breast implant coatings containing PUs in the late 1980s (phenylalanine) Understanding the biodegradation of polyurethanes .. considerable amounts of aspartame to silicone breast implants

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Ingredient DEHP-containing PVC devices .. phenylalanine .. di-2-ethylhexyl phthalate

Poly vinyl .. medical device plastics and is an endocrine disruptor

considerable amounts of aspartame to silicone breast implants

Unrecognized aspartame disease in silicone breast implant patients============================================================

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2003 FDA Science Forum Abstracts

The newly discovered cross-link between 2-deoxyribose and Phenylalanine may also ...... Our preliminary review of reports on silicone gel breast implants, ...http://www.cfsan.fda.gov/~frf/forum03/abs03ct.html - 463k - similar pages

Board W-01

Use of Safety Assessment to Support Regulatory Decision Making and Risk Communication Efforts in CDRH: DEHP in PVC Medical Devices

R.P.Brown1, M.E.Stratmeyer1, L.A.Alonge2, P.J.3, 1Office of Surveillance and Biometrics, 2Office of Device Evaluation, CDRH, FDA, Rockville , MD 20852

Science-based regulation is an integral part of the Total Product Life Cycle (TPLC) process for medical devices. The use of a science-based approach to support regulatory decision-making and risk communication activities in CDRH is illustrated by the use of the results of the safety assessment of di-2-ethylhexyl phthalate (DEHP) released from polyvinyl chloride (PVC) medical devices to support the development of a public health notification and a draft guidance document. The CDRH Office of Science and Technology (OST) recently conducted a safety assessment of DEHP released from PVC devices (http://www.fda.gov/cdrh/ost/dehp-pvc.pdf and concluded that male neonates undergoing certain medical procedures represent

a patient population at increased risk for developing adverse effects following exposure to DEHP-containing medical devices. Based on the results of the safety assessment, the CDRH Office of Surveillance and Biometrics (OSB) issued a Public Health Notification (http://www.fda.gov/cdrh/safety/dehp.html) providing guidance to health care providers on means to limit exposure of this patient population to DEHP. In addition, the CDRH Office of Device Evaluation (ODE) issued a draft guidance (http://www.fda.gov/cdrh/ode/guidance/1407.html) for the purpose of soliciting public comment on measures that manufacturers of DEHP-containing PVC devices can take to reduce patient

exposure to DEHP. This process illustrates the successful interaction among CDRH Offices to address a public health issue.

Publish Only C-PO-1

Using the MRI Itself to Measure the Temperature Increases of Implanted Medical Devices During MRI Examinations

L.A.ZarembaCDRH, Rockville MD

MRI examinations of patients with implanted medical devices can produce significant heating of these devices, which is a potential hazard to patients. However, the MRI itself can be used to measure the temperature increase of the implant. The proton resonant frequency changes by 0.01 ppm/0C. This can be used to estimate the temperature distribution using a technique called phase mapping in which a map of the phase of the image signal, rather than its magnitude, is obtained. Phase mapping tests have been conducted in a phantom on the 2 tesla MRI at MOD I. Maps were acquired using a gradient echo sequence with an echo time of 12 msec, producing a phase change of about .064 rad/0C at 2 tesla. The technique was used to examine the temperature distribution surrounding wire configurations simulating implanted medical devices.

Results were verified with a Luxtron fiberoptic temperature probe. Phase mapping has the advantage that it produces an image of the temperature distribution, while current methods using probes measure temperature at only a few points. The technique could be used as an alternative to temperature probes in the ASTM standard test method for measuring the heating of implanted medical devices during MRI.

