Integration of clinical perspective into biomimetic bioreactor design for orthopedics

Abstract

The challenges to accommodate multiple tissue formation metrics in conventional bioreactors have resulted in an increased interest to explore novel bioreactor designs. Bioreactors allow researchers to isolate variables in controlled environments to quantify cell response. While current bioreactor designs can effectively provide either mechanical, electrical, or chemical stimuli to the controlled environment, these systems lack the ability to combine all these stimuli simultaneously to better recapitulate the physiological environment. Introducing a dynamic and systematic combination of biomimetic stimuli bioreactor systems could tremendously enhance its clinical relevance in research. Thus, cues from different tissue responses should be studied collectively and included in the design of a biomimetic bioreactor platform. This review begins by providing a summary on the progression of bioreactors from simple to complex designs, focusing on the major advances in bioreactor technology and the approaches employed to better simulate in vivo conditions. The current state of bioreactors in terms of their clinical relevance is also analyzed. Finally, this review provides a comprehensive overview of individual biophysical stimuli and their role in establishing a biomimetic microenvironment for tissue engineering. To date, the most advanced bioreactor designs only incorporate one or two stimuli. Thus, the cell response measured is likely unrelated to the actual clinical performance. Integrating clinically relevant stimuli in bioreactor designs to study cell response can further advance the understanding of physical phenomenon naturally occurring in the body. In the future, the clinically informed biomimetic bioreactor could yield more efficiently translatable results for improved patient care.

Keywords: biomimetic; bioreactor; bone; cartilage; clinical relevancy; multiple stimuli; orthopedics.

FIGURE 1

Various applications for TE bioreactors

FIGURE 2

Histological data after 4 months of electrical stimulation with a spinal implant device in the lumbar spines of ovine models. Adapted from Friis et al

FIGURE 3

Bioreactors throughout time with key products represented. Adapted from Zhang, YP, Sun J, Ma Y. Biomanufacturing: history and perspective. J Ind Microbiol Biotechnol. 2017;44(4,5):773‐784

FIGURE 4

A schematic depicting the differences and similarities between batch, fed‐batch, and continuous batch systems in a spinner flask. (a) Batch system where media is introduced a singular time. (b) Fed‐batch system where nutrients are added more than one time. (c) Continuous batch system where a constant perfusion of nutrients is introduced, and waste is eliminated

FIGURE 5

Schematic of the various types of bioreactors: (a) static culture, (b) spinner flasks, (c) rotating wall vessels, (d) perfusion flow bioreactors, (e) compression bioreactors, and (f) tubular flow. Adapted from Chen C, Hu Y. Bioreactors for tissue engineering. Biotechnol Lett 2006;28:1415‐1423

FIGURE 6

Flow diagram illustrating Frost's “mechanostat” theory. The model is represented as a simple feedback loop where bone is remodeled by sensing the change in bone mass and activating modeling/remodeling to better resist loads. Additional factors that can influence stages in the process are also included

FIGURE 7

Flowchart illustrating the practical application of a clinically relevant biomimetic bioreactor for specific patient needs