OSEL - Research Program Areas >> bisphenol A, endocrine disruptors) released from medical device

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- Research Program Areas - Host Responses: Tissue-Materials ... The data on potential adverse effects

of medical device materials and

chemicals

gathered ... bisphenol A, endocrine disruptors) released from medical device ...

http://www.fda.gov/cdrh/osel/programareas/Tissuematerials.html

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January 27, 2005 Program

Area: Host Responses: Tissue-Materials Interactions,

Tissue-Device Interactions Scope:

The OSEL "Host Responses: Tissue-Materials Interactions, Tissue-Devices

Interactions" Program encompasses an interconnected program of laboratory

research, risk assessment, and standards development activities designed to

provide a scientific basis for regulatory decision making in CDRH. The data on

potential adverse effects of medical device materials and chemicals gathered

from pre-clinical experimental approaches in this Program are used to reduce

uncertainties in assessing risks to patients exposed to physical and chemical

insults, and protect their health. Background:

In 1983, the Bureau of Radiological Health and the

Bureau of Medical Devices were merged into the Center for Devices and

Radiological Health. This merger presented the new Center with a disparity

between the research programs devoted to radiation issues and those devoted to

medical device issues. In addition, a discontinuity existed between classical

chemical toxicology and the potential adverse health effects posed by exposure

to medical devices. To address this need, OSEL expanded the existing radiation

research program to include medical device toxicology. More recently, the

program has evolved to address the development of toxicological and

microbiological approaches to risk assessment and investigation of biological

issues relating to infection control and tissue-engineered medical products

(TEMPs). Program

Description: The "Host Responses:

Tissue-Materials Interactions, Tissue-Device Interactions" research

program encompasses two major areas: 1) Biological Effects of Chemicals and

Medical Device Materials, and 2) Infection Control. 1)

Biological Effects of Chemicals and Medical Device Materials OSEL is

conducting a wide range of projects designed to examine the biological effects

of chemicals released, intentionally or unintentionally, from medical device

materials or the tissue-device interactions themselves. The general goals of

these studies are to evaluate the safety of these chemicals and materials and

to develop or refine test methods that improve preclinical testing of device

materials. Studies in this area fall into several subcategories: Immunological/ Inflammatory/ Proliferative effects.

OSEL is conducting research to examine the immunological, inflammatory, and

proliferative effects of materials and chemicals released from materials,

including examination of the stimulation of chronic inflammation by particles

using both in vitro and in vivo models, and the induction of allergic responses

by material constituents, such as natural rubber latex proteins and metals. In

addition, OSEL is conducting research on the ability of compounds incorporated

into a device (e. g., drug-eluting coronary stents) that are intentionally

released in order to mitigate inflammatory or cell proliferative responses

induced by the device. Toxicity of compounds released from medical device materials.

OSEL is involved in investigation of the adverse effects of compounds (e. g.,

metals, DEHP, ethylene oxide, bisphenol A, endocrine disruptors) released from

medical device materials using small and large animal models, the development

of toxicity tests specific for medical device materials (e. g., polymers that

cure in situ), and the development of biomarkers to detect early cell and

tissue damage caused by compounds released from devices. Biological effects of nanotechnology products and tissue

engineered medical products (TEMPs). The development

of TEMPs and nanoparticles in health care delivery is at the cutting edge of

medical device technology. OSEL is developing test methods to examine the

potential tissue interactions of these materials and medical devices, such as

TEMPs scaffold materials and nanoparticles, in patients receiving the device

and on the cells and tissues that are components of the device. 2)

Infection Control Infection

at the site of an implanted device represents a potentially devastating event,

often requiring surgical intervention to remove the device. Prevention of

infection is the key to infection control and a wide range of CDRH-regulated

devices are required to ensure sterility in surgical procedures. OSEL

scientists have addressed the issues of infection control through the

development of cleaning procedures for new and reusable devices; examination of

disinfection and sterilization equipment and procedures; assessment of chemical

sterilant residuals on devices; development of test methods to ensure that

barriers such as surgical drapes, gowns and gloves are tested for effectiveness

in preventing transmission of microorganisms; and evaluation of the impact of

bacterial adherence to materials (biofilms and endotoxins) on infection risks. Relevance

