Go back to Part 8
(This is a re-typed copy of original Dow Corning Corporation documents. They are not to be reproduced for any reason whatsoever.)
Dow Corning Corporation
File No.: 2726-1
Series No.: I-0035-5
Authors: Benjamin H. Franklin
Ronald B. Annelin
Department: Health & Environmental Services
Date: December 12. 1975
SUBCUTANEOUS IMPLANTS OF DEVELOPMENTAL PROSTHETIC GELS IN MONKEYS AND RATS: EXAMINATION OF TISSUE DEPOSITION AND URINARY, FECAL, AND RESPIRATORY ELIMINATION ROUTES
Reported By Benjamin Franklin*
Ronald B. Annelin*
Checked By (Signature unreadable)
(*Signatures on original.)
DISTRIBUTION
R. Annelin W. Larson
F. Dennett C. Lentz
B. Franklin S. Peters
?. Hobbs L. Tyler
A. Isquich TIS
PRODUCED BY DCC & DCW 2
[F]. . .ormulations of prosthetic gel were injected subcutaneously . . . [into] . . . Rhesus monkeys and rats to study systemsic migration, local tissue reaction and differences in the reaction of rats and monkeys to the implantation of various gel formulations. Systemic migration was measured by determination of silicon levels in urine, feces, expired air, and tissue. The urine of one monkey, which was injected with the standard gel (E-2457-23, 2) showed a significant increase in total silicon after implantation: however, there was no increase in methylethylketone extractable silicon in the urine. There was a slight, but insignificant, increase in organosoluble silicon recovered in the feces of some of the treated monkeys. There was no detectable silicon in the toluene scrubbed expired pulmonary air. Total silicon tissue levels in some organs of the injected monkeys were higher than in the control monkey, particularly the lymph nodes, adrenals and bone marrow. Hexane extracts of these tissues indicated that organosoluble silicon was present in the lymph nodes of two out of three monkeys injected with the new production gel formulation (E-2457-59, 2). In the rats, dosed with the new production gel (E-2533-17, 1), only the axillary lymph nodes showed an increase in total silicon; a similar increase in hexane extractable silicon was not observed. This high total level in the rat axillary lymph nodes was not reproduced in additional studies contained in this report.
None of the injected monkeys had any grossly observable tissue reaction to the prosthetic gel. With the exception of the low cross-linker formulation (E-2533-17,1), all prosthetic gels remained at the injection site and were well encapsulated. Under the conditions of study, the low cross-linker formulation moved along tissue planes and formed only a very thin capsule. None of the new gel formulation appear to be more susceptible to systemic migration than the standard formulation, which has been implanted with apparent safety in humans for the previous . . .[ten]. . . years.
INTRODUCTION
A series of in vivo experiments were conducted on the current prosthetic gel formulation and on three formulations developed by the Medical Products Business of Dow Corning Corporation. The objectives of these experiments were to: (A) Determine the extremes of gel formulation that are biologically acceptable for implantation (i.e., lack of systemic migration and local tissue reaction greater than that found in the standard formulation); (B) Identify prosthetic gel formulations possessing unique physical properties which could warrant further investigation; (C) Development of a reliable method for determining the fate of prosthetic gels in biological systems.
PROCEDURES
PROSTHETIC GELS:
Four prosthetic gel formulation were furnished by Medical Products for these experiments and were identified as follows:
(1) Standard gel: Book #E-2457-23, 2
Formulation: 88.6% 01-0043
8.5% DC-360 fluid
2.25% E-25037
0.05% MDF-0069
(2) New Production gel: Book #E-2457-59, and E-2533-17, 1
Formulation: 80% DC-360 fluid
19% XFL-0043
1% XFL-0049
0.05% MDX-0069
(3) High Fluid gel: Book #E-2457-59, 1
Formulation: 84% DC-360 fluid
2.5% XFL-0043
13.5% E2-5057
1 ppm MDX-0069
(4) Low Cross-linker gel: Book #E-2457-59, 3 and E-2533-17, 2
Formulation: 79.1% DC-360 fluid
19.8% 01-0043
1.1% XF1-0049
0.04% MDF-0069
The gels were sterilized as indicated in Table I.
RHESUS MONKEY IMPLANTS:
Eight male Rhesus monkeys were used in this study. Initially, four monkeys were injected with one of the four prosthetic gels (Table I). These monkeys were placed in primate restraining chairs four days prior to dosing for collection of control samples of urine and feces.
Throughout the experiment the animals were maintained on a strict dietary regime of 50 grams PURINA[1] monkey chow and 100-150 ml of tap water daily. On the fifth day, each monkey was anesthetized with 0.1 ml of SERNYLAN[2] i.m. and received a gel formulation as listed in Table I. The target does of 5.0 gm/kg body weight was placed in equal aliquots in the medical aspect of each thigh using the following technique. The gels were aspirated into hexane-rinsed PLASTIPAK[3] syringes using sterile technique. The implant sites were shaven, washed and rinsed with distilled water. A pocket for the prosthetic gel was made by blunt dissection of the subcutaneous tissue with a 3" long 13 ga thin wall hypodermic needle. The required amount of prosthetic gel was injected through the needle and the wound closed by a single suture.
The four monkeys were then fitted with a latex rubber dam and placed in a primate metabolic chamber designed to allow expired respiratory air to be collected without contamination by volatile silicone from the feces, urine, flattus, or the implant site (W.H. Statt and D. R. Bennet, Dow Corning Report 4244, Appendix VI). Expired air feces and urine were sampled periodically over the next seven days. At the end of this period the animal was returned to its cage. Fifteen days after implantation the monkeys were autopsied and various tissues were analyzed for silicon.
Additional monkeys were dosed in the following manner. MG-CM was an untreated control monkey. MG-5 and MG-6 were dosed with the production gel formulation (E_2533-17, 1) in the manner previously described. MG-7 was dosed with the low cross-linker formulation (E-2533-17, 2) in the following sites to examine encapsulation and movement: 4 grams in each breast beneath the nipple; 4 grams in the medial aspect of each thigh; and 8 grams in the back between the scapulae.
RAT IMPLANTS:
Three experiments were conducted in Sprague-Dawley rats to examine the effects of the prosthetic gels on tissue levels of silicon. One gram of the gel was implanted in each rat using the method described for the monkeys, except the implant site was the back between the scapulae. The first experiment consisted of 15 control rats and 10 treated rats dosed with formulation E-2533-17, 1 and sacrificed 15 days after implantation. The same tissues analyzed for silicone in the monkey were samples in rats. A second rat study examined total silicon levels in only the axillary lymph nodes two weeks after implantation of the new production prosthetic gel (E-2533-17, 1) and the standard gel, (E-2457-23, 2). The final study examined the silicon content of the axillary lymph nodes 1, 2, 4, 7, 10 and 12 days after implantation of the new production prosthetic gel
Go on to Part 10: Appendix 2