Elsevier

Biomaterials

Volume 34, Issue 33, November 2013, Pages 8416-8423
Biomaterials

The spatiotemporal control of erosion and molecular release from micropatterned poly(ethylene glycol)-based hydrogel

https://doi.org/10.1016/j.biomaterials.2013.07.026Get rights and content

Abstract

Hydrogels have been extensively studied as a carrier of various hydrophilic molecular compounds and cells for local delivery and subsequent controlled release. One of key design parameters in the hydrogel assembly is an ability to control spatiotemporal gel degradation, in order to tailor release rates of multiple drugs and also regulate phenotypic activities of co-cultured cells. To achieve this goal, this study presents a simple but innovative implantable, microfabricated hydrogel patch that undergoes micropatterned surface erosion at controlled rates and subsequently discharges two molecular compounds of interests at desired rates. This device was prepared by first fabricating a non-degradable poly(ethylene glycol) dimethacrylate (PEGDMA) hydrogel patch containing micro-pockets of controlled spacing and subsequently filling micro-pockets with a hydrogel of poly(ethylene imine) (PEI) and PEG diacrylate (PEGDA) that was tailored to degrade at controlled rates. Separate incorporation of vascular endothelial growth factor (VEGF)121 and VEGF165, known to orchestrate vascular development, into the PEI-PEGDA gel and PEGDMA hydrogel resulted in enhanced neovascularization at the implantation sites due to bimodal, sequential release of two VEGF isoforms. We believe that the hydrogel patch fabricated in this study will be highly useful to better understand a broad array of complex biological processes and also improve the efficacy of molecular cargos in varied applications.

Introduction

Hydrogels have been extensively studied as a carrier of various agricultural, nutritional, and pharmaceutical products, in order to localize molecular cargos in target sites and also release them at controlled rates [1], [2], [3], [4]. Recently, efforts are increasingly made to assemble gel systems carrying dual or multi-molecular compounds and releasing them in a bimodal, sequential manner because of its potential to significantly improve molecular efficacy [5], [6]. One popular approach is to use hydrogels with different degradation rates as building blocks for a desired sequential release platform; however, there are still grand challenges in spatially organizing gel blocks with desired degradation rates [7], [8].

Alternatively, certain studies encapsulated nano- or microparticles into a degradable material, so molecules laden into the matrix are released faster than other molecules incorporated into particles [9], [10]. However, these approaches are often plagued by the significant initial burst of molecules from particles, which results in simultaneous dual molecular release. One approach to potentially resolve this challenge is to bind molecular cargos to a gel matrix using photolytically cleavable linkers, so the gel releases them through light-induced local hydrogel degradation [11]. However, such approaches often require complex material synthesis and purification, thus raising material costs. Additionally, for an implant system, it is not particularly easy to stimulate localized degradation at implantation sites without a small surgery.

In response to these challenges, we hypothesized that a non-degradable hydrogel patch fabricated to load degrading gels in its multiple micro-pockets would allow us to sequentially release dual molecular cargos in a bimodal manner. To examine this hypothesis, we prepared poly(ethylene glycol) dimethacrylate (PEGDMA) hydrogel patch containing micro-pockets of controlled size and spacing, and filled them with the rapidly degrading hydrogel formed from Michael-type cross-linking reaction of poly(ethylene imine) (PEI) and poly(ethylene glycol) diacrylate (PEGDA) (Scheme 1a). The PEI-PEGDA gel undergoes hydrolytic degradation due to cleavage of amino ester linkages between PEI and PEGDA (Scheme 1b).

To evaluate molecular releasing function of the hydrogel patch, two isoforms of vascular endothelial growth factor (VEGF121 and VEGF165), known to orchestrate vascular sprouting and maturation, were separately incorporated into the PEI-PEGDA gel and poly(lactic-co-glycolic acid) (PLGA) microparticles embedded in the PEGDMA hydrogel (Scheme 1c). The PLGA microparticles were used as the VEGF165 carrier, in order to limit initial VEGF165 burst and also attain the sustained release from the PEGDMA hydrogel [12]. The microfabricated gel patch laden with VEGF121 and VEGF165 was implanted on the chicken chorioallantoic membrane (CAM), and its efficacy to stimulating neovessel growth was compared with patches devised to release VEGF121 and VEGF165 simultaneously.

Section snippets

Microfabrication of hydrogel patch

PEGDMA gel patch containing micro-pockets was prepared by cross-linking 10 wt % aqueous mixture of PEGDMA (Mw = 1000 g mol−1, Polysciences, Inc.) and 2.5 mg of PLGA microparticles (with a lactide:glycolide ratio of 50:50, Mw = 6000–10,000 g mol−1, DURECT, Co.) pre-mixed with Irgacure 2959 at a concentration of 0.01 wt %. The mixture was placed in a space between a glass slide and the polydimethylsiloxane (PDMS) (Sylgard 184, Dow Corning) stamp separated by a spacer of 1 mm. The mixture was

Fabrication and characterization of hydrogel patch

The PEGDMA hydrogel patch which presented multiple micro-pockets with regular spacing on its surface was prepared by exposing the aqueous PEGDMA solution to UV light. The pre-gel solution was cross-linked under the PDMS stamp, following a conventional soft lithography process (Fig. 1a and b). The PDMS stamp was fabricated to present vertical posts with 300 μm diameter and 200 μm height. The spacing between the vertical posts was kept constant at 500 μm. Therefore, photo-cross-linking reaction

Conclusion

The PEGDMA hydrogel patch containing multiple micro-pockets filled with rapidly degrading PEI-PEGDA gel could present spatially organized surface erosion. The degradation rate of PEI-PEGDA gel in the micro-pockets could be tuned by altering the molar ratio between PEI and PEGDA. Furthermore, the bimodal, sequential macromolecular release profile could be attained by separately loading protein molecules into the PEI-PEGDA gel and PLGA microparticles embedded in the PEGDMA hydrogels. Therefore,

Acknowledgments

This work was supported by US Army Telemedicine & Advanced Technology Research Center (W81XWH-08-1-0701), National Science Foundation (CAREER: DMR-0847253), American Heart Association (Scientist Development Grant 0830468Z), and University of Illinois's Institute for Genomic Biology (Proof of Concept Award). (Supporting Information is available online from Wiley InterScience or from the author).

References (23)

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