# New Insights on Mechanical Stimulation of Mesenchymal Stem Cells for Cartilage Regeneration
## 1 Introduction  
Scientific minds have always expressed a stubborn yearn to master the creation of artificial biological elements in order to emulate the delicate machinery of the human body. The idea of being able to control cell destiny and replace malfunctioning parts of the body with brand new tissues and organs has led to remarkable progress in biological fields such as tissue engineering and regenerative medicine. A promising application of this concept relies on the use of stem cells to originate functional and specialized tissues [1]. Mesenchymal stem cells (MSCs) constitute a specific subtype of multipotent stem cells, which can differentiate into a variety of cell types and offer the advantage of obtaining pure stem cell populations [2]. One of the most challenging ambitions in regenerative biomedicine is to restore damaged articular cartilage, as it is one of the most challenging tissue types to heal by virtue of its anatomical and structural complexity. More precisely, the avascular, alymphatic, and aneural natureof the cartilage, combined with the fact that it is characterized by the chondrocyte cell type only, limits its ability to self-repair [3].  
Conventional treatment and modern therapies to treat this singular tissue, ranging from injections to surgical procedures, still suffer, in many instances, from wide variation in clinical outcome, complications, specificity, and effectiveness and a lack of well-grounded long-term reliability [4]. Joint injection is an easy and minimally invasive procedure for the delivery of MSCs as anti-inflammatory mediators and immune-modulating factors [5]. Pain relief, improvement in articular function, and regeneration of cartilage following this treatment have been observed in a growing number of studies [6; 7; 8]. However, the efficacy of this procedure is controversial, since after injection, cells might not survive or remain in situ in the long term [9; 10]. [PERSON] et al., observed MSCs migrating and engraftting into the damaged cartilage as early as the first day after injection [11]; in contrast, in another recent study, MSCs were mostly found in the synovium but not in the cartilage surrounding the defect [12]. Disappearance of the injected cells within the joint may be due to failure in the extracellular matrix (ECM) attachment mechanism [12]. Although intra-articular injection of MSCs appears to be safe during the short term [13], further investigations, such as randomized controlled trials, are necessary to explore long-term adverse events and reduce the heterogeneous nature of the studies in terms of design, cell number, exogenous factors, and administration protocols.  
Tissue engineering has raised interest as a reasonable approach to manage pathologies like osteoarthritis [1]. The latter is a degenerative disease characterized by progressive loss of articular cartilage, synovial inflammation, osteophyte formation, and joint space narrowing that lead to overall stiffness, pain, and loss of mobility of the affected joint. The bases of this escalating damage rely on a compromised balance between anabolic and catabolic mechanisms, which can be consequent to several risk factors like ageing, muscle atrophy, metabolic disorders, inflammatory conditions, injuries and overload, or wrong biomechanics of the joint [14]. This review aims to explore cartilage dynamics and understand what kind of biophysical principles will be beneficial for the engineering-based treatment of degenerative and rheumatic diseases of the joints.