Biodegradable Metallic Stents

Master of biomedical Engineering - Biomaterials Project

Cinthia E. M. Kramer, Sergio Eduardo Ávila Pérez, Marc Rulló Besora

INTRODUCTION
1. Introduction
Coronary artery disease (CAD) is the third
leading cause of death worldwide. It is
characterized by a narrowing of the artery
due to plaque deposits beneath the
endothelium, reduced blood flow, and
insufficient nutrients and oxygen supply to
the cardiac muscle, which can lead to
myocardial infarction or transient cerebral
ischemic attacks and stroke.
This condition can be treated by employing fluoroscopic and/or endoscopic guidance
to place special devices called stents into the afflicted channel. [1] [2].
Stents are hollow structures that are small,
complex, cylindrically and are constructed into a
sequential ring with a sequence of struts and
connecting parts.
Aim: Keep the path of human arteries through the
body open.
• Properties of the ideal Stent [1]
Figure 1.3: Ideal stent property graphic.
• Properties of real Stents
Common Stent Metals and Alloys [1]
Iron (Fe), stainless steel (316L), Tantalum (Ta), Nitinol (Ni-Ti), Cobalt-Chromium (Co-
Cr), Magnesium (Mg), Platinum-Iridium (Pt-Ir)
• Main Complications of Stent Placement
Restenosis
Figure 1.4: Re-narrowing or blockage of a previously-
treated artery by coronary angioplasty [3]
• Evolution of cardiovascular Stents [1]
Bare Metal (BMS) Drug Eluting Stent (DES)
STENTS
1986 2002 / 2008
• Stainless steel (316L), Co-• Improved radial force
Cr, Pt-Ir, Ta, Ni-Ti and radiopacity
• Permanently implanted • Anti-inflammatory
Features
Figure 1.1: Coronary artery disease
Figure 1.2: Stent placement procedure.
Stent Thrombosis
Figure 1.5: Presence or formation of blood cots
in a vessel or on stented area [4]
Figure 1.6
Bioresorbable
2011 - Today
• Temporary support
(scaffold)
• Biocompatible,
2. Biodegradable Stents - 3. Zn-based biodegradable stents 4. Discussion – 5. Conclusion
2.1 Principle of the Biodegradability of metallic Stents 3.2 Properties 4. Discussion
Using an essential transition metal of • Physiochemical Properties Functionality
the human body for the stent, makes it
Zn-based alloys have low melting temperatures below The development of new generations of stents aims to improve mechanical properties,
bioresorbable. The degradation takes
420 degrees, and low reactivity which is good for safety, biocompatibility, stability, reendothelialization and to reduce adverse effects
place due to a series of anodic and
manufacturing [7]. The molecular structure of the BM is such as restenosis, thrombosis, inflammation, neointimal hyperplasia, etc.
cathodic reactions on the BMs surface.
a bulk metallic glass (BMG): Multi component metallic These problems could be solved with biodegradable stents which showed a lot of
These depend on the composition of
alloys with disordered atomic distribution (glassy potential, wherefore its investigation is very senseful. But still drawbacks and challenges
the alloy, especially meaning the size
structure). The Metallic glasses are materials which have might arise when starting into clinical studies, as each individuum could react very
and distribution of local anodes
the properties of both metals and glasses, meaning differently. For instance, in some the stents could be degraded much faster or slower
(oxidation of less noble metal) and
metallic bonds but amorphous atomic orientation. than anticipated.
cathodes (reduction of more noble
[8][9][1] Its structure bring many advantages in the
Figure 1.1: Concept of degradation of metallic stent surface [5]. metal). [5]
mechanical properties and biological integrity as Production
First the metal is oxidated and then forms the metal oxide, which is then dissolved by metallic glasses, have proven to show significantly As stated, before ideal alloys are being determined and investigated already e.g., Zn–
Figure 3.2.1: Atomic distribution,
negative charged ions such as Cl- which are present in body fluids (see figure 1.1). better corrosion resistance compared to their amorph and crystalline [11] 0.5Mg extruded alloy shows a good combination of mechanical performance and
crystalline counterparts degradation rate. This alloy also showed good behavior in laser cutting tests as the
2.2 Metallic biodegradable Biomaterials for Stent Applications
analysis found that neither grain coarsening nor texture modification occurred close to
• Mechanical Properties the laser cut edge. [7]
Property\Stent Mg-based Fe-based Zn-based
Biocompa- (-) Excessive release of (-) Corrosion products () Excess Zn in the The tensile strength of pure Zn is too low for stent applications, but in form of
tibility degradation products damage artery on a body is harmful to
metallic glass with additional Mg enhanced performance (see Figure 3.2.3).
[5] long term [5] vital organs
[Mustead] In general, metallic glasses are strong, ductile, malleable and brittle. Also
(+) electronegative (-) Disadvantages of (+) daily dose of Zn harder than steel, non-toxic and resist to wear stress and corrosion, they are easy
