Natural-Y M??me Polyurethane versus Smooth Silicone: Analysis of the Soft-Tissue Interaction from 3 Days to 1 Year in the Rat Animal Model

Picha, George J.; Goldstein, Jeffrey A.; Stohr, Erich

doi:10.1097/00006534-199006000-00011

Cited by 58 publications

(23 citation statements)

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“…The model-predicted results in this study confirmed that carcinogenic degradation products that are produced from implanted PU foam are stored in target organs and small amounts are excreted in animals and humans (2,(20)(21)(22)(23)(24)251). Although there is no data available at this time to show a cause and effect relationship between the use of this PU foam and production of cancer in humans, the lifetime duration of exposure of the device, the high tissue uptake, and slow dearance of 2,4-TDA from breast implants are important factors contributing to the potential hazard of 2,4-TDA released from the PU foam-covered breast implants in humans (30).…”

Section: Discussionsupporting

confidence: 70%

“…One of the degradation products of TDI is 2,4-toluenediamine (2,4-TDA). Data in experimental animals showed that the PU foam cover degraded within [6][7][8][9][10][11][12] months of implantation (2). This result was consistent with the clinical observations in patients with Meme breast implants (3,4).…”

supporting

confidence: 79%

“…This corresponds to a lifetime average daily dose (LADD) of 11.93 x 10-mg/kg/day, assuming that the lifetime of the implant was 10 years (10/70). Therefore (2)(3)(4). Although the susceptibilities of the PU foam to water, buffer, oxygen, and enzymes at physiological conditions are known (2-9), the actual leach rate of 2,4-TDA in vivo is not well documented.…”

Section: Discussionmentioning

confidence: 99%

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A physiologically based pharmacokinetic model for 2,4-toluenediamine leached from polyurethane foam-covered breast implants.

Luu

Hutter

Bushar

1998

Environ Health Perspect

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Physiologically based pharmacokinetic (PBPK) modeling was used to -m the low-dose exposure of patients to the carcinogen 2,4-toluenediamine (2,4-TDA) rdeased from the adation ofthe polyester urethane foam (PU) used in Meme silicone breast implants. The tissues are represnted as five compartments: liver, Idney, gasrointestinal tract, slowly perfused tissues (e.g., fat), and richly perfused tissues (e.g., muscle). The PBPK model w tted to the plasma and urine concentrations of 2,4-TDA and its metabolite 4-AAT (4-N-aetyl-2-amino toluene) in rats given low doses of 2,4-TDA intravenously and subcutaeously. The rat modaldwas extrapolated to simulate oral and implant routes in rats. After adjusting for human physiological parmeters, the model was then used to predict the bioavailability of 2,4-TDA released from a typical 4. Polyurethanes have been used in breast implant covers, pacemaker leads, hemodialyzer potting material, and other medical applications. The degradation of polyurethanes in vivo has long been a concern due to both the release of potentially harmful materials as well as mechanical failure. The composition of the polyurethane degradation products depends on the original formulation of the polymer. The polyester urethane (PU) foam cover of the Meme breast implant (or Replicon; Surgitek Corporation, Racine, WI) was made from a polyester resin and a 80:20 mixture of 2,4-toluene diisocynate and 2,6-toluene diisocyanate (2,4-TDI, 2,6-TDI) (1). One of the degradation products of TDI is 2,4-toluenediamine (2,4-TDA). Data in experimental animals showed that the PU foam cover degraded within 6-12 months of implantation (2). This result was consistent with the clinical observations in patients with Meme breast implants (3,4). Our own in vitro studies indicated that 2,4-TDA was slowly released over time by hydrolytic degradation when PU foam samples were incubated under mild physiological conditions (5,6). The amount and rate of 2,4-TDA production observed in vitro varied with the conditions of PU foam exposure (7-9). The carcinogenicity of 2,4-TDA was studied extensively in mice, rats, and other species (10)(11)(12)(13)(14)(15)(16)(17)(18)(19) (25). The kinetic behavior of 2,4-TDA and its metabolite were derived from the implant PBPK model for both rats and humans. The simulated results were compared to the available independent data for validation (10-13,22,2,) with an experimentally determined value of 88 ng 2,4-TDA/g foam/day as previously reported (5,6). The degradation of the PU foam in vivo was assumed to produce only one product, 2,4-TDA (29). The PBPK model for 2,4-TDA accounts for hepatic metabolism, which is known to produce an active metabolite (18,19). Although there were at least eight known metabolites of 2,4-TDA in the liver, 2,4-TDA was assumed only to have one metabolite, 4-acetylamino-2-aminotoluene (4-AAT), in this model for simplicity (19,29). The rate of production of 4-AAT was controlled by an adjustable selectivity in the model (19). The selectivity was defined as the fraction of metabolite...

