The influence of chondrocyte source on the manufacturing reproducibility of human tissue engineered cartilage
The influence of chondrocyte source on the manufacturing reproducibility of human tissue engineered cartilage
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DOI：
10.1016/j.actbio.2021.07.003
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发表时间：
2021-08-14
影响因子：
9.7
通讯作者：
Bonassar，Lawrence J.
中科院分区：
文献类型：
--
作者：
Middendorf，Jill M.;Diamantides，Nicole;Bonassar，Lawrence J.
多种人类组织工程化软骨结构在高级临床试验中显示出希望，但识别制造重复性的重要指标仍然是一个挑战。FDA指南建议在植入前测量多种机械性能，因为这些性能可能会影响植入物的长期成功。此外，这些工程化的软骨机械可能对自体软骨细胞来源敏感，软骨细胞来源是一种固有的不规则制造起始材料。如果有任何机械特性对自体软骨细胞来源的变化敏感，则可能需要在植入前测量这些特性，以确保制造的重复性和质量。因此，这项研究确定了由于软骨细胞来源的原因，人类组织工程软骨构建物的压缩、摩擦和剪切性能的变异性。从7个不同的软骨细胞来源创建了200多个结构，并使用3个不同的力学实验进行了测试。在受限压缩下，由于软骨细胞来源的不同，压缩特性(骨料弹性系数和水力渗透性)会有数量级的变化。由于软骨细胞来源和患者体内的高度变异性，摩擦系数变化了5倍。相反，剪切模数不受软骨细胞来源变化的影响。最后，对局部压缩和剪切力学的测量表明，基于软骨细胞来源的随深度变化的应变场具有可变性。由于软骨细胞来源在工程软骨的压缩和局部力学性能方面造成了大量的变异性，这些力学特性可能是制造重复性的重要指标。意义陈述尽管FDA建议在制造过程中测量人类组织工程软骨构建物的力学性能，但制造变异性对构建力学的影响尚不清楚。作为首批测量数百个人类组织工程软骨构建物的多种力学性能的研究之一，我们发现压缩性能对自体软骨细胞来源的变化最敏感，软骨细胞来源是一种固有的不规则制造变量。这种对自体软骨细胞来源的敏感性表明，在植入之前应该测量压缩特性，以评估制造的重复性。
Multiple human tissue engineered cartilage constructs are showing promise in advanced clinical trials but identifying important measures of manufacturing reproducibility remains a challenge. FDA guidance suggests measuring multiple mechanical properties prior to implantation, because these properties could affect the long term success of the implant. Additionally, these engineered cartilage mechanics could be sensitive to the autologous chondrocyte source, an inherently irregular manufacturing starting material. If any mechanical properties are sensitive to changes in the autologous chondrocyte source, these properties may need to be measured prior to implantation to ensure manufacturing reproducibility and quality. Therefore, this study identified variability in the compressive, friction, and shear properties of a human tissue engineered cartilage constructs due to the chondrocyte source. Over 200 constructs were created from 7 different chondrocyte sources and tested using 3 distinct mechanical experiments. Under confined compression, the compressive properties (aggregate modulus and hydraulic permeability) varied by orders of magnitude due to the chondrocyte source. The friction coefficient changed by a factor of 5 due to the chondrocyte source and high intrapatient variability was noted. In contrast, the shear modulus was not affected by changes in the chondrocyte source. Finally, measurements on the local compressive and shear mechanics revealed variability in the depth dependent strain fields based on chondrocyte source. Since the chondrocyte source causes large amounts of variability in the compression and local mechanical properties of engineered cartilage, these mechanical properties may be important measures of manufacturing reproducibility.Statement of significanceAlthough the FDA recommends measuring mechanical properties of human tissue engineered cartilage constructs during manufacturing, the effect of manufacturing variability on construct mechanics is unknown. As one of the first studies to measure multiple mechanical properties on hundreds of human tissue engineered cartilage constructs, we found the compressive properties are most sensitive to changes in the autologous chondrocyte source, an inherently irregular manufacturing variable. This sensitivity to the autologous chondrocyte source reveals the compressive properties should be measured prior to implantation to assess manufacturing reproducibility.