Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling.
Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling.
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DOI：
10.1016/j.biomaterials.2015.09.005
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发表时间：
2015-12
期刊：
影响因子：
14
通讯作者：
Guelcher SA
中科院分区：
文献类型：
--
作者：
Guo R;Merkel AR;Sterling JA;Davidson JM;Guelcher SA
对治疗大面积皮肤缺损的疗法的需求不断增长，最近引起了人们对刺激再生伤口愈合的支架设计的兴趣。虽然许多研究已经将生物制剂的局部递送作为一种修复方法进行了研究，但越来越多的证据强调了植入支架的机械性能对伤口愈合的贡献。在本研究中，我们使用模板熔融沉积建模（t-FDM）工艺设计了聚（酯聚氨酯）支架，以测试基质模量与胶原纤维相当的支架增强再生与纤维化反应的假设。我们制造了基材模量为 5 – 266 MPa 的 t-FDM 支架，以研究基材模量对大鼠皮下植入模型愈合的影响。对于使用基质模量（Ks = 24 MPa）与胶原纤维相当的支架治疗的伤口，血管生成、细胞浸润、胶原沉积和胶原纤维的方向变化最大化。这些支架中再生反应的增强与成纤维细胞中 Wnt/β-catenin 信号传导的下调以及巨噬细胞向恢复性 M2 表型的极化增加相关。这些观察结果强调了支架的基质模量是调节伤口愈合中再生与疤痕表型的关键参数。我们的研究结果进一步指出，具有与天然基质相匹配的基质模量的支架作为改善皮肤愈合的治疗方法的潜在用途。
The growing need for therapies to treat large cutaneous defects has driven recent interest in the design of scaffolds that stimulate regenerative wound healing. While many studies have investigated local delivery of biologics as a restorative approach, an increasing body of evidence highlights the contribution of the mechanical properties of implanted scaffolds to wound healing. In the present study, we designed poly(ester urethane) scaffolds using a templated-Fused Deposition Modeling (t-FDM) process to test the hypothesis that scaffolds with substrate modulus comparable to that of collagen fibers enhance a regenerative versus a fibrotic response. We fabricated t-FDM scaffolds with substrate moduli varying from 5 – 266 MPa to investigate the effects of substrate modulus on healing in a rat subcutaneous implant model. Angiogenesis, cellular infiltration, collagen deposition, and directional variance of collagen fibers were maximized for wounds treated with scaffolds having a substrate modulus (Ks = 24 MPa) comparable to that of collagen fibers. The enhanced regenerative response in these scaffolds was correlated with down-regulation of Wnt/β-catenin signaling in fibroblasts, as well as increased polarization of macrophages toward the restorative M2 phenotype. These observations highlight the substrate modulus of the scaffold as a key parameter regulating the regenerative versus scarring phenotype in wound healing. Our findings further point to the potential use of scaffolds with substrate moduli tuned to that of the native matrix as a therapeutic approach to improve cutaneous healing.