Why compliance is not good enough.

Although reducing risks for medical devices is an element of product liability risk management, reducing risks for medical device manufacturers is the ultimate objective. With so much riding on the product development pipeline, what can manufacturers do to ensure a successful launch and healthy return on their investment? We argue in this editorial that the operating environment for the medical device industry is so dynamic that compliance is not enough. Instead, we suggest that risk abatement must become a part of a medical device manufacturer's operating strategy. We outline a robust risk abatement strategy involving corporate cultural changes, scenario modeling tools, and implementation systems.

Novel anti-silicone surface-associated antigen antibodies (anti-SSAA(x)) may help differentiate symptomatic patients with silicone breast implants from patients with classical rheumatological disease.

The frequency of novel autoreactive antibodies to silicone surface associated antigens (anti-SSAA(x)) was measured in healthy control patients, symptomatic patients with breast implants, asymptomatic patients with breast implants, and control patients with classical rheumatological diseases. The frequencies of elevated anti-SSAA(x) antibodies in 310 symptomatic breast implant patients were 17.4% anti-SSAA(fn), 12.9% anti-SSAA(col1), and 7.4% anti-SSAA(col3) and 7.1% anti-SSAA(fbgn) [Normal (n = 173) = 0.6% for all four tests] (p < .005). In 11 asymptomatic breast implant patients, the frequencies of elevated values for the same anti-SSAA's were 0%, 9%, 0%, and 0% respectively, while in 50 patients with rheumatoid arthritis, the frequencies were 4%, 0%, 6% and 2% respectively. The anti-SSAA(x) profile for symptomatic patients with breast implants was different than the profile for control healthy patients (p < .005 on all eight tests) but differed significantly by two measures, anti-SSAA(fbgn) and anti-SSAA(col3), from the profile for the 19 patients with systemic lupus erythematosus. We conclude that anti-SSAA(x) antibodies levels in symptomatic patients with breast implants are elevated, that the antibodies are associated with symptoms, and that they differ both qualitatively and quantitatively from healthy controls, asymptomatic patients with breast implants, and symptomatic patients with classical rheumatological diseases.

Surface-modified diamond nanoparticles as antigen delivery vehicles.

Recognition of antigens by immunocompetent cells involves interactions that are specific to the chemical sequence and conformation of the epitope (antigenic determinant). Adjuvants that are currently used to enhance immunity to antigens tend to either alter the antigen conformation through surface adsorption or shield potentially critical determinants, e.g., functional groups. It is demonstrated here that surface-modified diamond nanoparticles (5-300 nm) provide conformational stabilization, as well as a high degree of surface exposure to protein antigens. By enhancing the availability and activity of the antigen in vivo, a strong, specific immune response can be elicited. Results are demonstrated for mussel adhesive protein (MAP), a substance for which conventional adjuvants have proven only marginally successful in evoking an immune response. Surface-modified diamond nanoparticles as antigen delivery vehicles are a novel example of the exciting marriage of materials science, chemistry, and biology.

Preservation of surface-dependent properties of viral antigens following immobilization on particulate ceramic delivery vehicles.

B-cell stimulation for the purpose of evoking an effective neutralizing humoral immune response is a surface phenomenon that is exquisitely specific to antigen conformation. Consequently, successful delivery of antigen, such as would be desired in a vaccine, entails preservation of an antigen's apparent native surface (conformational) properties. Prior to testing the actual vaccinating efficacy of delivered antigens, the surface properties could be assessed through a variety of in vitro and in vivo assays in which the measurement standard would be the properties of the antigens in their native state (whole virus). Using surface modified nanocrystalline carbon and calcium-phosphate ceramic particulates (carbon ceramics and brushite), we evaluated the surface activity of immobilized non-nuclear material extracted from HIV-1. Physical characterization showed that the particles with immobilized antigen ("HIV decoys") measured 50 nm in diameter (HIV = 50-100 nm) and exhibited the same zeta potentials as whole (live) HIV. In vitro testing showed that the HIV decoys were recognized by both conformationally nonspecific and specific monoclonal antibodies, were recognized by human IgG from HIV antibody-positive patients, and could promote surface agglomeration among malignant T-cells similar to live HIV. Last, in vivo testing in three vaccinated animal species showed that the HIV decoys elicited humoral and cellular immune responses similar to that evoked by whole (live) HIV.

Histopathologic study following administration of liposome-encapsulated hemoglobin in the normovolemic rat.

