Skip to main content

Mesenchymal stem cell-derived exosomes: a potential cell-free therapy for orthodontic tooth stability management

Abstract

Orthodontic relapse (OR) occurs at a rate of over 70%. Retention is the current attempt at prevention, but it requires a considerable amount of time and cannot fully block OR. It’s imperative to find a safe and effective method for managing post-orthodontic tooth stability. Periodontal bone remodeling is one crucial biological foundation of OR. Mesenchymal stem cell-derived exosomes (MSC-Exo) show promise in relapse management by regulating periodontal bone remodeling. MSC-Exo can prevent relapse by regulating periodontal ligament function, osteoclast activity, osteoblast differentiation, macrophage polarization, and periodontal microcirculation. In recent years, exosome-loaded hydrogels, which achieve controlled exosome release, have demonstrated efficacy in promoting bone regeneration and remodeling, offering promising prospects for OR management. This review aims to highlight the use of MSC-Exo-based therapy for preventing OR, offering new insights for future research focused on improving tooth stability and enhancing orthodontic anchorage.

Background

The goal of orthodontic treatment is to obtain and maintain an optimal occlusion, characterized by well-coordinated functional dentition and facial morphology. However, the ensuing disturbances of the local mechanical environment due to the removal of orthodontic appliances might cause the teeth to drift away from their corrected position. This inevitable and unfavorable post-treatment tooth movement is defined as orthodontic relapse (OR), which remains one of the biggest challenges in orthodontics. Despite correct diagnosis and treatment planning followed by effective retention, OR still occurs at a high percentage. Studies have shown that more than 70% of patients experience OR after removal of retainers [1]. The relapse rate exceeds 19% after 3 years of orthodontic treatment [2]. Lifelong retention is the only strategy recommended to prevent OR [3].

The periodontal ligament (PDL) is a highly mechanoresponsive tissue. Mechanical forces play a vital role in maintaining periodontal homeostasis by triggering a well-orchestrated response of all PDL components. Orthodontic tooth movement (OTM) is facilitated by continuous alveolar bone resorption by osteoclasts adjacent to the compression side of the tooth root along with the stimulation of new bone formation by osteoblasts on the tension side — a process known as periodontal remodeling [4]. This involves complex processes such as osteoimmunology, cell signaling, mechanotransduction, and extracellular matrix (ECM) alteration. During OTM, different mechanical stresses (shear, compression, and tension) on teeth are transferred to the alveolar bone through PDL and activate a chain of genetic and protein modifications. Periodontal ligament cells (PDLC) perceive mechanical stimuli and convert them into cellular signals, leading to release of extracellular factors that modulate the local microenvironment. OR undergoes the same biological process as OTM but in the opposite direction.

Given the similarity in physiological processes between OTM and OR, chemical agents that reduce the rate of OTM by targeting periodontal bone remodeling pathways may also be effective in modulating OR. After decades of investigations, evidence shows that various medications and biologic factors can potentially modulate the process. The local administration of medicines, such as tetracycline [5], atorvastatin [6], simvastatin [7], raloxifene [8], osteoprotegerin [9], etc., showed an inhibitory effect on OR in a rat OTM model. Although specific medicines do have a potential effect on OR, the associated deleterious effects on other tissues must be carefully considered. None of these approaches have reached the point where they can be routinely used in the clinic. It’s urgent to find a safe and effective approach for post-orthodontic tooth stability management.

OR activity and the effect of retention on OR

OR activity

According to previous animal experiment observations, OR curves are characterized by exponential decay curves, consisting of two phases, namely a rapid relapse phase and a long-term relapse phase (Fig. 1) [10]. This pattern occurs regardless of the force applied during active OTM or the total OTM distance. OR might get initiated immediately once the teeth are no longer restrained by orthodontic appliances [11]. During the rapid relapse phase, approximately 70–80% of total relapse occurs [10, 12]. This phase only lasts for a few days before transitioning into the long-term relapse phase, where the relapse lasts for several weeks at a drastically decreased speed [10, 13]. However, in animal studies of OR, OTM distances were primarily measured using silicone dentition models or solely photographs, which introduces considerable manual measurement error. To enhance accuracy, micro-CT is suggested to be applied in future studies.

The effect of retention on OR

The long-term use of retainers is often suggested to reduce OR. In most animal studies of OR, however, the efficacy of retention is scarcely evaluated. According to the present two studies that compared the effect of retention on mouse and dog OR models, the total amount of relapse was decreased by approximately 58 − 65% compared to the group without retention (Fig. 1) [14, 15]. Intriguingly, Eric [14] pointed out that the duration of the relapse period is independent of retention, and retention has no significant reducing effect on relapse when OTM distance is smaller than 2 mm, indicating that relapse is partly retention-responsive.

Fig. 1
figure 1

A schematic diagram of relapse curves with or without retention

Hypotheses of OR

Although the question of OR has been raised for decades, its biological mechanism is still not fully elucidated. OR involves a complex interplay between various cell types, including PDLCs, osteoclasts, osteoblasts, and macrophages, as illustrated in the diagram (Fig. 2). Current hypotheses regarding OR can be categorized into two aspects:

Periodontal ligament (PDL) remains under tension

The role of PDL remodeling in OR remains controversial. Traditionally, it was believed that PDL remains stretched after removal of orthodontic appliance, creating stretch-induced tension that contributes to rapid relapse. This theory has been supported by evidence showing that surgical fiberotomy, proteolytic nanoparticles targeting collagen type-I fibers and antifibrotic medications like sulforaphane can block this rapid relapse phase [16,17,18]. However, this theory has been challenged by histological findings indicating that collagen turnover in the PDL is fast enough for the gingival fiber system to completely remodel during orthodontic treatment [19]. Additionally, the persistence of OR despite normally stretched transseptal fibers suggests that collagen turnover might not be the primary factor in the OR process [10].