Board D-09

Development of an HPLC Method for the determination of Formaldehyde in Human Vaccines

H.Wang, A.V.Del Grosso, J.C.May, OVRR

Formaldehyde is often used in bacterial vaccines either as a stabilizer or inactivating agent. Vaccines against anthrax, diphtheria, hepatitis A, influenza, Japanese encephalitis, and tetanus contain residual amounts of free formaldehyde. Less than 0.02% formaldehyde is permitted in vaccine products by FDA based on four decades of safety research. However, the chemical analysis methods used in determining the formaldehyde content of vaccines rely mainly on cumbersome colorimetric procedures (e.g. Hantzsch reaction, Schiff reaction). The aim of this research is to develop a faster and better HPLC method using pre-column chemical derivatization. The selected derivatization reactions such as 2, 4-Dinitrophenylhydrazine, 4-Nitrobenzylhydroxylamine, 1, 3-Cyclohexanedione and Dansyl Hydrazine were compared based on chemical properties of the

derivatization reagents, Conditions required for derivatization reaction, derivative stability and HPLC detection sensitivity. HPLC analytical results for several Anthrax Vaccine Absorbed samples were compared to those obtained by traditional colorimetric methods. The recovery of formaldehyde was tested by spiking the vaccine samples since the yields of the derivatization reactions were found either less than quantitative or immeasurable.

Board G-10

Nanotechnology biosensor to identify microbial contamination of foods, biologics, and medical devices

S.Gummalla1, P.R.Krause2, K.Merritt3, V.M.Hitchins3, D.J.Kopecko2, A.R.Mtungwa3, M.M.Wekell4, R.Bhiladvala5, H.G.Craighead5, R.H.Hall6, 1CFSAN, FDA, Laurel MD, 2CBER, FDA, Bethesda MD, 3CDRH, FDA, Rockville MD, 4ORA, FDA, Jamaica NY, 5Cornell University, Ithaca NY, 6NIAID, NIH, Bethesda NY

This study investigated the development of nanoelectromechanical cantilever (NEMC)-based attogram bio-detectors. Nanometer scale cantilevers are like mini diving boards and can be fabricated so that they naturally resonate in air (0.5-5 MHz). This frequency decreases in direct proportion to the mass attached to the cantilever, thereby forming a hypersensitive mass-sensing platform. Preliminary work included microbiology feasibility tests, confirmatory detection, and bio-specificity of cantilever surfaces. Results showed that silicon nitride (SiN) surface of cantilevers can be derivatized with anti-bacterial and anti-virus antibodies so as to serve as platforms for immunospecific target binding. PCR methods developed for detection of Escherichia coli O157 (EHEC) showed artificially inoculated EHEC in

Apple juice and Beef extract, could be isolated by silicon nitride chips coated with antibody for these organisms. Bacillus thuringiensis spores targeted via anti-B. anthracis antibody were able to be microbiologically re-cultured confirming spores were immunospecifically bound to SiN surface. PCR and scanning electron microscopy showed Adenovirus (Adv) particles were bound to the SiN surface of chips via anti-AdV antibody. Poly vinyl pyrollidone (10%) was found to serve as a good blocking agent and enhanced the biospecificity of target attachment. Finally, we have developed a model for biofilm formation by showing that SiN is a suitable substrate for colonization of Staphylococcus epidermis. Further experiments are planned using already developed prototype pathogen detection chips with cantilevers for bacterial

and spore detection.

Board J-07

Does Bisphenol A, a medical device material, mimic the actions of beta-estradiol on heat shock protein and HSF-1 expression in the uterus?

A.D.Papaconstantinou1, P.L.Goering1, T.H.Umbreit1, K.M.Brown2, 1CDRH, FDA, Rockville MD , 2Department of Biological Sciences, Washington University, Washington DC

Bisphenol A (BPA) is used in the manufacture of medical tubing and other medical device plastics and is an endocrine disruptor. There is increased concern for patient exposure due to leaching of BPA from these medical plastics. We have shown that the effects of BPA and b-estradiol (E2) on uterine heat shock protein (hsps) levels are mediated through the estrogen receptor (ER), but the nature of the ER involvement remains unknown. The objective of the present experiment was to examine the role of PKC and ER on E2- and BPA-regulated hsp expression. Ovariectomized mice were treated subcutaneously with corn oil, E2 or BPA alone or in combination with the antiestrogen ICI 182, 780 (ICI) or the PKC inhibitor GF 109203X (GF), and uteri were collected at 6 or 24 hours post-administration. The results demonstrate that the

effects of E2 and BPA on uterine hsps may be mediated through the ER, but only those of E2 may be mediated through heat shock factor-1, which controls transcription of hsp genes. PKC may be involved only in the regulation of hsp72 by E2 and of hsp90a by BPA. We conclude that E2 and BPA may be regulating uterine hsp90a and hsp72 expression through differential mechanisms.

