response, albeit a relatively mild one, for the purpose of an artificial tendon sheath.

CLINICAL EXPERIENCE Silicone rubber implants have continued to fulfill their promise as a relative nonreactive, safe tissue substitute. However, within recent years, the extensive experience of many clinicians shows that an appreciable minority of patients developed a relatively thick capsular response with compression of the implant. This may necessitate a secondary operation with release of the fibrous capsule, and some have advocated introduction of a steroid solution.6 The clinician may try to explain the increased fibrous reaction in some patients on the basis of a resolving hematoma, lack of compression, early or late motion, and try to modify these factors with or without the use of steroids, hopefully to the patient’s advantage. However, these factors are difficult to evaluate without knowing the degrees of tissue reactivity to be expected from the implant materials themselves.

CHEMISTRY I n 1964, Braley’ expressed concern relative to the loose use of the word silicone. He pointed out that this is a generic term which is far from precise, as it covers a large family of very diverse materials. The plastic surgeon is often not aware of the exact chemical nature of these tissue implants which he uses in such large numbers. He may be aware that these are silicone elastomers xn the form of long-chain polymers consisting of an alternation of oxygen and silicon atoms, in which the silicon atoms e x h carry two organic side groups. Most commonly, these groups are methyl, and the polymer is called poly(dimethylsiloxane), noted by Blocksma and Rraley’ (Fig. 1). He may or may not be aware of the fact that fillers (usually fume silica), are added to increase the frequency of cross-bonding and thereby the strength of the material, as noted by Speim8 Usually a heat-activated catalyst vulcanizing agent is used to stimulate the formation of crosslinkages. Products of this reaction are considered

TISSUE REACTIVITY OF SILICONE RUBBER IMPLANTS

859

I

I

Molecular weight 290,000 About 4,000 Units/Chain

Fig. 1. Structure of silicones.

potentially toxic but as they are volatile to varying degrees, it is assumed that they are driven off when the product is heat-cured. If the plastic surgeon was familiar with the Journal of Macromolecular Science and Chemistry, he would find out that the three commonly used medical-grade heat-vulcanized silicone rubber (Silastic 370, Silastic 372, and Silastic 373) use a variable amount of fume silica filler for ~ t r e n g t h . ~Also, the vulcanizing agent for these compounds is usually dichlorobenzoyl peroxide (DCBP) which, when cleaved by heating, forms radical fragments which then abstract hydrogen atoms from the methyl groups on the silicone polymers. The methyl radicals thereby formed couple together, forming crosslinkages between the silicone chains. At the same time a t least three by-product molecules are formed by reactions between fragments of DCBP or between one of these fragments and hydrogen atom, these being dichlorophenyl dichlorobenzoate, dichlorobenzene, and dichlorobenzoic acid, of which the first and last named are the least volatile. One might question whether if some of these catalytic breakdown products were to remain in the prosthetic material, they thereafter might alter tissue reactivity. I n evaluating the quantitative composition by weight of Silastic 372 prior t o the heat-curing process, the material was found to be approximately $ silica filler and 2% catalyst (DCBP) which agrees with the data of Nilaslo (Fig. 2 ) . I n order t o avoid the complicating factor of possible entrapment of catalyst or break down products, one of us (E.M.) suggested the use of a radiation cure process. The source used is a Van de Graaff generator (3.7 million eV). The pentration depth was 1 cm, and the dose was 20 Mrad. The time involved was eight periods of 30 seconds ( 2 . 5 & h a d each) or a total of 240 seconds. The crosslinking is primarily the result of formation of methylene (CH2) radicals randomly along the chains, which thereafter couple t o form a n

GIFFORD, MERRILL, AND MORGAN

860

A

B

65-68% Poly(dirnethylsiloxane) 30-33Oh Silica Filler

C

2%

2,4-DCBP

Fig. 2 . Composition of Silastic 372 as uncured gum by wt

ethyl (-CHZ CH2-) bridge. Thus, the end result is similar t o DCBP crosslinking except that no molecular residues are left in the silicone rubber.