Unfinished periodontal remodeling and osteoclast activity on the relapse direction

Periodontal bone remodeling has gained increased attention in recent studies on OR. Osteoclasts, as multinucleated cells responsible for bone resorption, play a crucial role in this process [20]. When orthodontic force is applied, woven bone begins to form on the tension side. However, the bone turnover is not complete at the end of orthodontic treatment [15]. The newly deposited bone remains a disorganized fiber structure with poor mineralization, making it susceptible to external force and subsequent osteoclastic resorption. Initial resorptive activity can create a temporary void adjacent to the PDL neighboring the tooth roots, which facilitates the rapid relapse [9]. At the end of active orthodontic treatment, osteoclasts begin to distribute along the alveolar bone on the relapse direction [21]. The number of osteoclasts is positively correlated with the relapse activity [10, 18]. As OR progresses, the number of osteoclasts decreases over time [10]. Inhibition of osteoclast activity through bisphosphonates or Nrf2 activation has been shown to reduce OR by over 70% [22, 23], which further confirms the role of osteoclasts in OR.

Fig. 2
figure 2

A schematic diagram that summarizes the role of periodontal ligament cell (PDLC), osteoclast, osteoblast, and macrophage in orthodontic relapse

Exosomes and mesenchymal stem cells-derived exosomes (MSC-Exo)

Exosomes are tiny extracellular vesicles secreted by cells through exocytosis, with an average diameter of 100 nm. These vesicles contain various constituents of a mother cell that releases them, including DNA, RNA, lipids, and metabolites. They also carry transmembrane proteins, heat shock proteins, lipoproteins, and some transport-related proteins, which serve as markers for exosome identification and help target them to specific cells [24]. Exosomes are produced by almost all cell types, among which those sourced from mesenchymal stem cells (MSCs) are most widely studied. They also exist in various body fluids such as plasma, urine, and saliva. The biogenesis of exosomes is influenced by many external factors like cell type, microenvironment, growth factors, and cytokines, which results in the heterogeneity of exosomes. Encapsulated by lipid membranes derived from their parental cells, exosomes show inherent biocompatibility and specific homing effect, which means they can target and enter specific cells or tissues under certain conditions. This is mediated by surface molecules such as integrins and glycans. They can be taken up by recipient cells via receptor–ligand binding, endocytosis, or membrane fusion, allowing them to regulate the function and behavior of distant recipient cells. This positions them as crucial intercellular communicators [25].

Research has highlighted the pivotal roles of exosomes in cell-to-cell communication and immune modulation under various physiological and pathological conditions. Unlike the undesirable side effects that medications may bring about, stem cells and their exosomes are easier to target to treatment sites and have lower immunogenicity. This has made them the focus of regenerative medicine in recent years [26].

MSCs are self-renewing, multipotent, and regenerative progenitor cells. They can be differentiated into mesenchymal lineages, namely osteoblasts, chondrocytes, adipocytes, and endothelial cells [27]. MSCs can be easily isolated from different and accessible adult tissues like peripheral blood, skin, and dental pulp [28]. As prolific producers of exosomes, MSCs ensure sustainable and reproducible production of exosomes [29]. Compared with stem cells, exosomes have more advantages in promoting tissue regeneration and have lower risks of triggering immune response and tumorigenesis [30]. MSC-Exo have been shown to have therapeutic effects on various orthopedic diseases, including osteoporosis, osteoarthritis, and bone fractures, through their regulation of bone remodeling and angiogenesis [31,32,33,34].

MSC-Exo as a potential cell-free therapy for OR

Research has demonstrated the efficacy of various MSC-Exo in modulating periodontal bone remodeling, laying a foundation for its potential use in OR prevention. These include regulating PDLC function, inhibiting osteoclast activity, facilitating osteogenesis, modulating macrophage polarization, and promoting periodontal microcirculation (Table 1; Fig. 3). The following sections will elucidate these processes in detail.

MSC-Exo regulates PDLC function

PDL is a specialized connective tissue that surrounds the roots of teeth, functioning as a stress absorber and redistributor to the adjacent alveolar bone [35]. Orthodontic force can dramatically alter the pattern and density of PDL collagen [18]. The normal structure of the PDL is replaced by type III collagen fibers during OTM. These disorganized fibers are rapidly remodeled, restoring the normal PDL structure within 3 weeks of OR [11]. Additionally, PDL tends to thicken on the tension side and thin on the opposite compression side during OTM but recovers its original width shortly after the withdrawal of orthodontic force [36]. The force-induced degradation of PDL structure is closely linked to the instability of post-orthodontic teeth, and its recovery during early relapse corresponds with the rapid relapse ratio [18].

Among the heterogeneous cell populations within the PDL, PDLCs and periodontal ligament stem cells (PDLSCs) are the main components responsible for PDL remodeling and extracellular matrix (ECM) deposition. These cells can differentiate into periodontal cell types in vitro and generate PDL complex structures in vivo [37].

PDLCs play a significant role in modulating local bone metabolism [38]. The dynamic interaction of PDLCs, including osteoblasts, fibroblasts, cementoblasts, and ECM components, is crucial for alveolar bone formation and regeneration [39]. In the absence of mechanical forces, PDL cells attract osteoclast precursors through the presentation of intercellular adhesion molecule 1 (ICAM1) and support the expression of osteoclastogenesis-promoting molecules such as RANKL, macrophage colony-stimulating factor (M-CSF), HMGB1, and tumor necrosis factor-α (TNF-α) [40]. When mechanical forces are applied, PDLCs respond by upregulating the expression of osteogenic markers, including osterix (Osx), runt-related transcription factor 2 (Runx2), and osteoprotegerin (OPG), meanwhile downregulating the osteoclastogenic marker receptor activator of nuclear factor kappa-B ligand (RANKL) [41].

Multiple signaling pathways are involved in maintaining cellular homeostasis of PDLSCs and PDLCs. Mechanical stimulation modulates the proliferation and differentiation of PDLSCs, with Wnt signaling being critical for their activation [42, 43]. When mechanical loading is applied, it not only activates the Wnt pathway but also induces cytoskeletal rearrangements. This process involves the mechanosensory protein complex linking to a kinase cascade system, triggering the transcription of various regulatory genes in response to mechanical forces [44]. Force-induced processes like pyroptosis, apoptosis and autophagy in PDLSCs are also essential for maintaining alveolar bone homeostasis and regulating periodontal remodeling [45,46,47]. Compressive force can alter cell morphology and suppress collagen expression in CD90+ PDLSCs, which recovers to its original status after force withdrawal. Inhibition of the collagen expression in PDLSCs by blocking TGF-β can interrupt PDL collagen recovery and alleviate early relapse [18].

