Cobalt Chromium Toxicity

The 510 (k) process and metal on metal hip implants

Currently, various medical devices enter the marketplace via a regulatory pathway, the 510(k) process, monitored by the Food and Drug Administration (FDA). The 510(k) process loosely evaluates for safety and effectiveness, and approves the clearance of new medical devices based on ones that are substantially similar and previously cleared.

There are 3 classes of devices:

  1. Class 1: low-risk devices (e.g. toothbrushes, dental floss, band aids). Class 1 devices are subject to minimal regulatory controls. 
  2. Class 2: moderate- risk devices (e.g. powered wheelchairs). Class 2 devices require greater regulatory controls. 
  3. Class 3: highest-risk devices (e.g. metal on metal hips, replacement heart valves). Class 3 devices are supposed to undergo the highest level of regulatory control known as Premarket Approval, or PMA. 

According to the FDA, Premarket Approval (PMA) requires manufacturers to submit an application if they intend to market any new products containing new materials or differing in design from products already on the market. A PMA submission must provide valid scientific evidence collected from human clinical trials showing the device is safe and effective for its intended use.

However, many class 3 devices do not undergo PMA. They are cleared through the 510 (k) process, claiming substantial equivalence to preamendment devices, or comparable devices already on the market. Unfortunately, this allows companies a means of avoidance in testing their products for safety and effectiveness before releasing them on the market.

 NEJM — The 510(k) Ancestry of a Metal-on-Metal Hip Implant

In Depth Study Provides Closer Look between Metal on Metal Hip Prostheses and Cobalt-Chromium Toxicity

There is recent interest in the health consequences attributed to metal on metal hip implants and toxic levels of chromium and cobalt released from bearing surfaces and metallic junctions. There are various sources of cobalt and chromium exposure such as occupational and environmental.  Nowadays, concern over cobalt and chromium toxicity is focused on the corrosion of biomedical implants, like metal on metal (MoM) prostheses. The effect of toxicity from these metal ions is dependent on a multitude of factors. For instance, in an industrial setting, toxicity is influenced by the duration of exposure, ion concentration, and entry routes into the body (i.e. skin or respiration). On the other hand, the release of cobalt and chromium ions from MoM devices is an internal exposure rather than external. However, toxicity from MoM implants is contingent on duration of exposure and chemical composition of the implant. According to the article, “It has been determined that these implants release particulate metal debris in the form of corrosion with or without abrasion particles.”

Patients who underwent MoM hip replacement have a range of 5-100 parts per billion of chromium and 5-300 parts per billion of cobalt present in their blood and tissues. In addition, patients also suffer from adverse local tissue reactions (ALTR) and adverse reaction to metallic debris (ARMD) leading to tissue necrosis, pseudotumors, and lesions. The reactions are caused by a combination of metal toxicity and a hypersensitivity reaction. Analysis of tissue recovered from patient with MoM implants revealed necrosis from metal wear debris and corrosion products in the surrounding tissue. Elevated levels of cobalt and chromium ions were also detected in the collected tissue samples in comparison to controls. The study demonstrated a 2.5 fold increase of tissue cobalt levels and a 9 fold increase of tissue chromium levels in patients with MoM hips compared to the controls.

It is natural to have trace amounts of chromium and cobalt because they are required for certain metabolic functions. Glucose metabolism requires chromium to increase the effects of insulin on carbohydrates. Cobalt is involved with Vitamin B12’s biological activity. Only a few specific proteins use the metals and therefore require only trace amounts. However, cobalt and chromium are extremely toxic at high concentrations. The study indicates the effects of cobalt toxicity include irreversible cardiomyopathy, vision or hearing impairments, hypothyroidism, and polycythemia. The effects of chromium toxicity are associated with damage to multiple tissues and kidney and liver failure. Patients implanted with MoM hip prostheses develop an “accelerated inflammatory reaction frequently associated with tissue necrosis and cellular toxicity”. This is known to cause necrotic tissue and formation of pseudotumors.  Furthermore, cobalt and chromium toxicity can interfere and impair certain biological mechanisms and functions and lead to necrotic and apoptotic cell death.

