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首页> 外文会议>World biomaterials congress >Simvastatin release from poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) microspheres
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Simvastatin release from poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) microspheres

机译：辛伐他汀从掺有聚（β-氨基酯）微球的聚（乳酸-乙醇酸）支架中释放

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Introduction: The ultimate goal of this research was to fabricate and characterize polymeric scaffolds composed of at least two components to mimic natural tissue structure at specific defect sites. Using degradable hydrogel microspheres (MS) as porogens allows for controlled pore opening after implantation as well as the potential for drug release during degradation. The controlled pore opening also allows the scaffolds to withstand the necessary mechanical properties at the implant site while degrading at a rate consistent with tissue regeneration. In the present study, systems composed of poly(lactic-cc-glycolic acid) (PLGA) and poly(β-amino ester) (PBAE) loaded with simvastatin were examined to determine the drug release, mass loss and pattern of porosity development to design application-based scaffolds. Materials and Methods: PLGA (50:50, Ⅳ: 0.554.75 dL/g, acid-terminated; Durect Corporation) MS were fabricated using a water/oil/water double emulsion technique. The resultant microspheres were sieved to ＜250 μm. The hydrogel (HG) macromer was synthesized through a step-wise reaction between polyethylene grycol) diacrytate (PEGDA; Polysciences), and isobutylamine (Sigma-Aldrich) at a 1.2:1 diacrylate:amine molar ratio at 85 °C for 120 hrs. To create cross-linked hydrogel MS, the macromer was weighed and combined with 0.2 wt% 2,2-dimethoxy-2 phenylacetophenone (initiator) in 80 wt% dichloromethane (solvent). All percentages are based on the initial macromer mass. Microspheres were then made by creating a single emulsion of macromer followed by UV photopolymerization. Simvastatin was loaded directly to the HG MS by dissolving simvastatin in reagent alcohol at three different concentrations of 100,150 and 200 mg/mL and pipetting drug solution over HG MS at a ratio of 5 uL per mg of HG MS. The drug loaded lyophilized HG MS were then mixed with PLGA microspheres at a 400:100 wtwt ratio and heated in novel compression mold system capable of producing radially- and axially-graded scaffolds. Scaffolds were fabricated with simvastatin-loaded HG MS incorporated in PLGA matrix. All three sets of samples were incubated in 3 mL phosphate-buffered saline (PBS), pH 7.4, on a plate shaker at 37°C for almost 40 days. Samples were removed at predetermined time points to measure swelling, mass loss, pore formation, and drug release. Results and Discussion: Scaffolds with lower simvastatin concentration exhibited a slightly faster degradation rate that statistically was shown insignificant (Figure 1). This accelerated degradation may likely be due to the hydrophobic nature of simvastatin that decreased water infiltration to the bulk of the HG MS and hence decreased swelling and degradation. The burst release of 20-25% (Figure 2) on day 1 was most likely the diffusion of loosely bound drug on the HG MS combined with partial swelling and degradation of loaded HG MS, resulting in similar pattern for all three systems. Subsequently, the bulk of residual drug was released in a sustained manner over the next 2-3 weeks. Simvastatin release in these systems was a combination of diffusion, swelling, and degradation from the HG MS embedded in the PLGA matrix. The scaffold structures experienced deformation from day 22 and on as PLGA degradation rate increased and bulk PLGA walls began to thinning and eventually collapsing on day 36. Conclusions: The combined effect of drug loaded HG MS imbibed within a PLGA matrix can be advantageous to design functionally graded scaffolds that mimic specific natural tissues. HG MS can be used as porogen to generate porosity that allows for aqueous infiltration and cell migration in tissue regeneration. In this study, hydrophilic HG MS system loaded with hydrophobic drug were shown to be applicable for a longer lasting matrix with a sustained drug release in potential load-bearing applications. The overall goal is for the porogen to degrade at a controlled rate while releasing specific drug(s) depending on the application and time it requires for that specific tissue to regenerate.
机译：简介：这项研究的最终目标是制造和表征至少由两种成分组成的聚合物支架，以模仿特定缺陷部位的天然组织结构。使用可降解的水凝胶微球（MS）作为致孔剂可实现植入后可控的开孔以及降解过程中药物释放的可能性。受控的孔开口还允许支架在植入部位承受必要的机械性能，同时以与组织再生一致的速率降解。在本研究中，考察了由辛伐他汀负载的聚乳酸-cc-乙醇酸（PLGA）和聚（β-氨基酯）（PBAE）组成的系统，以确定药物的释放，质量损失和孔隙发展模式。设计基于应用程序的支架。材料与方法：采用水/油/水双重乳液技术制备PLGA（50：50，Ⅳ：0.554.75 dL / g，酸封端; Durect Corporation）MS。将所得的微球筛分至＜250μm。水凝胶（HG）大分子单体是通过聚丙二醇）双丙烯酸酯（PEGDA; Polysciences）与异丁胺（Sigma-Aldrich）以二丙烯酸酯：胺的摩尔比在85°C进行120 hrs的逐步反应合成的。为了产生交联的水凝胶MS，称量大单体并与0.2重量％的2，2-二甲氧基-2苯基苯乙酮（引发剂）在80重量％的二氯甲烷（溶剂）中合并。所有百分比均基于初始大分子单体质量。然后通过产生大分子单体的单一乳液，然后进行紫外线光聚合来制备微球。辛伐他汀通过将辛伐他汀以100,150和200 mg / mL的三种不同浓度溶解在试剂酒精中，然后以5％MS / mg HG MS的比例吸管药物溶液，直接加载到HG MS中。然后将载有药物的冻干HG MS与PLGA微球以400：100 wtwt的比例混合，并在能够产生径向和轴向渐变支架的新型压缩模具系统中加热。支架是用PLGA基质中装有辛伐他汀的HG MS制成的。将所有三组样品在37℃的平板振荡器上，在3 mL pH 7.4的磷酸盐缓冲盐水（PBS）中孵育近40天。在预定的时间点取出样品，以测量溶胀，质量损失，孔形成和药物释放。结果与讨论：辛伐他汀浓度较低的脚手架的降解速度稍快，从统计学上看是无关紧要的（图1）。这种加速降解可能是由于辛伐他汀具有疏水性，从而降低了水向HG MS主体的渗透，从而减少了溶胀和降解。第1天突然释放20-25％（图2），这很可能是结合松散结合的药物在HG MS上的扩散，加上部分HG MS的部分溶胀和降解，导致所有三个系统的模式相似。随后，在接下来的2-3周中，大量残留药物以持续方式释放。在这些系统中，辛伐他汀的释放是嵌入PLGA基质中的HG MS扩散，溶胀和降解的组合。从第22天开始，随着PLGA降解速率的增加，支架结构发生变形，并且PLGA的壁开始变薄并最终在第36天塌陷。结论：将药物负载的HG MS吸收到PLGA基质中的综合作用对于功能设计是有利的模仿特定自然组织的分级支架。 HG MS可以用作致孔剂以产生孔隙度，从而允许水渗透和组织再生中的细胞迁移。在这项研究中，负载疏水性药物的亲水性HG MS系统显示可用于更长的基质，并且在潜在的承重应用中具有持续释放的药物。总体目标是使致孔剂以受控​​的速率降解，同时释放特定药物，具体取决于特定组织再生所需的应用和时间。

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