Gogolewski S, Jovanovic M, Perren S M, Dillon J G, Hughes M K
Department of Polymers, AO/ASIF Research Institute, Davos, Switzerland.
J Biomed Mater Res. 1993 Sep;27(9):1135-48. doi: 10.1002/jbm.820270904.
The tissue response and in vivo molecular stability of injection-molded polyhydroxyacids--polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA, 5-22% VA content)--were studied. Polymers were implanted subcutaneously in mice and extirpated at 1, 3, and 6 months in order to study tissue response and polymer degradation. All polymers were well tolerated by the tissue. No acute inflammation, abscess formation, or tissue necrosis was observed in tissues adjacent to the implanted materials. Furthermore, no tissue reactivity or cellular mobilization was evident remote from the implant site. Mononuclear macrophages, proliferating fibroblasts, and mature vascularized fibrous capsules were typical of the tissue response. Degradation of the polymers was accompanied by an increase in collagen deposition. For the polylactide series, the inflammatory response after 1 month of implantation was less for materials containing the D-unit in the polymer chain, whereas in the case of the polyhydroxybutyrate/valerates, the number of inflammatory cells increased with increasing content of the valerate unit in the polymer chain. Between 1-3 months, there was slightly more tissue response to the PHB and PHB/VA polymers than to PLA. This response is attributed to the presence of leachable impurities and a low molecular weight soluble component in the polyhydroxybutyrate/valerates. At 6 months, the extent of tissue reaction was similar for both types of polymers. All polylactides degraded significantly (56-99%) by 6 months. For a poly(L-lactide) series, degradation rate in vivo decreased with increasing initial molecular weight of the injection-molded polymer. Several samples showed pronounced bimodal molecular weight distributions (MWD), which may be due to differences in degradation rate, resulting from variability in distribution of crystalline and amorphous regions within the samples. This may also be the result of two different mechanisms, i.e., nonenzymatic and enzymatic, which are involved in the degradation process, the latter being more extensive at the later stage of partially hydrolyzed polymer. The PHB and PHB/VA polymers degraded less (15-43%) than the polylactides following 6 months of implantation. Generally, the polymer with higher valerate content (19%, 22%) degraded most. The decrease in molecular weight was accompanied by a narrowing of the MWD for PHB and copolymers; there was no evidence of a bimodal MWD, possibly indicating that the critical molecular weight that would permit enzyme/polymer interaction had not been reached. Weight loss during implantation ranged from 0-50% for the polylactides, whereas for the PHB polymers weight loss ranged from 0-1.6%.
研究了注塑成型的聚羟基酸——聚乳酸（PLA）、聚（3-羟基丁酸酯）（PHB）和聚（3-羟基丁酸酯-co-3-羟基戊酸酯）（PHB/VA，VA含量为5-22%）的组织反应和体内分子稳定性。将聚合物皮下植入小鼠体内，并在1、3和6个月时取出，以研究组织反应和聚合物降解情况。所有聚合物在组织中耐受性良好。在植入材料附近的组织中未观察到急性炎症、脓肿形成或组织坏死。此外，在远离植入部位处未发现明显的组织反应性或细胞动员。单核巨噬细胞、增殖的成纤维细胞和成熟的血管化纤维囊是典型的组织反应。聚合物的降解伴随着胶原蛋白沉积的增加。对于聚乳酸系列，聚合物链中含有D-单元的材料在植入1个月后的炎症反应较小，而对于聚羟基丁酸酯/戊酸酯，炎症细胞数量随着聚合物链中戊酸酯单元含量的增加而增加。在1-3个月之间，PHB和PHB/VA聚合物的组织反应比PLA略多。这种反应归因于聚羟基丁酸酯/戊酸酯中存在可浸出杂质和低分子量可溶性成分。在6个月时，两种类型聚合物的组织反应程度相似。到6个月时，所有聚乳酸均显著降解（56-99%）。对于聚（L-乳酸）系列，体内降解速率随着注塑聚合物初始分子量的增加而降低。几个样品显示出明显的双峰分子量分布（MWD），这可能是由于降解速率的差异，这是由样品中结晶区和非晶区分布的变化引起的。这也可能是两种不同机制的结果，即非酶促和酶促机制，它们参与降解过程，后者在部分水解聚合物的后期更为广泛。植入6个月后，PHB和PHB/VA聚合物的降解程度低于聚乳酸。一般来说，戊酸酯含量较高（19%，22%）的聚合物降解最多。分子量的降低伴随着PHB及其共聚物MWD的变窄；没有双峰MWD的证据，这可能表明尚未达到允许酶/聚合物相互作用的临界分子量。植入期间聚乳酸的重量损失范围为0-50%，而PHB聚合物的重量损失范围为0-1.6%。
