Introduction: The novel drug-eluting stents (DES) consists of absorbable polymers, such as poly (lactic acid) (PLA), which are progressively degraded and absorbed by human body. These polymers are designed to deliver the entire amount of an incorporated drug as degradation proceeds.1 As PLA degrades through hydrolysis, it is highly susceptible to heat and humidity, which makes radiation sterilization an efficient alternative to conventional DES sterilization methods like EO.2 However, irradiating these absorbable devices may cause the loss of functional properties, which is often the most important characteristic effect of polymer irradiation.3 Ionizing radiation is well known to compromise polymer properties due to radiolytically-induced chain scission. In addition, residual free radicals could remain in the terminally sterilized devices, which may reduce the stability and shelf life of absorbable cardiovascular implants by causing polymer degradation before device application. Our research explored the impacts of E-beam sterilization on polymeric components in cardiovascular absorbable implants by using PLA tubing as stent surrogates. Our study clarified the impacts of high-energy radiation sterilization on the safety and performance of cardiovascular absorbable implants by exploring the impacts of radiation on polymer properties; free radical decay kinetics in different environments; and polymer degradation as a function of irradiation sterilization.
Materials and Methods: PLLA (Purac PL38) extruded tubing was irradiated with electron beam (10 MeV) to 20, 30 and 40 kGy in the presence of air or argon. Electron Paramagnetic Resonance (EPR) was performed post-irradiation in air and argon using a Bruker X-band spectrometer. EPR Samples were stored and measured at room temperature. The relative concentrations of free radicals in the PLLA samples were determined at various time points up to 8 hours after irradiation. The sterilized samples were weighed and added to 10 mL PBS buffer (pH = 7.4) for degradation studies at 37 °C up to six months. The PLLA samples were periodically tested for pH, molecular weight by Gel Permeation Chromatography (GPC), and thermal properties by Differential Scanning Calorimetry (DSC).
Result and Discussion: A rapid decay in free radical concentration was observed for irradiated PLLA for all absorbed doses, as shown in Figure 1. The decay rate of free radicals is much faster for PLLA irradiated in air due to the existence of oxygen. Immediately after irradiation, an increase in crystallinity was observed with increasing radiation dose. Similarly, crystallinity was observed to increase as degradation proceeds in vitro. These increases have been attributed to preferential chain scission (during irradiation) and hydrolysis (post-irradiation) in the amorphous regions leaving a more highly-ordered crystalline structure of PLA. E-beam sterilization also cause a significant decrease in PLA molecular weight, about 40-50% after irradiation. Despite a dramatic decrease in molecular weight, no mass loss or visible changes were observed immediately post-irradiation. The major mass loss was observed after 6 month degradation in vitro.
Conclusions: Our research seeks to quantitatively assess the impact of E-beam irradiation on the stability and degradation of absorbable implants with PLA tubing. Our study indicated that both polymer properties and degradation behavior strongly depends on irradiation conditions (e.g. dose).
FDA Critical Path Initiative; Dr. Stephanie Watson, Dr. Fred Bateman and Dr. Deborah Stanley from National Institute of Standards and Technology
References:
[1] Rihal CS. What physicians should know about coronary stents. Clin & Health Aff; 2008.
[2] AAMI. Compatibility of materials subject to sterilization: Technical information report (AAMI TIR17:2008); 2008.
[3] Byron J. Lambert, et al. Radiation and Ethylene Oxide Terminal Sterilization Experiences with Drug Eluting Stent Products, AAPS PharmSciTech, Vol. 12, No. 4, December 2011.