The emerging biological functions of MSC-Exo in regulating PDLSCs have garnered significant attention. Gingival MSC-derived exosomes (GMSC-Exo) can promote the osteogenic differentiation of PDLSCs via the cross-regulation of NF-κB and Wnt/β-catenin signaling pathways in a periodontal inflammatory environment [48]. Dental pulp stem cell-derived exosomes (DPSC-Exo), the optimal choice among oral MSC-derived exosomes, can enhance the proliferation, migration, and osteogenesis of PDLSCs and regulate inflammation by inhibiting the IL-6/JAK2/STAT3 signaling pathway [49]. Additionally, DPSC-Exo can alter the cell cycle and apoptosis of PDLCs by modulating MAPK and Wnt signaling pathways [50, 51]. These properties highlight the potential of MSC-Exo, especially oral MSC-derived exosomes, to enhance PDLSCs and PDLCs function and inhibit orthodontic relapse.

MSC-Exo inhibits osteoclast activity

Osteoclasts originate from the monocyte/macrophage hematopoietic lineage cells, which circulate in the bloodstream and adhere to the bone tissue [52]. During OTM, osteoclasts break down bone tissue, creating space to facilitate tooth movement and new bone formation. It’s been suggested that OR activity is positively correlated with the number of osteoclasts in the relapse direction [21]. After the withdrawal of the orthodontic appliance, newly formed bone tissue is absorbed and degraded by enhanced osteoclast activity, creating spaces for OR [9].

Osteoclast differentiation, survival, and activation are primarily regulated by two essential factors: M-CSF and RANKL [53]. In the presence of M-CSF, RANKL binds to its receptor RANK on osteoclast precursors. This process recruits the adapter protein TNF receptor-associated factor 6 (TRAF6), which triggers multitudinous intracellular signaling cascades, including mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB) and nuclear factor of activated T-cells 1/2 (NFATc1/2) [54]. NFATc1, a master regulator of osteoclast differentiation, governs the expression of numerous genes involved in bone resorption, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and Atp6v0d2. Once activated, osteoclast precursors fuse into multinucleated osteoclasts, attach to the bone surface, and dissolve mineralized bone matrix by secreting acid and lysosomal enzymes [55].

Exosome-based regulation of osteoclast differentiation is an emerging area of research. Exosomes can influence osteoclast differentiation by delivering signaling molecules, modulating the microenvironment, and interacting with other cells involved in bone remodeling. Studies have demonstrated that MSC-Exo has the capacity to downregulate osteoclast activity. Local injection of bone marrow mesenchymal stem cell-derived exosomes (BMMSC-Exo) can inhibit the osteoclastogenesis of human monocytes by directly inhibiting osteoclast formation targeting 3’-untranslated regions of osteoclast stimulatory transmembrane protein (OCSTAMP) and C-X-C motif chemokine ligand 12 (CXCL12) [56]. GMSC-Exo can also reduce periodontal osteoclast differentiation by targeting the Wnt/β-catenin-mediated RANKL pathway, providing a therapeutic approach for periodontitis [57]. Additionally, orofacial mesenchymal stem cell-derived exosomes, which have a high expression level of miR-206-3p, inhibit osteoclastogenesis by suppressing NFATc1 [58]. These findings highlight the potential of MSC-Exo in regulating osteoclast activity and preventing OR. Ongoing research continues to uncover more details about the specific mechanisms and molecules involved in the regulation of osteoclast differentiation by MSC-Exo, paving the way for innovative treatments in orthodontics and bone health.

MSC-Exo modulates osteoblast differentiation

Osteoblasts, derived from pluripotent MSCs in the bone marrow, are crucial for bone matrix synthesis, secretion, and mineralization [59]. Under the influence of Runx2 and other factors, MSCs differentiate into osteoprogenitor cells, which further turn into immature osteoblasts. These immature osteoblasts secrete ECM components to form the osteoid and mineralize it by releasing vesicles containing calcium and phosphate ions. As the mineralization progresses, immature osteoblasts gradually transform into fully functional osteoblasts. This differentiation process is primarily driven by key signaling pathways, including Wnt, TGF-β/BMP, and Notch.

In animal studies of OR, the newly formed alveolar bone exhibits numerous bone cell lacunae, indicating its immature state [7, 60]. After the active OTM, osteoblasts are seen lining along the newly deposited alveolar bone in the direction of relapse, suggesting incomplete periodontal bone remodeling [10]. In this context, promoting alveolar bone remodeling is an effective way to prevent OR. For instance, raloxifene has been shown to reduce OR by inducing bone formation through elevated expression of osteoblastogenesis and mineralization-related proteins [8, 61]. Similarly, local delivery of simvastatin can inhibit OR by enhancing the expression of bone morphogenetic protein-2 (BMP-2), collagen type I and osteocalcin [60].

Emerging evidence shows that exosomes mediate the cell-to-cell communication in the process of osteoblastic differentiation. Interestingly, MSC-Exo has been proven to regulate the activity of osteoblasts and affect their proliferation and differentiation. For example, BMSC-Exo can improve osteoporosis by promoting differentiation, enhancing cell proliferation and alkaline phosphatase (ALP) activity of hFOB1.19 [62, 63]. MSC-Exo can also promote osteoblast activity by upregulating key osteogenic genes, such as Runx2, partly due to the presence of pro-osteogenic miRNAs (miR-27a, miR-196a and miR-206) that activate classical osteogenic pathways [64, 65]. These effects of MSC-Exo on osteoblast activity highlight their potential as therapeutic tools for various orthopedic conditions, such as osteoporosis, bone fractures, and bone tissue engineering. Considering that insufficient remodeling of alveolar bone is a primary cause of OR, MSC-Exo could be a promising strategy to suppress unwanted post-orthodontic tooth movement. However, the specific molecular mechanisms underlying these effects warrant further investigation.

