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U.S. Department of Health and Human Services

About FDA

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FY 2001 Device Performance Analysis and Modeling

Many device failures that occur are related to materials problems, both for implantable and non-implantable types of devices. The development of chemistry- and materials-oriented test methods and performance requirements for devices is important for studying and predicting device failure modes and establishing performance criteria that will help ensure device safety and effectiveness. Such test methods and performance requirements minimize the regulatory burden on the agency and industry through the development and use of consensus standards and/or Guidance Documents. The development of these types of documents, especially if minimum performance criteria can be developed, would greatly aid manufactures and reviewers alike and lead to improved products by preventing failures through known mechanisms. Alternatively, manufactures could certify conformance to these standards as part of FDAMA.

There are three major areas of focus for this program area. The first is assessing those devices that rely on chemical measurements or mass transfer for their performance. The second is developing bench test methods and requirements related to mechanical performance, reliability, and materials changes, such as strength, elongation, gas mechanics parameters, durability, abrasion resistance, and corrosion resistance. The third is developing computer and animal models that simulate clinical conditions, which can be used to supplement bench data in predicting device clinical performance and failure modes. Included in this is the development of experimental pathology methods for evaluating device performance in vivo.

ODE is being provided with the extensive technical sections for a manufacturer's guidance for gaseous fluorocarbon retinal tamponades. As a result of this work, a computer-based biological model to better understand the mode of action, adverse effects, and the performance of the tamponade is being developed. With this model scientists are able to predict clinical adverse ocular pressures and the duration of the gas bubble in the eye from the molecular properties of the gas and conditions of use. Other biochemical and biological properties of the gases are being used in the construction of the guidance. Also, work is being done on in vivo polymerized medical devices in order to provide ODE with the technical and test sections for a manufacturer guidance document. Traditional testing according to ISO 10993 is of dubious applicability to these devices. The tests in the guidance need to relate the chemistry of the starting, intermediate and finished materials to the performance and biocompatibility of the device. Just completed is a three-center study of the performance of self-monitoring blood glucose meters. Four of the most prevalent meters along with three lots of test strips were evaluated against the hexokinase comparative method that was itself checked against a NIST standard reference serum. One hundred and fifty blood samples were used. Results were compared against the Clarke error grid and found to be clinically acceptable. This finding strongly supports CDRH's emphasis on user errors for these devices.

Work in the second major program area resulted in the development and validation of several standards for endovascular stents, which will be incorporated into guidance and help expedite product review in a very high workload area. Also, data were obtained on whether or not magnetic resonance (MR) imaging equipment adversely affects the performance of oxygen regulators. This work was undertaken in response to recent problems with projectile accidents and equipment malfunctions in the MR suite involving oxygen cylinders and other devices. It was determined that effects of MR on oxygen regulator performance are clinically insignificant and the results and methods will be published for the information of the agency, health care workers and industry. Work in the third major area included development of an animal model for evaluating tissue engineered cardiovascular devices and explant pathology methods for evaluating tissue engineered vascular grafts. This work provided critical and timely information on methods for assessing the safety and effectiveness of these new and rapidly emerging types of technologies.

Endovascular Stents Standards Development

Key words: recoil; standards; stents; test method; vascular stents

Figure 1. Chart measuring the recoil of three stent designs

Fig. 1 The recoil of three stent designs was measured using five different test methods. Method A is the final, published ASTM method; Method B is a method described in an early ASTM draft. Literature values (from Barragan, et al., 2000) are shown for reference.

OST continues to lead the effort to develop consensus standards for endovascular stents. The goal is to develop a series of standardized bench tests that, together, may be predictive of clinical performance (see table) and facilitate premarket reviews for these devices. During 2001, the first two ASTM standards for stents, F2079 Test Method for Measuring Recoil of Balloon-Expandable Stents, and F2081 Guide for the Characterization and Presentation of the Dimensional Attributes of Vascular Stents, were published. OST engineers performed a critical laboratory evaluation of the published test method for recoil (figure 1) to determine if a) it could be implemented on most contemporary designs, b) the results were repeatable, c) the results correlated with clinical experience, and d) the modifications to the method could improve the data (see bar chart). As a result of this effort, revisions to the published standard have been proposed and balloted.

The standards development activity continues at an aggressive pace, with six additional standards at various stages of development. These include test methods for fatigue testing, securement on the delivery system, radiopacity, longitudinal flex strength, and radial stiffness, and a guide for performing finite element stress analysis.

