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TEI Biosciences Inc
Technical Notes (TN001)
TECHNICAL NOTE
Risk Analysis and Management of TSEs
SUMMARY
- TissueMend® is a biological, collagen membrane derived from the dermis of cows.
- In view of the bovine spongiform encephalopathy (“mad cow disease”) epidemic in the U.K., concerns are high,
particularly in Europe, as to the safety of bovine derived medical devices.
- Transmissible spongiform encephalopathies (TSEs) are widely believed to be caused by aberrant prion proteins.
The World Health Organization (WHO), Food and Drug Administration (FDA), and the Commission of the
European Communities, have issued directives ensuring the safety of bovine derived food and medical products.
- To ensure the safety of TissueMend®, TEI Biosciences has adopted a series of five effective methods known to
these agencies to minimize TSE risks
(1) source materials are traceable to herds having no known incidences of BSE
(2) source materials are from animals certified fit for human consumption
(3) the source material is bovine dermis, a Category IV WHO designated tissue indicating no detectable
TSE infectivity of the tissue source
(4) the source material is of fetal origin; per the World Health Organization, infectious TSE agents have not
been identified in any fetal bovine tissues
(5) all source materials are exposed to sodium hydroxide, a recognized prion inactivant
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
In January 1993, the height of Europe’s “Mad cow disease” epidemic, nearly 1,000 new bovine spongiform
encephalopathy (BSE) cases were reported weekly in the United Kingdom. Since being first diagnosed in Great
Britain over 15 years ago, 95% of all BSE cases have occurred in the United Kingdom. Epidemiological evidence
has established that the outbreak of BSE was related to and amplified by the practice of feeding rendered ruminant
carcasses, i.e., cattle, sheep, and goats, to young calves. In contrast, after over a decade of safeguards and active
monitoring by FDA and USDA of American herds, not even a single case of BSE has been confirmed in the United
States. Recent results of a study conducted by the Harvard Center for Risk Analysis confirms that “BSE is
extremely unlikely to become established in the U.S.”
In addition to cows, transmissible spongiform encephalopathies (TSEs) are generally recognized in several
species. Scrapie in sheep and goats has been noted for hundreds of years. Similarly, chronic wasting disease
(CWD) in elk and deer have been reported for several decades. Susceptibility to TSEs has been confirmed in mink,
cats, mice, hamsters, and pigs. Since the early 1900s, Creutzfeldt-Jakob disease (CJD), has been recognized in
humans. CJD has had a relatively constant world wide incidence of 1 case/million/year for decades. In March of
1996, variant CJD (vCJD) was first described in England and appears to be linked to exposure, probably through
food, to BSE in cattle. Thus far, close to 100 cases of vCJD have been confirmed almost exclusively to the U.K.
Another human TSE, kuru in Papua New Guinea, is believed to be transmitted in the course of funerary rituals
involving brains of human corpses.
PRIONS, INFECTIOUS TISSUES, AND INACTIVATION METHODS
The contaminant or infectious agent responsible for TSEs and the associated progressive, degenerative
neurological disease, is widely believed related to a self replicating, abnormally folded isoform of normal cellular
membrane proteins called prions. Though prions can be transmitted from one host to another, they are not
comparable to traditional “germs” such as bacteria, viruses, protozoa or fungi. What causes the abnormal prion
folding to occur, why hosts cannot develop immunity to these proteins, and what factors might cause or transmit
TSEs are still poorly understood.
Better understood are the tissues which can contain infectious prions and effective methods of inactivating the
infectious agents responsible for TSEs. Based on scientific evidence, the World Health Organization (WHO) has
designated four tissue infectivity categories:
WHO Categories of Infectivity in Bovine Tissues and Body Fluid
Category
Designation
Tissues
I
High infectivity
brain, spinal cord, eye
II
Medium infectivity
spleen, tonsil, lymph nodes, ileum, colon, CSF, dura mater
III
Low infectivity
Peripheral nerves, nasal mucosa, thymus, bone marrow, liver, lung, pacreas
IV
No detectable infectivity
skin, connective tissues, fetal tissues, striated muscle, milk, serum,
feces, and saliva
Inactivation of TSE agents is different from other known pathogens. Conventional dry heat, formaldehyde,
ethanol, hydrogen peroxide, ethylene oxide, and gamma radiation sterilization processes have all proved
ineffective in inactivating infectious prions. Instead, WHO recognized effective prion inactivation treatments
include exposure to sodium hydroxide, bleach, and, on some prion strains, steam sterilization.
TEI RESPONSE AND RATIONALE
TEI ensures minimal risk of infectious prion contamination by employing five independent steps known to
eliminate infectious prions in the TissueMend® manufacturing processing. First, TissueMend® is derived from
dermal bovine tissues, which, per WHO designation, has no known detectable prion infectivity. In other words,
even in an animal with confirmed BSE, WHO reviewed studies have demonstrated that the dermis from an infected
cow is not infectious. Further, TissueMend® is derived from fetal bovine tissues which are also considered safe as
no detectable levels of TSE infectious prions have been identified in fetal tissues. In addition, TissueMend® is
exposed to sodium hydroxide, a known prion inactivant. Finally, the source tissues only come from BSE-free North
American herds. These herds are subject to USDA inspection to ensure that tissues used by TEI only come from
animals certified for human consumption. While ensuring a product with minimal risk of prion contamination,
these five steps also ensures that TissueMend® is compliant with FDA and European regulatory requirements.
REFERENCES
HHS Fact Sheet, Federal agencies take special precautions to keep “Mad Cow Disease” our of the United States, U.S. Department of Health and
Human Services, 23 August (2001)
FDA guidance document, Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices), 6
November (1998)
WHO Information Fact Sheet No. 113, Bovine spongiform encephalopathy (BSE), June 2001.
WHO Information Fact Sheet No. 180, Variant Creutzfeldt-Jakob disease (vCJD), June 2001.
Report of a WHO (World Health Organization) Consultation on Medicinal and Other Products in Relation to Human and Animal Transmissible
Spongiform Encephalopathies—With the Participation of the Office International des Epizooties (OIE)—Geneva, Switzerland, 24-26 March (1997)
WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies. Report of a WHO Consultation, Geneva, Switzerland, 2326 September (1999)
Draft Commission Directive of Medical Devices Incorporating Tissues or Derivatives from Animals for which a TSE Risk is Suspected.
Commission of the European Communities, Brussels, 29 July (2002)
G Grey et al., Evaluation of the Potential for Bovine Spongiform Encephalopathy in the United States, Harvard Center for Risk Analysis (2001)
SJ Ryder et al. The neuropathology of experimental bovine spongiform encephalopathy in the pig. J Comp Pathol 122:131-43 (2000)
JC Darboud, Inactivation of prions in daily medical practice. Biomed & Pharmacother 53:34-8 (1999).
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