EXPERIMENTAL METHODS We elected to compare tissue reactivity of implants fabricated in the shape of a coin-like disk measuring 25 mm in diameter and 1.5-2 mm in thickness (approximately the dimensions of a common quarter) (see Fig. 3). The test animal was the Sprague-Dawley rat, prepared by shaving the back and anesthetized with ether. The back was prepped with Betadine solution. A pocket was created by introduction of air under the panniculus carnosus (after the fashion of Selye).l1 An incision was made adjacent t o the sac so that the disk could be placed within the sac as far away as possible from the incision, which was closed with metal clips. I n this fashion, it was felt that reaction secondary to the trauma of surgery would be minimized as much as possible. Group I (17 rats) had placement of silica-filled Dow Corning Corporation S-2000 U. silicone gum cured with lo7 rad by the 3 million eV Van de Graaff generator of the High Voltage Research Laboratory, M.I.T. The character of these disks were

B 1 I-

CURED POLY (DIMETHY LSILOXANE) I M P L A N T

GROUP I

I 7*

With silica f i l l e r

Without

filler

_

_

GROUP AT

Medical grade silastic 3 7 2

GROUP Z7

Air pouch ( n o implant)

_

____________ -

rorx

37"

"Sprague

Fig. 3. Experimental method.

Dawley

_

~

TISSUE REACTIVITY O F SILICONE RUBBER IMPLANTS

861

similar t o medical-grade Dow Corning Silastic “vulcanized” block of medium consistency and were similarly opaque. Group I1 (16 rats) had placement of unfilled silicone implants (the polymer alone without the addition of silica, Stauffer-Wacer Silicones Corporation Grade 06093) cured with 1.5 X lo7 rad by the same Van de Graaff generator. These disks are crystal-clear but with relatively poor t e n d strength, and split with sharp bending. Group I11 (3 rats) had implants carved from medical-grade medium consistency Silastic 372 blocks (solid in the cured ‘(vulcanized” form) t o as nearly as possible the same dimensions as the above mentioned implants. Group IV (2 rats) merely had an air sac raised without any surgery or placement of a n implant. The rats were sacrificed at 28, SO, and 146 days. The final group was sacrificed approximately 1.5 years after the date of original implantation in order to determine if there was any possible long-term adverse effects of the implants. At the time of sacrifice, these showed all implants to be surrounded by a capsule of fibrous tissue, which to gross examination was universally under 1 mm in thickness. Microscopic slides (Fig. 4) were made of the tissue capsule. It was not always easy t o determine the exact extent of fibroplastic reaction of the tissues stimulated by the presence of the foreign body, which on occasion tended to blend with the surrounding tissues, which presumably were somewhat compressed. For this reason, the fibrous reaction was not measured in fractions of millimeters; rather the amount of fibrous reaction was graded on a crude scale of 1-5. Although the numbers are small, there was universally less fibrous reaction from the unfilled implants (Group 11) in comparison t o the filled (Group I) implants (Fig. 5 ) . Results in the final group (sacrificed approximately 1.5 years after implantation)were consistent with the above findings. One animal in group I developed a fibroma measuring 5 mm in diameter in the fibrous capsule adjacent t o the filled silicone prosthesis.

DISCUSSION Because of the low numbers involved, we feel justified in saying only that these studies suggest that cured silicone rubber without filler causes less tissue reaction than t h a t with filler. The smaller number of disks fashioned from Dow Corning Medical Grade Silastic

862

GIFFORD, MERRILL, AND MORGAN

(b)

Fig. 4. High-power photomicrograph of tissue reaction from radiation-cured implants: (a) without SiOz filler; (b) with Si02filler.

TISSUE REACTIVITY OF SILICONE RUBBER IMPLANTS TISSUE

3+

i

REACTIVITY

IN R A T S

. 0

0

0 0

4 + -

A

A

863

.

0.

*

A AA A

-

A AA I

I

,

I

Fig. 5 . Summary of experimental results: ( 0 )cured poly(dimethylsi1oxane) with silica filler; (A)cured poly(dimethy1siloxane) without filler; (0) medicalgrade Silastic 372 (Dow Corning); ( A ) no implant (air only).