Liposome encapsulated hemoglobin is being developed as an artificial resuscitative fluid for in vivo oxygen delivery. In the present report, we examine the effect of accumulation of liposome encapsulated hemoglobin on the structure of reticuloendothelial organs following administration of liposome encapsulated bovine hemoglobin in the normovolemic rat. We have also examined the administration of the liposome vehicle, tetrameric bovine hemoglobin, and liposome encapsulated bovine hemoglobin that had been lyophilized with 300 mM trehalose and rehydrated just before injection. Following injection into the tail vein, rats were sacrificed and liver, spleen, kidney, and lung harvested at 2 h, 24 h, 1 week, and 2 weeks for analysis. Gross pathologic findings of animals injected with liposome encapsulated hemoglobin showed statistically significant splenomegaly with a waxy parenchymal pallor at early time points. Microscopic findings indicate that the liver and spleen are principally involved with liposome encapsulated hemoglobin removal over the course of 24 h with transient cytoplasmic vacuolization in tissue resident phagocytes as evidenced by both light and electron microscopic examination. Presence of liposome encapsulated hemoglobin in these vacuoles was confirmed by oil red O and prussian blue stains. Splenic weight was observed to decline after 24 h but still remained significant above sham-treated controls at 2 weeks and could be correlated with increased hematopoietic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Inflammatory intermediates produced by tissues encasing silicone breast prostheses.

Silicone prostheses, when implanted within the soft tissues of the breast, evoke an inflammatory reaction. In response to silicone exposure, inflammatory mediator production by individual cells has been observed in various experimental studies. In this study, inflammatory mediator production by periprosthetic tissues (whole organ) was measured. The mediator levels were correlated with both the tissue histopathology of the periprosthetic capsules and the clinical symptoms noted by each patient. Tissue surrounding breast implants removed at surgery from ten women (average age and implant duration 40 and 7 years respectively) was cultured in vitro for 24 hours. Control tissues consisting of (a) augmentation mammaplasty skin scars from eight additional patients and (b) knee synovium from seven orthopedic surgery patients with arthritis undergoing primary joint arthroplasty were similarly cultured. The mediators [interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and prostaglandin E2 (PGE2)] liberated into the culture media were measured by an enzyme linked immunosorbent assay. When compared to controls, the mediator levels of IL-6 and TNF-alpha were substantially greater, although IL-2 and PGE2 were lower. Levels varied greatly from patient to patient: in pg/ml per 10 g tissue, IL-2 ranged from 10 to over 1,000; TNF-alpha from 100 to 1,000; IL-6 from 100 to 1,000,000; and PGE2 from 100 to 10,000. The correlation between TNF-alpha and PGE2 levels was .5 between IL-6 and PGE2 was .6, and between IL-6 and TNF-alpha was .77. The correlation between TNF-alpha and IL-6 was statistically significant at a p-value less than .01. Elevated levels of TNF-alpha production were associated with an increased number of macrophages and overall tissue cellularity (p < .05). No significant relationship was observed between mediator production and clinical symptoms. We conclude that overall cellularity, specifically macrophages, in the periprosthetic capsule may lead to TNF-alpha production but that cytokine production by periprosthetic tissues alone is not a predictor of clinical symptomatology in patients with silicone breast prostheses.

Physicochemical and immunological basis of silicone pathophysiology.

Silicones, model biomaterials with almost ubiquitous applications, are the focus of a contentious debate. In this review, we will consider both established physicochemical phenomena and immunological phenomena; and then consider the human clinical phenomena that relate directly to them. We will explore the two competing theories of the biological activity of silicones, and we will discuss the weaknesses in the various arguments that silicone is inert. We conclude that from a pathophysiological perspective, silicones should be expected to be bioactive materials and that the physicochemical and immunological data at the experimental level are compelling.

Self-reported signs and symptoms in breast implant patients with novel antibodies to silicone surface associated antigens [anti-SSAA(x)].

