Advances in Application of Mechanical Stimuli in Bioreactors for Cartilage Tissue Engineering

Abstract

Articular cartilage (AC) is the weight-bearing tissue in diarthroses. It lacks the capacity for self-healing once there are injuries or diseases due to its avascularity. With the development of tissue engineering, repairing cartilage defects through transplantation of engineered cartilage that closely matches properties of native cartilage has become a new option for curing cartilage diseases. The main hurdle for clinical application of engineered cartilage is how to develop functional cartilage constructs for mass production in a credible way. Recently, impressive hyaline cartilage that may have the potential to provide capabilities for treating large cartilage lesions in the future has been produced in laboratories. The key to functional cartilage construction in vitro is to identify appropriate mechanical stimuli. First, they should ensure the function of metabolism because mechanical stimuli play the role of blood vessels in the metabolism of AC, for example, acquiring nutrition and removing wastes. Second, they should mimic the movement of synovial joints and produce phenotypically correct tissues to achieve the adaptive development between the micro- and macrostructure and function. In this article, we divide mechanical stimuli into three types according to forces transmitted by different media in bioreactors, namely forces transmitted through the liquid medium, solid medium, or other media, then we review and summarize the research status of bioreactors for cartilage tissue engineering (CTE), mainly focusing on the effects of diverse mechanical stimuli on engineered cartilage. Based on current researches, there are several motion patterns in knee joints; but compression, tension, shear, fluid shear, or hydrostatic pressure each only partially reflects the mechanical condition in vivo. In this study, we propose that rolling-sliding-compression load consists of various stimuli that will represent better mechanical environment in CTE. In addition, engineers often ignore the importance of biochemical factors to the growth and development of engineered cartilage. In our point of view, only by fully considering synergistic effects of mechanical and biochemical factors can we find appropriate culture conditions for functional cartilage constructs. Once again, rolling-sliding-compression load under appropriate biochemical conditions may be conductive to realize the adaptive development between the structure and function of engineered cartilage in vitro.

Extruded Bioreactor Perfusion Culture Supports the Chondrogenic Differentiation of Human Mesenchymal Stem/Stromal Cells in 3D Porous Poly(ɛ‐Caprolactone) Scaffolds

“…The role of mechanical signals in the regulation of MSC fate has been demonstrated and explored for a broad range of tissue engineering strategies . In CTE, mechanical stimuli such as fluid flow‐induced shear stress, compression, tension, and hydrostatic pressure have been applied alone or combined using bioreactor systems and demonstrated to promote the chondrogenic potential of MSC . However, the molecular mechanisms involved in the MSC mechanotransduction signaling are not fully understood .…”

“…Integrated CTE approaches have also employed the use of external cues to augment MSC chondrogenic potential. Such signaling cues can be biochemical (e.g., growth factors, TGF‐β superfamily, fibroblast growth factor (FGF)‐2, or small molecules such as kartogenin), environmental (e.g., low oxygen concentrations compared to atmospheric air, hypoxia, to recapitulate the in vivo oxygen tensions of articular cartilage (1% O 2 in the deep zone to 6% O 2 in the superficial zone) as well as of most MSC niches (1–5% O 2 ) or physical factors (e.g., mechanical/electrical stimulation) . In fact, low oxygen tension culture conditions (generally between 3% and 5% O 2 ) have been employed to enhance MSC chondrogenesis in porous CTE scaffolds .…”

“…Bioreactor technology has been successfully employed for the expansion of MSC and/or for chondrogenic priming, prior to tissue substitute fabrication. In CTE strategies, commercially and tailor‐made bioreactor devices have been developed, to apply controlled and dynamic mechanical stimuli to cell‐seeded scaffolds aiming to generate cartilage‐like tissue in vitro by a closer mimicking of the articular motion forces . Examples of mechanical loading applied through bioreactor platforms to regulate MSC chondrogenic differentiation in CTE settings include direct compression, hydrostatic pressure, direct shear stress, fluid‐induced shear stress, or multimodal biaxial combining different stimuli .…”

Bioreactor for mobilization of mesenchymal stem/stromal cells into scaffolds under mechanical stimulation: Preliminary results

“…The mesh is kept in place by a ring anchored to the construction using screws (6). The scaffold holder is placed as an independent movable unit within the cylindrical container (1) and it is covered up by a cap (7) containing the piston and spring. The cartridge is made of sterilizable materials.…”

“…Furthermore, mechanical stimulation contributes to the synthesis of ECM components by chondrocytes even if isolated from patients with osteoarthritis [6]. Thus, mechanical loading plays a pivotal role for the nutrients delivery, waste disposal, repair and AC healthiness [7]. Bioreactors are biotechnological devices used in cartilage engineering to evaluate diverse mechanical stimulation strategies as compression, tension, hydrostatic pressure and shear stress, acting on natural cartilage tissue or cartilage-like constructs [8][9][10][11].…”