Phototherapy techniques for the management of musculoskeletal disorders: strategies and recent advances

Zhang, Zhenhe; Wang, Rong; Xue, Hang; Knoedler, Samuel; Geng, Yongtao; Liao, Yuheng; Alfertshofer, Michael; Panayi, Adriana C.; Ming, Jie; Mi, Bobin; Liu, Guohui

doi:10.1186/s40824-023-00458-8

Phototherapy techniques for the management of musculoskeletal disorders: strategies and recent advances

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Published: 28 November 2023

Volume 27, article number 123, (2023)
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Biomaterials Research Aims and scope

Phototherapy techniques for the management of musculoskeletal disorders: strategies and recent advances

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Zhenhe Zhang^1,2^na1,
Rong Wang³^na1,
Hang Xue^1,2^na1,
Samuel Knoedler^4,5^na1,
Yongtao Geng^1,2,
Yuheng Liao^1,2,
Michael Alfertshofer⁶,
Adriana C. Panayi^4,7,
Jie Ming³,
Bobin Mi^1,2 &
…
Guohui Liu^1,2

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Abstract

Musculoskeletal disorders (MSDs), which include a range of pathologies affecting bones, cartilage, muscles, tendons, and ligaments, account for a significant portion of the global burden of disease. While pharmaceutical and surgical interventions represent conventional approaches for treating MSDs, their efficacy is constrained and frequently accompanied by adverse reactions. Considering the rising incidence of MSDs, there is an urgent demand for effective treatment modalities to alter the current landscape. Phototherapy, as a controllable and non-invasive technique, has been shown to directly regulate bone, cartilage, and muscle regeneration by modulating cellular behavior. Moreover, phototherapy presents controlled ablation of tumor cells, bacteria, and aberrantly activated inflammatory cells, demonstrating therapeutic potential in conditions such as bone tumors, bone infection, and arthritis. By constructing light-responsive nanosystems, controlled drug delivery can be achieved to enable precise treatment of MSDs. Notably, various phototherapy nanoplatforms with integrated imaging capabilities have been utilized for early diagnosis, guided therapy, and prognostic assessment of MSDs, further improving the management of these disorders. This review provides a comprehensive overview of the strategies and recent advances in the application of phototherapy for the treatment of MSDs, discusses the challenges and prospects of phototherapy, and aims to promote further research and application of phototherapy techniques.

Graphical Abstract

Nanomedicine for the Treatment of Musculoskeletal Diseases

Conclusions and Perspectives

Application of advanced biomaterials in photothermal therapy for malignant bone tumors

Article Open access 15 November 2023

Introduction

The musculoskeletal system comprises the bones, cartilage, muscles, tendons, and ligaments, playing a critical role in providing structural support and coordinating movements within the human body. This complex system possesses intrinsic regenerative capabilities, however, its reparative capacity is subject to inherent limitations, especially concerning the regeneration of cartilage, tendons, and ligaments [1]. Pathological conditions, including trauma, infections, autoimmune diseases, and the physiological aging process, can induce irreversible damage to the musculoskeletal system, thus culminating in musculoskeletal disorders (MSDs) [54]. By applying external force to compress the SMPU/Mg scaffold above the transition temperature and temporarily fixing the shape below the transition temperature, they obtained small volumes of SMPU/Mg scaffold, which allowed the scaffold to be implanted into cranial defects with minimal wounds (Fig. 4A). Under NIR irradiation, the scaffolds gradually warmed up due to the photothermal effect, recovering their original shape to match the shape of the bone defect when the temperature exceeded the transition temperature (Fig. 4B-E). This process accelerated cranial defect repair through the release of Mg²⁺ (Fig. 4F). In another study, Wang et al. employed cryogenic four-dimensional (4D) printing to create a hierarchical porous nanocomposite scaffold comprising BP nanosheets, osteogenic peptides, and β-tricalcium phosphate/poly (lactic acid-co-trimethylene carbonate) for irregular bone defects based on computed tomography (CT) scan data [58]. Under photothermal conditions at 45°C, the scaffold’s shape was restored to match the irregular bone defects, facilitating bone repair through the release of osteogenic peptides.

Despite the promising potential of photothermal-responsive shape memory polymer scaffolds for bone repair applications, several considerations must be addressed in future studies. First, selecting an appropriate transformation temperature is pivotal. Transition temperatures below body temperature may cause the materials to recover their shape prematurely during implantation, whereas excessively high transition temperatures could lead to tissue damage around the scaffolds or inactivation of growth factors loaded within the materials. In addition, many shape memory polymers exhibit limited degradation ability, necessitating research efforts to adapt material degradation to the physiological process of bone repair. This can be achieved by carefully choosing suitable SMP materials or modifying existing SMP materials to enhance their degradation properties.

