Ebru Oral

Surface modifications and molecular imprinting of polymers in medical and pharmaceutical applications

Recent developments in the field of biomaterials are based on molecular design of polymers with improved surface and bulk properties. Novel techniques of surface modification by addition of tethered chains can lead to materials with the ability to recognize biological and pharmaceutical compounds. Methods based on molecular imprinting can increase the recognition capabilities of such systems. Chain tethering can also can improve the mucoadhesive behavior of a delivery device and the effectiveness of a drug by allowing targeting and localization of a drug at a specific site. Acrylic-based hydrogels are well-suited for mucoadhesion due to their flexibility and nonabrasive characteristics which reduce damage-causing attrition to the tissues in contact. However, the adhesive and drug delivery capabilities of these devices can continue to be improved as presently known bioadhesive materials are modified and more bioadhesive materials are discovered. Tethering of long PEG chains on PAA hydrogels and their copolymers can be achieved by grafting reactions involving thionyl chloride, followed by PEG grafting. The ensuing materials exhibit mucoadhesive properties due to enhanced anchoring of the chains with the mucosa. Theoretical calculations can lead to optimization of the tethered structure.

Vitamin E-stabilized UHMWPE for Total Joint Implants: A Review

BackgroundOsteolysis due to wear of UHMWPE limits the longevity of joint arthroplasty. Oxidative degradation of UHMWPE gamma-sterilized in air increases its wear while decreasing mechanical strength. Vitamin E stabilization of UHMWPE was proposed to improve oxidation resistance while maintaining wear resistance and fatigue strength.Questions/purposesWe reviewed the preclinical research on the development and testing of vitamin E-stabilized UHMWPE with the following questions in mind: (1) What is the rationale behind protecting irradiated UHMWPE against oxidation by vitamin E? (2) What are the effects of vitamin E on the microstructure, tribologic, and mechanical properties of irradiated UHMWPE? (3) Is vitamin E expected to affect the periprosthetic tissue negatively?MethodsWe performed searches in PubMed, Scopus, and Science Citation Index to review the development of vitamin E-stabilized UHMWPEs and their feasibility as clinical implants.ResultsThe rationale for using vitamin E in UHMWPE was twofold: improving oxidation resistance of irradiated UHMWPEs and fatigue strength of irradiated UHMWPEs with an alternative to postirradiation melting. Vitamin E-stabilized UHMWPE showed oxidation resistance superior to that of irradiated UHMWPEs with detectable residual free radicals. It showed equivalent wear and improved mechanical strength compared to irradiated and melted UHMWPE. The biocompatibility was confirmed by simulating elution, if any, of the antioxidant from implants.ConclusionsVitamin E-stabilized UHMWPE offers a joint arthroplasty technology with good mechanical, wear, and oxidation properties.Clinical RelevanceVitamin E-stabilized, irradiated UHMWPEs were recently introduced clinically. The rationale behind using vitamin E and in vitro tests comparing its performance to older materials are of great interest for improving longevity of joint arthroplasties.

Vitamin E diffused, highly crosslinked UHMWPE: a review

Highly crosslinked UHMWPE has become the bearing surface of choice in total hip arthroplasty. First generation crosslinked UHMWPEs, clinically introduced in the 1990s, show significant improvements compared to gamma sterilised, conventional UHMWPE in decreasing wear and osteolysis. These crosslinked UHMWPEs were thermally treated (annealed or melted) after irradiation to improve their oxidation resistance. While annealing resulted in the retention of some oxidation potential, post-irradiation melted UHMWPEs had reduced fatigue strength due to the crystallinity loss during melting. Thus, the stabilisation of radiation crosslinked UHMWPEs by the diffusion of the antioxidant vitamin E was developed to obtain oxidation resistance with improved fatigue strength by avoiding post-irradiation melting. A two-step process was developed to incorporate vitamin E into irradiated UHMWPE by diffusion to obtain a uniform concentration profile. Against accelerated and real-time aging in vitro, this material showed superior oxidation resistance to UHMWPEs with residual free radicals. The fatigue strength was improved compared to irradiated and melted UHMWPEs crosslinked using the same irradiation dose. Several adverse testing schemes simulating impingement showed satisfactory behaviour. Peri-prosthetic tissue reaction to vitamin E was evaluated in rabbits and any effects of vitamin E on device fixation were evaluated in a canine model, both of which showed no detrimental effects of the inclusion of vitamin E in crosslinked UHMWPE. Irradiated, vitamin E-diffused, and gamma sterilised UHMWPEs have been in clinical use in hips since 2007 and in knees since 2008. The clinical outcome of this material will be apparent from the results of prospective, randomised clinical studies.

