Y. Ikada

Surface modification of polymers for medical applications

Most of the conventional materials do not meet the demands required for both their surface and bulk properties when used as biomaterials. An effective approach for developing a clinically applicable biomaterial is to modify the surface of the material which already has excellent biofunctionality and bulk properties. This review article focuses on the surface modification of polymers by grafting techniques, which have long been known in polymer chemistry but are not yet widely applied to biomaterials. A grafted surface can be produced primarily either by graft polymerization of monomers or covalent coupling reaction of existing polymer molecules onto the substrate polymer surface. The major surface properties that should be modified include two kinds of biocompatibility. One is the surface property that elicits the least foreign-body reactions and the other is the cell- and tissue-bonding capability. In addition, physiologically active surfaces with, for instance, selective adsorbability may be required. Attempts to produce these biocompatible or biospecific surfaces by grafting techniques are briefly overviewed in this article.

Prevention of fatigue cracks in ultrahigh molecular weight polyethylene joint components by the addition of vitamin E.

Flaking-type wear, so-called delamination, is often observed in polyethylene joint components. This is thought to occur partly due to crack formation and propagation at grain boundaries. This study examined the effect of vitamin E on the crack formation and/or propagation in UHMWPE by using 2-dimensional sliding fatigue testing and micro indenter testing. An in vitro sliding fatigue test was performed under two simplified articulating movements, and the cracks produced were observed by scanning acoustic tomography (SAT). Gamma-irradiated ultrahigh molecular weight polyethylene (UHMWPE) specimens demonstrated a smaller area of accumulated cracks as compared to virgin specimens, when the loading movement was reciprocated on a single linear locus. However, four out of five gamma-irradiated UHMWPE specimens exhibited severe flaking-like destruction under the complicated sliding condition, suggesting that gamma irradiation accelerated crack propagation under multidirectional loading. All the gamma-irradiated vitamin-E-containing specimens demonstrated no subsurface crack formation and no flaking-like destruction. Results using micro indenter testing showed that the dynamic hardness at grain boundary was higher than that in grain, and was increased by gamma irradiation. This hardening at grain boundary was reduced by adding vitamin E. It is possible that the presence of vitamin E prevents crack propagation partly due to reduced hardness at grain boundaries. The gamma-irradiated vitamin-E-containing UHMWPE is a promising material to prevent flaking-like destruction of polyethylene joint components.

A new biological glue from gelatin and poly(L-glutamic acid)

This study describes the potentiality of hydrogels composed of gelatin and poly(L-glutamic acid) (PLGA) as a biological glue for soft tissues and compares its effectiveness with that of a conventional fibrin glue. Water-soluble carbodiimides (WSC) were used to crosslink the aqueous mixture of gelatin and PLGA. The mixed aqueous solution of gelatin and PLGA set to a hydrogel by use of WSC as rapidly as BOLHEAL fibrin glue. An addition of PLGA to gelatin aqueous solution reduced not only its gelation time but also the WSC concentration necessary for hydrogel formation. The cured hydrogel exhibited firm adhesion to the mouse skin and other soft tissues with a higher bonding strength than BOLHEAL fibrin glue. Cohesive failure in the hydrogel was observed when the gel-tissue bond was broken, in contrast to BOLHEAL fibrin glue. The bonding strength of the gelatin-PLGA hydrogel became higher with the increasing PLGA concentration. The inflammatory reaction around the gelatin-PLGA hydrogel subcutaneously implanted in mice was mild, and the hydrogel was gradually absorbed with time in vivo. A toxicity test demonstrated that the concentration of WSC necessary as a biological glue was low enough not to induce its toxicity.

A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier

We prepared a composite of D,L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur, and the effective concentration of the antibiotic was measured in the cortex, the cancellous bone, and the bone marrow. In all bone tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.

Rapidly curable biological glue composed of gelatin and poly(l-glutamic acid)

The tissue adhesion property of a hydrogel cross-linked with water-soluble carbodiimide (WSC) was investigated and compared with that of the conventional fibrin glue. The biodegradable hydrogel was composed of gelatin and poly(L-glutamic acid) (PLGA). This study focused on the mouse skin bonding by the WSC-formed hydrogel prepared from a low-molecular-weight (Mw) gelatin whose aqueous solution did not spontaneously set to a gel at 25 degrees C, in contrast to the conventional gelatin with high Mw. At polymer concentrations lower than the incipient gelation concentration, the bonding strength of mouse skin by the WSC-cross-linked gelatin-PLGA hydrogel increased with an increase in the concentration of gelatin and PLGA, irrespective of Mw of gelatin. When compared at the highest gelatin concentration which did not cause gelation, the bonding strength of the hydrogel composed of lower Mw gelatin and PLGA was higher than that of higher Mw gelatin hydrogel with or without PLGA or the conventional fibrin glue. The mixed aqueous solution from the gelatin with Mw of 10,000 and PLGA was gelled by use of WSC as rapidly as the fibrin glue. It was concluded that the gelatin-PLGA hydrogel is a safe biological glue with the adhesion property superior to the fibrin glue.