to FDA And Public Health Impact: The experimental studies

in this laboratory research program generate independent data for use in

assessing toxicological risks and for developing standards and guidance

documents. OSEL remains at the forefront in medical device toxicology and for

developing methods for risk assessment. Specifically, OSEL serves as an

independent source of data on medical device toxicology and risk assessment for

risk managers in CDRH Offices. These data and risk assessment provide a

scientific basis for development of important pre-clinical and post-market

activities, such as development of ASTM standards for testing biological

responses to particles both in vivo

(F1904-98) and in vitro

(F1903-98), ISO standards (e. g., ISO 10993-17) for establishing tolerable

intake values, Federal rule-making (e. g., for natural rubber latex protein

content in gloves and condoms), and for risk management decision-making in the

Center (e. g., FDA Public Health Notification for DEHP in medical plastics). Five

Year Objectives: Long-term objectives include: 1)

develop and establish test methods and models for evaluation of potential

adverse effects of medical device materials, and medical devices, including

elucidation of new, clinically relevant, and sensitive biomarkers to predict

adverse effects in the preclinical stages of product development, and 2)

characterize the potential adverse effects using pre-clinical laboratory models

and utilizing the data to predict the likelihood of adverse effects in humans. Project

Abstracts: Abstract

-Toxicity of Chemicals released from Medical Device Materials FDA is

concerned with the biological effects of low levels of chemicals released,

intentionally or unintentionally, from medical device materials. For example,

medical devices that contain plastics are used in a large variety of medical

procedures preformed in clinical and hospital settings. During certain medical

procedures, the possibility exists of exposure of patients to chemicals that

could leach out of the plastics; these plastics include IV and blood bags, where

the chemicals could leach from the plastic and into the solution inside the

bag. Recently, there has been public and Congressional concern about

"endocrine disruptor" compounds, such as DEHP and bisphenol A, that

can release from medical plastics and potentially disrupt normal hormonal

function, even at very low doses. Chemicals (such as metals and polymers)

released from orthopedic implants could leach directly into the body and blood

of patients. Medical devices may release chemicals used in manufacturing

(accelerants used for making latex gloves) or sterilization (ethylene oxide

residues) of medical products. In many cases, the doses received by patients

are unknown, but are likely to be small; however, the exposure of patients that

could exist for extended time spans is of concern. In OSEL labs, we want to

determine and understand 1) which chemicals are released from or leach out of

medical products and at what rate, 2) the dose to the patient, 3) the adverse

effects of the chemicals in laboratory models (in vivo and in vitro), and 4)

the tolerable intake levels for these chemicals in patients to protect their

health using the information gathered from this research project. The benefits

of this research to FDA/ CDRH include the discovery of new biomarkers/

endpoints that are more sensitive to low doses of chemicals that will 1) allow

us in the preclinical laboratory and regulatory setting to predict which

chemicals released will have adverse effects, and 2) ultimately allow

physicians in the clinical setting to intervene at an early stage to protect

patients' health. Abstract

-Preclinical assessment of cardiovascular devices and adjunctive therapies OSEL

investigates the safety and effectiveness of a range of interventional

cardiovascular and minimally invasive devices and related adjunctive

therapeutics using various swine models. An integral part of these

investigations is the assessment of the animal models currently used and the

development of more predictive models of device use and related failure modes.

Together, these models and the study of the models addresses the problems of

identification and assessment of regulatory science issues associated with

novel interventional and combination therapeutics. The models under study

include normal swine as well as animals with vasculopathy induced by obesity

(atherogenic high fat/ high cholesterol diets), mechanical manipulation

(balloon angioplasty or stenting), hormonal manipulation (castration, hormone

replacement therapy), hemodynamic alterations (vascular ligation, fistulas)

and/ or metabolic manipulation (diabetes mellitus). The results of these

studies 1) define preclinical regulatory issues for current and emerging

technologies, including device and combination products for the treatment of

primary cardiovascular disease, vascular restenosis resulting from medical

intervention, and thermal ablative technologies, 2) identify the critical

safety issues for current and emerging technologies based on failure modes

analysis, and 3) directly impact on the effectiveness and consistency of the

Center's preclinical review of device applications prior to entry into clinical

trials and market access. Abstract

– Biological Effects of TEMPS Materials and Nanoparticles The

development of TEMPs introduces a variety of new materials, not previously used

in prosthetic devices, or familiar materials used for new clinical indications,

whose conditions for safe and effective use must be evaluated and established.