MSC-Exo modulates macrophage polarization

Macrophages are immune cells that engulf and digest cellular debris, pathogens, and cancer cells through phagocytosis [66]. They are typically classified into two types: M1 and M2 macrophages. M1 macrophages release inflammatory factors such as IL-1, IL-6, and TNF-α, initiating osteoclastogenesis. In contrast, M2 macrophages secrete TGF-β and IL-10, inhibiting osteoclast formation and supporting bone deposition.

During OTM, macrophages play a multifaceted role as progenitors of osteoclasts, modulators of inflammation, and effectors of mechanical force [67]. M1 macrophages are the predominant subtype that functions in OTM [68]. In the early stage of OTM, orthodontic force upregulates the expression of monocyte chemotactic protein 1 (MCP-1) in periodontal tissues, contributing to monocyte recruitment to regional sites [69]. Once recruited, macrophages polarize toward the M1 phenotype due to local compressive force and various inflammatory factors [70]. M1 macrophages then promote alveolar bone resorption and inflammation-mediated bone remodeling due to their production of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and M-CSF [68, 71]. Additionally, macrophages secrete matrix metalloproteinases (MMPs) to degrade ECM components and cellular debris during periodontal tissue remodeling in OTM [72].

M2 macrophages, although crucial for the cessation of bone resorption and promoting bone formation, are less understood in the context of OTM [73, 74]. Studies suggest that the M1/M2 ratio reduces during the retention phase, which might be important for tissue healing and protecting against orthodontically associated root resorption [68, 75]. Therefore, promoting macrophage polarization towards M2 phenotype could be an effective strategy for OR management.

Recent research has extensively evaluated the impact of MSC-Exo on macrophage polarization. DPSC-Exo can reduce macrophage M1 polarization through the ROS/MAPK/NF-κB signaling pathway in treating spinal cord injury [76]. Similarly, exosomes from adipose stem cell-derived exosomes (ADSC-Exo) regulate M1/M2 macrophage polarization to promote bone healing via miR-451a/MIF [77]. BMSC-Exo increases the ratio of M2 to M1 polarization by inhibiting Akt phosphorylation [78]. Given the dual role of macrophages in OTM — promoting inflammation and bone resorption, as well as tissue remodeling and repair — modulating their polarization by MSC-Exo presents as a novel approach to ensuring proper tooth movement and maintaining periodontal health.

MSC-Exo promotes periodontal microcirculation

Periodontal microcirculation plays a crucial role in the regulation of OTM and OR. Vascular endothelial cells within this complex system interact with bone cells, such as osteoblasts, osteoclasts, and mesenchymal stromal cells, leading to the formation of microcapillary networks around newly formed bone tissue [79]. Two primary subtypes of vascular endothelial cells, H-type and L-type, are involved in osteogenesis, with H-type vessels playing a dominant role [80]. Notch signaling in H-type vascular endothelial cells is significant for osteogenic-angiogenic coupling [81].

Local microcirculation facilitates the recruitment of immune cells, such as macrophages, to the site of tooth movement, contributing to the inflammatory response and tissue remodeling. This process underscores the importance of local microvessel formation and nutrient supply through microvessels for tissue regeneration and repair during OTM [82]. Changes in periodontal microcirculation significantly influence OTM, with local blood vessel formation affecting interstitial tissue fluid pressures and alveolar remodeling. The number and density of periodontal blood vessels correlate with the processes of OTM and OR, highlighting the critical role of vascular dynamics in these phenomena [83].

Recent studies have shown the successful application of MSC-Exo to promote angiogenesis in bone remodeling process, especially in maxillofacial bones [84, 85]. For example, PDLSC-derived exosomes (PDLSC-Exo) can promote the bone regeneration of calvaria defects by promoting the vascularization process through increasing the vascular endothelial growth factor (VEGF)/ vascular endothelial growth factor receptor 2 (VEGFR2) expression [86]. Human exfoliated deciduous teeth-derived exosomes (SHED-Exo) contribute to periodontal bone regeneration by promoting neovascularization, attributed to the upregulated expression of angiogenesis-related genes VEGFR2, CXCL12, and fibroblast growth factor-2 (FGF-2) [84]. In this context, modulations of periodontal microcirculation to enhance periodontal remodeling present a promising therapeutic approach for preventing OR.

Fig. 3
figure 3

A schematic diagram illustrating the mechanisms of MSC-Exo in modulating periodontal bone remodeling and preventing orthodontic relapse

Table 1 The efficacy of various MSC-Exo in the regulation of PDLSC/ PDLC function, osteoclast activity, osteoblast differentiation, macrophage polarization and periodontal microcirculation

MSC-Exo loaded biomaterials for OR management

 Minimizing invasive procedures is crucial for post-orthodontic tooth stability management, making injectable biomaterials like hydrogels a preferred choice for exosome delivery. Hydrogels, soft and wet materials that resemble the natural ECM in structure and composition, have garnered increasing attention in the biomedical engineering field [87]. Due to their plasticity, porosity, biocompatibility, and injectability, hydrogels are considered ideal candidates for tissue engineering, controlled drug delivery, and various other biomedical applications [88].

Exosomes offer substantial potential in tissue engineering, but their rapid degradation in vivo poses a challenge for clinical applications. For instance, subcutaneously injected exosomes are typically cleared within a day [89]. To address this issue, researchers are exploring the use of scaffolds to facilitate the loading and controlled release of exosomes, offering a stable and effective method for their application in vivo. Various techniques, including direct attachment, chemical cross-linking, specific binding, freeze-drying, and 3D printing, have been developed to combine exosomes with scaffolds [90]. Encapsulating exosomes in hydrogels can prolong their half-life and ensure a slower and more controlled release of exosomes in vivo for several weeks [89, 91,92,93].

Typically, exosome-scaffold combinations exhibit an initial rapid release followed by a slower and stabilized release over a period of more than a week, contrasting sharply with the rapid degradation seen with directly injected exosomes. For example, exosomes loaded onto ionically cross-linked alginate hydrogels release over 50% within the first three days, with the remainder releasing slowly over time [89]. In freeze-dried scaffolds, exosome release rates are 71.4% and 75.4% at 14 and 28 days, respectively [94]. Meanwhile, radial scaffolds created via 3D printing retain more than 56% of exosomes after 14 days in vitro [90].

