A Guide for Using Mechanical Stimulation to Enhance Tissue-Engineered Articular Cartilage Properties

Abstract

The use of tissue-engineered articular cartilage (TEAC) constructs has the potential to become a powerful treatment option for cartilage lesions resulting from trauma or early stages of pathology. Although fundamental tissue-engineering strategies based on the use of scaffolds, cells, and signals have been developed, techniques that lead to biomimetic AC constructs that can be translated to in vivo use are yet to be fully confirmed. Mechanical stimulation during tissue culture can be an effective strategy to enhance the mechanical, structural, and cellular properties of tissue-engineered constructs toward mimicking those of native AC. This review focuses on the use of mechanical stimulation to attain and enhance the properties of AC constructs needed to translate these implants to the clinic. In vivo, mechanical loading at maximal and supramaximal physiological levels has been shown to be detrimental to AC through the development of degenerative changes. In contrast, multiple studies have revealed that during culture, mechanical stimulation within narrow ranges of magnitude and duration can produce anisotropic, mechanically robust AC constructs with high cellular viability. Significant progress has been made in evaluating a variety of mechanical stimulation techniques on TEAC, either alone or in combination with other stimuli. These advancements include determining and optimizing efficacious loading parameters (e.g., duration and frequency) to yield improvements in construct design criteria, such as collagen II content, compressive stiffness, cell viability, and fiber organization. With the advancement of mechanical stimulation as a potent strategy in AC tissue engineering, a compendium detailing the results achievable by various stimulus regimens would be of great use for researchers in academia and industry. The objective is to list the qualitative and quantitative effects that can be attained when direct compression, hydrostatic pressure, shear, and tensile loading are used to tissue-engineer AC. Our goal is to provide a practical guide to their use and optimization of loading parameters. For each loading condition, we will also present and discuss benefits and limitations of bioreactor configurations that have been used. The intent is for this review to serve as a reference for including mechanical stimulation strategies as part of AC construct culture regimens.

Keywords: articular cartilage; compression; hydrostatic pressure; mechanical stimulation; shear; tension.

FIG. 1.

Waveforms representing common loading patterns used in mechanical stimulation studies. (a) Continuous passive loading, (b) intermittent passive loading, (c) continuous dynamic loading, and (d) intermittent dynamic loading. The x-axis represents the duration of the experiment, where t = 0 represents the commencement of mechanical stimulation, t = x represents the duration of applied stimulation, and τ represents the wave period (frequency = 1/τ). In (b) and (d), t = y − x is the amount of time the tissue is in static culture between mechanical stimulation treatments. The y-axis represents the magnitude of load, which is commonly measured in units of stress, strain, or mass.

FIG. 2.

Arrows indicate the direction of mechanical loads acting on tissue-engineered articular cartilage during mechanical stimulation. (a) Direct compression, (b) biaxial tension (top), uniaxial tension (bottom), (c) shear, and (d) hydrostatic pressure.

FIG. 3.

The importance of optimizing mechanical stimulation parameters: Insufficient mechanical stimulation results in low levels of signaling and nutrient diffusion causing low cell viability, ECM content, and mechanical properties. Excessive mechanical stimulation impairs mechanotransduction pathways by physically damaging ECM and sending chondrocytes to apoptosis, which leads to low mechanical properties. Optimized mechanical stimulation yields high cell viability, robust ECM, and improved mechanical properties by delivering nutrients and signaling cells to produce robust ECM components. ECM, extracellular matrix.