The effects of high dose irradiation on the cross-linking of vitamin E-blended ultrahigh molecular weight polyethylene

Vitamin E-stabilized, highly cross-linked ultrahigh molecular weight polyethylene (UHMWPE) is a promising oxidation and wear resistant UHMWPE with improved mechanical strength in comparison with the first generation, irradiated and melted UHMWPE. One approach of incorporating vitamin E in UHMWPE is through blending of vitamin E in UHMWPE powder followed by consolidation and radiation cross-linking. However, radiation cross-linking efficiency of UHMWPE decreases in the presence of vitamin E. Therefore an optimum vitamin E concentration and radiation dose level need to be determined to achieve a cross-link density comparable to 100-kGy irradiated and melted UHMWPE, which has shown excellent wear properties in vivo. We investigated the cross-link density and mechanical properties of vitamin E-blended UHMWPEs as a function of vitamin E concentration in the blend and gamma irradiation doses up to 200kGy. We found that 0.3wt% vitamin E-blended UHMWPE could not be cross-linked above a cross-link density achieved at a radiation dose of 65kGy for virgin UHMWPE and 1.0wt% vitamin E-blended UHMWPE could not be cross-linked above a cross-link density achieved at a radiation dose of 25kGy for virgin UHMWPE even when the these UHMWPEs were irradiated to a radiation dose of 200kGy. In addition, higher plasticity at vitamin E concentrations at and above 0.3wt% indicated that increased chain scissioning may be prevalent. Since the wear resistance of this irradiated UHMWPE would be expected to be low, vitamin E concentrations equal to or above 0.3wt% are not recommended for subsequent irradiation to achieve a wear resistant cross-linked UHMWPE. The long-term oxidative stability of irradiated blends with low vitamin E concentrations has yet to be studied to determine an optimum between cross-link density and long-term oxidative stability.

A new mechanism of oxidation in ultrahigh molecular weight polyethylene caused by squalene absorption

Although synovial fluid lipids were found to absorb in ultrahigh molecular weight polyethylene (UHMWPE) total joint implants in vivo, their effect on the oxidation of the polymer was not known. Current understanding of the oxidation and oxidative stability of UHMWPE joint implants is focused on the presence or elimination of radiation-induced free radicals, which are long-lived and can react with oxygen over the long term. Recently, we found unexplained oxidation in irradiated and melted UHMWPE components that were exposed to bodily fluids then stored on the shelf despite being free of detectable free radicals at the time of implantation. Thus, we hypothesized that lipids absorbed from the synovial fluid in vivo could initiate and accelerate oxidation of UHMWPE even in the absence of detectable residual free radicals. We found that squalene, a precursor in cholesterol synthesis and a synovial fluid lipid with unsaturated bonds, accelerated oxidation in irradiated and melted UHMWPE under in vitro accelerated aging conditions. This result represents a paradigm shift in our understanding of oxidative stability of UHMWPE and prompts further investigation of in vivo oxidation mechanisms as well as the development of relevant in vitro aging models.

Improved resistance to wear and fatigue fracture in high pressure crystallized vitamin E-containing ultra-high molecular weight polyethylene

Higher crystallinity and extended chain morphology are induced in ultra-high molecular weight polyethylene (UHMWPE) in the hexagonal phase at temperatures and pressures above the triple point, resulting in improved mechanical properties. In this study, we report the effects of the presence of a plasticizing agent, namely vitamin E (alpha-tocopherol), in UHMWPE during high pressure crystallization. We found that this new vitamin E-blended and high pressure crystallized UHMWPE (VEHPE) has improved fatigue strength and wear resistance compared to virgin high pressure crystallized (HP) UHMWPE. This suggested different mechanisms of wear reduction and fatigue crack propagation resistance in UHMWPE.

A surface crosslinked UHMWPE stabilized by vitamin E with low wear and high fatigue strength

Wear particle-induced periprosthetic osteolysis has been a clinical problem driving the development of wear resistant ultrahigh molecular weight polyethylene (UHMWPE) for total joint replacement. Radiation crosslinking has been used to decrease wear through decreased plastic deformation; but crosslinking also reduces mechanical properties including fatigue resistance, a major factor limiting the longevity of joint implants. Reducing UHMWPE wear with minimal detriment to mechanical properties is an unaddressed need for articular bearing surface development. Here we report a novel approach to achieve this by limiting crosslinking to the articular surface. The antioxidant vitamin E reduces crosslinking efficiency in UHMWPE during irradiation with increasing concentration, thus we propose to spatially control the crosslink density distribution by controlling the vitamin E concentration profile. Surface crosslinking UHMWPE prepared using this approach had high wear resistance and decreased crosslinking in the bulk resulting in high fatigue crack propagation resistance. The interface region did not represent a weakness in the material due to the gradual change in the crosslink density. Such an implant has the potential of decreasing risk of fatigue fracture of total joint implants as well as expanding the use of UHMWPE to younger and more active patients.

