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Bio-Design and Manufacturing  2022 Vol.5 No.3 P.465-480

http://doi.org/10.1007/s42242-022-00198-z


A 3D in vitro co-culture model for evaluating biomaterial-mediated modulation of foreign-body responses


Author(s):  Betul Cakmak, Pelin Saglam-Metiner, Goze Beceren, Yu S. Zhang & Ozlem Yesil-Celiktas

Affiliation(s):  Department of Bioengineering, Faculty of Engineering, Ege University, 35100 Izmir, Turkey; more

Corresponding email(s):   ozlem.yesil.celiktas@ege.edu.tr

Key Words:  Biomaterial, Macrophage polarization, Genotoxicity, Biocompatibility, Immune response


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Betul Cakmak, Pelin Saglam-Metiner, Goze Beceren, Yu S. Zhang & Ozlem Yesil-Celiktas. A 3D in vitro co-culture model for evaluating biomaterial-mediated modulation of foreign-body responses[J]. Journal of Zhejiang University Science D, 2022, 5(3): 465-480.

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Abstract: 
The immune response after implantation of a biomaterial may shorten the functional life of the implant, depending on the degree of the response. In this study, we used a polyacrylamide-alginate (PAAm-Alg) hydrogel, which has been previously characterized as a biocompatible material and shown to enhance regeneration of cartilage in vivo, along with a graphiteenhanced hydrogel (PAAm-Alg-G) as a non-biocompatible counterpart, to evaluate macrophage attachment and polarization to pro- or anti-inflammatory phenotypes. The performance of each biomaterial in the presence of fibroblasts and chondrocytes was validated by an in vitro model which demonstrated modulation of the foreign-body response. A blend of 5% gelatin methacryloyl and 0.1% methacrylated hyaluronic acid was optimized to mimic the extracellular matrix (ECM) and support cell viability, proliferation, migration, and functionality at an initial concentration of 3.25 × 105 cells/mL. The PAAm-Alg-G hydrogel localized in the simulated ECM showed cytotoxic and genotoxic effects for both fibroblasts and chondrocytes, while exhibiting a proliferative effect on macrophages with elevated immune response. The M1/M2 ratio was 0.73 for PAAm-Alg hydrogel but 2.64 for PAAm-Alg-G, leading to significant M1 dominance (p < 0.0001), as expected, on day 13. Moreover, loading PAAm-Alg hydrogel with transforming growth factor beta-3 (TGF-β3) resulted in a slightly more balanced M1/M2 ratio of 0.87 (p > 0.05). The interleukin-6 (IL-6) concentration secreted in the presence of PAAm-Alg hydrogel (4.58 pg/mL) significantly decreased (p < 0.0001) on day 13, while the increase (p < 0.0001) in interleukin-10 (IL- 10) concentration (120.73 pg/mL) confirmed the switch from a pro-inflammatory to an anti-inflammatory response. Predicting immune responses by developing a simplistic yet powerful three-dimensional in vitro model provides advantages in preparing for clinical use of biomaterials.

土耳其Ozlem Yesil-Celiktas等 | 一种用于评估生物材料介导异物反应调节的3D体外共培养模型

本研究论文聚焦体外组织模型在免疫反应体外评估上的应用。生物材料植入后的免疫反应可能会在不同程度上缩短植入物的寿命或影响植入物的功能。在这项研究中,研究人员使用聚丙烯酰胺 - 海藻酸盐(PAAm-Alg)水凝胶(已被表征为生物相容性材料,并被证明可以增强体内软骨再生),以及石墨增强水凝胶(PAAm-Alg-G)作为非生物相容性对照,以评估巨噬细胞附着和极化至促炎或抗炎表型。不同生物材料在成纤维细胞和软骨细胞存在下的性能通过体外模型得到验证,而因此该模型也证明了对异物反应的调节功能。该模型使用混有细胞的5%甲基丙烯酰基明胶和0.1%甲基丙烯酸化透明质酸的水凝胶来模拟细胞外基质(ECM)并支持细胞活性、增殖、迁移和功能等。在模拟ECM中植入的PAAm-Alg-G水凝胶对成纤维细胞和软骨细胞均表现出细胞毒性和遗传毒性,同时对具有增加免疫应答的巨噬细胞表现出促增殖作用。在第13天,PAAm-Alg水凝胶的M1 / M2比值为0.73,而PAAm-Alg-G为2.64,导致显著的M1表型优势。此外,转化生长因子 β-3(TGF-β3)加载 的PAAm-Alg 水凝胶使得M1 / M2 比值稍微平衡为 0.87。在PAAm-Alg水凝胶存在下分泌的白细胞介素-6(IL-6)浓度在第13天显著降低,而白细胞介素-10(IL-10)浓度的增加则证实了从促炎到抗炎反应的转变。通过开发简单而强大的三维体外模型来预测免疫反应在生物材料的临床应用和转化方面具有独特优势。

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