In research animals, the immune adjuvant activity of silicone in eliciting antibodies to associated protein antigens is now well established. In humans, the immune adjuvant activity of silicone remains controversial. Clusters of data from various research groups are beginning to define the boundary conditions for future large epidemiological studies. In that spirit, this manuscript reports pilot clinical data from a serological study conducted 3 years ago and reported previously in this journal. Sera from a self-selected symptomatic population of patients with breast implants were assayed for elevated concentrations of antibodies showing binding avidity to silicone surface associated antigens [anti-SSAA(x)]. In that study of 249 patients, two distinct statistically significant subgroups were identified on the basis of the serological assay alone: patients without any elevated anti-SSAA(x) (negative) and patients with elevated anti-SSAA(x) (positive) (p < 0.001). In this study, a clinical survey returned by 226 of those patients was correlated with the previously acquired serological findings. The 11 most common clinical complaints reported by the 199 anti-SSAA(x) negative patients and by the 27 anti-SSAA(x) positive were compared and their frequencies analyzed. The 199 anti-SSAA(x) negative patients, as a group, showed a lower frequency of a variety of signs and symptoms compared to the 27 anti-SSAA(x) positive patients. Statistically significant differences were seen in three of the symptoms: fever, foot pain, and sleep disturbance (p < 0.05). In addition, the syndrome of fever in the absence of local chest pain was a significantly associated with anti-SSAA(x) positivity (p < 0.001).

Surface-modified nanocrystalline ceramics for drug delivery applications.

Drug delivery systems comprised of various types of carriers have long been the object of pharmacological investigation. The search has been stimulated by the belief that carriers will lead to reduced drug toxicity, dosage requirements, enhanced cellular targeting and improved shelf-life. Among the carriers investigated are complex polymeric carbohydrates, synthetic proteins and liposomal structures. For the past four years, we have been experimenting with a radically new class of carriers comprised of surface-modified nanocrystalline ceramics. While the ceramics provide the structural stability of a largely immutable solid, the surface modification creates a glassy molecular stabilization film to which pharmacological agents may be bound non-covalently from an aqueous phase with minimal structural denaturation. As a consequence of maintained structural integrity and owing to concentration effects afforded by the surfaces of the nanocrystalline materials, drug activity following surface immobilization is preserved. We have used successfully surface-modified nanocrystalline ceramics to deliver viral antigens for the purpose of evoking an immune response, oxygenated haemoglobin for cell respiration and insulin for carbohydrate metabolism. The theoretical principles, technical details and experimental results are reviewed. Surface-modified nanocrystalline materials offer an exciting new approach to the well-recognized challenges of drug delivery.

Drug delivery systems for the future.

Parenteral drug delivery systems have the potential to make drugs both safer and more effective. While research in this field has been active for over 30 years, the current fiscal constraints of health care delivery add a greater degree of urgency to finding a working system. The three competing technologies currently under development include prodrug or zymogen-like systems, simple soluble macromolecular systems, and complex particulate multicomponent systems. In this review, the advantages, disadvantages, and areas for further development of these three basic technology systems are compared and contrasted; the biophysical constraints are considered; and a model solution system using surface modified nanocrystalline ceramics is described.

A pathophysiological examination of the biophysics and bioreactivity of silicone breast implants.

Historically, silicones have been considered biologically inert materials, and have therefore been used widely in a variety of medical applications. Recently, controversy has arisen concerning the bioreactivity of silicone; reports of adverse inflammatory and immunological complications that may be evoked by silicone breast implants have appeared in the medical literature and have received great attention from the lay press. The phenomena said to be associated with silicones may be attributed pathophysiologically to the inherent surface activity of silicone. The human body's initial response to the silicone of breast implants is the adsorption of various plasma proteins, including clotting and complement proteins, to the implant surface. Other macromolecules in the biological milieu may follow. The conformational integrity of this adsorbed macromolecular layer affects much of the subsequent biological reaction. Clinically silent inflammation, locally significant inflammation, inflammation with constitutional symptoms, and inflammation with immunological activation are possible consequences.

Silicone breast implant pathology. Clinical data and immunologic consequences.

Silicone breast prostheses are medical devices, implanted subcutaneously or subpectorally, that are designed to replace or augment the volume occupied by breast glandular tissue. They are generally effective in creating tissue mounds, and their apparent medical benefit is primarily psychological. Recent data on immunologic phenomena associated with silicone exposure suggest to us that silicone breast implants may interact with native tissue in a way that is analogous to implantable vaccinating devices. Background information, clinical findings, and possible immunologic consequences are presented.

Animal model of porous polyethylene orbital implants.

Ophthalmologists continue to search for the ideal orbital implant for the anophthalmic socket. The successful long-term clinical performance of an implantable prosthesis is highly dependent on the materials from which the device is fabricated. Among the materials issues are chemistry, surface texture, and porosity. Polyethylene, a polymer comprised of simple hydrocarbon chains, is highly resistant to biological degradation and possesses mass and fabrication properties that would be favorable in an orbital implant. In this report, our early experimental experience with porous polyethylene orbital enucleation implants is reported. Our findings are sufficiently encouraging to warrant further exploration and refinement of the polyethylene device examined.

