Elsevier

Biomaterials

Volume 22, Issue 21, November 2001, Pages 2893-2899
Biomaterials

Evaluation of porous networks of poly(2-hydroxyethyl methacrylate) as interfacial drug delivery devices

https://doi.org/10.1016/S0142-9612(01)00035-7Get rights and content

Abstract

Long-term implantable drug delivery devices are desirable to achieve rapid and reliable delivery of bioactive substances to the body. The limitation of most implantable devices is the resulting chronic inflammatory response and fibrous encapsulation of the implant, which prevents effective drug delivery for prolonged periods. One method of overcoming this problem is the addition of an intermediary that could prevent capsule formation. Biocompatible materials with interconnected pore structures greater than 8–10 μm have been shown to support the ingrowth and maintenance of vascularized tissue. In this investigation, we evaluate the efficacy of using porous hydrogel sponges for the tissue interface in an implantable drug delivery device. Porous networks of poly(2-hydroxyethyl methacrylate) (PHEMA) were synthesized using a thermally initiated free-radical solution polymerization. To characterize the microstructure of the PHEMA networks, scanning electron microscopy and mercury porosimetry were used. By altering the solvent fraction in the reaction mixture, PHEMA sponges were synthesized with interconnected pores ranging in size from from 6 to 15 μm with porosities of 55% to 87%. Following the in vitro evaluation, sponges were attached to the distal end of a 20-gauge catheter tubing, and implanted subcutaneously and intraperitoneally. After 5 months implantation, insulin was infused into the devices from external pumps and rapid insulin absorption was observed in conjunction with dramatic lowering of blood glucose levels. From histological evaluation of explanted devices, we observed highly vascularized tissue surrounding the mesenteric implants. These results indicate that it may be possible to use PHEMA sponges for a tissue intermediary for long-term implantable drug delivery devices.

Introduction

The primary aim of controlled drug delivery is complete optimization; that is the ability to deliver, to the desired location, a precise therapeutic dose for a finite period of time [1], [2], [3]. With such a system, one could achieve high bioavailablity with minimal side effects and drug exposure. These are important when considering the cost of some of the protein-based drugs currently being developed. Such an ideal drug delivery system capable of rapid on/off delivery and control is not achievable through the oral route due to the lag time resulting from absorption through the intestinal walls, and first pass metabolism. While injections allow for rapid uptake, the ability to sustain delivery is limited and repeated injections can become uncomfortable for the patient. One configuration that can achieve this goal is a fully implantable, long-term drug delivery system [1], [2]. These systems could possibly be used in a closed loop configuration that would no longer require patient compliance for delivery.

One of the primary obstacles preventing a long-term implantable delivery device is the foreign body response [4], [5]. Typically, this response results in three characteristic layers [6]. The initial response results in the formation of a primary layer of macrophages and/or foreign body giant cell formations. These cells secrete the second layer composed of dense fibrous tissue 30–100 μm in thickness. A third layer of highly vascularized tissue surrounds this fibrous wall. This response is indefinitely stable except for a decrease in cellularity of the primary layer. The dense nature of the fibrous layer greatly impedes the diffusion of most chemical species, hence rendering any implanted drug delivery device inoperable [7].

One technique that has been used to prevent this fibrous capsule formation is the addition of a tissue-implant intermediary [4], [8]. If a material possesses a continuous porous structure 8–10 μm or greater, macrophages are capable of invading the device [9], [10]. Under these conditions, vascularized tissue may grow into the implant preventing the foreign body response from occurring. It is important that the implant material be non-immunogenic, non-teratogenic, and non-toxic in order for this vascularized tissue to remain healthy long term [5]. To this end, hydrogels may be excellent candidates for a tissue-implant intermediary.

Hydrogels are three-dimensional hydrophilic structures that are capable of absorbing a large amount of water [11], [12]. These swollen networks have been of considerable interest in biomaterials as well as drug delivery applications due to their higher water content and soft nature. In the hydrated state, they have a mechanical behavior and water content similar to soft tissue, and as a result they exhibit excellent biocompatibility.

Poly(2-hydroxyethyl methacrylate) (PHEMA) is a hydrogel that can be easily synthesized into a macroporous, spongy material. Unlike traditional hydrogels which are transparent, homogenous networks with a porous structure measured in nanometers, these spongy hydrogels are actually a two phase opaque system with micron-sized, macroporous structure. The first uses of PHEMA sponges were pursued in the late 1960s for breast augmentation and nasal cartilage replacement [13], [14], [15]. In the 1980s, some work was done with pancreatic islet sequestering using PHEMA sponges [16], [17]. However due to long-term calcification problems, PHEMA sponges have not been considered for implants until the work of Chirila on the use of these materials for anchoring a keratoprosthesis [18], [19], [20], [21].

In this paper, we evaluate the use of PHEMA sponges as means of forming the tissue-implant intermediary for an implantable drug delivery device. The structure of the sponges was characterized using scanning electron microscopy (SEM) and mercury porosimetry. Also, preliminary implantation and infusion studies were performed using a catheter supported model device.

Section snippets

Polymer synthesis

All chemicals were used as received unless otherwise stated. The initiator, 2,2 azo- bisisobutryonitrile (AIBN, Aldrich Chem. Co., Milwaukee, WI) was combined in 1 wt% with the monomer, 2-hydroxy ethyl methacrylate (HEMA, Aldrich Chem. Co., Milwaukee, WI). Tetra (ethylene glycol) dimethacrylate (TEGDMA, Polysciences, Inc., Warrington, PA) was added in 1 mol% of the total monomer content as the crosslinking agent. This mixture was then diluted to 10–40 vol% with deionized water (18 MΩ, Barnstead

Polymer synthesis

Synthesis of PHEMA sponges has been well documented [14], [19], [22], [23], however in this work some additional steps were added to address concerns over solubility and heterogeneity. Because, AIBN is not fully soluble in water, it was necessary to dissolve it in pure HEMA first, and then dilute this mixture to the desired volume using DI water. Sample preparation and reactions were performed the same day due to the AIBN recrystalizing over time. Nitrogen was bubbled through the reaction

Conclusion

The goal of this work was to evaluate the efficacy of macroporous, PHEMA sponges as interfacial drug delivery devices. PHEMA sponges were synthesized using a thermally initiated free-radical solution polymerization. By altering the solvent fraction in the reaction mixture, sponges were synthesized with interconnected pore sizes ranging from 6 to 15 μm with porosities ranging from 55% to 87%. Since it was possible to form networks with pore sizes greater than 8–10 μm, macroporous, PHEMA sponges

Acknowledgements

This work was supported by grant from The Whitaker Foundation and a Drexel University/Jefferson University seed grant.

References (30)

  • R.L. Walton et al.

    Tissue engineering of biomaterials for composite reconstructionan experimental approach

    Ann Plast Surg

    (1993)
  • A.G. Mikos et al.

    Prevascularization of porous biodegradable polymers

    Biotech Bioengng

    (1993)
  • S.A. Weslowski et al.

    Porosityprimary determinant of ultimate fate of synthetic vascular grafts

    Surgery

    (1961)
  • Peppas N. Hydrogels in medicine and pharmacy, vol. I: Fundamentals. Boca Raton, FL: CRS Press,...
  • Lowman AM, Peppas NA. Hydrogels. In: Mathoiwitz E, editor. Encyclopedia of controlled drug delivery. New York: Wiley,...
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