There are mainly three ways of preparing exosomes-loaded hydrogels: The “breathing method” takes advantage of the hydrogel’s water retention and absorption properties. After removing excess water from the swollen hydrogel using a solvent, the exposed voids can be filled with exosomes. However, the effectiveness of this method depends on the appropriate pore size of the hydrogel to accommodate the exosomes; too small, and the loading process may fail; too large, and there is a risk of premature exosome leakage [95]. Another approach involves directly mixing exosomes with the hydrogel precursor solution using a crosslinking agent or through simple physical mixing. Additionally, polymers capable of self-assembly, such as hyaluronic acid-adamantane, can be added to the exosomes suspension, rapidly forming a hydrogel that encapsulates exosomes [96]. Another technique involves mixing exosomes with polymers and co-injecting them with a crosslinking agent into the target site using a double-lumen syringe. This method allows for gel formation directly at the application site, but it is essential to select non-toxic crosslinking agents to avoid adverse reactions in vivo [97].

Studies have reported the application of hydrogels in bone remodeling and regeneration, particularly in periodontal bone. For instance, a clinical trial utilizing basic fibroblast growth factor-gelatin hydrogels in patients with periodontal alveolar bone loss showed significant improvements in periodontal bone regeneration [98]. Additionally, controlled release of bisphosphonate risedronate with a topically administered gelatin hydrogel has shown its efficacy in decreasing OR by inhibiting osteoclast activity [99]. Intriguingly, MSC-Exo-loaded exosomes have shown efficacy in bone healing. BMSC-Exo loaded on bilayer-hydrogels can regulate macrophage polarization and scavenge reactive oxygen species to promote cartilage repair [100]. Similarly, the combination of PDLSC-Exo with collagen hydrogels has yielded promising results in a rat model for alveolar bone regeneration by enhancing osteogenic properties [101].

Conclusions, challenges, and future prospectives

Despite the effective use of orthodontic retainers, OR remains at a high rate. It is presumed that periodontal bone remodeling plays a major role in OR. Studies have shown that promoting periodontal bone remodeling by inhibiting osteoclastogenesis and enhancing osteogenesis is effective in preventing OR, suggesting a strong link between local bone metabolism and OR.

Exosomes, as natural carriers of biochemical signaling molecules, are secreted by almost all cell types. Their constituents can vary depending on the disease state, making exosomes possible for disease diagnosis and treatment. MSC-Exo, with or without biomaterials, has shown promising application prospects in preventing OR. Oral stem cells-derived exosomes are particularly advantageous due to their easy availability, excellent immune regulation and regeneration abilities.

This review summarizes novel strategies using MSC-Exo in orthodontic tooth stability management and discusses the possible mechanisms, outlining new directions for developing advanced therapeutic materials aimed at reducing the retention period and enhancing long-term post-orthodontic stability. While MSC-Exo-based therapies hold significant potential as a novel approach for managing orthodontic tooth stability, several challenges remain that must be addressed before clinical application. Variability in exosome content, based on cell sources, cell types, and culture conditions, may result in differences in biological functions. This highlights the need for standardized exosome isolation, purification, and characterization methods, as well as determining optimal dosing and treatment protocols for sustained efficacy. Furthermore, the long-term safety and potential immunogenicity of repeated exosome treatments require careful investigation. Future research should focus on elucidating the specific mechanisms underlying their efficacy in managing orthodontic tooth stability and conducting comprehensive clinical trials to establish their safety and effectiveness in managing OR.

Data availability

Not applicable.

Abbreviations

ADSC-Exo:

Adipose stem cell-derived exosomes

ALP:

Alkaline phosphatase

BMMSC-Exo:

Bone marrow mesenchymal stem cell-derived exosomes

BMP-2:

Bone morphogenetic protein 2

CTSK:

Cathepsin K

CXCL12:

C-X-C motif chemokine ligand 12

DPSC-Exo:

Dental pulp stem cell-derived exosomes

ECM:

Extracellular matrix

FGF-2:

Fibroblast growth factor-2

GMSC-Exo:

Gingival mesenchymal stem cell-derived exosomes (GMSC-Exo)

ICAM1:

Intercellular adhesion molecule 1

M-CSF:

Macrophage colony-stimulating factor

MAPKs:

Mitogen-activated protein kinases

MCP-1:

Monocyte chemotactic protein 1

MSCs:

Mesenchymal stem cells

MSC-Exo:

Mesenchymal stem cell-derived exosomes

MMPs:

Matrix metalloproteinases

NF-κB:

Nuclear factor-κB

NFATc1/2:

Nuclear factor of activated T-cells 1/2

OCSTAMP:

Osteoclast stimulatory transmembrane protein

OPG:

Osteoprotegerin

OR:

Orthodontic relapse

Osx:

Osterix

OTM:

Orthodontic tooth movement

PDL:

Periodontal ligament

PDLC:

Periodontal ligament cells

PDLSC:

Periodontal ligament stem cells

PDLSC-Exo:

PDLSC-derived exosomes

RANK:

Receptor activator of nuclear factor κB

RANKL:

Receptor activator of nuclear factor κB ligand

Runx2:

Runt-related transcription factor 2

SHED-Exo:

Human exfoliated deciduous teeth-derived exosomes

TNF-α:

Tumor necrosis factor-α

TRAF6:

TNF receptor-associated factor 6

TRAP:

Tartrate-resistant acid phosphatase

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2

References

  1. Little RM, Riedel RA, Artun J. An evaluation of changes in mandibular anterior alignment from 10 to 20 years postretention. Am J Orthod Dentofac Orthop. 1988;93(5):423–8.

    Article  CAS  Google Scholar 

  2. Lang G, et al. Retention and stability–taking various treatment parameters into account. J Orofac Orthop. 2002;63(1):26–41.

    Article  PubMed  Google Scholar 

  3. Littlewood SJ, et al. Retention procedures for stabilising tooth position after treatment with orthodontic braces. Cochrane Database Syst Rev. 2016;20161:pCd002283.

