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Pharmaceutical Research

, 37:33 | Cite as

Analysis of In Vitro Cytotoxicity of Carbohydrate-Based Materials Used for Dissolvable Microneedle Arrays

  • Ezgi P. Yalcintas
  • Daniel S. Ackerman
  • Emrullah Korkmaz
  • Cheryl A. Telmer
  • Jonathan W. Jarvik
  • Phil G. Campbell
  • Marcel P. Bruchez
  • O. Burak OzdoganlarEmail author
Research Paper
  • 45 Downloads

Abstract

Purpose

Dissolvable microneedle arrays (MNAs) can be used to realize enhanced transdermal and intradermal drug delivery. Dissolvable MNAs are fabricated from biocompatible and water-soluble base polymers, and the biocargo to be delivered is integrated with the base polymer when forming the MNAs. The base polymer is selected to provide mechanical strength, desired dissolution characteristics, and compatibility with the biocargo. However, to satisfy regulatory requirements and be utilized in clinical applications, cytotoxicity of the base polymers should also be thoroughly characterized. This study systematically investigated the cytotoxicity of several important carbohydrate-based base polymers used for production of MNAs, including carboxymethyl cellulose (CMC), maltodextrin (MD), trehalose (Treh), glucose (Gluc), and hyaluronic acid (HA).

Methods

Each material was evaluated using in vitro cell-culture methods on relevant mouse and human cells, including MPEK-BL6 mouse keratinocytes, NIH-3T3 mouse fibroblasts, HaCaT human keratinocytes, and NHDF human fibroblasts. A common laboratory cell line, human embryonic kidney cells HEK-293, was also used to allow comparisons to various cytotoxicity studies in the literature. Dissolvable MNA materials were evaluated at concentrations ranging from 3 mg/mL to 80 mg/mL.

Results

Qualitative and quantitative analyses of cytotoxicity were performed using optical microscopy, confocal fluorescence microscopy, and flow cytometry-based assays for cell morphology, viability, necrosis and apoptosis. Results from different methods consistently demonstrated negligible in vitro cytotoxicity of carboxymethyl cellulose, maltodextrin, trehalose and hyaluronic acid. Glucose was observed to be toxic to cells at concentrations higher than 50 mg/mL.

Conclusions

It is concluded that CMC, MD, Treh, HA, and glucose (at low concentrations) do not pose challenges in terms of cytotoxicity, and thus, are good candidates as MNA materials for creating clinically-relevant and well-tolerated biodissolvable MNAs.

Key Words

cytotoxicity biomaterials dissolvable microneedles carboxymethyl cellulose maltodextrin trehalose glucose hyaluronic acid in vitro skin cells 

Abbreviations

CMC

Carboxymethyl cellulose

DMEM

Dulbecco’s Modified Eagle’s Medium

FBS

Fetal bovine serum

FDA

U.S. Food and Drug Administration

Gluc

Glucose

GMP

Good manufacturing practices

HA

Hyaluronic acid

ISO

International Organization for Standardization

MD

Maltodextrin

MNA

Microneedle array

PBS

Phosphate-buffered saline

Treh

Trehalose

Notes

Author Contributions

Conceptualization, E.P.Y, E.K., P.G.C., and O.B.O.; Methodology, E.P.Y., E.K., D.S.A., P.G.C., and M.P.B.; Investigation, E.P.Y., D.S.A., E.K., and P.G.C.; Resources, O.B.O., P.G.C., M.P.B., and J.W.J.; Writing - original draft, E.P.Y. and E.K.; Writing - review editing, E.P.Y., E.K., P.G.C., M.P.B., J.W.J., C.A.T., and O.B.O.; Visualization, E.P.Y., E.K., and D.S.A.; Supervision, E.K., P.G.C., M.P.B., J.W.J., and O.B.O.; Project administration, P.G.C., O.B.O., and M.P.B.; Funding acquisition; O.B.O., P.G.C., M.P.B., and J.W.J.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Ezgi P. Yalcintas
    • 1
  • Daniel S. Ackerman
    • 2
    • 3
  • Emrullah Korkmaz
    • 1
  • Cheryl A. Telmer
    • 3
  • Jonathan W. Jarvik
    • 2
    • 3
  • Phil G. Campbell
    • 3
    • 4
  • Marcel P. Bruchez
    • 2
    • 3
    • 5
  • O. Burak Ozdoganlar
    • 1
    • 4
    • 6
    Email author
  1. 1.Department of Mechanical EngineeringCarnegie Mellon UniversityPittsburghUSA
  2. 2.Department of Biological SciencesCarnegie Mellon UniversityPittsburghUSA
  3. 3.Molecular Biosensor and Imaging CenterCarnegie Mellon UniversityPittsburghUSA
  4. 4.Department of Biomedical EngineeringCarnegie Mellon UniversityPittsburghUSA
  5. 5.Department of ChemistryCarnegie Mellon UniversityPittsburghUSA
  6. 6.Department of Materials Science and EngineeringCarnegie Mellon UniversityPittsburghUSA

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