Bone Infection

Open bone injuries and the application of orthopedic implants pose an increased risk of bacterial invasion and colonization [65]. Upon infection of the bone, bacteria stimulate inflammatory cells to secrete various inflammatory factors, upregulate osteoblast RANKL/OPG ratios, promote osteoclast formation, and induce osteoclast apoptosis, resulting in an imbalance between bone resorption and bone formation and impaired bone repair [66]. Globally, the reported annual incidence of osteomyelitis is 21.8 out of hundred thousand people, and this figure continues to rise each year [67]. Unfortunately, due to specific pathogenic factors such as intracellular infection, osteocyte lacuno-canalicular network (OLCN) invasion, biofilm formation, and abscess formation, eradicating bacteria often proves challenging, leading to recurrence of bone infection in approximately 17% of patients [68, 69]. PDT and PTT, as non-contact, broad-spectrum and highly effective anti-infection techniques, have shown great potential in the treatment of bone infections. Here, we summarize the mechanisms associated with PDT- and PTT-based phototherapy techniques in the treatment of infected bone defects (Fig. 5).

Antibacterial PDT and PTT

Antibacterial PDT is mainly mediated by the generation of hydroxyl radicals (•OH), singlet oxygen (¹O₂) and superoxide anions (O₂^•−) catalyzed by photosensitizers upon light excitation. These ROS induce oxidative damage to polysaccharides, lipids, proteins, and nucleic acids, leading to cell membrane disruption, DNA damage, and enzyme inactivation, ultimately causing bacterial death [9]. The multifaceted antibacterial mechanisms of ROS confer PDT with a broader antibacterial spectrum and reduced susceptibility to resistance compared to antibiotics, making it highly effective in the treatment of bone infections. In one study, the photosensitizer toluidine blue was used in PDT for osteomyelitis in rats, resulting in more than 99% reduction in bacterial load after 30 days of treatment, without bone resorption or microabscesses observed [70].

In addition to provide a favorable anti-infection microenvironment, bone repair can also be actively promoted by incorporating osteogenic drugs [71]. Yuan et al. introduced carbon-ZnO into PLLA, imparting the scaffold not only with excellent antibacterial properties via PDT but also promoting the formation of mineralized nodules in human osteoblast-like MG-63 cells through the release of Zn²⁺ [72]. Recently, **e et al. designed a self-assembled bilayer hydrogel with spatiotemporal modulation of the immune microenvironment for osteomyelitis treatment [48]. The upper layer of this hydrogel was an AC₁₀A hydrogel loaded with Ag₂S QDs@DSPE-mPEG₂₀₀₀-Ce6/Aptamer (AD-Ce6/Apt), while the lower layer was an AC₁₀ARGD hydrogel loaded with MSCs. After implantation, the upper hydrogel first released AD-Ce6/Apt, which exhibited direct antibacterial effects via ROS generated by PDT and enhanced the antibacterial effect by recruiting and inducing macrophage M1 polarization via the generated ROS in the first 3-4 days. After this, the lower hydrogel released MSCs to promote macrophage M2 polarization for anti-inflammation and induced MSCs osteogenic differentiation for fracture healing.

Photothermal materials exert broad-spectrum antibacterial effects through photothermal conversion under laser irradiation, raising the local temperature to induce bacterial membrane rupture, protein denaturation, and DNA damage [9]. While bacteria can develop mechanisms such as reducing uptake, inactivating, and promoting efflux of anti-microbial substances, they are unable to develop resistance to heat generated by PTT. Combining antibacterial PTT with pro-bone repair drugs represents an effective strategy for treating infected bone defects. For instance, Yuan et al. constructed a composite coating of BP and hydroxyapatite (BPs@HA) on the implant surface, which employed PTT at 50°C to eliminate bacteria, alleviate inflammation, and promote fracture healing through the bioactive coating (Fig. 6A-C) [73]. To prevent tissue damage from high temperature, Wu et al. proposed a "Sequential Photothermal Mediation" strategy for treating infected bone defects [74]. In this study, BP nanosheets with zinc sulfonate ligand (ZnL₂) were integrated onto hydroxyapatite scaffolds (ZnL₂-BPs@HAP). The PTT temperature was controlled at 47-50°C for the initial three days to eliminate bacteria and reduce inflammatory cell infiltration. Subsequently, the PTT temperature was lowered to 40-42°C to minimize tissue damage while accelerating bone regeneration through mild PTT and the release of Zn²⁺ and PO₄^3-.

Combined therapy

Heat generated by PTT and ROS generated by PDT are the primary antibacterial pathways in phototherapy. However, it is essential to acknowledge that these therapeutic modalities can potentially be harmful to healthy tissues [13]. To mitigate these concerns and optimize treatment outcomes, researchers are exploring the development of multifunctional antibacterial bone implants that reduce reliance on monotherapy and minimize associated tissue damage. Currently, a range of studies is investigating the combination of PTT or PDT with chemotherapy and CDT, as well as incorporating physical structures to achieve synergistic antibacterial effects in the treatment of bone infections (Table 1).

