Effect of microneedle design on pain in human volunteers

Abstract

Objectives: To design microneedles that minimize pain, this study tested the hypothesis that microneedles cause significantly less pain than a 26-gauge hypodermic needle, and that decreasing microneedle length and the number of microneedles reduces pain in normal human volunteers.

Methods: Single microneedles with lengths ranging from 480 to 1450 microm, widths from 160 to 465 microm, thicknesses from 30 to 100 microm, and tip angles from 20 to 90 degrees; and arrays containing 5 or 50 microneedles were inserted into the volar forearms of 10 healthy, human volunteers in a double-blinded, randomized study. Visual analog scale pain scores were recorded and compared with each other and to the pain from a 26-gauge hypodermic needle.

Results: All microneedles investigated were significantly less painful than the hypodermic needle with microneedle pain scores varying from 5% to 40% of the hypodermic needle. Microneedle length had the strongest effect on pain, where a 3-fold increase in length increased the pain score by 7-fold. The number of microneedles also affected the pain score, where a 10-fold increase in the number of microneedles increased pain just over 2-fold. Microneedle tip angle, thickness, and width did not significantly influence pain.

Discussion: Microneedles are significantly less painful than a 26-gauge hypodermic needle over the range of dimensions investigated. Decreasing microneedle length and number of microneedles reduces pain.

Figure 1

Schematic of a microneedle illustrating its typical geometry and characteristic dimensions of length, width, thickness and tip angle investigated during the pain study.

Figure 2

Representative microneedles used for insertion. Scanning electron microscopy images of microneedles used in the length study (A), tip-angle study (B), width study (C), thickness study (side view) (D) and number of microneedles study (E). A 5 mm-long, 26-gage hypodermic needle was used as a positive control (F). All images are at the same magnification.

Figure 3

Microneedle devices and stained skin penetration sites. Brightfield microscopy images of microneedles assembled into devices: a single microneedle affixed to a teflon rod holder (A), a five-microneedle array assembled as an adhesive patch (B) and a 50-microneedle array assembled as an adhesive patch (C). Brightfield microscopy images of the skin surface of human forearms after inserting microneedles and applying gentian violet to stain the sites of microneedle insertion, which demonstrates microneedle penetration into the skin, using: a single microneedle (D), an array of five microneedles (E) and an array of 50 microneedles (F). Arrows in (D) and (E) point to the stained insertion sites.

Figure 4

The effect of microneedle length. Box plots of pain scores after insertion of 480, 700, 960 and 1450 μm long single microneedles (160 μm wide, 45 μm thick and a tip angle of 55°): raw visual analog scale (VAS) pain scores (A) and the normalized pain scores (B), which were calculated as the ratio of the microneedle raw VAS score and the 26-gage hypodermic needle raw VAS pain score for the same subject. The normalized pain score of the hypodermic needle (i.e., 100%) is represented by the horizontal dotted line in (B). The small open circles represent individual data points. Each dotted rectangular box represents the interquartile range (i.e., 25 – 75%) of the pain score for a particular microneedle length, with a horizontal line at the median value. The vertical lines (whiskers) extend from the box boundary to the maximum and the minimum data points within one and a half times the interquartile range. The solid diamonds represent the mean pain scores for each insertion. The numbers above each box present the percentage of subjects who reported the insertions to be painless (i.e., VAS pain score of zero).

Figure 5

The effect of the number of microneedles. Box plots of normalized pain scores after insertion of microneedle arrays having 5 and 50 microneedles. All microneedles were 620 μm long, 160 μm wide, 45 μm thick and had a tip angle of 55°.

Figure 6

The effect of microneedle tip angle. Box plots of normalized pain scores after insertion of 480 and 960 μm long single microneedles each with a tip angle of 20°, 55° and 90°. All microneedles were 160 μm wide and 45 μm thick.

Figure 7

The effect of microneedle thickness and width. Box plots of normalized pain scores after insertion of 30, 45 and 100 μm thick single microneedles each 700 μm long, 160 μm wide and with a tip angle of 55° (A); and 160, 245 and 465 μm wide single microneedles each 700 μm long, 45 μm thick and with a tip angle of 55° (B).