Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles

Abstract

Background: Microneedles have previously been used to deliver insulin to animal models, but not in human subjects. This study tested the hypothesis that hollow microneedles can deliver insulin to modulate blood glucose levels in subjects with type 1 diabetes in a minimally invasive manner.

Methods: This study was carried out in two adults with type 1 diabetes and evaluated bolus delivery of lispro insulin using a hollow microneedle compared to a catheter infusion set (9 mm). The study first determined the minimum insulin delivery depth by administering insulin from microneedles inserted 1, 3.5, and 5 mm into the skin of fasting subjects and then assessed the efficacy of insulin delivery from microneedles inserted 1 mm into the skin to reduce postprandial glucose levels. Blood samples were periodically assayed for plasma free insulin and plasma glucose levels for up to 3.5 h.

Results: The first phase of the study indicated that microneedles inserted at the shallowest depth of 1 mm within the skin led to rapid insulin absorption and reduction in glucose levels. Bolus insulin delivery followed by consumption of a standardized meal in the second phase revealed that microneedles were effective in reducing postprandial glucose levels. Subjects reported no pain from microneedle treatments, and there were no adverse events.

Conclusions: This study provides the first proof of concept that hollow microneedles can effectively deliver bolus insulin to type 1 diabetes subjects in a minimally invasive manner.

FIG. 1.

(Top) A 1-mm hollow microneedle in a holder compared to (bottom) a 9-mm infusion catheter.

FIG. 2.

Microneedle-based insulin delivery at 1, 3.5, and 5 mm insertion depths in comparison to 9-mm catheter control (Phase 1). (a) Plasma free insulin level and (b) corresponding plasma glucose level response. Microneedle-based insulin delivery at 1 mm led to high insulin absorption and rapid glucose level reduction. (c) AUIC for 0–1 h and (d) change in plasma glucose levels from 0 to 1 h. Within 1 h of insulin bolus, the 1-mm microneedle (MN) delivery case led to an AUIC more than twice that of the catheter control and produced a higher change in plasma glucose levels.

FIG. 3.

Microneedle-based insulin delivery at 1 mm insertion depth in comparison to 9-mm catheter control following consumption of a standardized meal immediately after insulin bolus (Phase 2). (a) Postprandial plasma free insulin level profile and (b) corresponding plasma glucose level response. Microneedle-based delivery led to rapid decline in postprandial plasma glucose levels. (c) AUIC for 0–1 h and 0–2 h and (d) change in plasma glucose levels from 0 to 2 h. Microneedle (MN)-based insulin delivery led to an AUIC slightly more than double that of the catheter control for both 0–1 h and 0–2 h periods and larger reduction in plasma glucose levels. Similarity of results from the two microneedle runs demonstrates reproducibility.

FIG. 4.

Surface view of the abdominal infusion site before, immediately after, and at 30-min intervals after insulin delivery in Subject 2. (A) Insulin infusion site for microneedle-based delivery. A raised skin wheal was seen immediately after delivery. Over time, the wheal subsided, and skin returned to normal. (B) Insulin infusion site for catheter-based delivery. Moderate erythema was seen at the point of catheter insertion and slight erythema in the vicinity of the insertion site. The erythema decreased over time but still remained mild at 2 h. Color images available online at www.liebertonline.com/dia.