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The official Product Staging System grew in combination with the
Product Management Groups instituted in 1967. In 1968, Dow Corning started
updating the breast implant, a process that would take approximately seven
years. First, in 1968, they developed the seamless envelope, which provided a
smoother finish and a more natural appearance.
Now came the tough part. Doctors were requesting a softer, more natural gel formulation, so the breast implant product team went to work. Research scientist Jack Roberts worked on the new gel formulation the closest. By the first half of 1971, he had found one, and sent it for preliminary toxicity testing. Dow Corning employed a standard, widely used chemical test involving human embryonic cells. This test, commonly referred to as the CPE (CytoPathic Effect) test, was extremely sensitive, and was one of the few tests where cells would react to silicone contact. (However, such a reaction was rare even with this test.) The experimental gel was introduced to some of these embryonic cells, to investigate if any changed. As stated, although the cells rarely reacted adversely, they did so when introduced to this gel. However, such a reaction did not necessarily indicate that the gel was unsuitable for medical use. Dow Corning had two options: complete a large, expensive battery of tests to determine if this gel was suitable for implantation, or substitute a similar polymer into the original test.
Dow Corning chose the second option, since Roberts already had a gel similar to the first. Although Roberts' second gel overcame the embryonic cell hurdle, it also had to undergo a penetration test to measure its stiffness. (For example, the gelatin we eat is a fairly stiff gel.) Roberts and associates allowed a weighted probe to descend for a span of time into the gel. The farther into the gel the probe made it, the softer the gel. After tracking this characteristic in the second attempt gel, Roberts found that this gel was growing softer over time. This tendency was undesirable for an implant gel, since softer consistency could cause more diffusion through the envelope. Also, if the implant ruptured, more gel would migrate from the area of implantation. Thus, this gel, too, was rejected. All in all, by 1973, two ideas had made it to Stage II of the Product Development stages, where the PMG had to narrow application possibilities for the actual product, look into what the manufacturing system could handle, and perform preliminary toxicity tests, even though no FDA regulations required them to do so.
So, we arrive at June of 1974. Roberts had joined another product team, and Kim Anderson had joined the mammary prosthesis team in his place. She was a chemist by training and had been with Dow Corning since February of 1970. Taking over where Roberts left off, Anderson sought to understand the objectives of her mission clearly. As the team members explained to her, they had been trying to develop a more responsive implant gel, one that more closely simulated the behavior of actual breast tissue. (Although the Cronin had been quite an improvement medically and aesthetically over the sponge, it could still be better.) Meanwhile, during Dow Corning's progression toward this gel, its competitors had marketed new gels, softer and more responsive. An important restriction given to Anderson was to include only ingredients in her gel formulations that had previously been safety-tested, and/or had successful medical implant histories. This reduced the silicones from which Anderson could formulate the new gel, but seemed to ensure a safer implant for the customer.
Anderson set to work, manipulating and reformulating combinations of materials already used in medical implants, building upon Roberts' and the PMG's work. Although Anderson's gel utilized essentially the same ingredients as that in the Cronin (called the "firm gel" from now on), her more-responsive product had several important innovations. As stated previously, silicone gel consists of two parts: a cross-linked network which contains the liquid swelling agent. In the firm gel, the swelling agent constituted 50% of the gel, with 40% of that a vinyl polymer, and the last 10% PDMS.
In the new gel, Anderson was able to increase the cross-linked density of the network:
This increase provided more places for the swelling agent to reside, although the area of each location was smaller. Thus, Anderson was able to infuse a greater amount of the swelling agent (fluid) into the network of PDMS molecules. By increasing the amount of cross-linking, Anderson was enhancing the viscous component of the gel, allowing 30% more fluid (liquid swelling agent) to be infused. Thus, the new implant gel was 80% swelling agent, 75% of which was PDMS, and 5% of which was the vinyl polymer. This process resulted in a new gel that assumed the shape of its container more quickly than the prior firm gel, and recovered more quickly when depressed, hence, the reference to the new gel as "more responsive." With these characteristics, it behaved more like a natural breast. As a comparison, we look to the gelatin we eat for clarification. It is 99% water, with 1% cross-linked network. As we know, the gelatin, once formed, will retain the shape of its original container, and will not conform to a new container's outline.