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Section: Discussionsupporting

confidence: 70%

supporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A physiologically based pharmacokinetic model for 2,4-toluenediamine leached from polyurethane foam-covered breast implants.

Luu

Hutter

Bushar

1998

Environ Health Perspect

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“…Implanted biomaterials frequently trigger inflammatory responses which may, in turn, presage serious iatrogenic consequences such as stress cracking of pacemaker leads (1,2), osteolysis adjacent artificial joints (3)(4)(5), and fibrosis and capsule contracture affecting mammary prostheses (6)(7)(8)(9)(10). The causes of these adverse responses are still obscure, particularly in view of the nontoxic, nonimmunogenic, and chemically inert nature of most implantable biomaterials.…”

Section: Introductionmentioning

confidence: 99%

Molecular determinants of acute inflammatory responses to biomaterials.

et al. 1996

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The frequent inflammatory responses to implanted medical devices are puzzling in view of the inert and nontoxic nature of most biomaterials. Because implant surfaces spontaneously adsorb host proteins, this proteinaceous film is probably important in the subsequent attraction of phagocytes. In fact, earlier we found that acute inflammatory responses to experimental polyethylene terephthalate implants in mice require the precedent adsorption of one particular host protein, fibrinogen. The present investigations were aimed at defining the molecular determinants of fibrinogen-mediated acute inflammatory responses to implanted biomaterials. We find: ( a ) plasmin degradation of purified fibrinogen into defined domains reveals that the proinflammatory activity resides within the D fragment, which contains neither the fibrin cross-linking sites nor RGD sequences; ( b ) the major (and, perhaps, exclusive) proinflammatory sequence appears to be fibrinogen ␥ 190-202, previously shown to interact with CD11b/CD18 (Mac-1). The chemically synthesized peptide, cross-linked to albumin (which itself does not promote inflammatory responses), mimics the proinflammatory effect of adsorbed native fibrinogen; and ( c ) this sequence probably promotes inflammatory responses through interactions with Mac-1 because phagocyte accumulation on experimental implants is almost completely abrogated by administration of recombinant neutrophil inhibitory factor (which blocks CD11b-fibrin(ogen) interaction). We conclude that improved knowledge of such surface-proteinphagocyte interactions may permit the future development of more biocompatible implantable materials. ( J. Clin. Invest. 1996. 97:1329-1334.)

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“…In view of the inert and nontoxic nature of most biomaterials, it is puzzling that tissue contact implants very often acquire an extensive overlay of phagocytic cells (1-9). These phagocytes have been implicated in a number of subsequent adverse effects such as osteolytic changes around joint implants (7,10,11), stress cracking of pacemaker leads (12,13), degradation of biomaterial implants (14,15), and fibrosis surrounding mammary prostheses and many other types of implants (16)(17)(18)(19).…”

mentioning

confidence: 99%

Mast cells mediate acute inflammatory responses to implanted biomaterials

Tang

Jennings

Eaton

1998

Proc. Natl. Acad. Sci. U.S.A.

250

185

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Implanted biomaterials trigger acute and chronic inf lammatory responses. The mechanisms involved in such acute inf lammatory responses can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces. We earlier observed that two chemokinesmacrophage inf lammatory protein 1␣͞monocyte chemoattractant protein 1-and the phagocyte integrin Mac-1 (CD11b͞CD18)͞surface fibrinogen interaction are, respectively, required for phagocyte chemotaxis and adherence to biomaterial surfaces. However, it is still not clear

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Natural-Y M??me Polyurethane versus Smooth Silicone: Analysis of the Soft-Tissue Interaction from 3 Days to 1 Year in the Rat Animal Model

Cited by 58 publications

References 0 publications

A physiologically based pharmacokinetic model for 2,4-toluenediamine leached from polyurethane foam-covered breast implants.

A physiologically based pharmacokinetic model for 2,4-toluenediamine leached from polyurethane foam-covered breast implants.

Molecular determinants of acute inflammatory responses to biomaterials.

Mast cells mediate acute inflammatory responses to implanted biomaterials

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