Materials used as scaffolds to support tissue for repair or to promote

regeneration of host tissues, include polymeric and natural materials, such as

alginates and chitosans. The field of nanotechnology is closely linked to TEMPs

and involves man-made and natural materials used for TEMPs scaffolds comprised

of nanoparticles (less than 100 nm). Nanoparticles formed by mechanical

stresses on the device migrate to various tissues, e. g., brain, initiating

proliferative, inflammatory or other untoward responses, which may have a

long-term impact on the host, such as alterations in immune status, development

of chronic inflammation, or tumor development. OSEL develops experimental in vivo and in vitro models for preclinical

evaluation of TEMPs scaffold materials (and chemicals released from them) and

nanoparticles in order to predict potential adverse effects on patients, and to

understand the mechanisms by which these work and how to ensure that the

products are safe and effective. The biological behavior (transport, fate, and

effects) of nanoparticles is poorly understood and OSEL will be required to

develop methods to fill critical knowledge gaps in this area. Products of

concern that contain nanoparticles include sunscreens and TEMPs scaffold

materials. In OSEL laboratories, two major approaches have been developed to evaluate

biological effects of these materials -an in vivo animal model to examine the

chronic proliferative, inflammatory, and immunotoxic responses of TEMPs

materials and nanoparticles, and an in vitro cell culture approach to evaluate

responses in specific cells and tissues. Target tissues for various materials

are determined based on the nanoparticles distribution in animals exposed to

particles. The evaluation of biological responses in cell cultures includes

analyses and validation of specific responses to injected materials, as well as

an indication of the general functional activity of critical cell types, such

as macrophages, lymphocytes and eosinophils. Specific cellular and molecular

effects of injected materials may represent useful preclinical and clinical

biomarkers for predicting potential chronic proliferative and inflammatory

responses and development of various chronic immunological diseases. Abstract

– Reuse and Infection Control As

hospitals and healthcare facilities seek to reduce the cost of medical

procedures, devices once developed for single-use, are now being reprocessed

and reused many times over. Reprocessing may be performed by the healthcare

facility or the device may be shipped to a third-party reprocessor. Examples of

devices that are reprocessed include surgical saw blades, ultrasound probes,

laparoscopy scissors, electrosurgical electrodes and biopsy forceps. Concern

over the reprocessing of single-use devices includes the possible transmission

of human adventitious agents (HIV, hepatitis, etc.) and dangerous device

malfunctions because of material breakdown due to multiple cleanings and

multiple use of a device that was initially designed to be used only once. OSEL

leads FDA's effort to evaluate the safety and effectiveness of cleaning

protocols and in developing proposed test soils for validation of cleaning

protocols. A validated cleaning protocol is necessary in order to present the

device for proper sterilization. A used device, whether intended for single use

or reuse, is exposed to biological matter, e. g., tissue, blood, body fluids,

and microorganisms. If the biological material is not removed immediately from

the device, it provides a nidus for microorganism growth and the development of

biofilm. Formation

of biofilm presents a tenacious barrier to effective cleaning and

sterilization. To confront these issues, adequate and validated cleaning

methods must be conducted to remove this matter and prevent it from being

transmitted by the device when it is reused the next patient. OSEL/ HSB

researchers evaluate cleaning protocols, develop "test soils" for

validation of cleaning protocols, and develop methods to prevent or breach

biofilm. This involves laboratory work on single use devices, simulation

soiling of devices, reviews of submissions from reprocessors, and literature

updates. OSEL also addresses the proper cleaning of reused medical devices and

safety of patients exposed to reused medical devices by actively contributing

to development of international standards. A well-defined standard is necessary

if both the reprocessors of medical devices and the regulatory agencies that

protect the public health are to agree on compliance with existing FDA policies

or to set new standards for how to reprocess used devices. Updated

January 27, 2005

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