Source: Molecular analysis of chromium and cobalt-related toxicity

Risk of Infection Secondary to Immunosuppression From Metal on Metal Wear

There is literature and research suggesting a risk of infection from wear products in metal on metal (MOM) hip implants. According to this article, wear products may hinder the immune system via accelerating bacterial growth, possible antibiotic resistance, and a heavy metal reaction. MOM implants were popularized as a result of their supposed longevity. However, metals employed in MOM hip implants degrade from wear, corrosion, and over time. MOM bearings release small amounts of metal ions or particles, and in relatively high numbers results in corrosion. Metal debris in the body prompts an inflammatory response. An inflammatory response stems from various pathological changes in the body. Metal debris can cause adverse local tissue reactions (ALTR), hypersensitivity, and osteolysis (destruction of bone). Recent studies found metal debris presents an ideal environment for bacterial growth.

A major concern for patients is the release of metal into the tissues secondary to wear and corrosion from MOM hip devices. Specifically, rough particles from MOM implants cause local damage, such as ALTR. This results in an increase of metal particles and ions released into the blood stream and surrounding tissues. The article highlights that the nature, size, and amount of particles can determine the effects it has on the body, and subsequently, the body’s reaction to those effects. Metal ions are generated even in MOM implants with corrosion-resistant alloys. Different types of corrosion cause metal particle release. For instance, fretting corrosion causes damage on the surfaces of articulating structures from movement. Cobalt- chromium alloys release metal ions which can produce toxic effects in the body. The article states that cobalt levels were approximately 6 fold higher in patients post MOM implantation compared to pre-implantation. There is a correlation between wear rates and the amount of metal ion levels; the higher the wear rate, the higher the level of metal ions.

Corrosion from MOM implants can influence the immune system and the immune response via different organs and their immune related mechanisms. Metal ions travel in the body through lymph and blood hindering the immune response. The study reveals that simply having a foreign body is enough to require only a small amount of bacteria to cause an infection. Ion release may damage DNA. Cobalt chromium particles can actually damage DNA via its cellular barrier. Metal particles pose the possibility for carcinogenesis. Patients with MOM implants also have a decrease in the immune cells responsible for destroying tumor cells.

The spleen and liver are vital organs regarding immunological mechanisms.  The spleen is vulnerable to corrosion byproducts which alter the number of immunocompetent cells. This illustrates how metal ions reduce the defense against immunocompromising organisms like bacteria. A recent study indicates that chromium ions can collect in the liver. Elevated metal ions in the liver may stimulate hepatocellular necrosis (death of liver cells). Corrosion products from cobalt chromium implants inhibit the release of cells necessary to kill bacteria. The cobalt chromium particles produce toxicity because they create a low pH concentration in the cells that try to destroy bacteria. In addition, bacteria have developed mechanisms to resist metal toxicity, and as a result, are also becoming resistant to antibiotics. This has significant consequences since patients with MOM prostheses are more susceptible to infection at the implant site.

Source: Effects of metal-on-metal wear on the host immune system and infection in hip arthroplasty

Examining the correlation between prostheses failure and elevated metal ion levels in patients with metal on metal hip implants

This study focuses on whether or not higher metal ions in the blood could help determine the likelihood of prostheses failure in patients with metal on metal (MOM) implants or total hip arthroplasty. The study involved 597 patients who received hip implants approximately one year prior. Patients with failed prostheses and patients with non-failed prostheses were compared via their blood metal ion levels. A prosthetic was considered a failure if they were revised, a revision was pending, or the patient reported poor hip function.

Patients with failed implants had elevated cobalt and chromium blood levels compared to patients with non-failed hips.  Patients with failed hip resurfacing (replacement of the joint’s articular surface) had less blood cobalt levels than patients with failed total hip arthroplasty (surgical removal of the femur’s neck and insertion of a stem deep within the bone connecting with the pelvic socket and liner). There was not a significant difference in blood chromium levels between the two procedures.