Bench Data vs. Clinical Outcome

  Stent Restenosis Rate Recoil Metal Area
  GRII 43% 11% 16%
  Wiktor 47% 8% 8%
  Micro II 25% 7% 14%
  Multilink 15% 5% 15%
  Palmaz-Schatz 20% 5% 20%

Table 1


Promoted Ignition Testing of Medical Oxygen Regulators

Key words: oxygen regulator, fire, explosion, standard, ignition test

A promoted ignition test was developed with NASA to reduce the frequency and severity of fires that have been occurring in medical oxygen regulators. The test exposes regulators to an ignition event simulating worst-case conditions that occur clinically. Most recently, variations of one regulator model were tested to evaluate test method reproducibility and utility in assessing the safety of regulator design changes (figures 2 and 3). Scientists are also conducting round robin testing to facilitate finalization of the standard. Many manufacturers have revised their regulator designs to comply with the standard, and since then there have been no fires reported with such regulators.

Figure 2. Oxygen regulator exploding
Fig. 2 Oxygen regulator exploding during test
Figure 3. Remains of exploded regulator
Fig. 3 Remains of exploded regulator after test

Mechanical Stability Analysis of Robotic Surgical Arm

Key words: robotics, robotic assisted surgery

In response to an ODE request, OST conducted a stability analysis of a robotic arm used in minimally invasive surgical procedures. After examining technical information and experimental data provided by the arm’s manufacturer, OST performed an analysis of the arm‘s mechanical stability. Of particular interest was the arm’s susceptibility to vibration when it was attached to the operating bed rails. Measurements of vibrational magnitude and duration that resulted from an applied force were taken at the arm’s maximum and minimum stable configurations. Scientists conducted tests with a simulated bed railing in the laboratory and at the Bethesda Naval Hospital using actual operating tables. Analyzed results were forwarded to ODE with recommendations concerning the device stability.

This is one of the newest types of devices reviewed in CDRH. Based on the media coverage and manufacturer interest in remote surgical devices, it is anticipated that the laboratory support for this product application is the first of many to come.

The Effect of a 2T Magnetic Field on Flow Delivered by Oxygen Regulators

Key words: MRI, oxygen regulator, flow rate, magnetic field

Not too long ago, a 6-year-old boy undergoing an MRI scan was killed by a portable oxygen cylinder that was pulled into the scanner’s magnetic field. Investigation of the incident led to questions about the operation of oxygen regulators in large magnetic fields in and near MR imagers. OST scientists obtained 17 oxygen regulators from several manufacturers, of types used with portable "E" gas cylinders. Flow rates were measured outside the 5-gauss line, and at two worst-case locations at the entrance to the bore of the FDA MOD-1 2T MRI scanner where the static magnetic field strength is 0.45 T and the spatial gradient field is 200 gauss/cm.

Flow rates for some regulators were changed by the magnetic field, with some increased and some decreased, though the magnitudes of the changes may not be clinically significant. In general, for the regulators tested, researchers observed greater differences between labeled and measured flow outside the magnetic field than differences between measured flow inside and outside the magnetic field. In some regulators, scientists observed a definite attractive force exerted on the regulator, though no force was great enough to pull the oxygen bottle from their hands. Interestingly, the flow rates of these regulators were not altered by the magnetic field more than the flow rates of the other tested regulators that did not exhibit an attractive force. The test results demonstrate that it is not possible to make general conclusions about the effects of large magnetic fields on oxygen regulators. This lack of a consistent effect is valuable information for the regulator users and manufacturers.

 Comparative Ocular Analyses in an Animal Model of Diabetes Mellitus

Adult female sand rat (6 months old) and pup (3 weeks old)Adult female sand rat (6 months old) and pup (3 weeks old)
Sand rats (8 months old) with (right side) and without (left side) cataracts
Sand rats (8 months old) with (right side) and without (left side) cataracts

Approximately 16 million Americans have diabetes mellitus, a complex group of syndromes that have in common a disturbance in the oxidation and utilization of glucose, which is secondary to a malfunction of the beta cells of the pancreas. There are at least two types and several subtypes. Type I (juvenile) or insulin-dependent diabetes mellitus (IDDM) is more likely to develop early in life, requires insulin injections to control the hyperglycemia, and accounts for 5-10% of all cases. Type II (adult) or non-insulin-dependent diabetes mellitus (NIDDM) is related to some "inappropriate" insulin secretion, occurs in 90-95% of the diabetic population, and is often well controlled by diet. Approximately 60% of the new cases are diagnosed in women. The prevalence of diabetes is higher in Native American, African-American (reportedly 50-60% higher), and Hispanic women than in white women. Thus, these women are at greater risk of developing long term complications. The complications of diabetes include heart disease, stroke, high blood pressure, kidney disease, nervous system disease, amputations, dental disease, and complications during pregnancy.

