UNIVERSITA’ DEGLI STUDI DI ROMA TOR...

MAGNESIUM ALLOYS FOR BIOMEDICAL APPLICATIONS

A REVIEW

UNIVERSITA’ DEGLI STUDI DI ROMATOR VERGATA

OUTLINE

Magnesium and its alloys

Biodegradable/bioresorbable materials

Toxicity

Characterization

Applications

IMPURITY ELEMENTS

Iron, nickel and copper are extremely deleterious because of low solubility limits and provide active cathodic sites.

At the same concentration, the detrimental effect of these elements decreases asfollows: Ni, Fe, Cu

Tolerance limits are influenced by the presence of third elements: the iron tolerancelimit for magnesium-aluminum alloys depends on the Mn concentration

IRON

• Galvanic coupling

• Al-Fe compound is cathodic to the Mg matrix

• 7% Al → 5wt-ppm Fe

• 10% Al → too low to be determined

NICKEL

IMPURITY ELEMENTS

MANGANESE

• Mn enhances ductility

• Mn does not improve corrosion resistance, but reduces the harmful effect ofimpurities

• 1% Mn sharply decreased the corrosion rate of Mg when Fe And Cu impuritycontents exceed their tolerance limits

Two possible routes

1. Mn combines with Fe in the molten Mg alloy and forms an intermetalliccompound which settles to the melt bottom, lowering Fe content

2. Mn encapsulates Fe particles, making them less active as local cathodes

IMPURITY ELEMENTS

ALLOYING ELEMENTS

ALUMINUM

• Solid solution

• Mg17Al12

• Al improves the corrosion resistance (passivating element)

ZINC

• Zn can increase the tolerance limits and reduce the effect of impurities once the tolerance limit has been exceeded

• The addition of 1% Zn to pure Mg raises the tolerance limit for Ni

• Zn improved the tolerance for Mg-Al alloys for Fe, Ni, Cu

CALCIUM

• Ca contributes to solid solution strengthening and precipitation strengthening

• Grain refining agent

• In binary Mg-Ca alloys Mg2Ca is formed while in Al containing alloys Al2Ca formsfirst. Both phases improve creep resistance due to solid solution strengthening and precipitation strengthening

•It is well tolerated in the human body since it is an essential cation

ALLOYING ELEMENTS

LITHIUM

• Li is able to change the lattice structure from h.c.p. to b.c.c.

• It can be used to enhance ductility and formability of Mg alloys but it has a negative effect on strength

RARE EARTH ELEMENTS (RE)

RE elements are chemically classified by their ionic radii in three groups:

1. Light RE elements (from La to Pr)

2. Medium Re elements (from Nd to Gd)

3. Heavy RE elements (from Tb to Lu)

•Large solid solubilities in Mg: Y, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu

• Limited solubility in Mg: Nd, La, Ce, Pr, Sm, Eu

• RE is kept in solid solution → solid solution strenghtening

• RE can form complex intermetallic phases with Al or Mg → obstacles for dislocationmovements

ALLOYING ELEMENTS

Mg ALLOYS FOR BIOMEDICAL APPLICATIONS


The purpose of biodegradable imlants and coatings is to support tissue regenerationand healing in a specific application by material degradation and concurrent implantreplacement through the surronding tissue

Biodegradable materials have an advantage over existing biodegradable materialssuch as polymers, ceramics or bioactive glasses in load bearing applications thatrequire a higher tensile strenght and a Young’s modulus that is closer to bone

Mg2+ is an essential element and present in large amounts (the fourth most abundant cation) in the human body

Rapid corrosion is an intrinsic response of magnesium alloys to chloride containing solutions, including the human body fluid or blood plasma

The degradation of magnesium alloys leads to hydrogen evolution and alkalization

In the human body, the evolved hydrogen bubbles from a corroding magnesium implant can be accumulated in gas pockets next to the implant, which will delay healing of the surgery region and lead to necrosis of tissues, because the gas pockets can cause separation of tissue layers

In the worst case when large hydrogen bubbles are present in the blood circulating system, there will be a risk that the bubbles may block the blood stream, causing death of a patient


The local alkalization can unfavorably affect the pH dependent physiological reaction balances in the vicinity of the magnesium implant and may even lead to an alkaline poisoning effect if the local in vivo pH value exceeds 7.8 in that region.