    Google Scholar 

  4. King GJ, Keeling SD, Wronski TJ. Histomorphometric study of alveolar bone turnover in orthodontic tooth movement. Bone. 1991;12(6):401–9.

    Article  CAS  PubMed  Google Scholar 

  5. Vieira GM, et al. A novel analysis via Micro-CT imaging indicates that chemically modified Tetracycline-3 (CMT-3) inhibits tooth relapse after Orthodontic Movement: a pilot experimental study. Int J Dent. 2019;2019:p3524207.

    Article  Google Scholar 

  6. Dolci GS, et al. Atorvastatin-induced osteoclast inhibition reduces orthodontic relapse. Am J Orthod Dentofac Orthop. 2017;151(3):528–38.

    Article  Google Scholar 

  7. Han G, et al. Effects of simvastatin on relapse and remodeling of periodontal tissues after tooth movement in rats. Am J Orthod Dentofac Orthop. 2010;138(5):550.e1-7; discussion 550-1.

    Article  Google Scholar 

  8. Azami N, et al. Raloxifene administration enhances retention in an orthodontic relapse model. Eur J Orthod. 2020;42(4):371–7.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hudson JB, et al. Local delivery of recombinant osteoprotegerin enhances postorthodontic tooth stability. Calcif Tissue Int. 2012;90(4):330–42.

    Article  CAS  PubMed  Google Scholar 

  10. Franzen TJ, Brudvik P, Vandevska-Radunovic V. Periodontal tissue reaction during orthodontic relapse in rat molars. Eur J Orthod. 2013;35(2):152–9.

    Article  PubMed  Google Scholar 

  11. Maltha JC, et al. Relapse revisited—animal studies and its translational application to the orthodontic office. Semin Orthod. 2017;23:390–8.

    Article  Google Scholar 

  12. Aoki Y, et al. Dynamics and observations of long-term orthodontic tooth movement and subsequent relapse in C57BL/6 mice. Exp Anim. 2023;72(1):103–11.

    Article  CAS  PubMed  Google Scholar 

  13. Liu XC, et al. [Effect of psoralen on the stability after orthodontic tooth movement in rats]. Shanghai Kou Qiang Yi Xue. 2019;28(5):455–9.

    PubMed  Google Scholar 

  14. van Leeuwen EJ, et al. The effect of retention on orthodontic relapse after the use of small continuous or discontinuous forces. An experimental study in beagle dogs. Eur J Oral Sci. 2003;111(2):111–6.

    Article  PubMed  Google Scholar 

  15. Qi J, et al. Establishment of an orthodontic retention mouse model and the effect of anti-c-Fms antibody on orthodontic relapse. PLoS ONE. 2019;14(6):e0214260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim KN, et al. Antifibrotic effects of sulforaphane treatment on gingival elasticity reduces orthodontic relapse after rotational tooth movement in beagle dogs. Korean J Orthod. 2020;50(6):391–400.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zinger A, et al. Proteolytic nanoparticles replace a Surgical Blade by Controllably Remodeling the oral connective tissue. ACS Nano. 2018;12(2):1482–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Feng L, et al. PDL progenitor-mediated PDL recovery contributes to Orthodontic Relapse. J Dent Res. 2016;95(9):1049–56.

    Article  CAS  PubMed  Google Scholar 

  19. Henneman S, et al. Local variations in turnover of periodontal collagen fibers in rats. J Periodontal Res. 2012;47(3):383–8.

    Article  CAS  PubMed  Google Scholar 

  20. Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res. 2013;92(10):860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yoshida Y, et al. Cellular roles in relapse processes of experimentally-moved rat molars. J Electron Microsc (Tokyo). 1999;48(2):147–57.

    Article  CAS  PubMed  Google Scholar 

  22. Kanzaki H, et al. Nrf2 activation attenuates both orthodontic tooth movement and relapse. J Dent Res. 2015;94(6):787–94.

    Article  CAS  PubMed  Google Scholar 

  23. Kaipatur NR, et al. Impact of bisphosphonate drug burden in alveolar bone during orthodontic tooth movement in a rat model: a pilot study. Am J Orthod Dentofac Orthop. 2013;144(4):557–67.

    Article  Google Scholar 

  24. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478).

  25. Konala VB, et al. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy. 2016;18(1):13–24.

    Article  CAS  PubMed  Google Scholar 

  26. Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther. 2018;9(1):63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Crapnell K, et al. Growth, differentiation capacity, and function of mesenchymal stem cells expanded in serum-free medium developed via combinatorial screening. Exp Cell Res. 2013;319(10):1409–18.

    Article  CAS  PubMed  Google Scholar 

  28. Gronthos S, et al. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97(25):13625–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yeo RW, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336–41.

    Article  CAS  PubMed  Google Scholar 

  30. Peng H, et al. Exosome: a significant nano-scale drug delivery carrier. J Mater Chem B. 2020;8(34):7591–608.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang L, et al. Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion. Stem Cell Res Ther. 2020;11(1):38.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Huang Y, et al. Bone marrow mesenchymal stem cell-derived exosomal miR-206 promotes osteoblast proliferation and differentiation in osteoarthritis by reducing Elf3. J Cell Mol Med. 2021;25(16):7734–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu W, et al. Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 2020;103:196–212.

    Article  CAS  PubMed  Google Scholar 

  34. Holliday LS, et al. Exosomes: novel regulators of bone remodelling and potential therapeutic agents for orthodontics. Orthod Craniofac Res. 2017;20(Suppl 1):95–9.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Li Z, et al. Stress Distribution and Collagen Remodeling of Periodontal Ligament during Orthodontic Tooth Movement. Front Pharmacol. 2019;10:1263.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Rizk M, et al. Periodontal ligament and alveolar bone remodeling during long orthodontic tooth movement analyzed by a novel user-independent 3D-methodology. Sci Rep. 2023;13(1):19919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Seo BM, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004;364(9429):149–55.

    Article  CAS  PubMed  Google Scholar 

  38. Jin SS, et al. Mechanical force modulates periodontal ligament stem cell characteristics during bone remodelling via TRPV4. Cell Prolif. 2020;53(10):e12912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal Res. 2005;40(4):287–93.

