The Application of Multiple Biophysical Cues to Engineer Functional Neocartilage for Treatment of Osteoarthritis. Part I: Cellular Response

Abstract

Osteoarthritis (OA) is a complex disease of the joint for which current treatments are unsatisfactory, thus motivating development of tissue engineering (TE)-based therapies. To date, TE strategies have had some success, developing replacement tissue constructs with biochemical properties approaching that of native cartilage. However, poor biomechanical properties and limited postimplantation integration with surrounding tissue are major shortcomings that need to be addressed. Functional tissue engineering strategies that apply physiologically relevant biophysical cues provide a platform to improve TE constructs before implantation. In the previous decade, new experimental and theoretical findings in cartilage biomechanics and electromechanics have emerged, resulting in an increased understanding of the complex interplay of multiple biophysical cues in the extracellular matrix of the tissue. The effect of biophysical stimulation on cartilage, and the resulting chondrocyte-mediated biosynthesis, remodeling, degradation, and repair, has, therefore, been extensively explored by the TE community. This article compares and contrasts the cellular response of chondrocytes to multiple biophysical stimuli, and may be read in conjunction with its companion paper that compares and contrasts the subsequent intracellular signal transduction cascades. Mechanical, magnetic, and electrical stimuli promote proliferation, differentiation, and maturation of chondrocytes within established dose parameters or "biological windows." This knowledge will provide a framework for ongoing studies incorporating multiple biophysical cues in TE functional neocartilage for treatment of OA.

Local deformation in a hydrogel induced by an external magnetic field

“…23,24 The chondrocytes respond to the mechanical stimuli by multiple regulatory pathways, with consequences on transcription, translation and post-translational modifications that further control extra cellular matrix production and function. 4,34 Integrins, growth factor receptors, cytoskeletal filaments, nuclei, stretch-activated ion channels and cartilage ECM proteins are just some of the signaling molecules that contribute to biosynthesis, remodeling, or repair of the tissue as mechanotransduction response to mechanical loading. 14,15 Tissue Engineering is an integrative area of biotechnology and engineering that 3 focuses on restoring or improving tissue function with cells and materials.…”

Quantitative volumetric Raman imaging of three dimensional cell cultures

“…Several optical imaging techniques based on endogenous biomolecules have previously been used to provide detailed visualization of the morphology and spatial distribution of biological structures46789101112. One of these, Raman spectroscopy, which is an inelastic light scattering technique, can provide label-free biochemical information.…”

Magnetic field application or mechanical stimulation via magnetic microparticles does not enhance chondrogenesis in mesenchymal stem cell sheets

“…In vivo, an estimated 8 mT static field induced healing of osteochondral defects in rabbits compared to sham-operated groups 15 and a 1.6 mT pulsed electromagnetic field (4.5 ms duration (222 mHz) single pulse repeated at 15 bursts/s, 8 hr/day) accelerated chondrogenesis during endochondral ossification 28 . These few studies illustrate that magnetic fields by themselves may influence chondrogenesis in specific circumstances, although the mechanisms behind its actions are poorly understood 5, 24 . Potential reasons why enhanced chondrogenesis was not observed in our system compared to these reports may be differences in cell type, and magnetic field gradient magnitudes, frequencies and durations.…”

“…Typically, the role of mechanical stimuli on tissue regeneration is investigated on the macroscopic scale where external stimuli like hydrostatic, compressive, tensile and/or shear stress are applied to bulk tissue. Studies have shown that cartilage-like properties of tissue engineered constructs can be enhanced by bioreactor-induced loading 2, 4, 5 . Mechanobiology on the microscale has also been investigated, often using magnetic particles 6 .…”