A strategy to solve these problems is to slow down the biodegradation (i.e. corrosion) of magnesium alloys, so Mg2+ ions, H2 bubbles and OH- ions will be generated more slowly, which will allow the human body to gradually adjust or deal with the biodegradation products

A corrosion resistant coating can significantly delay the initiation of biodegradation.

A delayed degradation process is critical to a biodegradable implant, as the implant needs to fully function for a certain period of time before the surgery region start healing

The corrosion resistant film formed on a magnesium implant should also be wear resistant, so the film will not be damaged by scratching during implanting



Bulk properties dictate the mechanical properties of biomaterials

Tissue–biomaterials interactions are surface phenomena and are governed by surface properties

INFLUENCE OF THE BIOLOGICAL ENVIRONMENT

•The presence of biological macromolecules can influence the rate of corrosion byinterferring in some way with the anodic or cathodic reactions

•The biological molecules could upset the equilibrium of the corrosion reactions byconsuming one or other of the products of the anodic or cathodic reaction. Forexample, proteins can bind to metal ions and transport them away from the implantsurface: this will upset the equilibrium across the charged double layer allow furtherdissolution of the metal

•The stability of the oxide layer depends on the electrode potential and the pH of the solution. Proteins often have electron-carrying roles and thus can affect the electrodepotential, and bacteria can alter the pH of the local environment through the generation of acidic metabolic products

•The stability of the oxide layer is also dependent on the availability of oxygen.

•The adsorption of proteins onto the surface of materials could limit the diffusion ofoxygen to certain regions of the surface. This could cause preferential corrosion ofthe oxygen-deficient regions and lead to the breakdown of the passive layer

•The cathodic reaction often results in the formation of hydrogen.

• In a confined region, the buildup of hydrogen tends to inhibit the cathodic reactionand thus restricts the corrosion process. If the hydrogen can be eliminated, then the active corrosion can proceed.

•It is possible that bacteria in the vicinity of an implant could utilize the hydrogen and thus play a crucial role in the corrosion process

INFLUENCE OF THE BIOLOGICAL ENVIRONMENT

TOXICOLOGY

The presence of aluminium is generally regarded as a risk factor, being implicated in the onset of different degenerative pathologies, e.g. Alzheimer’s disease (AD), muscle fiber damage, and decreased osteoclast viability

The linkage between aluminium and AD is controversially discussed, starting a debate whether aluminium is deposited in brain as a result of AD or whether it acts as its inducer or accelerator and concluding that is neurotoxic and cannot be disregarded as a factor in AD

On the other hand, binary Mg-Al alloy did not show negative effects on the viability of blood vessel related cells, human umbilical vein endothelial cells and rodent vascular smooth muscle cells

Open pore AZ91D scaffolds implanted in rabbits showed a good biocompatibility and reacted in vivo with an appropriate inflammatory host response

TOXICOLOGY

Aluminium

TOXICOLOGY

RE Elements

It should be underlined that RE alternative option is not fully investigated and the mid-and long-term effects of these elements need to be clarified.

RE metals can be expected to exhibit a slower degradation than the major alloy component magnesium.

It can be expected, that they remain at the implantation site even after complete degradation of magnesium. Because of this local accumulation the remaining rare earth metals may exhibit adverse effects on the surrounding cells.

