The past few decades have witnessed a dramatic increase in the development of polymeric biomaterials. These biomaterials have to undergo a sterilization procedure before implantation. However, many sterilization procedures have been shown to profoundly affect polymer properties. Poly(ethylene glycol) hydrogels have gained increasing importance in the controlled delivery of therapeutics and in tissue engineering. We evaluated the effect of ethylene oxide (EtO), hydrogen peroxide (H(2)O(2)), and gamma sterilization of poly(ethylene glycol) hydrogels on properties relevant to controlled drug delivery and tissue engineering. We observed that the release of cyclosporine (CyA) (an immunosuppressive drug that is effective in combating tissue rejection following organ transplantation) was significantly affected by the type of sterilization. However, that was not the case with rhodamine B, a dye. Hence, the drug release characteristics were observed to be dependent not only on the sterilization procedure but also on the type of agent that needs to be delivered. In addition, differences in the swelling ratios for the sterilized and unsterilized hydrogels were statistically significant for 1:1 crosslinked hydrogels derived from the 8000 MW polymer. Significant differences were also observed for gamma sterilization for 1:1 crosslinked hydrogels derived from the 3350 MW polymer and also the 2:1 crosslinked hydrogels derived from the 8000 MW polymer. Atomic force microscopy (AFM) studies revealed that the roughness parameter for the unsterilized and EtO-sterilized PEG hydrogels remained similar. However, a statistically significant reduction of the roughness parameter was observed for the H(2)O(2) and gamma-sterilized samples. Electron spin resonance (ESR) studies on the unsterilized and the sterilized samples revealed the presence of the peroxy and the triphenyl methyl carbon radical in the samples. The gamma and the H(2)O(2)-sterilized samples were observed to have a much higher concentration of the radical pecies when compared with the EtO and the unsterilized samples.

A simple and effective technique of improving delivery of hydrophobic drugs from swellable systems is presented. Conventional methods of drug loading in hydrogel systems are limited by the characteristics of the pharmacological agent. The approach we present uses complexants to modulate drug release. Crosslinked poly(ethylene glycol) (PEG) hydrogels were synthesized, characterized, and used for vascular applications. The release of cyclosporine (CyA) from PEG hydrogels is significantly altered by the sterilization techniques. It was hypothesized that the release of CyA from PEG hydrogels can be modulated by using complexants. A cyclodextrin-CyA complex solution was prepared and used for drug loading. The sterilized PEG hydrogels that were loaded using the cyclodextrin-CyA complex solution had favorable release characteristics compared with the release from PEG hydrogels that were loaded using the conventional technique. Hence, drug release from swellable systems can be tailored by the application of this strategy.

Anastomotic intimal hyperplasia (IH) is a major cause of both autologous vein and synthetic vascular graft failure. We have previously published data suggesting that cyclosporin may reduce the development of IH in a canine model. However, systemic administration of cyclosporin could create serious adverse effects. Therefore, it is our long-term goal to test the hypothesis that the controlled local release of cyclosporin from a polymeric vascular wrap will prevent the development of IH. To test this hypothesis, we developed a controlled release vascular wrap (sheet/ring) using a poly(ethylene glycol) (PEG) hydrogel. Sterilization of the polymers was performed using the ethylene oxide and hydrogen peroxide sterilization methods. It was found that except for one combination (8000 molecular weight and 1:1 crosslinking ratio), the differences in the swelling ratios for the sterilized and unsterilized hydrogels were not statistically significant. Release studies from unsterilized and ethylene oxide-sterilized PEG hydrogels were conducted. It was found that release lasted for approximately 50 h for sterilized as well as unsterilized PEG hydrogels. Acute animal studies, to test the deployment of both the polymeric sheets and rings to the adventitial surface of native arteries and veins, were completed successfully.

Polymeric drug delivery platforms have been receiving increasing attention in the past decade. The pharmaceutical industry is evaluating modes of delivery for their prized therapeutics at every step of the design cycle. Not only can the drug delivery platform transport drug molecules effectively, it can also improve patient compliance, offer greater patient convenience, and extend product lifecycles as patents expire. A large number of successful drug delivery systems have been developed as a result of an almost arbitrary selection of constituents and configurations. However, the development of advanced drug delivery systems relies on a judicious and careful selection of components, configurations, and geometries, which can be facilitated through mathematical modeling of controlled release systems. Mathematical modeling aids in predicting the drug release rates and diffusion behavior from these systems by the solution of an appropriate model, thereby reducing the number of experiments needed. It also aids in understanding the physics of a particular drug transport phenomenon, thus facilitating the development of new pharmaceutical products. The objective of this article is to review the spectrum of mathematical models that have been developed to describe drug release from polymeric controlled release systems. The mathematical models presented in this article have been grouped under diffusion controlled systems, swelling controlled systems, and erosion controlled systems as proposed by Langer and Peppas. Simple empirical or semi-empirical models and complex mechanistic models that consider diffusion, swelling, and erosion processes simultaneously are presented.

The effects of several sterilization procedures on a poly(ethylene glycol) (PEG) hydrogel have been examined by electron spin resonance (ESR) spectroscopy. The crosslinked polyurethanes were synthesized by reacting PEG with a tri-functional isocyanate. The free radical concentration of unsterilized, ethylene oxide (EtO), hydrogen peroxide (H(2)O(2)), and gamma sterilized hydrogels were monitored over time. Free radical presence was observed for all the treatments, unsterilized and sterilized PEG hydrogels. The unsterilized and the EtO sterilized samples elicited similar levels of free radical intensity whereas, the H(2)O(2) and gamma sterilized samples had a significantly higher free radical concentration. The spectra reveal overlapping resonances of a peroxy and a triphenylmethyl radical. The concentration of the free radicals increase for all the treatments over time except for the gamma sterilized sample. The increase is significantly higher in the H(2)O(2) sterilized sample. A tentative model is proposed to explain the reaction pathway leading to the production of the free radicals. The observed increases in the free radical concentrations of the EtO and hydrogen peroxide sterilized hydrogels over a five-month-period make it difficult to predict properties that are affected by free radical concentrations. In that light, gamma sterilization, that does not induce a change in free radical concentrations over a five month period, could be the sterilization method of choice for PEG hydrogels that could potentially be stored for undetermined periods of time prior to application.

The long-term clinical success of autologous vein and synthetic vascular grafts are limited because of the development of anastomotic intimal hyperplasia (IH). We have previously published data suggesting that cyclosporine (CyA) may reduce the development of IH in a canine model (Hirko et al., J Vasc Surg 1993;17:877-887). However, systemic administration of CyA could create serious adverse effects. Therefore, it is our long-term goal to test the hypothesis that the controlled local release of CyA from a polymeric vascular wrap would prevent the development of IH. To test this hypothesis, we developed a controlled release polymeric ring that could be placed around anastomotic sites to deliver therapeutic drugs locally. The ring is a composite polymeric device consisting of poly(DL-lactide-co-glycolide) (PLGA) microspheres embedded in a poly(ethylene glycol) hydrogel. Several in vitro studies were conducted to evaluate the effects of different sterilization procedures on the properties of the device. It was determined that gamma sterilization was the preferred sterilization method of choice for this device. In vivo studies were conducted on a swine model to evaluate the biocompatibility of the ring. The histological findings of the ring implants at 2 and 4 weeks demonstrate the biocompatibility of this device.