Regulating Macrophages through Immunomodulatory Biomaterials Is a Promising Strategy for Promoting Tendon-Bone Healing

Abstract

The tendon-to-bone interface is a special structure connecting the tendon and bone and is crucial for mechanical load transfer between dissimilar tissues. After an injury, fibrous scar tissues replace the native tendon-to-bone interface, creating a weak spot that needs to endure extra loading, significantly decreasing the mechanical properties of the motor system. Macrophages play a critical role in tendon-bone healing and can be divided into various phenotypes, according to their inducing stimuli and function. During the early stages of tendon-bone healing, M1 macrophages are predominant, while during the later stages, M2 macrophages replace the M1 macrophages. The two macrophage phenotypes play a significant, yet distinct, role in tendon-bone healing. Growing evidence shows that regulating the macrophage phenotypes is able to promote tendon-bone healing. This review aims to summarize the impact of different macrophages on tendon-bone healing and the current immunomodulatory biomaterials for regulating macrophages, which are used to promote tendon-bone healing. Although macrophages are a promising target for tendon-bone healing, the challenges and limitations of macrophages in tendon-bone healing research are discussed, along with directions for further research.

Immunomodulatory multicellular scaffolds for tendon-to-bone regeneration

“…Therefore, in combination with in vitro experiment results, it could be hypothesized that this excellent repair effect may be attributed to the immunomodulatory function and bidirectional bioactivities of multicellular scaffolds based on MS nanoparticles. On the one hand, a growing number of reports have identified excessive inflammation response as a cause for the regeneration of disorganized scar structures at the tendon-to-bone interface ( 5 , 28 , 59 ). The researchers found that there were more M2 macrophages and less M1 macrophages at the well-healed tendon-to-bone interface ( 22 ).…”

“…As is known to all, the immune environment usually determines the outcome of tissue damage repair (25)(26)(27). An appropriate inflammatory response facilitates the initiation of tissue repair, whereas excessive inflammation can, in turn, impede the progression of tissue repair and stimulate the development of pathological fibrosis/scar structures at the site of injury, thereby depriving the biomaterial of its intended function (25,(28)(29)(30). Hence, in addition to the ability to induce the regeneration of multiple tissues, ideal tendon-to-bone tissue engineering scaffolds need to fully take full account of the immunomodulatory functions of the 3D biological microenvironment.…”

Durable immunomodulatory hierarchical patch for rotator cuff repairing

“…As observed in the SR group in this study, without external intervention, the reconstructed RC tissue will continue to exhibit inflammatory infiltration, potentially leading to another tendon tear [ [34] , [35] , [36] ]. Therefore, many studies have employed anti-inflammatory drugs to promote RC regeneration [ 37 ]. However, current methods can only provide anti-inflammatory effects in the early stages, although the repair of the tendon-to-bone interface is a chronic process.…”

Nanofibrous scaffolds for the healing of the fibrocartilaginous enthesis: advances and prospects

“…In summary, nanofibrous scaffolds have great potential for application in the field of promoting fibrocartilaginous enthesis healing. [37][38][39][40][41]…”