With the added swelling agent, the task force was concerned about the diffusion rate of the swelling agent in the gel. Would more of it escape through the elastomer envelope? Anderson and colleagues compared the behavior of the new and old gel in identical seamless envelopes. Colleagues measured the strength of the envelope with the new gel and found it was comparable to its strength with the old gel. Anderson found the more responsive gel diffusion amount to be the same or slightly less than the diffusion of the old gel, which was only .78 grams over 2 years of implantation, that is less than 1/5 of a thimble.
To sum up, Anderson's more responsive gel more closely copied the behavior of natural breast tissue, without any more diffusion than the old gel, while utilizing the same chemicals, albeit in a different ratio.
By December of 1974, Anderson's formulation had achieved Stage III status. Anderson's formulation had passed the toxicity test of Stage II, and since she was focused on developing an implant gel, her formulation already had a marketable application. Also, the Legal and Health & Environmental Sciences departments had already stepped in, examining the researcher's lab sheets and results for patentability, and the product's biocompatability.
Other team members had invented new sterilized packaging. Thus, the Implant Development team (PMG) had created a product with three advances instead of one:>
1. the seamless envelope of 1968, with new shapes available (See left.)
2. a more responsive gel
3. sterile packaging. (Prior to this development, the surgeons sterilized the implants via autoclave before implantation.)
Meanwhile, with the arrival of new, more resilient prostheses, the implant market competition had grown very keen. Given Dow Corning's reputation as a pioneer of silicone products, doctors were requesting a new implant from the well-trusted name.
Dow Corning geared up to engineer a major effect on the breast implant market with this new, improved product. By introducing these three improvements together, Dow Corning would create a larger impact on the market. They created a special Mammary Task Force in January of 1975, to complete the final development of this new product for marketing by June. However, Dow Corning knew that two more issues had to be addressed before the new gel could go to market:
1. Can we manufacture the product?
2. We need further demonstration that the new product will be suitable for long-term implementation [in humans][47].
While Anderson had been working on the new gel formulation, she had simultaneously addressed a manufacturing issue. Presently, the gel was divided into Parts A and B for production, with the ratio of ingredients needed A to B at 100:1. This incongruent ratio would not allow for true simultaneous production in Dow Corning's batch processing. (Since a batch of A required 100 times the number of ingredients as B, it took much more time.) In order to improve efficiency, DCC asked Kim Anderson to divide the batch ingredients for production more equitably. Her work ended in the masterbatching of the gel, with the ratio of ingredients needed A:B a much more equitable 3:1, allowing for improved efficiency in production. The new gel formula could essentially drop into this new process, and the question of whether Dow Corning could manufacture the new formulation was easily answered in the affirmative.
Anderson and the development team moved on to the second issue, concerning the safety of the product. In addition to Anderson, other scientists on the task force included a biocompatability expert along with Anderson's laboratory manager. With the second question, they found disagreement between the chemists and the biologists, since biologically inert and chemically inert do not mean the same thing. Chemists consider a material chemically inert if it is non-reactive and long-lasting. For example, silicone is considered chemically inert because it is difficult to break its Si-O backbone, requiring the introduction of a strong acid or base. From the biologists' vantage point, the body attempts to metabolize water insoluble materials such as silicone to make them water soluble (and thus excretable). Such materials, including silicone, are not biologically inert. Still, there was only one case where a silicone was biologically active on its own: the silicone found in phenyl-containing material, which is shaped the same as a steroid. Thus, this silicone acted like the steroid, much like a key that fits the same lock. This material was not used in breast implants.
In the chemists' opinion, no additional testing of the new gel was needed, since it utilized only components which had been previously tested and used in the original gel, already implanted without incident in humans for ten years. On the other side stood the biologists, arguing that since the new responsive gel was made from a new combination of those ingredients, it needed further testing. Since the new gel was much softer than that used in the Cronin implant, the biologists recommended to management that a ninety-day rabbit study and a two to four week monkey study of the worst case scenario, the insertion of silicone gel without any elastomer envelope. Since the biologists were the experts in this area, their recommendations were taken. Dow Corning made the product introduction contingent on passing the tests recommended by the biologists. This was in addition to the typical manufacturing requirements.
In March/April 1975, the results of a Dow Corning two-week study on the effect of silicone gels injected subcutaneously into rats and monkeys were delivered. The current Cronin gel acted as the control gel, and the scientists at Dow Corning tried out three new gels, including the New Production gel, the one they tentatively planned on producing; an experimental High-fluid gel; and a Low-cross linker gel. Goals of this study included:
-finding the range of biologically acceptable gels for human implantation,
-determining if any of the gels displayed special characteristics, with marketable potential and future research expected,
-creating an acceptable means for ascertaining the behavior of such gels in biological systems/organisms.