Highly Cross-Linked Ultrahigh Molecular Weight Polyethylene With Improved Fatigue Resistance for Total Joint Arthroplasty : Recipient of the 2006 Hap Paul Award

Eliminating postirradiation melting and stabilizing the residual free radicals of radiation cross-linked ultrahigh molecular weight polyethylene (UHMWPE) with vitamin E resulted in improved fatigue crack propagation resistance without compromising wear resistance. We designed a cantilever postbending test to determine the bending fatigue resistance of alpha-tocopherol-doped, irradiated UHMWPE (alpha-TPE) in comparison to conventional UHMWPE. The bending fatigue behavior of alpha-TPE was comparable to conventional UHMWPE. Upon accelerated aging, the fatigue resistance of alpha-TPE was substantially better than that of conventional UHMWPE. alpha-TPE has shown improved wear and oxidation resistance, migration stability of vitamin E, and improved mechanical properties. The use of this material may be beneficial in total knee arthroplasty where its improved fatigue properties may be an advantage under high stresses.

In vivo biological response to vitamin E and vitamin-E-doped polyethylene.

BACKGROUND Cross-linking has decreased the wear of ultra-high molecular weight polyethylene, a cause of osteolysis leading to total joint replacement failure. Compared with melting or annealing, doping cross-linked ultra-high molecular weight polyethylene with vitamin E stabilizes free radicals from irradiation while maintaining mechanical properties and wear resistance. This study was done to determine the local tissue effects of free vitamin E and vitamin E eluted from ultra-high molecular weight polyethylene implants in the joint space. METHODS Three studies were performed. First, pure vitamin E and solubilized vitamin E were injected into rabbit knees to simulate vitamin-E elution from radiation cross-linked ultra-high molecular weight polyethylene; second, vitamin-E-doped, irradiated ultra-high molecular weight polyethylene plugs were implanted into dorsal subcutaneous pouches of rabbits to determine the local effects of vitamin-E elution from radiation cross-linked ultra-high molecular weight polyethylene; and, third, two groups of vitamin-E-doped, irradiated acetabular liners (high surface and uniform vitamin-E concentration profiles) were compared with undoped, control ultra-high molecular weight polyethylene liners in a canine model of total hip replacement to determine the effect of possible vitamin-E elution on bone ingrowth and the local tissue response to it in a load-bearing environment. RESULTS Injection of solubilized vitamin E resulted in histologically normal surrounding soft tissue at both two and twelve-week follow-up intervals, while injection of pure vitamin E resulted in acute and chronic inflammation at the time of the two-week follow-up. Both control and vitamin-E-doped subcutaneous plugs showed inflammation associated with surgery at two weeks of follow-up, but showed stable fibrous encapsulation without inflammation at twelve weeks of follow-up. In the canine total hip replacement model, there was no qualitative difference in local tissue appearance and no significant difference in the percent bone ingrowth and the percent bone density between the control and vitamin-E groups. CONCLUSIONS These investigations showed that vitamin-E-doped ultra-high molecular weight polyethylene plugs and total hip replacement components are well tolerated in both a small and a large-animal model with no observed adverse effects on the surrounding tissues at twelve weeks of follow-up.

Increasing irradiation temperature maximizes vitamin E grafting and wear resistance of ultrahigh molecular weight polyethylene

Vitamin E stabilization of radiation crosslinked ultrahigh molecular weight polyethylene (UHMWPE) for total joint implants can be done by blending of UHMWPE resin powder with vitamin E, followed by consolidation and irradiation of the blend. It is well known that vitamin E prevents crosslinking in UHMWPE during ionizing radiation. We hypothesized that there would also be a significant amount of grafting of vitamin E onto UHMWPE during irradiation. Spectroscopic analysis of radiation crosslinked vitamin E-blended UHMWPE before and after extraction with boiling hexane showed vitamin E grafting in up to 30% of the blended vitamin E. Grafting increased with irradiation temperature. We also discovered that increasing irradiation temperature resulted in better preservation of active vitamin E in the polymer and increased crosslinking efficiency of UHMWPE. As a result, warm-irradiated vitamin E-blended UHMWPEs had significantly less wear than those irradiated at ambient temperature. It may be desirable to graft vitamin E on UHMWPE to decrease the possibility of elution and increase long-term stability. Warm irradiation of vitamin E blends may present an advantage in increasing vitamin E potency, as well as decreasing the wear of UHMWPE, which is crucial in decreasing the incidence of periprosthetic osteolysis in total joint replacement patients.