Board V-03

Breast Implant Rupture During Mammography

S.L.Brown, J.F.Todd, H.D.Luu, FDA, Rockville MD

Women with breast implants are at the same risk for breast cancer as other women and are urged to undergo screening mammography. FDA regulates both breast implants and mammography quality. We were recently alerted to the issue of breast implant rupture during mammography by a letter from a consumer. We searched the Manufacturer and User Facility Device Experience (MAUDE) database for adverse events in women with breast implants during mammography. MAUDE includes mandatory and voluntary reports submitted to the FDA on adverse events associated with the use of medical devices. Our preliminary review of reports on silicone gel breast implants, saline breast implants, and mammography equipment identified 41 reports that mentioned breast implant rupture during mammography. These events were reported to the FDA between 1992 and 2002. We review these

reports and discuss characteristics of implants that may increase risk of rupture during mammography.

· [MS WORD] NEW TERMS A-Z UPDATED 09/01//2007

Allergan Inamed® (silicone-filled breast implants by Inamed) ...... Travasol, ingredient phenylalanine, 490 mg injection solution) ...http://www.hynessight.com/documents/TermsSept.doc - similar pages

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· ASPARTAME PRODUCTS AS A POTENTIAL DANGER TO INFANTS, CHILDREN, AND ...

, H. J.: Unrecognized aspartame disease in silicone breast implant patients. Townsend Letter for Doctors & Patients 1998; May: 74-75. ...http://www.wnho.net/aspartame_potential_danger.htm - 17k - similar pages

* Phenylalanine is in Aspartame==================March 2006 Endocrine Society and American Academy of Neurology).

Each of these disorders and the underlying mechanisms is detailed in my books, especially Aspartame Disease: An Ignored Epidemic. They tend to be magnified in patients with unrecognized hypothyroidism (underactive thyroid), hypoglycemia (low blood sugar reactions), diabetes and phenylketonuria (PKU). Persons with PKU lack the enzyme needed for handling phenylalanine, one of the amino acids. (Its dramatic increase in the body can cause severe neurological and other damage if aspartame abstinence and other dietary precautions are not instituted.)

Exposure of the fetus to considerable phenylalanine and methanol

Maternal malnutrition associated with nausea, vomiting, diarrhea, and a reduction of calories

Transmission of aspartame and its breakdown components via the mother's milk

The increased "allergic load," thereby risking future hypersensitivity problems

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· Aspartame Disease: An FDA-Approved Epidemic - Articles

Examples include attributing the symptoms of weight-conscious women consuming considerable amounts of aspartame to silicone breast implants in expensive ...http://articles.mercola.com / sites / articles / archive / 2004 / 01 / 07 / aspartame-disease-part-t... - 74k - similar pages

· Biomaterials : Understanding the biodegradation of polyurethanes ... >

.... that associated with the PU-covered silicone breast implants [15] and [16]. ..... In vitro degradation studies of PUs containing a phenylalanine diester ...http://linkinghub.elsevier.com/retrieve/pii/S0142961205004692 - similar pages

Understanding the biodegradation of polyurethanes: From classical implants to tissue engineering materials

J.P. Santerrea, b, c, , , K. Woodhouseb, c, G. Laroched, e and R.S.

Labowf

aFaculty of Dentistry, University of Toronto , Toronto , Ont. , Canada M5G 1G6

bInstitute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto , Ont. , Canada M5S 3G9

cDepartment of Chemical Engineering and Applied Chemistry, University of Toronto , Toronto , Ont. , Canada M5S 3E5

dDepartment of Mining, Metallurgical, and Materials Engineering, Université Laval, Qué. , Canada G1K 7P4

eUnité de Biotechnologie et de Bioingénerie, Centre de recherce de l’Hôpital St -François d’Assise, CHUQ, 10 rue de l’Espinay, Qué. , Canada G1L 3L5

fUniversity of Ottawa Heart Institute, 40 Ruskin St. , Ottawa , Ont. , Canada K1Y 4W7Available online 18 July 2005.

