Fostering tissue engineering and regenerative medicine to treat musculoskeletal disorders in bone and muscle

Abstract

The musculoskeletal system, which is vital for movement, support, and protection, can be impaired by disorders such as osteoporosis, osteoarthritis, and muscular dystrophy. This review focuses on the advances in tissue engineering and regenerative medicine, specifically aimed at alleviating these disorders. It explores the roles of cell therapy, particularly Mesenchymal Stem Cells (MSCs) and Adipose-Derived Stem Cells (ADSCs), biomaterials, and biomolecules/external stimulations in fostering bone and muscle regeneration. The current research underscores the potential of MSCs and ADSCs despite the persistent challenges of cell scarcity, inconsistent outcomes, and safety concerns. Moreover, integrating exogenous materials such as scaffolds and external stimuli like electrical stimulation and growth factors shows promise in enhancing musculoskeletal regeneration. This review emphasizes the need for comprehensive studies and adopting innovative techniques together to refine and advance these multi-therapeutic strategies, ultimately benefiting patients with musculoskeletal disorders.

Keywords: Bone; Muscle; Musculoskeletal disorders; Regenerative medicine; Tissue engineering.

Graphical abstract

Fig. 1

Specific areas of the human body affected by different musculoskeletal disorders. Red, green, and black text indicate musculoskeletal diseases caused by the immune system; genetic factors; and social, behavioral, and environmental condition, respectively.

Fig. 2

Bone regeneration is a finely choreographed process unfolding over distinct phases. The initial step (week 1) involves hematoma formation, where the coagulation cascade triggers pro- and anti-inflammatory events orchestrated by IL-1, IL-6, TNF-α, VEGF, and RANKL, engaging M1 and M2 macrophages, Th1 and Th2 cells, and fibroblasts. During weeks 2–3, soft callus formation with angiogenesis is observed, driven by IL-6, TNF-α, VEGF, and RANKL, involving endothelial cells, hypertrophic chondrocytes, and osteoblasts. During weeks 4–17, hard callus formation is observed, marked by matrix mineralization and woven bone development facilitated by IL-6, TGF-β, VEGF, and MMPs, with the participation of endothelial cells, osteocytes, osteoblasts, and osteoclasts. The subsequent phase, spanning weeks 18–52, encompasses bone remodeling with TGF-β and MMPs influencing endothelial cells, osteocytes, osteoblasts, and osteoclasts, refining the healed fracture and ultimately restoring functional bone structure. This intricate temporal and cellular orchestration is fundamental for bone tissue's successful regeneration. The figure presented here is based on Y. Niu et al.'s work [42].

Fig. 3

Muscle regeneration is a complex and carefully controlled process that involves different phases, each with its own set of contributing cells and specific timing. The first phase (week 1) is the activation of satellite cells, which involves the formation of hematoma and initiating pro-inflammatory and anti-inflammatory events by cytokines such as IL-1, IL-6, TNF-α, and TGF-β. This phase requires the participation of various cells, such as satellite cells, macrophages, mast cells, neutrophils, eosinophils, natural killer (NK) cells, dendritic cells, and B cells. The second phase, which occurs within weeks 1–2, involves the proliferation and differentiation of myoblasts, which then transition into myocytes. This phase is influenced by factors such as IGF-1, FGF, HGF, IL-4, and IL-13 and requires the active involvement of macrophages, mast cells, T cells, Treg cells, and fibroblasts. The third phase, spanning weeks 2–4, is characterized by fusion and maturation, which involves the deposition of extracellular matrix (ECM), scar tissue formation, and myofiber development. This stage is regulated by IGF-1, TGF-β, BMPs, and myostatin, with mast cells and fibroblasts playing critical roles. Together, these steps ensure the effective regeneration and restoration of muscle tissue integrity. The figure presented here is based on the work of Muire et al. [45].

Fig. 4

Tissue engineering and regenerative medicine can be used to evade the immune system and harness its features for therapeutic purposes. Mesenchymal stem cells (MSCs) can potentially reduce the damage caused by the immune system. The biomolecules secreted by MSCs can cause a transition of M1-like cells to M2-like macrophages, which significantly promotes anti-inflammation and reduces inflammation. This is achieved by down-regulating Th1 and Th17 cells while positively stimulating T regs and Th2 cells. MSCs can influence the immune system by releasing specific factors that regulate various immune cells. The release of IFNγ, TNFα, IL-2, IL-8, and IL-12 inhibits natural killer (NK) cells. B cells are regulated through PGE-2, IDO, CCL-2, and PD-1. IL-10 and PGE-2 control dendritic cells, while IL-6 regulates neutrophils. This well-coordinated interplay highlights the potential of MSCs to fine-tune immune responses and offers promising therapeutic options for tissue engineering and regenerative medicine.

Fig. 5

Natural or synthetic biomaterials interact with biological systems to trigger, treat, or support affected areas by leveraging their diverse properties. These materials can repair or regenerate tissues through mechano-therapy, utilizing vibration, tension, and compression forces. Their porosity and patterning ensure biocompatibility by supporting cell growth and ensuring non-toxicity. Furthermore, they have specific chemical properties, including surface charge and functional groups. These characteristics influence cellular processes such as adhesion, proliferation, and migration, providing benefits beyond structural support in tissue engineering and regenerative medicine.

Fig. 6

External stimuli activate specific molecular pathways within cells, triggering unique molecular changes. Electrical stimulation activates the Akt pathway (a), changes in topography stimulate the Wnt pathway (b), while a magnetic field engages the JAK-STAT pathway (c). Ultrasound activates the ERK/MAPK-P38 pathway (d), and light wavelengths modulate the Ras-Raf-MEK pathway (e). These pathways control cellular behavior in response to external stimuli, promoting cell proliferation, differentiation, and migration.

Fig. 7

Scheme for treating bone and muscle musculoskeletal disease using regenerative medicine and tissue engineering. Musculoskeletal disorders can be treated by combining techniques that involve evading and harnessing the immune system, providing structural support, and regeneration. These three targets are achieved using interconnected components such as cell therapy, biomaterials, and biomolecules. For example, MSCs can manipulate the immune system to prevent it from attacking healthy tissue, while scaffolds or other biomaterials provide structural support. Finally, regeneration can be achieved using specific medications or biological agents, such as growth factors and mRNA, that promote bone and muscle tissue regeneration.

Fig. 8

Illustration of multiple strategies combined to achieve fast and improved tissue engineering and regeneration. First, 3D printing creates scaffolds from chitosan and PCL via hot melt extrusion. These scaffolds are then enriched with growth factors to promote cell proliferation and differentiation. In vitro electrical stimulation is applied to MSCs to enhance their proliferation, aiding mass production. For in vivo applications, electrical stimulation accelerates tissue recovery by modulating cellular activities and promoting anti-inflammatory responses. The integrated approach facilitates the tailoring of treatments to meet the specific requirements of individual patients and the characteristics of their musculoskeletal disorders. This method signifies a sophisticated and comprehensive grasp of tissue engineering and regenerative medicine, offering the potential for more effective and long-lasting solutions for those affected by various musculoskeletal conditions.