The incidence of RE on bone marrow cells needs a detailed investigation because the clearance from the bone is known to be very slow

Ionic RE easily form colloid in blood and the resulting colloid material is taken by phagocytic cells of the liver and spleen

RE ions cause haemolysis at very low concentrations, in the range 3 - 17•10-7 M/L, by inducing domain and pore formation of the erythrocyte membrane

Light RE elements are known to be hepatotoxic

Pr is the most toxic element leading to animal death in comparable concentrations used for Ce, probably due to the low clearing rate

Pr and Nd induce chromosome aberrations in mice in vivo

Short-term effects of RE on primary cells and cell lines revealed that La and Ceshowed the highest cytotoxicity

The investigation of RE metals used in magnesium-based vascular stents revealed no major adverse effects on the proliferation of smooth muscle cells when added as low concentrated alloying elements, while led to the upregulation of inflammatory genes at high concentrations

A coronary magnesium stent weighs about 10 mg

If the rare earth concentration is assumed with 5–10% and the total degradation time is anticipated within three months (90 days), the daily amount of released metal ions is calculated to result in 6–12 µg assuming linear degradation kinetics.

TOXICOLOGY

RE Elements

BIOLOGICAL EVALUATION OF MEDICAL DEVICES

Tests for in vitro cytotoxicity

Extracting conditions should attempt to simulate or exaggerate the clinical use conditions so as to determine the potential toxicological hazard without causing significant changes in the test sample.

The choice of the extraction vehicle(s) taking into account the chemical characteristics of the test sample shall be justified and documented. For mammalian cell assays one or more of the following vehicles shall be used:

a) culture medium with serum;

b) physiological saline solution;

c) other suitable vehicle.

EN ISO 10993-5

The extraction shall be conducted under one of the following conditions and shall be applied according to the device characteristics and specific conditions for use:

a) (24 ± 2) h at (37 ± 1) °C;

b) (72 ± 2) h at (50 ± 2) °C;

c) (24 ± 2) h at (70 ± 2) °C;

d) (1 ± 0,2) h at (121 ± 2) °C.

Extraction conditions described above, which have been used to provide a measure of the hazard potential for risk estimation of the device or material, are based on historical precedent. Other conditions, e.g. prolonged or shortened extraction times at 37 °C, which simulate the extraction that occurs during clinical use or provide an adequate measure of the hazard potential, may be used, but shall be justified and documented. For medical devices that are in short-term contact (no greater than 4 h cumulative contact duration) with intact skin or mucosa and that are not implanted, this may include extraction times of less than 24 h but no less than 4 h, as given in a) to c).

Cell culture medium with serum should only be used in accordance with a) because extraction temperatures greater than (37 ± 1) °C can adversely impact chemistry and/or stability of the serum and other constituents in the culture medium.

BIOLOGICAL EVALUATION OF MEDICAL DEVICES

Tests for in vitro cytotoxicity

INFLUENCE OF TEST SOLUTIONS

The selection of the suitable simulated biological fluid to determine the accurate degradation performance of magnesium alloys during initial exposure is crucial tothe understanding of cell response and in vivo behaviour

The body fluid is a system with good buffering capability

Hank’s solution contains similar contents of inorganic ions as body plasma, the concentrations of hydrocarbonates in Hank’s solution (~4.2 mM/L) is much lowercompared to that in plasma (~27 mM/L). Hydrocarbonates consitute one of the mostimportant buffers in body fluids and provide about 53% buffering capability ofplasma.

DEGRADATION MEASUREMENT IN HANK’S SOLUTION IS NOT CONVINCED

The buffering capability of DMEM seems too high

The degradation rates in c-SBF and DMEM are similar but ten times higher thanthose in Hank’s solution, 0.9% NaCl solution and PBS

In vitro investigations carried out to predict in vivo degradation behavior by testingMg in inorganic-based SBF at ambient temperature and without pH control havefailed

The pH of human serum is kept constant by the complex biochemistry of the physiological system. In contrast, a corrosion cell is a confined static environment of variable pH as corrosion proceeds.

OH- ions are released during the corrosion of Mg, thereby raising the pH, which in turn reduces the corrosion rate

METHODOLOGIES AND LIMITATIONS

Stent metallici (acciaio inossidabile, nitinol…)Drug eluting stents (DES)Stent bioriassorbili

STENT

1. Too rapid degradation rates exceeding the achievable clearance rate of the alloy components.

2. Release and accumulation of hydrogen due to the corrosion of magnesium leading to vascular damage.

3. Local alkalosis due to the corrosion of the magnesium alloy leading to vascular damage.

4. Inferior mechanical properties or inadequate stent designs contributing to early stent fatigue fractures leading to mechanical negative interference with the vessel wall.