Abstract

After almost half a century of use in the health field, polyurethanes (PUs) remain one of the most popular group of biomaterials applied for medical devices. Their popularity has been sustained as a direct result of their segmented block copolymeric character, which endows them with a wide range of versatility in terms of tailoring their physical properties, blood and tissue compatibility, and more recently their biodegradation character. While they became recognized in the 1970s and 1980s as the blood contacting material of choice in a wide range of cardiovascular devices their application in long-term implants fell under scrutiny with the failure of pacemaker leads and … breast implant … coatings containing PUs in the late 1980s. During the next decade PUs became extensively researched for their relative sensitivity to biodegradation and the desire to further understand the biological mechanisms for in vivo biodegradation. The advent of molecular biology into mainstream biomedical engineering permitted the probing of molecular pathways leading to the biodegradation of these materials. Knowledge gained throughout the 1990s has not only yielded novel PUs that contribute to the enhancement of biostability for in vivo long-term applications, but has also been translated to form a new class of

bioresorbable materials with all the versatility of PUs in terms of physical properties but now with a more integrative nature in terms of biocompatibility. The current review will briefly survey the literature, which initially identified the problem of PU degradation in vivo and the subsequent studies that have led to the field's further understanding of the biological processes mediating the breakdown. An overview of research emerging on PUs sought for use in combination (drug+polymer) products and tissue regeneration applications will then be presented.

Keywords: Degradation; Biodegradation; Polyurethanes; Oxidation; Hydrolysis; Enzymes; Implants; Polymers; Macrophages; Bioresorbable; Biostability; Tissue regeneration; Scaffolds

Nomenclature

BD

butanediol

CE

cholesterol esterase

CXE

carboxyl esterase

EB

environmental biodegradation

ED

ethylene diamine

ESC

environmental stress cracking

FBGC

foreign body giant cell

HDI

hexane diisocyanate

HDI431

HDI:PCN:BD (4:3:1)

HMDI

hydrogenated MDI

IL-1

interleukin-1

LDI

lysine diisocyanate

MDA

methylene diamine

MDI

4,4′-methylene-bis-phenyl diisocyanate

MDI321

MDI:PCN:BD (3:2:1)

MDM

monocyte-derived macrophage

MIO

metal ion oxidation

MSE

monocyte specific esterase

PCL

polycaprolactone

PCN

1,6-hexyl 1,2-ethyl carbonate diol

PEO

polyethylene oxide

PEU

polyether-PU

PHB

,ω dihydroxy-oligo[®-3-hydroxybutyrate-co-®-3-hydrocyalerate)-ethyleneglycol]

PHSPN

prolyl-histidyl-seryl-prolyl-asparagine

PMA

phorbol myristate acetate

PMN

neutrophil

PRRARV

prolyl-argininyl-argininyl-alanyl-argininyl-valine

PS

polystyrene

PTMO

polytetramethylene oxide

PU

polyurethane

RGD

argininyl-glycyl-aspartate

ROS

reactive oxygen species

SEM

scanning electron microscopy

TDA

toluene diamine

TDI

toluene diisocyanate

WVP

water vapour permeance

XPS

X-ray photoelectron spectroscopy

Article Outline

Nomenclature

1. Polyurethanes (PUs) and their breakdown

1.1. Chemistry of PUs

1.2. Bulk degradation of PUs in biomedical devices

1.3. Biostability of implanted medical devices

2. Environmental biodegradation (EB) and its molecular reactions on PU structure

2.1. Molecular reactions between biological agents and PUs

2.2. Contribution of hard-segment structure in biodegradation

2.3. Influence of strain on molecular interactions of polymers and biological agents

2.4.Environmental biodegradation

2.5. Considerations for the design of new PUs

3. Action of PUs on inflammatory cells: effect on EB

3.1. PU degradation and inflammatory cells

3.2. Implication of MDM-derived hydrolytic enzymes

3.3. Effect of PU chemistry on hydrolytic enzyme synthesis and release

4. Design of biodegradable PUs for the in vivo environment

4.1. Polyethylene oxide and PCL containing biodegradable PUs

4.2. Use of other soft segments in biodegradable PUs

4.3. Biodegradable hard segments

5. Summary

Acknowledgements

References

Fig. 1. Model for environmental biodegradation of polyurethanes.

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