Cross linking encapsulated hemoglobin with solid phase supports: lipid enveloped hemoglobin adsorbed to surface modified ceramic particles exhibit physiological oxygen lability.

To reduce hemoglobin toxicity, a cross linking agent is generally used. To preserve hemoglobin function, an allosteric modifier is generally used. Historically, the use of one has precluded the use of the other. A potential solution to this problem was investigated. Hemoglobin AO was adsorbed irreversibly to carbohydrate coated nanosized diamond particles and then encapsulated in a standard mixture of phospholipids. Endotoxin free preparations with concentrations of bound hemoglobin near 10 g/dl were achieved with as little as 0.1 g/dl of free hemoglobin and remained stable over a 48 hour period. By transmission electron microscopy these particles appeared roughly spherical and measured approximately 75 nanometers well below that of alveolar capillary vessels. In shallow pH gradients, liquid electrophoresis demonstrated that such constructs exhibit Bohr effect behavior by the induction of a dramatic surface charge inversion at around pH 6.8. To evaluate oxygen lability, oxygen saturation trials were conducted in isosmolar physiological salts. Normal sigmoidal binding behavior of O2 over a typical pO2 gradient could be modulated by systemic levels of pyridoxyl-5-phosphate. Constructs with a P50 as low as 12 mm Hg could be increased to 37 mm Hg with the allosteric effector. Viscosity and bio distribution studies are to follow. The use of solid phase nanocrystalline supports to cross link hemoglobin may reduce the toxicity of free hemoglobin while still enabling the use of allosteric modifiers.

Immunology of silicone breast implants.

Understanding the immunology of silicone breast implants, at present, consists of reconciling an increasingly large body of data with an older, established, but otherwise unsubstantiated theory. Despite the variety of silicone breast implants, there are nevertheless certain phenomena that occur with all silicone gel-filled devices. Recent clinical findings suggest that in some patients, silicone will act as an adjuvant on native macromolecules and render them immunogenic. The purpose of this review is to highlight biophysical and clinical phenomena that warrant further investigation.

High-purity resident tissue macrophage isolates from human synovium and periprosthetic tissues using immunomagnetic techniques.

Destruction of periarticular and periprosthetic bone by activated macrophages, a process often termed "macrophage mediated osteolysis," is recognized as a leading mechanism of aseptic arthroplasty failure. To develop effective interventional approaches and increase the longevity of implanted joint prostheses, the pathobiology of activated human-synovium-derived macrophages needs to be better characterized. The first step toward achieving this research objective is the acquisition of pure populations of macrophages from human synovial tissue. A simple, fast, and highly efficient method for isolating a relatively pure population of macrophages from periprosthetic tissue received from either primary or secondary arthroplasty is presented. This technique uses murine monoclonal antibodies (IgG) that recognize a phagocyte-specific marker, CD68, for primary binding, and sheep anti-murine IgG antibodies bound to polystyrene-coated magnetic microspheres for secondary binding. While the primary antibody specifically labels CD68-positive phagocytes in the digestion of synovial and periprosthetic tissue, the secondary antibody bound to polystyrene-coated iron oxide beads facilitates the removal of CD68-positive cells from CD68-negative cells by anchoring the former with a magnet. This protocol requires centrifugation only in the washing steps, which reduces the frequency of cell death and altered cell morphology. The patient population includes three primary and eight revision arthroplasties. The tissue macrophage isolation protocol yielded on average 4 x 10(5) cells/g tissue, of which 91% were viable nonspecific esterase positive macrophages. The experimental results suggest that immunomagnetic beads coupled to anti-CD68 enable the isolation of a purified population of resident tissue macrophages suitable for further biologic characterization.

Synovial metallosis resulting from intraarticular intramedullary nailing of a distal femoral nonunion.

An 80-year-old man sustained a T-shaped supracondylar fracture of the femur associated with distal one-third shaft comminution. Initial failure of a 95 degrees angle blade plate was followed by insertion of an intraarticular intramedullary nail stabilized with static locking-screw fixation. A second failure of the implant was treated by extraarticular tension band condylar buttress plate osteosynthesis. Severe knee synovial metallosis was found at the time of removal of the intraarticular nail device.