Bioabsorbable zinc ion induced biphasic cellular responses in vascular smooth muscle cells Page: 1 of 10
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OPEN Bioabsorbable zinc ion induced
biphasic cellular responses in
vascular smooth muscle cells
Received: 17 February 2016 Jun Ma"2, Nan Zhao3 & Donghui Zhu,2
Accepted: 25 April 2016
Published: 01 June 2016 Bioabsorbable metal zinc (Zn) is a promising new generation of implantable scaffold for cardiovascular
and orthopedic applications. In cardiovascular stent applications, zinc ion (Zn2+) will be gradually
released into the surrounding vascular tissues from such Zn-containing scaffolds after implantation.
However, the interactions between vascular cells and Zn2+ are still largely unknown. We explored
the short-term effects of extracellular Zn2+ on human smooth muscle cells (SMCs) up to 24 h, and an
interesting biphasic effect of Zn2+ was observed. Lower concentrations (<80 M) of Zn2+ had no adverse
effects on cell viability but promoted cell adhesion, cell spreading, cell proliferation, cell migration, and
enhanced the expression of F-actin and vinculin. Cells treated with such lower concentrations of Zn2+
displayed an elongated shape compared to controls without any treatment. In contrast, cells treated
with higher Zn2+ concentrations (80-120 M) had opposite cellular responses and behaviors. Gene
expression profiles revealed that the most affected functional genes were related to angiogenesis,
inflammation, cell adhesion, vessel tone, and platelet aggregation. Results indicated that Zn has
interesting concentration-dependent biphasic effects on SMCs with low concentrations being beneficial
to cellular functions.
Biodegradable metals, namely magnesium (Mg), zinc (Zn) and iron (Fe), represent the new generation of
implantable medical scaffolds. Among them, Mg-based alloys have been widely explored in stent applications
because of their biodegradability, bioabsorbility, and low thrombogenicity'-4. However, the main drawbacks of
conventional Mg alloys are insufficient mechanical strength and rapid corrosion accompanied with hydrogen gas
evolution, pH increase, and premature loss of mechanical integrity5. Previous studies on surface treatment6 and
element alloying7 of Mg for stent application showed that these two methods enhanced the performance of Mg
and its alloys at some degree but not sufficiently. More sophisticated efforts are in need to fully overcome such
weaknesses of Mg materials. The outcomes of earlier clinical trials were also not ideal. The AMS INSIGHT trial
showed that absorbable metal stent (AMS) did not demonstrate efficacy in the long-term patency over standard
percutaneous transluminal angioplasty (PTA)8. Another PROGRESS-AMS trial revealed sound results immedi-
ately post implantation with diameter stenosis reducing from 61.5% to 12.6% and acute gain of 1.41 mm in diam-
eter. Then after 4 months, diameter restenosis increased to 48.4%, indicating a negative remodeling occurred9.
Fe-based alloys are interesting candidates for stent application as their mechanical properties are similar to
stainless steel"'0, a benchmark for stent materials. However, its low degradation rate cannot catch up with clinical
needs and lead to similar reactions found in permanent implants'0". Another concern is that the ferromagnetism
of Fe-based alloys negatively affects the compatibility with certain imaging devices, such as magnetic resonance
Zn is an alternative to Mg and Fe (or perhaps a better choice) for cardiovascular stent application after all
because of its better mechanical and corrosion properties. In fact, Zn has been used as alloying element for
Mg to enhance corrosion resistance'2, increase strength and ductility simultaneously", and decrease hydrogen
evolution'4. Because of its advantageous roles in alloy development and human nutrition, Zn was explored as
stent implant in a rat model. The degradation rate was slow and -70% cross section area remained within first
4 months, indicating the stably maintained mechanical integrity during healing process'5. The follow-up study
by the same group revealed low cell densities, low neointimal tissue thickness, and tissue regeneration within
'Department of Chemical, Biological and Bioengineering, North Carolina A&T State University, Greensboro, NC 27411,
USA. 2National Science Foundation (NSF)-Engineering Research Center for Revolutionizing Metallic Biomaterials,
Greensboro, NC 27411, USA. 3Department of Biomedical Engineering, Pennsylvania State University, State College,
PA 16801, USA. Correspondence and requests for materials should be addressed to D.Z. (email: email@example.com)
F PO I6:266611DOI: 10.1038/srep26661
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Ma, Jun; Zhao, Nan & Zhu, Donghui. Bioabsorbable zinc ion induced biphasic cellular responses in vascular smooth muscle cells, article, January 6, 2016; London, United Kingdom. (digital.library.unt.edu/ark:/67531/metadc984095/m1/1/: accessed October 18, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Engineering.