charge during permanent stents are release from stent is to shape and elastic enough to change form [8][9][5][1].
degradation → present. [7] significantly below
antithrombotic any risk [7] Zn–0.5Mg is the most promising material for stent applications with a good
potential [5] combination of strength, ductility, strain hardening exponent and an appropriate
rate of loss of mechanical integrity during degradation. [7]
Mechanical (-) Too short (< 6 (-) Too long [5] [6] () short – appropriate Figure 4.1: SEM images of Zn-0.5Mg tube cutted with laser cutter.[7]
Integrity months and unstable) [7]
Another obstacle is that laser micro cutting of Zn-Mg alloys requires inert gas
[5] [7]
conditions. The process gas O2 can be used with the conventional stent material
stainless steel. However, the use of O2 in Zn-Mg alloys leads to the formation of MgO in
Mechanical (+) Superior elastic (+) Main advantage: (-) too low, adding
the kerf, which acts as a refractory layer due to its high melting temperature, thus
properties moduli and tensile High radial strength alloying elements
strengths while because of and/or preventing the cutting process. [12].
degrading [Udriste 108] high elastic modulus thermomechanical However, the Mg content in the alloy is very low, which is reflected in the study by
[6] refinement of grain Mostaed et al. has proven to be the most efficient. The formation of MgO inside the
(-) Not strong enough size necessary [7] body is also unavoidable and does not impair the function of the stent. In addition, in
Figure 3.2.2: SEM images of Zn and Zn Alloys. Left: Zn (pure), middle: Zn-0.15Mg 0.15, right: Zn-0.5Mg. [7]
for the load-bearing the work of Demir et al. possible to preserve the chemical composition of a Mg-based
applications stent by removing the oxidized zones by chemical etching. [12][7]
[5]
However, a problem that arises in the next production step, the chemical etching step,
is the inevitable reduction in thickness [12]. This could affect the mechanical
Corrosion (-) Too fast and () Superior [1] (+) Between Mg and performance of the stent and therefore needs to be investigated and standardized to
Behaviour uncontrollable [5][1] Fe [7]
ensure the functionality of the stent.
The concern mentioned in the paper of Mostaed et. al on the impurities of industrial Zn
3. Zn-based biodegradable stents has yet to be proven as we were able to find 99.995% pure zinc from China for
US$1550-1700/ton while bulk stainless-steel costs around US$2000/ton. [7][13][14]
Most promising alloys are the Zn-Mg alloys as mechanical integrity and properties
can be enhanced with the additional component magnesium. Mg is well studied and
biocompatible, making it the perfect alloying element. The alloys are expected to 5. Conclusion
have superior mechanical properties while maintaining high biosafety. [7] Biodegradable stents are well on their way to entering clinical trials and are already
Figure 3.2.3: Zn and Zn Alloys mechanical property analysis. Left: Zn-Alloy HV alterations, right: Alterations of
showing great potential in vivo and in vitro in mammals. As their performance
3.1 Fabrication & manufacturing Youngs Modulus (YS), Ultimate tensile strength (UTS) and Elongation. [7] continues to improve with surface treatments and more alloys, these materials have
great potential to change the gold standard of stainless-steel stents. From an economic
1. Production of the Biomaterial and functional point of view (see table in 3), the Zn-based stents appear very promising,
Zn and Mg are both melted at 500 ºC in Figure 3.1.1. SEM Images of the laser microcut since conventional production steps for Zn-based stents work, which facilitates their
cylindrical mold made of steel, inside a stents produced using Ar [12] entry into mass production.
resistance furnace, produces cast cylindrical • Biological Integrity
billets with a length and diameter of 80 mm and
Zn is an essential element in human
15 mm, respectively. [7] Then hardened at 350 ºC
for 48h in order to homogenize the cast nutrition and is the second most Acknowledgements
structure followed by water quenching. Then Figure 3.1.2. SEM Images of the laser microcut abundant metal element in the human
stents using Ar after chemical etching at 10 body. It plays a crucial role in cell [1] - Alexandru Scafa Udriste, Adelina-Gabriela Niculescu, Alexandru Mihai Grumezescu and Elisabeta
cylindrical rods are obtained by extrusion Badila 2021.
seconds. [12]
around 300 degrees. The small tubes and the proliferation and in the immune and Cardiovascular Stents: A Review of Past, Current, and Emerging Devices
stents precursors. with outer and inner nervous system. But excess and long- [2] - https://www.myupchar.com/en/disease/coronary-artery-disease
diameters of 4 and 1.5 mm respectively. [7] term exposure to Zn is harmful to vital [3] - https://www.bostonscientific.com/en-US/medical-specialties/interventional-cardiology/coronary-
interventio ns/pci-product-portfolio/agent-ide-clinical-trial/understanding-isr-for-patients.html
organs such as the kidney, spleen,

