Evaluation of porous networks of poly(2-hydroxyethyl methacrylate) as interfacial 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)
- et al.
Poly(2-hydroxyethyl methacylate) sponges as implant materialsin vivo and in vitro evaluation of cellular invasion
Biomaterials
(1993) - et al.
The preparation of sub-200 nm poly(lactide-co-glycolide) microspheres for site specific drug delivery
J Control Rel
(1993) Ultrasound-induced degradation of PLA and PLGA during microsphere processinginfluence of formation variables
Euro J Pharm Biopharm
(1998)- Hertzog BA, Thanos C, Sandor M, Raman V, Edelman ER. Cardiovascular drug delivery systems. In: Mathoiwitz E, editor....
- Leach K. Cancer, drug delivery to treat—local & systemic. In: Mathoiwitz E, editor. Encylcopedia of controlled drug...
- Groves MJ. Parenternal drug delivery systems. In: Mathoiwitz E, editor. Encylcopedia of controlled drug delivery. New...
- et al.
Neovascularization of synthetic membranes directed by membrane microarchitecture
J Biomed Mater Res
(1995) - Mooney DJ, Langer RS. Engineering biomaterials for tissue engineering: the 10–100 micron size scale. In: Bronzino JD,...
Inflammatory responce to implants
Trans Am Soc Artif Intern Organs
(1988)- et al.
Islet immuno-isolationthe use of hybrid artificial organs to prevent islet tissue rejection
World J Surg
(1984)