372 (Group 111) did not appear to show any difference in reactivity from the radiation-cured silicone rubber with filler, but numbers were too few to draw any inference. Thus, the effect of protruding silica particles on blood coagulation, noted by Nilas, l o appears to have as a counterpart increased tissue reactivity to silicone used in implants. I n parallel with these studies, one of us (EM.)supervised a thesis carried out by Weathersby,12 in which it was clearly demonstrated that the whole-blood clott,ing time as measured by the modified Lee-White test could be extended from around 10 min for silica-filled silicone tubes to more than 20 min for tubes made from unfilled silicone. This work has been pursued by Weathersby and Kolobow .l 3 Dealing largely with plastic surgery in children of a growing age, one of us (G.H.G., Jr.) had used, as have others (including T h ~ m s o n ) , ~ inert materials for subcutaneous implants in order to achieve what in many cases is a significant improvement in appearance, although because of continued growth one or more additional procedures may be required. Naturally, the ideal solution to many problems would be autogenous tissue; however, i t requires more surgery a t the site of donor tissue. Also, when applied to a complex deformity involving bone and soft tissues in a rapidly growing child, autogenous tissue

864

GIFFORD, MERRILL, AND MORGAN

is, a t times, disappointing. Blocksma and Braley’ listed eight quantities present in an ideal synthetic soft tissue substiture, including lack of foreign body reaction, capability of resisting mechanical strains, and capability of fabrication in the form desired.

PROPOSITION Uncured silicone polymer can easily be made to have the consistency of putty, and so may be easily molded t o the desired shape. Therefore, it may be molded intraoperatively to the desired shape, dipped in a solution of polymer, without filler, so as to produce an exterior thin coating free of silica and cured by electron radiation from Van de Graaff generator (Fig. 6). The preferred dose level of 5-20 million rad is far in excess of that required for total sterilization of the prosthesis. (The Van de Graaff generator is frequently used for electron sterilization of frozen tissue prior t o implantation.) While a 3 million eV Van de Graaff generator is limited t o a depth of pentration of about 1.2 cm, rotation of the prosthesis in stages under the beam will insure proper crosslinking of samples up to 2.2 cm thick. The total dose can be delivered within less than 5 min. Thereby, i t can be implanted in the patient’s tissues under a single anesthesia within a matter of minutes after i t had been shaped on the operating table. This postulated plan of treatment has the advantages of avoiding the tedious and time-consuming job of carving a block of solid silicone rubber. It also allows for intraoperative fabrication of an implant with the strength of silicone rubber with filler, but with the decreased reactivity of the pure polymer.

0Uncured Poly(dimethylsiloxane) w i t h silica filler

& 5, -.

.__I

Immersion in liquid pure Polyldimethylsiloxctnel

Fig. 6. Proposed plan for rapid cure of silicone implants.

0

TISSUE REACTIVITY OF SILICONE RUBBER IMPLANTS

865

The above is proposed as a possible fruitful avenue for further investigation with hope that physical chemical techniques can be applied in this or a similar fashion to improve medical care. The authors are indebted to Mr. Kenneth Wright of the High Voltage Research Laboratory, M. I. T., for carrying out all of the irradiations.

References 1. S. Braley, Plast. Reconstr. Surg., 34, 632 (1964). 2. T. I). Cronin and F. J. Gerow, in Transactions of the Third International

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Congress of Plastic Surgery, T. R. Broadbent, Ed., Excerpta Medica Foundation, Amsterdam, 1964, pp. 41-49. N. M. Aszato and B. Kapiloff, Plast. Reconstr. Surg., 34, 414 (1964). H. G. Thomson, Plast. Reconstr. Surg., 51, 667 (1973). H. Conway, J. W. Smith, and M. P. Elliott, Plast. Reconstr. Surg., 46, 582 (1970). T. I). Cronin and R. L. Greenberg, Plast. Reconstr. Surg., 46, 1 (1970). R. Blocksma and S. Braley, Plast. Reconstr. Surg., 35, 366 (1965). A. C. Speirs and R. Blocksma, Plast. Reconstr. Surg., 31, 166 (1963). S. Braley, J. Macromol. Sci.-Chem., A4(3), 529 (1970). E. Nilas and E. E. Kupski, J. Biomed. Mater. Res., 4,369 (1970). H. Selye, Proc. SOC.Exper. BioZ. Med., 82, 328 (1953). P. K. Weathersby, Master of Science Thesis, Dept. of Chemical Engineering, 1971. T. Kolobow, E. W. Stool, P. K. Weathersby, J. Pierce, F. Hayano, and J. Sauadeau, Trans. Amer. SOC.Artif. Intern. Organs, 20, 269 (1974).

Received December 1, 1975

In vivo tissue reactivity of radiation-cured silicone rubber implants.

J. BIOMED. MATER. RES. VOL. 10, PP. 857-865 (1976) In vivo Tissue Reactivity of Radiation-Cured Silicone Rubber Implants* GEORGE H. GIE’FORD, JIt.,...
431KB Sizes 0 Downloads 0 Views