Guo R, Merkel A R, Sterling J A, Davidson J M, Guelcher S A
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA.
Research Service, Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Biomaterials. 2015 Dec;73:85-95. doi: 10.1016/j.biomaterials.2015.09.005. Epub 2015 Sep 11.
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 to 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.
治疗大面积皮肤缺损的疗法需求不断增长，这推动了近期对刺激再生性伤口愈合的支架设计的关注。虽然许多研究已将生物制剂的局部递送作为一种修复方法进行了调查，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作用。在本研究中，我们使用模板化熔融沉积建模（t-FDM）工艺设计了聚（酯氨酯）支架，以检验以下假设：具有与胶原纤维相当的基质模量的支架可增强再生反应而非纤维化反应。我们制备了基质模量在5至266 MPa之间变化的t-FDM支架，以研究基质模量对大鼠皮下植入模型愈合的影响。对于用具有与胶原纤维相当的基质模量（Ks = 24 MPa）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达到最大值。这些支架中增强的再生反应与成纤维细胞中Wnt/β-连环蛋白信号的下调以及巨噬细胞向修复性M2表型的极化增加相关。这些观察结果突出了支架的基质模量作为调节伤口愈合中再生与瘢痕形成表型的关键参数。我们的研究结果进一步指出，将基质模量调整为与天然基质相当的支架有可能作为一种治疗方法来改善皮肤愈合。
