Proteins secreted by cells are known to play a key role in modulating many biological functions such as cell signaling, differentiation and growth. The secretome, which is rich in a complex set of molecules secreted by living cells, could have the potential to heal tendons/ligaments. Recent advances in proteomics have characterized hundreds of growth factors and cytokines secreted by stem cells in particular to elucidate their ability to regenerate. A well-known growth factor, platelet-derived growth factor (PDGF), has been extensively studied for its role in tendon/ligament repair. In this review, we will discuss in detail current advances in tissue engineering of tendons and ligaments using scaffolds, stem cells, and cell secretion products for tendon and ligament repair. In addition, we will discuss the use of bioreactors and mechanical stresses for in vitro maturation of tendons and ligaments. Finally, an overview of the future direction of tissue engineering of tendons and ligaments is offered. There are four primary ligaments that connect these bones and help maintain joint stability. The collateral ligaments are located on either side of the knee. The medial ligament is called the medial collateral ligament and the external ligament is called the lateral collateral ligament. These two ligaments control the lateral movement of the knee. Collagen and elastin are the main components of the ECM of tendon and ligament tissue and the use of biomaterials with properties comparable to collagen and elastin makes sense [22]. The construction of native ECM is associated with the construction of the scaffold in tissue engineering.
Therefore, in order to develop a tendon/ligament, the tissue must also provide scaffold structures suitable for fixation, differentiation and growth of tenocytes or ligamentocytes. For the researcher, it is a challenge to study the behavior of tenocytes and ligamentocytes in a 2D model culture, because the influence, especially the mechanical cues, is not sufficiently influenced. To simulate the environment of the native tissue itself, a tightly controlled local environment is required with the ability to support and multiply cells while providing biological and mechanical signals in the aseptic state. These functions could be provided by modern bioreactors that can be adapted to support a specific tissue such as the tendon/ligament [161]. Tissue-engineered tendons/ligaments can be 3D grown in a controlled environment bioreactor, while receiving mechanical stimuli and chemical signals to control tissue maturation. Careful selection of biomaterials as scaffolds is important, as some biomaterials may not be able to withstand mechanical stress due to poor mechanical properties. From the literature search, we found several reports that examined the modern bioreactor for tendon/ligament technology. The high failure and recurrence rates of current tendon and ligament grafts have prompted researchers to explore new possibilities for tendon and ligament repair through tissue engineering. While this field offers limitless possibilities, many cannot be translated into clinical applications. A better understanding of how native tissues evolved and functioned could elucidate which are the best mixtures of the tissue engineering triad (cell, scaffolding, biological factor) to prepare the manipulated tendon and ligament that resemble native tissue. The electrospinning method has demonstrated its ability to produce highly aligned nanofibers that resemble the arrangement of collagen fibrils in native tendons and ligaments.
Stem cells and products secreted by cells are promising, but their application in clinical practice is still vague. Adequate standardization of clinical trials, preparation of the source of stem cells and secretory products are necessary to prove their effectiveness. The bioreactor, extended with mechanical stress characteristics, could dynamically influence the behavior of cells in the scaffold and mimic the physiological situation of the tendon and ligament. This technology offers the potential for a more accurate understanding of tissue formation and maturation in vitro and the ability to mass produce. Overall, more research is needed to quench our thirst for developing an ideal technical fabric. The future will be interesting because the development of new technologies is fast and robust. In the discussion above, the potential of stem cells in tendon/ligament repair was studied. Recently, however, a paradigm shift has taken place, implying that their beneficial effects may be limited not only to cell regeneration, but also to their transient paracrine activity.
Stem cells can secrete growth factors, cytokines and extracellular vesicles that can modulate the molecular composition of the environment to elicit resident cell responses.