Specifically, Dow Corning wanted to investigate any tissue reaction, tendency to systemic migration, or differences in general response to the gels among the monkeys and the rats. (For a general overview and methodology, see Appendix 1).
The scientists found higher levels of silicon in the lymph nodes of two of the three monkeys than in the control monkey. However, such elevated levels of silicon were to be expected due to the gradual gel diffusion. The lymphatic system is designed to rid the body of foreign substances such as silicone. Thus, when any silicone escaped through the envelope, macrophages attached themselves to it and moved it away from the diffusion site, depositing it in the lymph nodes. Dow Corning scientists had both anticipated and predicted such occurrences, and noted that the levels in the lymph nodes were not significant in either animal. Also, while one iteration of the study produced an increase in the silicon in the axillary lymph node of the rats, this result could not be reproduced. No "grossly observable" tissue reaction in the monkeys was seen.[48]
However, low cross-linker prosthetic formulation "E-2457-59, 3 (MG-4)" when implanted in the monkey did not encapsulate like the other formulations. Instead, the gel moved from its original implant site, along tissue surfaces. To further study this phenomena, another monkey was injected with the same formulation at multiple sites, and the final results were issued in December, 1975. Again, the prosthetic gel moved from its original site along tissue planes[49]. Although this was an experimental gel and not the one tentatively scheduled for production, Dow Corning was concerned about the migration of the low cross-linked gel. Due to the systemic traveling, Dow Corning narrowed the window of safety-acceptable gels to ensure that gels with this degree of softness were excluded.
In addition, Dow Corning also contracted out the requested rabbit study to Biometric, an independent research laboratory in New Jersey. (For details on the methodology, see Appendix 2. Also, since the FDA did not regulate implantable devices until 1976, no proof of safety was legally required. Dow Corning performed such safety-testing as a matter of good manufacturing protocol.) The experiment involved the four gels previously discussed, as well as 28 rabbits, certain of whom were to be sacrificed after 7, 14, 21, and 90 days to reveal what, if any, effects the injected silicone gels had on them. At the end of the first twenty-one days,
. . . There were no significant gross pathological findings observed at autopsy. Histopathologic exam reveals the continued presence of a mild to moderately acute granulomatous inflammatory reaction occurring in almost all of the implantation sites. The only difference separating this group from the previous two [7 and 14 days] is that the reaction in this group of rabbits is lessened slightly. . . Microscopic exam of the implant sites reveals a localized, mild to moderately acute granulomatous inflammatory reaction. This reaction lessened somewhat in the 21-day animals. Because this response was seen in almost every implant site and was unequally distributed around the circumference of the site, we feel that this reaction was due to the trauma of implantation and not due to the test gels.[50]
So far, the test results had indicated biocompatability. Eager to get its implants out, Dow Corning asked Biometric if the test could be shortened by 10 days without incident, and Biometric answered in the affirmative. After 80 days, the results were still promising:
There have been no significant gross pathological findings. . . At the 80 day period, this inflammatory region was observed in several instances, however, its severity was greatly reduced and was present in certain portions of the periphery of the implant site. The remainder of the site was normal. The majority of implant sites were entirely free of any reaction at all. These histopathologic changes observed during the 80 day course of this study were, in our opinion, due to the trauma of implantation and not due to the test gels.[51]
Thus , the extra studies were complete and could be added to the collection of independent and in-house research on silicone already available. Returning to Anderson in 1975, it was now near the end of April, and their target date was still June. Anderson knew that the product team had been working for upwards of four years on this project, and it seemed like the new gel's time had come. However, some people questioned the integrity of the implants, citing their thinner elastomer envelope as a possible problem, making the new implants more prone to diffusion. However, Anderson had tested this possibility, and she found that the implants with the new gel promoted a level of diffusion comparable to or slightly less than the Cronin, which had already been on the market without incident for ten years. The testing on the more responsive gel was complete, and the Mammary Task Force had to decide whether to produce this implant. They had asked Kim to make a preliminary recommendation. Kim thought: "Is there enough data? Is the testing we have done sufficient, since this product is going to be implanted in humans? Have I done everything I should have?" Anderson checked with the various scientists on the respective properties of the gel, who found it to be production-worthy according to the data already outlined.
Given the explanation of silicone; the original implant and its testing; the scientific evidence available; and the explanation of the product staging system, should this new implant go to market?
Go on to Part 8 (Endnotes)