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The goal of this work is the flaw-free, industrial-scale production of biological additive manufacturing of tissue constructs (Bio-AM). In pursuit of this goal, the objectives of this work in the context of extrusion-based Bio-AM of bone tissue constructs are twofold: (1) detect flaw formation using data from in-situ infrared thermocouple sensors; and (2) prevent flaw formation through preemptive process control. In realizing the first objective, data signatures acquired from in-situ sensors were analyzed using several machine learning approaches to ascertain critical quality metrics, such as print regime, strand width, strand height, and strand fusion severity. These quality metrics are intended to capture the process state at the basic 1D strand-level to the 2D layer-level. For this purpose, machine learning models were trained to classify and predict flaw formation. These models predicted print quality features with accuracy nearing 90%. In connection with the second objective, the previously trained machine learning models were used to preempt flaw formation by changing the process parameters (print velocity) during deposition—a form of feedforward control. With the feedforward process control, strand width heterogeneity was statistically significantly reduced, reducing the strand width difference between strand halves to less than 50 µm. Using this integrated process monitoring, detection, and control approach, we demonstrate consistent, repeatable production of Bio-AM constructs. 

Biological additive manufacturing (Bio-AM) has emerged as a promising approach for the fabrication of biological scaffolds with nano- to microscale resolutions and biomimetic architectures beneficial to tissue engineering applications. However, Bio-AM processes tend to introduce flaws in the construct during fabrication. These flaws can be traced to material nonhomogeneity, suboptimal processing parameters, changes in the (bio)-printing environment (such as nozzle clogs), and poor construct design, all with significant contributions to the alteration of a scaffold’s mechanical properties. In addition, the biological response of endogenous and exogenous cells interacting with the defective scaffolds could become unpredictable. In his Review, we first described extrusion-based Bio-AM. We highlighted the salient architectural and mechanotransduction parameters affecting the response of cells interfaced with the scaffolds. The process phenomena leading to defect formation and some of the tools for defect detection are reviewed. The limitations of the existing developments and the directions that the field should grow in to overcome said limitations are discussed.