• Non-degradability • Elution of biodegradable polymers and [4] - https://www.ahajournals.org/doi/10.1161/01.ATV.0000255308.41576.ae

• Prevents elastic recoil
• High rate of in-stent
restenosis and late-stage
thrombosis
Problems
1. Stent Fabrication liver, brain and heart and interferes
antiproliferative metallic materials Figure 3.1.3.SEM images of stents cut with Ar, taken [5] - Wei Yuan, Dandan Xia, Shuilin Wu, Yufeng Zheng, Zhenpeng Guan, Julietta V. Rau 2022. A review on
neointimal inhibitors • Reduce chronic Wires and tubes are the most widely used for in back scattered electron mode. [12] with the copper uptake. [7] current research status of the surface modification of Zn-based biodegradable metals
inflammation, restenosis, producing expandable and self-expanding Figure 3.2.4: Physiological roles of zinc. [10] [6] – Maryam Moravej and Diego Mantovani 2011. Biodegradeable Metals for Cardiovascular Stent
late stent thrombosis stents. But processing mini tubes for stents is Application: Interests and New Opportunities.
Experiments with rats showed that after 4.5 and 6 months in vivo, the corrosion [7] - E. Mostaed, M.Sikora-Jasinskaa, A. Mostaed, S.Loffredoa, A. G. Demira, B. Previtalia, D. Mantovanib, R.
• Currently in development not trivial and depends on the material used. It
• Restenosis (rate less than products were primarily benign compacted zinc oxide interspersed in zinc Beanlandc, M. Vedania 2016. Novel Zn-based alloys for biodegradable stent applications: Design,
must have a good response to laser irradiation development and in vitro degradation
BMS) carbonate. The same study showed that after partial degradation, they proved that
during strut cutting, and microstructural [8] - https://www.bulkmetallicglass.it/en/bulk-metallic-glass-blog/stent-innovative-bulk-metallic-glass-
• Late stent thrombosis Zn has an antiproliferative effect, guarding against restenosis after stent
stability after laser cutting. [7][12] Figure 3.1.4. SEM images of the stent after laser

• Chronic inflammatory
response
•
Keep the stent as a
foreign body throughout
the entire life.
Idea of Metallic Bioresorbable Stents:
corrosion resistance and superior mechanical properties, maintaining a long-term
mechanical stability in vivo.
application/]
• More dual antiplatelet implantation [7].
?
microcutting and chemical etching. [12] [9] - https://padeepz.net/metallic-glasses
therapy (DAPT) → more
Industrial processes are being adapted for the laser micro cutting stents, as this [10] - https://jps.biomedcentral.com/articles/10.1007/s12576-017-0521-4
bleeding However, any widely-used Zn-based alloys contain large amounts of Al, are
technique is most feasible. In the production cycle small diameter tubes are cut with a [11] - https://www.totalmateria.com/page.aspx?ID=CheckArticle&site=ktn&NM=485
• Abnormal coronary therefore potentially toxic and unsuitable for bio applications. New biodegradable [12] – Demir, A.G., khan Previtali, B., Biffi, C.A., 2013. Fibre laser cutting and chemical etching of AZ31 for
vasomotion Q-switched fibre laser (pulsed lasers with a high energy content) producing structures
Zn-based alloys with limited amounts of Al or other potentially harmful elements, manufacturing biodegraable stents. Adv. Mater. Sci. Eng., e692635, http://dx.doi.org/
shown in the figure. The last operation is chemical etching with an HNO3 ethanol 10.1155/2013/692635.
are of interest and crucial for stent application. [7]
solution to clean the deposited spatter on the stent surface [12]. [13] - https://m.made-in-china.com/company-hbcongjin/productlist/group/631408695
[14] - https://www.alibaba.com/premium/stainless_steel.html