Bruining M J, Blaauwgeers H G, Kuijer R, Pels E, Nuijts R M, Koole L H
Center for Biomaterials Research, University of Maastricht, The Netherlands.
Biomaterials. 2000 Mar;21(6):595-604. doi: 10.1016/s0142-9612(99)00223-9.
In ophthalmology, there is a need for novel degradable biomaterials for e.g. controlled drug release in the vitreous body. These degradable materials should feature both excellent biocompatibility, and well-defined kinetics of degradation. In most cases, poly(D,L-lactic acid), or poly(lactic-co-glycolic acid) are used. These materials, however, suffer from some serious drawbacks, since the degradation kinetics are difficult to control, especially since the so-called 'burst-degradation' occurs. Here, we describe a set of novel polymeric networks which largely consist of poly(dimethylamino ethyl methacrylate) (poly(DMAEMA)); these materials are crosslinked via a dimethacrylate molecule that contains two carbonate groups. This system is susceptible to hydrolytic scission. The degradation products do not exert a catalytic effect on the ongoing degradation reaction (i.e. there is no burst effect). We describe the synthesis of three of these materials, which differ merely with regard to the crosslinker content. These materials were characterized through DMTA, 1H NMR and FT-IR spectroscopy, and scanning electron microscopy. The reaction DMAEMA + 2-hydroxyethyl methacrylate (HEMA) was studied in detail, using 1H NMR spectroscopy, and these experiments revealed that the reaction of DMAEMA and HEMA produces a random (Bernouillian-type) copolymer. From this, we contend that the new materials have more or less uniform distribution of the crosslinks throughout their volume. Structural degradation of the three materials was studied in vitro, at pH 7.4, 9.1 and 12.0. It is found that the materials exhibit smooth hydrolysis, which can be controlled via the crosslink density and the pH, as was expected a priori. It should be noted that degradation of these materials produces non-hydrolysable, but water-soluble, oligo(DMAEMA) and poly(DMAEMA) molecules. We subsequently performed in vitro studies on the biocompatibility of these materials. The MTT cytotoxicity assay revealed that the materials were cytotoxic to chondrosarcoma cells. This is most probably due to local increase of the pH due to the basic character of the pending dimethylamino groups. Cytotoxicity remained virtually unchanged after extended washing with water. This indicates that the cytotoxicity is an intrinsic property of the material and was not caused by remnants of free monomer. Cytotoxicity was also seen in cell cultures (human fibroblasts isolated from donor corneas) which were grown in contact with the materials. It is concluded that the new materials have attractive degradation characteristics, but their cytotoxicity makes them unsuitable for applications in ophthalmology.
在眼科领域，需要新型可降解生物材料用于例如玻璃体中的药物控释。这些可降解材料应兼具优异的生物相容性和明确的降解动力学。在大多数情况下，会使用聚（D，L - 乳酸）或聚（乳酸 - 共 - 乙醇酸）。然而，这些材料存在一些严重缺陷，因为降解动力学难以控制，特别是会出现所谓的“突发降解”。在此，我们描述了一组新型聚合物网络，其主要由聚（甲基丙烯酸二甲氨基乙酯）（聚（DMAEMA））组成；这些材料通过含有两个碳酸酯基团的二甲基丙烯酸酯分子交联。该体系易受水解断裂影响。降解产物对正在进行的降解反应不产生催化作用（即不存在突发效应）。我们描述了其中三种材料的合成，它们仅在交联剂含量方面有所不同。这些材料通过动态热机械分析（DMTA）、核磁共振氢谱（1H NMR）、傅里叶变换红外光谱（FT - IR）以及扫描电子显微镜进行了表征。使用核磁共振氢谱对甲基丙烯酸二甲氨基乙酯（DMAEMA）与甲基丙烯酸羟乙酯（HEMA）的反应进行了详细研究，这些实验表明DMAEMA与HEMA的反应生成了无规（伯努利型）共聚物。由此我们认为，新材料在其整个体积内交联分布或多或少是均匀的。在体外pH值为7.4、9.1和12.0的条件下研究了这三种材料的结构降解。结果发现，正如先前所预期的，这些材料表现出可通过交联密度和pH值控制水解的平滑过程。应当指出的是，这些材料的降解产生不可水解但水溶性的低聚（DMAEMA）和聚（DMAEMA）分子。随后我们对这些材料的生物相容性进行了体外研究。MTT细胞毒性试验表明，这些材料对软骨肉瘤细胞具有细胞毒性。这很可能是由于悬垂的二甲基氨基基团呈碱性导致局部pH值升高。用水长时间冲洗后细胞毒性几乎保持不变。这表明细胞毒性是该材料的固有特性，并非由游离单体残留引起。在与这些材料接触生长的细胞培养物（从供体角膜分离的人成纤维细胞）中也观察到了细胞毒性。结论是，新材料具有吸引人的降解特性，但其细胞毒性使其不适用于眼科应用。
