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Mechanism of fluid infusion during microneedle insertion and retraction

https://doi.org/10.1016/j.jconrel.2006.02.017Get rights and content

Abstract

Previous work has shown that infusion flow rates can be increased by an order of magnitude by partially retracting microneedles after insertion into the skin. This study sought to determine the mechanism by which retraction increases fluid infusion by piercing human cadaver skin with single microneedles, fixing the skin after retracting microneedles to different distances, and examining skin microstructure by histology. We found that microneedle insertion to 1080 μm from the skin surface resulted primarily in skin indentation and only 100–300 μm penetration into the skin. This caused significant compaction of the skin, which probably pressed out most water and thereby dramatically lowered the flow conductivity of skin beneath the needle tip. Retraction of the microneedle allowed the skin to recoil back toward its original position, which relieved the skin compaction and increased local flow conductivity. Altogether, these results suggest that microneedle insertion to penetrate into the skin followed by microneedle retraction to relieve skin compaction is an effective approach to infuse fluid into the skin in a minimally invasive manner.

Introduction

Microneedles have been proposed as a novel drug delivery method that can capture the convenience of a transdermal patch and the efficacy of a hypodermic needle [1], [2]. These microscopic needles have been fabricated by adapting the tools of the microelectronics industry to penetrate typically hundreds of microns into the skin in a painless manner. Solid microneedles have been used to pierce the skin, after which a patch can be applied for passive or iontophoretic delivery across permeablized skin [3], [4], [5]. Solid microneedles have also been coated with drugs, proteins, DNA and vaccines for rapid dissolution within the skin [6], [7].

Drug delivery by injection through hollow microneedles has been demonstrated to deliver small (∼ 10 μl) quantities of insulin to animal models [8], [9] and even smaller quantities (1 μl) of methyl nicotinate to human subjects [10]. Achieving larger flow rates has been difficult, apparently due to low flow conductivity in the skin. To determine what limits flow into the skin from microneedles, we recently tested the hypothesis that infusion through hollow microneedles into the skin is limited by the resistance to flow offered by the dense dermal tissue compressed during microneedle insertion [11]. Consistent with this hypothesis, our previous study showed that by first inserting microneedles into the skin and then partially retracting before infusing fluid increased infusion flow rate by up to more than a factor of 10. Microneedle retraction similarly increased infusion of an insulin solution to diabetic rats in vivo [12]. In this study, we seek to further test this hypothesis and in particular determine what happens to the skin microstructure during microneedle insertion and retraction.

Section snippets

Materials and methods

The materials and methods used in this study have been described previously [11]. In brief, single glass microneedles were fabricated with an effective tip opening radius of 30 μm and a tip bevel angle of 38°. Microneedles were inserted into human cadaver abdominal skin (Emory University Body Donor Program, Atlanta, GA, obtained with approval from the Georgia Institute of Technology IRB), which had been stored at − 80 °C, warmed to room temperature, hydrated, cut into 4 × 4 cm pieces, and

Results

Our previous study tested the hypothesis that infusion through hollow microneedles into the skin is limited by the resistance to flow offered by dense dermal tissue compressed during microneedle insertion [11]. Consistent with this hypothesis, partial microneedle retraction out of the skin following needle insertion should relieve tissue compaction and thereby increase infusion into the skin. Indeed, insertion of a microneedle to a depth of 1080 μm without retraction resulted in very little

Discussion

Injection or infusion into the skin using hollow microneedles is an attractive drug delivery method, but has been difficult to achieve at large flow rates. This study provides an explanation for why infusion through microneedles is difficult, as well as strategies to overcome these difficulties. Because skin is elastic, needle insertion is associated with tissue deformation. The resulting skin compaction locally reduces flow conductivity and thereby makes infusion difficult. This explains why

Conclusion

This study supports the hypothesis that infusion through hollow microneedles into the skin is limited by the resistance to flow offered by dense dermal tissue compressed during microneedle insertion. In vitro microscopy studies showed that during microneedle insertion, most needle displacement caused skin indentation, while only a small fraction (i.e., 10–30%) of needle displacement was associated with penetration into the skin. This skin indentation locally compressed the skin, which is

Acknowledgements

We would like to thank Susan Brooks and the Emory University Body Donor Program for providing the human cadaver skin and Harvinder Gill for the helpful technical discussions. WM, JSM and MRP are members of the Georgia Tech Center for Drug Design, Development and Delivery. This work was supported in part by the National Institutes of Health.

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