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Poly(lactide-co-glycolide) microspheres and hydrogel delivery systems for soft tissue and cartilage tissue engineering applications.

机译：适用于软组织和软骨组织工程应用的聚（丙交酯-共-乙交酯）微球和水凝胶输送系统。

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摘要

Polymeric microspheres have been widely investigated as delivery systems and are clinically used today. We examined the use of poly(lactide-co-glycolide) (PLGA) microspheres in delivery systems for soft tissue engineering, chemotherapeutic delivery, and cartilage tissue engineering. Soft tissue defects due to trauma or tumor removal remain a clinical challenge. We examined the use of PLGA microspheres and adipose derived stem cells (ASCs) to fill in soft tissue defects. We first demonstrated the use of PLGA microspheres to increase ASC proliferation and survival by encapsulating fibroblast growth factor-2 (FGF-2). The released FGF-2 increased ASC proliferation and survival in vitro . Addition of the FGF-2 microspheres in an in vivo study resulted in an increase in angiogenesis. We then examined the ability of released adipogenic factors to induce the differentiation of ASCs into mature adipocytes. Oil red O staining and Western blots confirmed that adipogenesis was induced by the released factors. The second goal was to examine a delivery system to reduce the risk of local recurrence in breast cancer patients following a lumpectomy. Breast cancer lumps are commonly treated by tumor removal (lumpectomy) followed by radiation or chemotherapy, and both have adverse side effects. PLGA microspheres encapsulating doxorubicin were embedded with a natural scaffold, gelatin, to locally deliver chemotherapy and maintain the breast contour. Our results demonstrated a more controlled release from microspheres embedded within gelatin compared to microspheres alone. Released doxorubicin killed tumor cells in vitro. The implantation of the scaffolds in vivo resulted in tumor ablation. Local and systemic toxicity were not observed even though a dose 60 times the normal dose was given. Our next objective was to analyze the release of TGF-beta1 (TGF-beta1) from PLGA microspheres incorporated into a synthetic hydrogel, poly(ethylene glycol) (PEG)-genipin for cartilage repair. The release of TGF-beta1 was dependent upon the genipin concentration of the hydrogel. The released TGF-beta1 was bioactive, as demonstrated by the inhibition of mink lung cell proliferation. The final goal was to develop and characterize a hydrogel based on PEG-genipin to gel in situ. As such, we examined genipin and multi-branched aminated PEG. Gelation time was affected by pretreating genipin. Exposure of the genipin aqueous solution to air and oxygen decreased the gelation time. PEG structure also had an effect on gelation time. The gelation time was reduced by utilizing 4-arm PEG and increasing the temperature from 25°C to 37°C. The results of this thesis demonstrate the efficacy of PLGA microspheres embedded in hydrogels for use as delivery systems for soft tissue and cartilage tissue engineering. The delivery systems can be modified to tailor delivery rates, deliver multiple drugs/growth factors, tailor degradation, and promote tissue growth.
机译：聚合物微球已被广泛研究为递送系统，并在当今临床上使用。我们检查了聚（丙交酯-共-乙交酯）（PLGA）微球在用于软组织工程，化学疗法输送和软骨组织工程的输送系统中的使用。由于创伤或肿瘤去除导致的软组织缺陷仍然是临床挑战。我们检查了PLGA微球和脂肪衍生干细胞（ASC）填充软组织缺损的使用。我们首先证明了通过封装成纤维细胞生长因子2（FGF-2）来使用PLGA微球来提高ASC增殖和存活。释放的FGF-2增加了ASC的增殖和体外存活。在体内研究中添加FGF-2微球导致血管生成增加。然后，我们检查了释放的脂肪形成因子诱导ASC分化为成熟脂肪细胞的能力。油红O染色和Western印迹证实释放的因子诱导脂肪形成。第二个目标是检查一种分娩系统，以减少乳房肿瘤切除术后乳腺癌患者局部复发的风险。乳腺癌肿块通常通过切除肿瘤（肿块切除术），然后放疗或化疗来治疗，两者都有不利的副作用。将封装有阿霉素的PLGA微球与天然支架明胶包埋，以局部递送化学疗法并维持乳房轮廓。我们的结果表明，与单独的微球相比，包埋在明胶中的微球具有更好的释放控制。释放的阿霉素可在体外杀死肿瘤细胞。支架在体内的植入导致肿瘤消融。即使给予正常剂量60倍的剂量也未观察到局部和全身毒性。我们的下一个目标是分析PLGA微球中TGF-beta1（TGF-beta1）的释放，该PLGA微球被掺入合成水凝胶，聚乙二醇（PEG）-genipin中进行软骨修复。 TGF-β1的释放取决于水凝胶中京尼平的浓度。释放的TGF-beta1具有生物活性，如抑制水貂肺细胞增殖所证明的。最终目标是开发和表征基于PEG-genipin原位凝胶化的水凝胶。因此，我们检查了genipin和多支胺化的PEG。凝胶化时间受京尼平预处理的影响。将京尼平水溶液暴露于空气和氧气可缩短胶凝时间。 PEG结构也对胶凝时间有影响。通过使用4臂PEG并将温度从25°C升高到37°C，可以缩短胶凝时间。本文的结果证明了嵌入水凝胶中的PLGA微球作为软组织和软骨组织工程递送系统的功效。可以修改递送系统以调整递送速率，递送多种药物/生长因子，调整降解并促进组织生长。

著录项

  • 作者

    DeFail, Alicia J.;

  • 作者单位

    University of Pittsburgh.;

  • 授予单位 University of Pittsburgh.;
  • 学科 Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 190 p.
  • 总页数 190
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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