Hyperlipidemia impacts millions of people globally and has been the major risk factor for developing atherosclerosis and cardiovascular disease. Interestingly, hyperlipidemic subjects exhibit increased incidence of rotator cuff tendon injury (RCTI) and disorganization of tendon matrix. Low-density lipoproteins (LDL) and its oxidized form (ox-LDL) play a crucial role in hyperlipidemia-driven pro-inflammatory responses in multiple tissues including the tendon. The signaling of oxLDL upregulates the inflammatory cytokines, chemokines, adhesion molecules, and the activation of monocytes/macrophages/resident tendon cells and matrix metalloproteinases impairing the tendon homeostasis resulting in the alteration of extracellular matrix. In addition, the hyperlipidemia-driven immune response and subsequent oxidative stress promote degenerative responses in the tendon tissue. However, the pathological mechanisms underlying the occurrence of RCTI in hyperlipidemia and the effect of ox-LDL in tendon matrix are currently unknown. The present review focuses on the implications and perspectives of LDL/oxLDL on the increased incidence of RCTI.

Shoulder tendon injuries are the common musculoskeletal disorder resulting in significant pain and disability. These injuries are characterized by chronic inflammation and tissue degeneration. Tendon pathology exhibits poor innate healing ability, enhanced inflammation, disorganized collagen fibers, calcification, and scar tissue formation affecting the normal healing process. Extracellular vesicle, especially exosomes, treatment has been emerging as a potential regenerative strategy improving the outcomes and biomechanical properties, accelerating tenocyte proliferation and migration, reducing inflammation, and facilitating the healing at tendon–bone interface. In this article, we critically reviewed the potential role of exosomes in tendon regeneration and their applications to accelerate the healing response following injury. In addition, the article provides novel insights on the concept of “Smart Exosomes” by programming/manipulating the secretome contents and functions of exosomes in the management of shoulder tendon injury. Impact statement: The exosomes pose tremendous regenerative capacity in otherwise inherently poor tendon healing following shoulder injury. Understanding the exosome biology in the context of tendon injury offers immense opportunities for developing novel regenerative approaches. Herein, we focus on the novel concept of “Smart Exosomes” by programming the regenerative properties of exosomes as a next-generation management strategy for shoulder tendon injury.

Mesenchymal stem cells (MSCs) are adult stem cells that have the ability to self-renew and differentiate into several cell lineages including adipocytes, chondrocytes, tenocytes, bones, and myoblasts. These properties make the cell a promising candidate for regenerative medicine applications, especially when dealing with sports injuries in the knee. MSCs can be isolated from almost every type of adult tissue. However, most of the current research focuses on MSCs derived from bone marrow, adipose, and placenta derived products. Synovial fluid-derived MSCs (SF-MSCs) are relatively overlooked but have demonstrated promising therapeutic properties including possessing higher chondrogenic proliferation capabilities than other types of MSCs. Interestingly, SF-MSC population has shown to increase exponentially in patients with joint injury or disease, pointing to a potential use as a biomarker or as a treatment of some orthopaedic disorders. In this review, we go over the current literature on synovial fluid-derived MSCs including the characterization, the animal studies, and discuss future perspectives.

Objective: Alteration of the cellular microenvironment may influence the intra- and intercellular communication and contribute to cartilage injury and repair. The purpose of this study was to investigate how matrix elasticity/stiffness affects chondrogenic activities, including cell survival, phenotypic expression, and the release of both pro- and anti-inflammatory cytokines. Design: Human articular chondrocytes (HACs) cultured on traditional 2-dimensional (2D) plastic surfaces were compared with those cultured within 3D hydrogel matrices of varying stiffness. Chondrogenic proliferation, differentiation, and the expression of pro- and anti-inflammatory cytokines were evaluated. Both interleukin-1-beta (IL-1β) and human synovial fluid–derived cells (hSFCs) were introduced to study the effects of matrix stiffness on chondrocyte response. Results: Cells demonstrated the most robust chondrogenic differentiation and secreted the least pro-inflammatory cytokines when the matrix stiffness was close to their native microenvironment. The IL-1β effects were attenuated when HACs were co-cultured with hSFCs. Conclusion: Modifying the matrix stiffness to mimic the native cartilage microenvironment not only optimized chondrogenic expression but also was essential for the regulation of physiological homeostasis. This study proposed a new toolkit to study cell-molecule, cell-cell, and cell-matrix influence on cartilage physiology.

Objective: The goal of this pilot study was to investigate the effects of exosomes derived from synovial fluid-derived cells (SFDCs) cultured under normoxic conditions in a two-dimensional (2D) monolayer or encapsulated within a three-dimensional (3D) matrix for chondrogenic differentiation in vitro and cartilage defect repair in vivo. Design: Synovial fluid samples were obtained from three patients, and SFDCs were isolated and expanded either in a 2D monolayer culture or seeded within a transglutaminase cross-linked gelatin (Col-Tgel) to create a 3D gel culture. Exosomes derived from each environment were isolated and characterized. Then, their effects on cartilage-cell proliferation and chondrogenic differentiation were assessed using an in vitro organoid model, and their potential for enhancing cartilage repair was evaluated using a rat cartilage defect model. Results: SFDCs obtained from different donors reached a state of senescence after four passages in 2D culture. However, transferring these cells to a 3D culture environment mitigated the senescence and improved cell viability. The 3D-cultured exosomes exhibited enhanced potency in promoting chondrogenic differentiation, as evidenced by the increased expression of chondrogenic genes and greater deposition of cartilage-specific extracellular matrix. Furthermore, the 3D-cultured exosomes demonstrated superior effectiveness in enhancing cartilage repair and exhibited better healing properties compared to exosomes derived from a 2D culture. Conclusions: The optimized 3D culture provided a more favorable environment for the proliferation of human synovial cells and the secretion of exosomes compared to the 2D culture. The 3D-cultured exosomes exhibited greater potential for promoting chondrogenic gene expression in vitro and demonstrated improved healing properties in repairing cartilage defects compared to exosomes derived from the 2D culture.