ReviewElectro-responsive drug delivery from hydrogels
Introduction
“Intelligent” drug carriers which, once implanted in the body, release the right amount of drug at the right time and/or at the right place may enable us to precisely control the delivery of drugs.
Such carriers would be most useful in mimicking the in vivo pulsatile release of many endogenous chemicals, such as insulin, growth hormone, oestrogen, luteinising hormone, etc., which would result in improved drug treatment of disorders such as diabetes. A pulsatile drug profile in the body is desirable when the continuous presence of drug leads to down-regulation of receptors and the development of tolerance. These “smart” drug delivery vehicles would also enable the tailoring of medical treatment to individual patients, for example, for pain relief. Precise control of drug levels in the body can only be achieved if the drug carrier responds in a reproducible and predictable fashion to an internal or external chemical, physical or biological stimulus. The magnitude of the response must be dependent on the magnitude of the stimulus. At the same time, a carrier which is responsive to an externally-applied stimulus should not release drugs in response to the environment where it has been implanted such as body fluids, ions, etc. The drug load in the carrier must be high enough to allow a reasonable lifetime of the implant, which would ensure a low frequency of implant administration and increased patient compliance. The carrier should be non-toxic, non-irritant, biodegradable, biocompatible, easy to administer and should not need to be removed when drug-depleted.
Why hydrogels? A number of different drug delivery vehicles such as liposomes, microspheres, hydrogels, which respond to stimuli, e.g., temperature, pH, glucose, light, electric fields, ultrasound, infection, inflammation, etc., are currently being investigated in an attempt to optimise drug therapy [1], [2], [3], [4]. In this paper, electro-responsive hydrogels as “intelligent” drug carriers are reviewed. Hydrogels are especially interesting as drug-containing implants as they are said to resemble biological tissue due to their hydrophilic nature and three-dimensional polymeric network which can imbibe large amounts of water or biological fluids [5]. Their high water content could contribute to their biocompatibility and their rubbery nature could ensure minimal mechanical irritation to surrounding tissues while the low interfacial tension between the gel surface and the aqueous surrounding fluids would minimise protein adsorption and cell adhesion onto the gel [6]. Hydrogels also offer the possibility of fabrication in a variety of different shapes, e.g., rods, disks, films, microparticles, depending on the intended applications and sites of administration and can easily be washed, following production, to remove any undesired molecules such as unreacted initiators, monomers, etc. [7].
Why an electrical stimulus? An electric field as an external stimulus has advantages such as the availability of equipment which allows precise control with regards to the magnitude of current, duration of electric pulses, intervals between pulses, etc. There is already a large body of literature on the use of electric currents in vivo, in the form of iontophoresis and electroporation, in the field of dermal and transdermal drug delivery [8], [9], [10] and safe limits of electric field strengths for topical application have been determined. There is also a marketed product in the USA—Iontocaine®—which is a device used to deliver lignocaine by iontophoresis. Thus, electro-responsive delivery of drugs from hydrogels seems to be a feasible (if difficult) option for use in man. A possible scenario would be a biodegradable hydrogel which is implanted subcutaneously, for example in the arm. Biodegradability avoids the need to remove the hydrogel when all the drug has been released. When drug release is desired, an electro-conducting patch is applied on the skin directly over the gel. Electrodes are plugged into the patch and an electric field is applied onto the skin. The electric field stimulates the drug carrier situated under the skin and the drug carrier releases drug in response. The electro-conducting patch is removed when the required amount of drug has been released. Alternatively, the electro-conductive patch and electrodes could be in the form of a wristwatch worn over the implant site. An improvement over this scenario would be biodegradable hydrogel beads (microspheres, nanospheres) which could be injected subcutaneously or polymer solutions which could be injected as a liquid but which form a gel at body temperature. This would remove the need for surgical implantation of the drug delivery vehicle and have huge implications regarding cost of treatment and patient acceptability. Electro-responsive delivery from hydrogels and gel beads have been demonstrated, but, there is currently no literature on electro-responsive gels which form in situ in the body, following the injection of liquids.
Under the influence of an electric field, electro-responsive hydrogels generally deswell or bend, depending on the shape of the gel and its position relative to the electrodes. Bending occurs when the main axis of the gel lies paralled to (but does not touch) the electrodes whereas deswelling occurs when the hydrogel lies perpendicular to the electrodes [11]. Hydrogel bending has mainly been studied for the production of mechanical devices such as valves, artificial fingers/hands/muscles, switches, “soft-acutators” and “molecular machines” [12], [13] and will not be reviewed here. The focus of this review will, instead, be on the electrically-induced gel deswelling and other responses which affect the movement of solutes (hence, release) out of the gel. In the following sections, electro-responsive polymeric hydrogels, the electro-response of hydrogels and the in vitro and in vivo electro-responsive drug release from hydrogels are reviewed.
Section snippets
Electro-responsive gels
Electrically-responsive hydrogels are prepared from polyelectrolytes (polymers which contain relatively high concentrations of ionisable groups along the backbone chain [14]) and are thus pH-responsive, as well as electro-responsive. Most of the polymers studied have been polyanions, but polycations and an amphoteric polyelectrolyte [15] have also been used. Synthetic as well as naturally-occurring polymers, separately or in combination, have been used. Examples of naturally-occurring polymers
Response of hydrogels to an electric field
The response of polyelectrolyte hydrogels to an applied electric field has been studied by a number of investigators who have used different experimental set-ups such as those schematically shown in Fig. 1a–d. The gel may or may not be placed in an electro-conducting medium such as water, saline, buffer. One or both electrodes (e.g., carbon, platinum) may be in contact with the gel (Fig. 1a1, 1a2, 1b, 1d). When electrodes are not contacting, the gel is placed in a conducting medium (Fig. 1c).
Electro-responsive drug release from hydrogels
The mechanical response of polyelectrolyte hydrogels to an applied electric field can be used to control drug release from these gels. Drug may be incorporated into the hydrogels either during gel formation or after the gel has been formed by incubating the gel in a drug solution and allowing drug molecules to diffuse into the network. The electro-stimulated release of a variety of small and large, charged and uncharged guest molecules has been demonstrated. In most cases, drug is released when
In vivo electro-stimulated drug release
Electro-responsive drug delivery has been demonstrated in vivo, in rats, where a subcutaneously implanted hydrogel released its drug load in a pulsatile fashion following the application of an external electric field [41]. Fasted, anaesthetised rats were shaved on the back and the abdomen and ventral (anode) and dorsal (cathode) electrodes were applied to the abdomen and the back, respectively, with a cyanoacrylate adhesive. An insulin-loaded PDMAPAA gel was then implanted under the skin,
Conclusions and future perspectives
Hydrogels formed from polyelectrolyte polymers are electro-responsive. Upon the application of an electric field, they deswell, swell or erode, depending on the nature of the gels and the experimental set-up. Mechanisms of gel deswelling include: (i) a stress gradient generated within a gel which cannot migrate, but where the immobile polymeric charges are attracted to the oppositely charged electrode, (ii) neutralisation of polymeric charges by H+/OH− ions generated via electrically-induced
Acknowledgements
The author thanks Maria Shew for secretarial assistance and Chris Courtice for technical advice.
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