5. Toxic effects of the alloy compounds.

MAGNESIUM ALLOY STENTS

Di Mario et al. J Interv Cardiol 2004;17:391-5

Integrity of the magnesium alloy stent at 3 days

Reendothelialization starts to occur at 3 days postimplantation, and potentially prevents stent particles from embolizing distally

Magnesium alloy or the degraded products of the magnesium alloy do not cause any more inflammation than stainless steel stents.

There is a significant improvement in both percentage area stenosis and percentage diameter stenosis (10%), suggesting that positive remodeling of the vessels is taking place in the magnesium alloy stented vessels (3 months)

Degradation studies with the magnesium alloy stent demonstrated that at 56 days, once the stent completely degraded, the vessel area was actually larger compared to the 28-day time point, suggesting the capability of the vessel to remodel positively

Garg et al. J Am Coll Cardiol 2010;56:S43-78

Stents

Natural bone is a composite material made up of collagen fiber matrix stiffened by hydroxyapatite (HAP) (Ca10(PO4)6(OH)2) crystals that account for 69% of the weight of the bone.

The inorganic phase, HAP, is present in the form of small crystallites of dimensions 5 × 20 × 40 nm.

The organic phase is composed of type I collagen.

The elastic modulus of bone (17 GPa in tension in human femur) is intermediate between that of apatite and collagen.

BONE

BONE

• Bone-implant interface strength and osteointegration are significantly greater formagnesiun than conventional titanium materials

• Using biodegradable materials can avoid subsequent surgical intervention forimplant removal: morbidity related to repeated surgery is reduced

•Temporary implants are attractive in pediatric patients

•For Mg alloys to be used as viable implant materials, degradation rates should not exceed the healing rate of the affected tissue. For adults they should maintain their mechanical integrity at least for 12–18 weeks, while in pediatric trauma patients a shorter presence in the bone is tolerated

•The corrosion process depends not only on the element composition and its processing, but also on the corrosive environment to which the magnesium alloys are subjected

WZ21 implants maintain their integrity for 4 weeks and corrode subsequently with 0.5% volume loss per day; ZX50 alloys commence the degradation process immediately after implantation and degrade with 1.2% daily volume loss.

WZ21 alloys generate enhanced bone neoformation around the implant and give evidence for good osteoconductivity and osteoinductivity of magnesium.

Bone recovers after complete degradation of the magnesium implant, even in the case of massive gas formation (ZX50) and corresponding alterations of the bone.

The sample rods were implanted intramedullary into the femora of the guinea pigs after predrilling with a 1.5mm hand-operated drill (18 weeks).

While the AZ91D was more corrosion resistant than LAE442 in in vitro corrosion tests, the LAE442 proved to be more corrosion resistant than AZ91D in in vivo experiments. Both magnesium alloys revealed corrosion rates in vivo that where about four orders of magnitudes lower than those acquired from in vitro tests.

Alloy Mg Al Zn Li RE

AZ91D Balance 9 1

LAE442 Balance 4 4 2

Acceleration of corrosion could be due to different conditions existing along the implant surface

The corrosion product Mg(OH)2 as a main component of the corrosion layer is not stable in aqueous solutions, especially not in chloride containing environments

Local changes in electrochemical conditions could also be caused by locally passivated areas that are covered by newly formed bone. These locally different corrosive environments could cause local anodic and cathodic sites which could lead to locally accelerated corrosion rates following the morphology of pitting corrosion.

A further parameter influencing the corrosion rate could be proteins that tend to adhere to almost all solid surfaces in vivo.

This may explain the faster corrosion of AZ91D in vivo but it does not explain the more uniform corrosion morphology of LAE442 in vivo

References

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Hermawan H, Dubè D, Mantovani D. Developments in metallic biodegradable stents. Acta Biomater. 2010;6(5):1693-7

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Witte F et al. In vitro and in vivo corrosion measurements of magnesium alloys. Biomaterials. 2006;27(7):1013-8

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