    Article  CAS  PubMed  Google Scholar 

  40. Sokos D, Everts V, de Vries TJ. Role of periodontal ligament fibroblasts in osteoclastogenesis: a review. J Periodontal Res. 2015;50(2):152–9.

    Article  CAS  PubMed  Google Scholar 

  41. Li S, et al. Connexin 43 and ERK regulate tension-induced signal transduction in human periodontal ligament fibroblasts. J Orthop Res. 2015;33(7):1008–14.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang C, et al. Influence of different intensities of vibration on proliferation and differentiation of human periodontal ligament stem cells. Arch Med Sci. 2015;11(3):638–46.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Men Y, et al. Gli1 + periodontium stem cells are regulated by osteocytes and Occlusal Force. Dev Cell. 2020;54(5):639–e6546.

    Article  CAS  PubMed  Google Scholar 

  44. Chukkapalli SS, Lele TP. Periodontal cell Mechanotransduction. Open Biol. 2018;8(9):180135.

  45. Chen L, et al. Force-induced caspase-1-dependent pyroptosis regulates orthodontic tooth movement. Int J Oral Sci. 2024;16(1):3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen L, Mo S, Hua Y. Compressive force-induced autophagy in periodontal ligament cells downregulates osteoclastogenesis during tooth movement. J Periodontol. 2019;90(10):1170–81.

    Article  CAS  PubMed  Google Scholar 

  47. Xu Q, et al. Mechanoadaptive responses in the Periodontium are coordinated by wnt. J Dent Res. 2019;98(6):689–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hu Y, et al. Human gingival mesenchymal stem cell-derived exosomes cross-regulate the Wnt/β-catenin and NF-κB signalling pathways in the periodontal inflammation microenvironment. J Clin Periodontol. 2023;50(6):796–806.

    Article  CAS  PubMed  Google Scholar 

  49. Qiao X, et al. Dental Pulp Stem Cell-Derived exosomes regulate anti-inflammatory and Osteogenesis in Periodontal Ligament Stem cells and promote the repair of experimental periodontitis in rats. Int J Nanomed. 2023;18:4683–703.

    Article  CAS  Google Scholar 

  50. Wang M, et al. SHED-derived exosomes improve the repair capacity and osteogenesis potential of hPDLCs. Oral Dis. 2023;29(4):1692–705.

    Article  PubMed  Google Scholar 

  51. Sun J, et al. Exosomes Derived from Human Gingival mesenchymal stem cells attenuate the inflammatory response in Periodontal Ligament Stem cells. Front Chem. 2022;10:863364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Boyle WJ, Simonet WS, Lacey DL. Osteoclast Differ Activation Nat. 2003;423(6937):337–42.

    CAS  Google Scholar 

  53. Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol. 2002;20:795–823.

    Article  CAS  PubMed  Google Scholar 

  54. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7(4):292–304.

    Article  CAS  PubMed  Google Scholar 

  55. Yang D, Wan Y. Molecular determinants for the polarization of macrophage and osteoclast. Semin Immunopathol. 2019;41(5):551–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Feng W, et al. MiR-6924-5p-rich exosomes derived from genetically modified Scleraxis-overexpressing PDGFRα(+) BMMSCs as novel nanotherapeutics for treating osteolysis during tendon-bone healing and improving healing strength. Biomaterials. 2021;279:121242.

    Article  CAS  PubMed  Google Scholar 

  57. Nakao Y, et al. Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss. Acta Biomater. 2021;122:306–24.

    Article  CAS  PubMed  Google Scholar 

  58. Guo S, et al. GATA4-driven mir-206-3p signatures control orofacial bone development by regulating osteogenic and osteoclastic activity. Theranostics. 2021;11(17):8379–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Capulli M, Paone R, Rucci N. Osteoblast and osteocyte: games without frontiers. Arch Biochem Biophys. 2014;561:3–12.

    Article  CAS  PubMed  Google Scholar 

  60. Liu X, Muhammed FK, Liu Y. Simvastatin encapsulated in exosomes can enhance its inhibition of relapse after orthodontic tooth movement. Am J Orthod Dentofac Orthop. 2022;162(6):881–9.

    Article  Google Scholar 

  61. Yogui FC, et al. A SERM increasing the expression of the osteoblastogenesis and mineralization-related proteins and improving quality of bone tissue in an experimental model of osteoporosis. J Appl Oral Sci. 2018;26:e20170329.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Yang X, et al. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis. Aging. 2019;11(20):8777–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hu H, et al. Role of microRNA-335 carried by bone marrow mesenchymal stem cells-derived extracellular vesicles in bone fracture recovery. Cell Death Dis. 2021;12(2):156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Qin Y, et al. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci Rep. 2016;6:21961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Qi X, et al. Exosomes secreted by Human-Induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and Osteogenesis in osteoporotic rats. Int J Biol Sci. 2016;12(7):836–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pajarinen J, et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials. 2019;196:80–9.

    Article  CAS  PubMed  Google Scholar 

  67. Sima C, Viniegra A, Glogauer M. Macrophage immunomodulation in chronic osteolytic diseases-the case of periodontitis. J Leukoc Biol. 2019;105(3):473–87.

    Article  CAS  PubMed  Google Scholar 

  68. He D, et al. M1-like macrophage polarization promotes orthodontic tooth Movement. J Dent Res. 2015;94(9):1286–94.

    Article  CAS  PubMed  Google Scholar 

  69. Zeng M, et al. Orthodontic Force induces systemic inflammatory monocyte responses. J Dent Res. 2015;94(9):1295–302.

    Article  CAS  PubMed  Google Scholar 

  70. Schröder A, et al. Effects of Compressive and Tensile strain on macrophages during simulated orthodontic tooth Movement. Mediators Inflamm. 2020;2020:p2814015.

    Google Scholar 

  71. Hienz SA, Paliwal S, Ivanovski S. Mechanisms of bone resorption in Periodontitis. J Immunol Res. 2015;2015:p615486.

    Article  Google Scholar 

  72. Li Y, et al. Orthodontic tooth movement: the biology and clinical implications. Kaohsiung J Med Sci. 2018;34(4):207–14.

