Physiologically relevant oxidative degradation of oligo(proline) cross-linked polymeric scaffolds.
Physiologically relevant oxidative degradation of oligo(proline) cross-linked polymeric scaffolds.
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DOI：
10.1021/bm201328k
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发表时间：
2011-12-12
影响因子：
6.2
通讯作者：
Sung, Hak-Joon
中科院分区：
文献类型：
--
作者：
Yu, Shann S.;Koblin, Rachel L.;Zachman, Angela L.;Perrien, Daniel S.;Hofmeister, Lucas H.;Giorgio, Todd D.;Sung, Hak-Joon
慢性炎症介导的氧化应激是植入物排斥和失败的常见机制。因此，能够在这种环境中缓慢降解的聚合物支架可能为植入部位特定的、长期持续释放免疫调节剂提供一个可行的平台。本工作合成了不同长度的低聚体，并将其暴露在氧化环境中，通过高效液相色谱和凝胶渗透色谱对其在氧化条件下的加速降解进行了验证。然后，将聚乙二醇聚己内酯两嵌段共聚物(ε)与聚己内酯(PCL)进行羧化反应，得到4%聚乙二醇-86%聚己内酯-10%聚己内酯(cPCL=聚(羧基-ε-己内酯)，i%为摩尔比)的100 kDa三元共聚物。然后，用双胺化的聚乙二醇链--其中，pN表示聚乙二醇链两侧的脯氨酸低聚物的长度--对聚合物进行交联化。扫描电子显微镜观察到，聚合物基质的盐浸出形成了大孔和微孔结构的支架。失重和差示扫描量热测试表明，在氧化条件下，支架的降解速度加快。然后将永生化的小鼠骨髓来源的巨噬细胞种植在支架上，并在整个9天的研究期间通过添加γ-干扰素和脂多糖来激活。与对照支架相比，这种处理促进了巨噬细胞释放H_2O_2，并促进了含有Pro的支架的降解。通过扫描电子显微镜和X射线显微断层成像可以看出，支架的孔隙率增加证明了加速的降解。目前的研究为通过逐渐降解对氧化环境做出反应的支架的开发提供了洞察，为针对以慢性炎症和氧化应激为特征的疾病的治疗药物的受控释放提供了洞察力。
Chronic inflammation-mediated oxidative stress is a common mechanism of implant rejection and failure. Therefore, polymer scaffolds that can degrade slowly in response to this environment may provide a viable platform for implant site-specific, sustained release of immunomodulatory agents over a long time period. In this work, proline oligomers of varying lengths (Pn) were synthesized and exposed to oxidative environments, and their accelerated degradation under oxidative conditions was verified via high performance liquid chromatography and gel permeation chromatography. Next, diblock copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) were carboxylated to form 100 kDa terpolymers of 4%PEG-86%PCL-10%cPCL (cPCL = poly(carboxyl-ε-caprolactone); i% indicates molar ratio). The polymers were then crosslinked with bi-aminated PEG-Pn-PEG chains—where Pn indicates the length of the proline oligomer flanked by PEG chains. Salt-leaching of the polymeric matrices created scaffolds of macroporous and microporous architecture as observed by scanning electron microscopy. The degradation of scaffolds was accelerated under oxidative conditions, as evidenced by mass loss and differential scanning calorimetry measurements. Immortalized murine bone marrow-derived macrophages were then seeded on the scaffolds, and activated through the addition of γ-interferon and lipopolysaccharide throughout the 9-day study period. This treatment promoted the release of H2O2 by the macrophages, and the degradation of proline-containing scaffolds compared to the control scaffolds. The accelerated degradation was evidenced by increased scaffold porosity, as visualized through scanning electron microscoopy and X-ray microtomography imaging. The current study provides insight into the development of scaffolds that respond to oxidative environments through gradual degradation, for the controlled release of therapeutics targeted to diseases that feature chronic inflammation and oxidative stress.
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影响因子：
15.9
作者：
GALIS, ZS;SUKHOVA, GK;LIBBY, P
通讯作者：
LIBBY, P
影响因子：
10.8
作者：
Reddy, ST;Rehor, A;Swartz, MA
通讯作者：
Swartz, MA
影响因子：
1.7
作者：
Gimenez, S;Ponsart, S;Vert, M
通讯作者：
Vert, M
影响因子：
4.6
作者：
An, SG;Cho, CG
通讯作者：
Cho, CG
影响因子：
2.3
作者：
Schmedlen, RH;Elbjeirami, WM;West, JL
通讯作者：
West, JL