Sustained Release of Insulin-Like Growth Factor-1 from Bombyx mori L. Silk Fibroin Delivery for Diabetic Wound Therapy.

Meng-Jin Lin,Mei-Chun Lu,Hwan-You Chang

doi:10.3390/ijms22126267

Abstract

The goals of this study are to develop a high purity patented silk fibroin (SF) film and test its suitability to be used as a slow-release delivery for insulin-like growth factor-1 (IGF-1). The release rate of the SF film delivering IGF-1 followed zero-order kinetics as determined via the Ritger and Peppas equation. The release rate constant was identified as 0.11, 0.23, and 0.09% h−1 at 37 °C for SF films loaded with 0.65, 6.5, and 65 pmol IGF-1, respectively. More importantly, the IGF-1 activity was preserved for more than 30 days when complexed with the SF film. We show that the IGF-1-loaded SF films significantly accelerated wound healing in vitro (BALB/3T3) and in vivo (diabetic mice), compared with wounds treated with free IGF-1 and an IGF-1-loaded hydrocolloid dressing. This was evidenced by a six-fold increase in the granulation tissue area in the IGF-1-loaded SF film treatment group compared to that of the PBS control group. Western blotting analysis also demonstrated that IGF-1 receptor (IGF1R) phosphorylation in diabetic wounds increased more significantly in the IGF-1-loaded SF films group than in other experimental groups. Our results suggest that IGF-1 sustained release from SF films promotes wound healing through continuously activating the IGF1R pathway, leading to the enhancement of both wound re-epithelialization and granulation tissue formation in diabetic mice. Collectively, these data indicate that SF films have considerable potential to be used as a wound dressing material for long-term IGF-1 delivery for diabetic wound therapy.

Highlights

The skin is a large organ that plays an essential role in maintaining homeostasis and protecting the body from microorganism invasion
No significant changes in epidermal growth factor receptor (EGFR) expression and phosphorylation were noted for any of the treatment groups (Figure 7D,E). These results indicated that the promotion of wound recovery in db/db mice was related to the enhancement of the IGF-1 receptor (IGF1R) phosphorylation level in silk fibroin (SF) film insulin-like growth factor-1 (IGF-1) treatment
We have established a method to produce highly pure SF films, which served as an ideal matrix for IGF-1 sustained release following zero-order pharmacokinetics

Summary

Introduction

The skin is a large organ that plays an essential role in maintaining homeostasis and protecting the body from microorganism invasion. More than 6.5 million chronic skin ulcer cases primarily caused by blood pressure, venous stasis, or diabetes mellitus are reported annually in the United States, with treatment costs estimated to exceed USD 20 billion [4,5]. A gel formulation of recombinant platelet-derived growth factor-BB (REGRANEX® ) was approved for treating diabetic ulcers in the United States and Europe [10]. Despite their effectiveness, many growth factors exhibit a relatively short half-life in vivo, presumably due to enzymatic degradation in the wound bed [11,12]. To maintain an effective concentration of growth factors, a formulation of the factors combined with a suitable delivery vehicle, such as a liposome, micelle, dendrimer, or protein-based drug delivery system, is suggested [13,14,15]

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