Wang Raymond M, Johnson Todd D, He Jingjin, Rong Zhili, Wong Michelle, Nigam Vishal, Behfar Atta, Xu Yang, Christman Karen L
Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, China.
Biomaterials. 2017 Jun;129:98-110. doi: 10.1016/j.biomaterials.2017.03.016. Epub 2017 Mar 11.
Current assessment of biomaterial biocompatibility is typically implemented in wild type rodent models. Unfortunately, different characteristics of the immune systems in rodents versus humans limit the capability of these models to mimic the human immune response to naturally derived biomaterials. Here we investigated the utility of humanized mice as an improved model for testing naturally derived biomaterials. Two injectable hydrogels derived from decellularized porcine or human cadaveric myocardium were compared. Three days and one week after subcutaneous injection, the hydrogels were analyzed for early and mid-phase immune responses, respectively. Immune cells in the humanized mouse model, particularly T-helper cells, responded distinctly between the xenogeneic and allogeneic biomaterials. The allogeneic extracellular matrix derived hydrogels elicited significantly reduced total, human specific, and CD4 T-helper cell infiltration in humanized mice compared to xenogeneic extracellular matrix hydrogels, which was not recapitulated in wild type mice. T-helper cells, in response to the allogeneic hydrogel material, were also less polarized towards a pro-remodeling Th2 phenotype compared to xenogeneic extracellular matrix hydrogels in humanized mice. In both models, both biomaterials induced the infiltration of macrophages polarized towards a M2 phenotype and T-helper cells polarized towards a Th2 phenotype. In conclusion, these studies showed the importance of testing naturally derived biomaterials in immune competent animals and the potential of utilizing this humanized mouse model for further studying human immune cell responses to biomaterials in an in vivo environment.
目前对生物材料生物相容性的评估通常在野生型啮齿动物模型中进行。不幸的是，啮齿动物和人类免疫系统的不同特征限制了这些模型模拟人类对天然衍生生物材料免疫反应的能力。在此，我们研究了人源化小鼠作为测试天然衍生生物材料的改进模型的效用。比较了两种源自脱细胞猪或人尸体心肌的可注射水凝胶。皮下注射后三天和一周，分别分析水凝胶的早期和中期免疫反应。人源化小鼠模型中的免疫细胞，特别是辅助性T细胞，对异种和同种异体生物材料的反应明显不同。与异种细胞外基质水凝胶相比，同种异体细胞外基质衍生的水凝胶在人源化小鼠中引起的总浸润、人类特异性浸润和CD4辅助性T细胞浸润显著减少，而在野生型小鼠中未观察到这种情况。在人源化小鼠中，与异种细胞外基质水凝胶相比，辅助性T细胞对同种异体水凝胶材料的反应也较少向促重塑的Th2表型极化。在两种模型中，两种生物材料均诱导了向M2表型极化的巨噬细胞和向Th2表型极化的辅助性T细胞的浸润。总之，这些研究表明在具有免疫能力的动物中测试天然衍生生物材料的重要性，以及利用这种人源化小鼠模型在体内环境中进一步研究人类免疫细胞对生物材料反应的潜力。