One of the most threatening aspects of diabetes mellitus is the development of visual impairment or blindness consequent to cataract formation, retinopathy or glaucoma. Diabetes affects the (outer) lens, middle (vitreous), and inner (retina) areas of the eye. The incidence of cataracts is greatly increased over the age of 50 years, slightly more so in women, compared with non-diabetics. Rates of cataract formation are often 50% higher in NIDDM than in non-diabetic persons. The elevated glucose concentrations, seen in diabetes, equilibrates between the lens and the aqueous surrounding it, leads to shifts in water that alters the shape and the opacity of the lens. In retinopathy, problems develop as a result of fluid leaking from blood vessels into the eye or abnormal blood vessels forming in the eye. In either case, vision can be affected. If retinopathy is not found early or is not treated, it can lead to blindness. There are often no symptoms of retinopathy until the damage has occurred. Animal models are needed to study the progression and end organ effects of diabetes.

Psammomys obesus or the fat sand rat (sub-family- Gerbillinae; Family- Muridae) is a common rodent in the Middle East, inhabiting the semi-arid regions with salty soils from Algeria to Saudi Arabia. It has been introduced into the laboratory for special studies on diabetes and renal function. This animal is unique in that it develops mild to moderate obesity, hyperglycemia, and the complications of diabetes such as cataracts, pancreatic atrophy, impaired renal function and ketoacidosis by dietary induction. The rodent also naturally develops otic cholesteatoma, spondylosis and intervertebral disc degeneration. OST has successfully completed pilot studies that demonstrate the anatomical and physiological similarities between P. obesus and the human diabetic.

The studies proposed will employ noninvasive spectroscopic techniques to record biochemical changes associated with the progression of a subject from normal to diabetic. Experiments will be based on a near-infrared diode laser, a unique animal model, ophthalmic instrumentation, and use of multi-variate statistical methods to delineate correlations between optical spectra and traditional indicators of diabetes progression (progression of cataract, glucose intolerance, and pancreatic function). Blood glucose and insulin levels of the animals will be closely monitored, and relevant ocular structures will be analyzed with light and electron microscopy. OST scientists propose that measuring the molecular changes in an animal model during the development of diabetes mellitus using this combination of blood measurements, in vivo optical spectroscopy, and tissue microscopy using the rodent, Psammomys obesus, will enable unprecedented documentation and correlation of the progression of the diabetic ocular pathologies.

Close-up view of experimental set-up for prototype dynamic light scattering ocular probe, sand rat and anesthesia unit

Close-up view of experimental set-up for prototype dynamic light scattering ocular probe, sand rat and anesthesia unit.

Large Animal Models of Vascular Disease and Therapeutic Device Interventions

Key words: minimally invasive techniques, vascular disease, angioplasty, radiofrequency ablation, preclinical animal models

CDRH has established a Laboratory of Large Animal Research to develop and study models of cardiovascular disease and therapeutic device interventions. OST scientists are using the lab to study the response of the coronary and carotid arteries to initial balloon angioplasty injury and then to subsequent re-intervention with angioplasty or stents for the treatment of restenosis. Results to date indicate that both animal gender and hormone state have a strong influence on the proliferative response to injury. The proliferative response is much greater in males than in females. Removing the ovaries, as a model of female menopause, results in a response similar to that seen in the males.

OST scientists are also examining the biophysics of radio-frequency ablation for the treatment of hepatic and renal tumors. The relationship of ablation volume to blood flow is being investigated along with the electrical properties of tissue. The research goals include improved understanding of both the mechanisms of action and the failure modes for these interventions. Results to date indicate that decreasing renal blood flow significantly increases the size of the ablation lesions attained in the kidney.

Physiologically Based Pharmacokinetic Modeling for Device Applications

Key words: bisphenol A, octamethycyclotetrasiloxane, pharmacokinetics

OST has developed several pharmacokinetic models to predict the bioavailability of chemicals exposed during medical device applications. In the past, these models have included degradation products from implanted materials, exposure to dialysis reuse degradation products, and ultrasound contrast agents. In the past year OST scientists developed models for exposure due to inhalation or implantation of octamethycyclotetrasiloxane (D4) and inhalation, oral, or implantation bisphenol A. The bisphenol A model currently under development will also include a pharmacodynamic model to predict disruption of estrogen binding to plasma proteins albumin and sex hormone binding globulin.

The expertise of OST scientists in predicting the bioavailability of degradation products is useful in assessing the risk of new device applications.