1. Silk-based systems as a pla0orm for regula6ng basal insulin levels in diabe6cs
Alexander Wolfe, Jeannine Coburn, David L. Kaplan, Fiorenzo G. Omene>o
Tu@s University Department of Biomedical Engineering
Problem | Diabetes mellitus poses an increasingly prominent
global health concern; from 2012-2014 and addiPonal 4 million
Americans contracted the disease1, while worldwide the
number of cases conPnues to grow at an exponenPal rate2.
Diabetes management is made more difficult by the highly
individual needs of persons with the disease; regulaPon
requirements of both short-term and basal insulin levels vary
widely within the diabePc populaPon.
Significance | Despite these concerns, methods of managing
paPent basal insulin requirements (i.e. injectable systems)
remain relaPvely rudimentary in applicaPon. Consequently,
reduced paPent compliance has been observed in some cases
due to invasive and repePPve dosing along with reduced efficacy
resulPng from human error in dose calculaPons. UlPmately, we
seek to address these issues through the development of a silk-
based insulin delivery plaXorm that can effecPvely manage a
range of paPent basal insulin requirements.
Design & Methods | Microneedle (MN) plaXorms offer a more
subtle and elegant opPon for diabetes management. The end
goal of this research is to leverage the unique processing and
stabilizing properPes of silk protein5,6,7 to improve upon
exisPng MN insulin delivery systems3, 4. In this first project
phase we evaluated the feasibility of insulin release from both
film and MN systems – specifically, our evaluaPon focused on
the loading capacity of silk formats, high-level release profiles,
and applicable pharmacokinePc variables such as diffusivity. All
of these parameters were compared to relevant physiological
and pharmacological models.
Results | Fluorescently-labeled insulin release from silk film (I) and MN (II, III) systems can be tuned to match exisPng models of
basal insulin regulaPon8,9 :
I. WA film groups showed effecPve and predictable release kinePcs: > 80% of loading dose was released in under 10 hours
II. Insulin released from coated MNs into collagen gel model reached average subcutaneous diffusion distance (~100µm) within
2 hours
III. Axial diffusivity (IIIA) and penetraPon distance (IIIB) of coated MN release are in line with exisPng models (red line in IIIA)
and vary as a funcPon of height along needle profile
Conclusions | IniPal release results are promising with respect to known dosing values for basal insulin maintenance10 for subsets
of the diabePc populaPon, specifically children with Type 2 diabetes. Areas of concern include maintaining insulin stability /
bioacPvity during casPng and release, as well as the upper limit of loading capacity for the coated MN delivery format.
Accordingly, future studies will include a comprehensive analysis of insulin protein conformaPonal stability during fabricaPon and
release as well as in vitro viability analyses to assess potency of released insulin.
[1] StaPsPcs About Diabetes. (n.d.). Retrieved November 16, 2014, from h>p://www.diabetes.org/diabetes-basics/staPsPcs/
[2] Market Overview- Diabetes Mellitus. (2015). Retrieved October 6, 2015 from h>p://www.orgenesis.com/market/market-overview
[3] Yu J, Zhang Y, Ye Y, DiSanto R, Sun W, Ranson D et al. Microneedle-array patches loaded with hypoxia-sensiPve vesicles provide fast glucose-responsive insulin delivery. PNAS 112: 8260-8265 (2015).
[4] Gupta J, Felner E, Prausnitz MR. Rapid PharmacokinePcs of Intradermal Insulin Administered Using Microneedles in Type 1 Diabetes Subjects. Diab Tech Ther 13: 451-456 (2011).
[5] Tsioris K, Raja WK, Pritchard EM, PanilaiPs B, Kaplan DL, Omene>o FG. FabricaPon of Silk Microneedles for Controlled-Release Drug Delivery. Advanced Func6onal Materials. 26:330-335 (2011).
[6] Kaplan, DL ; Kuo, CK; Finley, V; Hu, X ; Pritchard, E. Effect of Silk Film Processing on Drug Delivery from Silk Films. Macromol Biosci. 13: 311-320 (2013).
[7] Hines DJ, Kaplan DL. Mechanisms of controlled release from silk fibroin films. Biomacromolecules. 3: 804-812 (2011).
[8] Buchwald P. A local glucose-and oxygen concentraPon-based insulin secrePon model for pancreaPc islets. Theo Biol Med Model. 8: 2-25 (2011).
[9] Caffrey J, Parker S, Poonka P. Insulin Diffusion from a PancreaPc Islet. Unpublished, Retrieved March 20, 2016 from h>p://www.isn.ucsd.edu/courses/beng221/problems/2011/project12.pdf
[10] Figure 1. Typical Basal Requirements. Reprinted from Diabetes Self-Management, by G Scheiner, 2011, retrieved from h>p://www.diabetesselfmanagement.com/managing-diabetes/treatment-approaches/geung-down-to-basals/