Surface modification of polyethylene balloon catheters for local drug delivery

Local drug delivery is an attractive approach to the associated problems of percutaneous transluminal coronary angioplasty (PTCA), including arterial injury. The objective of the present research was to deliver a high concentration of a potent anti-thrombin agent, argatroban (ARG), to the vessel wall in order to reduce arterial injury. Local delivery was accomplished by the ionic attachment of drug particles to a modified balloon surface. Surface graft polymerization of ionic monomers to a high-density poly(ethylene) (PE) substrate was performed utilizing ultra-violet (UV) methods. Acrylic acid (AAc) and 2(dimethylamino) ethyl methacrylate (DMAEMA) were successfully grafted onto PE surfaces. Surface grafting was verified by contact angle, X-ray photoelectron spectroscopy, and zeta potential measurements. The amount of ARG adsorbed onto the modified PE surface was highly dependent on the pH of the drug media for both anionic and cationic grafted monomers. The efficacy of local drug delivery to the arterial wall was analyzed using drug-immobilized PE balloon catheters in the rabbit common carotid artery model. High concentrations of ARG (280 nmol/g tissue) were found within the ballooned arterial segment immediately after angioplasty, followed by a decrease after blood flow was restored.

Controlled cisplatin delivery system using poly(D,L-lactic acid)

Cisplatin (CDDP)-containing poly(D,L-lactic acid) microspheres (CDDP-MS) and beads (CDDP-B) with an average molecular weight of the oligomer of 1.2 x 10(4) and 4% CDDP loading were prepared. In Tris buffer, 95% of CDDP disappeared from CDDP-MS within 3 d. In vitro and in vivo, CDDP-B released CDDP for 30-57 d, and for 21-42 d, respectively. The other CDDP-B with an average oligomer molecular weight of 9.6 x 10(3) with 5% lactic acid monomers, that contained 4% CDDP, showed a two-phase CDDP release pattern and CDDP disappeared within 41 d in vitro, and within 21 d in vivo. Histologically, tissue necrosis surrounding the CDDP-B was not severe.

Assessment of heat and storage conditions on γ-ray and electron beam irradiated UHMWPE by electron spin resonance

Electron spin resonance (ESR) spectroscopic study was undertaken to explore the nature of any remaining radicals in ultra-high molecular weight polyethylene (UHMWPE) after irradiation with gamma-rays and electron beams to a dose of 25 KGy in air or N2 environment. The decay of radicals was studied by observing the ESR intensity change as a function of time. The following post-irradiation conditions were employed: (1) storage in air or N2 at 25 degrees C, and (2) heat treatment in air or N2 at 80, 100, and 120 degrees C for time intervals up to 8 h. The study suggests that radicals remaining trapped in the matrix of UHMWPE could be dramatically scavenged by heat treatment, independently of the atmosphere during irradiation and the heating process. The melting temperature and mechanical properties of irradiated UHMWPE under the experimental conditions employed were shown not to alter significantly by heat treatment, except in the presence of air.

Pharmacologic Effects of Cisplatin Microspheres on Peritoneal Carcinomatosis in Rodents

Background. A new drug‐delivery formulation of cisplatin, whereby cisplatin was incorporated in lactic acid oligomer microspheres (CDDP‐MS), has been developed in dosage form for peritoneal carcinomatosis and has been designed to release 70% of the incorporated cisplatin slowly during a period of 3 weeks. In this study, its pharmacologic effects were examined in rodents.

New biodegradable oligoesters for pharmaceutical application.

Tartaric acid, malic acid, and glyceric acid were copolycondensed with glycolic acid at various molar ratios in feed to quickly synthesize biodegradable oligoesters. They were likely to have a moderately cross-linked structure with relatively low molecular weights and hydrophilic groups on the chains. In addition to macroscopic gels which were insoluble in any solvents, we could obtain the oligoesters which were insoluble in water but soluble in N,N-dimethylformamide. The degradation rate of the oligoesters was higher than that of lactic acid (LA) oligomers having molecular weights of a few thousands. On the contrary, their glass transition and flow temperatures were much higher than those of LA oligomers, indicating that their handling during the preparation of drug delivery dosage forms was much improved. The formulation of microspheres containing drugs from the oligoesters revealed that they were useful as biodegradable matrices having high degradation rates.