The presence and amount of the metal ions were good indicators of whether or not a hip would fail. There was a 23% increase in failure among patients with a total hip arthroplasty for each increase in 1 part per billion (µg/L) of metal ions. Whereas, patients with hip resurfacing had a 5% increase in failure with each increase in 1 part per billion (µg/L ) of metal ions.

In conclusion, there was a direct correlation between higher levels of blood metal ions and metal on metal hip resurfacing and total hip arthroplasty failures.

Source: Surveillance of Patients with Metal-on-metal hip resurfacing and total hip prostheses

Modularity and Total Hip Arthroplasty

Total hip arthroplasty (THA), also known as a hip replacement, involves replacing the hip joint with a prosthetic implant. The surgical procedure is supposed to improve a patient’s quality of life and function. The outdated method of hip replacements was called monoblock. Modularity, implants with at least one modular junction, is employed for total hip arthroplasty. Modularity involves prosthetic hip implant components available in multiple segments, or parts, rather than a single piece (monoblock implants). The popularity of modular implants results from their variations in leg length and size, degree of offset, and version. Modular implants are meant to accommodate a patient’s unique anatomy.

Unfortunately, corrosion, fretting, and fatigue failure of the implants are progressively occurring in the dual modular implants. Evidence suggests a revision rate of 8% to 15% among metal on metal total hip arthroplasty. As a result, modular implants are now under close supervision.

Modularity evolved with the development of the modular femoral head-neck junction. The modular head-neck junction utilizes metallic alloys head alternatives, leg length and offset adjustment, and bearing replacement resulting from wear. Modularity of the head-neck junction occurs at a taper functioning by joining two rotating components in the hip implant. The two components of the taper are a trunnion and bore. The trunnion compresses the bore when it expands, interlocking the two parts, creating stability. A larger head-neck taper may lead to an increased dislocation rate because the prosthesis is impacted faster by different range of motions. However, smaller tapers may lead to increased junction fretting and corrosion.

The article differentiates between two design features: metaphyseal neck-stem modularity (DePuy), and modular neck or proximal modular stems (Stryker). A metaphyseal modular stem has an implant with a distal junction placed distal to the femoral neck. Whereas the proximal modular stem has the distal junction proximal to the femoral neck. The taper connections undergo various physiological stresses depending on the location of the modular junction. Both tapers have the potential to cause neck-body dissociation, elevated levels of metal debris, fretting, and corrosion. Corrosion is the main source for modular implant failure.

Many modular femoral stems are composed of a cobalt-chromium or titanium alloy. The metal implant can corrode from stresses and disruptions. Metal ions are released secondary to the corrosion resulting in elevated serum metal ion levels. Corrosion and fretting cause loss of mechanical integrity of the implant, local tissue infiltration, and adverse local tissue reactions (ALTR). There are multiple sources for head-neck taper corrosion including crevice, fretting, and galvanic. Fluid can enter a gap between the trunnion and bore causing crevice taper corrosion. Fretting corrosion can occur from movement of the head relative to the neck; this is the main source for failure at the modular junctions. Crevice corrosion is reported in 35% to 40% of mixed-metal tapers, and 9% to 28% in single- alloy tapers.

Corrosion is time-sensitive and accelerated with mechanical stresses. Increased local and systemic metal particle exposure is connected to increased corrosion at the taper. Even in properly working metal on metal hip implants, cobalt chromium levels are roughly five fold higher than in patients with other hips. Head-neck interface corrosion results in inflammatory responses, local osteolysis and synovitis. Subsequently, metal particles were found in various organs. Corrosion byproducts stem from adversely affected metals at the taper junctions. Chromium phosphate is one such byproduct associated with femoral head-neck junction corrosion and substantial inflammation. This inflammation causes bone resorption and osteolytic reactions (bone loss). Corrosion and metallosis results in elevated cobalt levels in synovial fluid; this is linked to thyroiditis, auditory disturbances, and granulomatous lesions. Arthroprosthetic cobaltism, increased cobalt levels, is connected to systemic symptoms from malfunctioning hip implants.

Source: Modularity of the Femoral Component in Total Hip Arthroplasty 

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