    Article  PubMed  Google Scholar 

  73. Cai G, et al. Piezo1-mediated M2 macrophage mechanotransduction enhances bone formation through secretion and activation of transforming growth factor-β1. Cell Prolif. 2023;56(9):e13440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang D et al. PCLLA-nanoHA bone substitute promotes M2 macrophage polarization and improves alveolar bone repair in diabetic environments. J Funct Biomater. 2023;14(11):56.

  75. He D, et al. Enhanced M1/M2 macrophage ratio promotes orthodontic root resorption. J Dent Res. 2015;94(1):129–39.

    Article  CAS  PubMed  Google Scholar 

  76. Liu C, et al. Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury. J Nanobiotechnol. 2022;20(1):65.

    Article  CAS  Google Scholar 

  77. Li R, et al. Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF. Stem Cell Res Ther. 2022;13(1):149.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Liu W, et al. Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Res Ther. 2020;11(1):259.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Chim SM, et al. Angiogenic factors in bone local environment. Cytokine Growth Factor Rev. 2013;24(3):297–310.

    Article  CAS  PubMed  Google Scholar 

  80. Peng Y, et al. Type H blood vessels in bone modeling and remodeling. Theranostics. 2020;10(1):426–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hu Y, Li H. DLL4/Notch blockade disrupts mandibular advancement-induced condylar osteogenesis by inhibiting H-type angiogenesis. J Oral Rehabil. 2024;51(4):754–61.

    Article  CAS  PubMed  Google Scholar 

  82. Zhong J, et al. Photobiomodulation therapy’s impact on angiogenesis and osteogenesis in orthodontic tooth movement: in vitro and in vivo study. BMC Oral Health. 2024;24(1):147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Murrell EF, Yen EH, Johnson RB. Vascular changes in the periodontal ligament after removal of orthodontic forces. Am J Orthod Dentofac Orthop. 1996;110(3):280–6.

    Article  CAS  Google Scholar 

  84. Wu J, et al. Exosomes secreted by stem cells from human exfoliated deciduous Teeth promote alveolar bone defect repair through the regulation of Angiogenesis and Osteogenesis. ACS Biomater Sci Eng. 2019;5(7):3561–71.

    Article  CAS  PubMed  Google Scholar 

  85. Zhang Y, et al. Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell Prolif. 2019;52(2):e12570.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Pizzicannella J, et al. Engineered Extracellular vesicles from Human Periodontal-Ligament stem cells increase VEGF/VEGFR2 expression during bone regeneration. Front Physiol. 2019;10:512.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Wang KY, et al. Injectable stress relaxation gelatin-based hydrogels with positive surface charge for adsorption of aggrecan and facile cartilage tissue regeneration. J Nanobiotechnol. 2021;19(1):214.

    Article  CAS  Google Scholar 

  88. Zhao Z, et al. Capturing Magnesium ions via Microfluidic Hydrogel Microspheres for promoting Cancellous Bone Regeneration. ACS Nano. 2021;15(8):13041–54.

    Article  CAS  PubMed  Google Scholar 

  89. Shafei S, et al. Exosome loaded alginate hydrogel promotes tissue regeneration in full-thickness skin wounds: an in vivo study. J Biomed Mater Res A. 2020;108(3):545–56.

    Article  CAS  PubMed  Google Scholar 

  90. Chen P, et al. Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration. Theranostics. 2019;9(9):2439–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang FX, et al. Injectable Mussel-inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration. Biomaterials. 2021;278:121169.

    Article  CAS  PubMed  Google Scholar 

  92. Chen S, et al. Exosomes derived from mir-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration. Cell Prolif. 2019;52(5):e12669.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Zhang Y, et al. Umbilical mesenchymal stem cell-derived exosome-encapsulated hydrogels accelerate bone repair by enhancing angiogenesis. ACS Appl Mater Interfaces. 2021;13(16):18472–87.

    Article  CAS  PubMed  Google Scholar 

  94. Liu A, et al. Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated smad pathway. Biomaterials. 2021;272:120718.

    Article  CAS  PubMed  Google Scholar 

  95. Thomas V, et al. Breathing-in/breathing‐out approach to preparing nanosilver‐loaded hydrogels: highly efficient antibacterial nanocomposites. J Appl Polym Sci. 2009;111(2):934–44.

    Article  CAS  Google Scholar 

  96. Yang S, et al. MSC-derived sEV-loaded hyaluronan hydrogel promotes scarless skin healing by immunomodulation in a large skin wound model. Biomed Mater. 2022;17(3):034104.

    Article  CAS  Google Scholar 

  97. Wang C, et al. Engineering bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration. Theranostics. 2019;9(1):65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tamura T, et al. Periodontal regeneration using gelatin hydrogels incorporating basic fibroblast growth factor. Biomedical J Sci Tech Res. 2018;4(2):3820–4.

    Google Scholar 

  99. Utari TR, et al. The intrasulcular application effect of bisphosphonate hydrogel toward osteoclast activity and relapse movement. Saudi Dent J. 2021;33(5):292–8.

    Article  PubMed  Google Scholar 

  100. Lu X, et al. Exosomes loaded a smart bilayer-hydrogel scaffold with ROS-scavenging and macrophage-reprogramming properties for repairing cartilage defect. Bioact Mater. 2024;38:137–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhao Y et al. The experimental study of Periodontal ligament stem cells derived exosomes with Hydrogel accelerating bone regeneration on alveolar bone defect. Pharmaceutics. 2022;14(10):2186.

Download references

Acknowledgements

The authors declare that they have not use AI-generated work in this manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81570995) to Yong Cheng.

Author information

Authors and Affiliations

Authors

Contributions

BP conceived the study, made the figures and drafted the manuscript. LW, searched for relevant literatures and provided the comments. BP, GH and YC critically revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guangli Han or Yong Cheng.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peng, B., Wang, L., Han, G. et al. Mesenchymal stem cell-derived exosomes: a potential cell-free therapy for orthodontic tooth stability management. Stem Cell Res Ther 15, 342 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13287-024-03962-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13287-024-03962-3

Keywords