Table 1 Phototherapy-based antibacterial bone scaffolds

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Combining PDT and PTT has emerged as a highly effective strategy for treating bone infections. In this approach, bone implants generate heat through photothermal conversion under laser irradiation, which inhibits bacterial viability and increases bacterial cell membrane permeability, enhancing their susceptibility to ROS [9]. This enables fewer ROS and lower temperatures to eliminate infections, resulting in powerful antibacterial effects and less tissue damage. Recently, Li et al. prepared BMP-2 microsphere-coated BPs@PLGA scaffolds (BMP-2@BPs) for PTT and PDT of infected bone defects [44]. In vivo, mild PTT at 41°C, in synergy with PDT, killed over 99% of methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, the combination of mild PTT and BMP-2 effectively promoted the proliferation and osteogenic differentiation of periosteal-derived stem cells, accelerating the formation of new bone in infected cranial defects. Notably, infections often lead to localized nerve fiber necrosis, hindering the repair of infected bone defects [69, 75]. To address this, **g et al. developed a photosensitive conductive GBM hydrogel, gelatin methacrylate (GelMA) hydrogel loaded with magnesium-modified black phosphorus [75]. GBM hydrogel promoted Schwann cell migration and neurite outgrowth of PC12 cells via NGF secreted by Schwann cells and the released Mg²⁺ from hydrogel (Fig. 6D, E). In addition, GBM hydrogel showed potent bactericidal effects against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) via PTT and PDT (Fig. 6F). In vivo, GBM hydrogel effectively killed bacteria localized in infected skull defects under NIR irradiation, promoted NGF expression and the number of CGRP-positive nerve fibers (CGRP is a key mediator connecting nerve and bone regeneration), and accelerated the repair of S. aureus-infected skull defects (Fig. 6G-J).

Bacteria can exist in two forms: floating cells and microbial aggregates, with the latter known as biofilms, characterized by microbial aggregates embedded in extracellular polymeric substances composed of polysaccharides, proteins, extracellular DNA, and lipids [84]. Due to the physical barrier effect, biofilms exhibit enhanced resistance, up to 1000 times greater than planktonic bacteria, owing to biofilm heterogeneity, adaptive stress response, and the formation of persistent cells [85]. To disrupt biofilms, increasing the local temperature through PTT is a primary approach to increase penetration of antibacterial drugs. Yang et al. developed PLLA/ZIF-8@GO scaffolds that increased the local temperature to approximately 50°C through photothermal conversion, enhancing the penetration of the antibacterial agent Zn²⁺ and achieving highly efficient antibacterial properties [79]. Similarly, Yuan et al. constructed a composite coating containing mesoporous polydopamine (MPDA), indocyanine green (ICG), and arginylglycylaspartic acid (RGD) peptides on Ti surface to obtain Ti-M/I/RGD implant [86]. This innovative design facilitated the penetration of ICG into the biofilm and increased the permeability of bacterial cell membranes via PTT. Subsequently, ROS were generated via PDT, effectively disrupting biofilm integrity and eradicating bacteria.

Bone tumors

Bone tumors encompass primary tumors and metastatic bone tumors [7]. Among them, osteosarcoma is the most common primary solid malignant bone tumor, traditionally treated with complete surgical resection of the tumor and chemotherapy. However, despite the introduction of chemotherapy, the long-term survival rates of 65%-70% remain unsatisfactory, and chemotherapy inevitably causes serious side effects such as nausea, hair loss, and bone marrow suppression [87]. Bone metastasis, a common complication of various cancers, is typically incurable and leads to pain and pathological fractures, significantly impacting patients' quality of life and survival [88]. Given the limitations of traditional treatment modalities, phototherapy has garnered increasing attention in the treatment of osteosarcoma and bone metastases due to its remote controllability, high spatial and temporal resolution, and minimally invasive nature [111]. Copyright 2018, Wiley-VCH. F Schematic diagram of the anti-tumor mechanism of CuP@PPy-ZOL NPs via synergistic PDT/PTT/CDT. G 3D micro-CT reconstruction images of metastatic tumor tibia at different angles in a mouse model of breast cancer bone metastasis after different treatments. H Schematic diagram of the interaction mechanism of MDA-MB-231 cells with RAW264.7 cells and MC3T3-E1 cells before and after treatment. I Scanning electron microscope images and energy dispersive X-ray elemental map** of calcium on the cranial surface of RAW264.7 cells cultured with skull bone for 7 days after different treatments. Reproduced with permission [116]. Copyright 2023, Wiley-VCH

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Tumor metastasis to bone disrupts the tightly regulated balance between osteoclasts and osteoblasts, leading to osteoclast activation and inhibition of bone matrix production by osteoblasts, causing bone erosion and bone defects [117]. Restoring the balance between bone resorption and bone regeneration can be achieved by inhibiting osteoclast activity, thereby inhibiting bone metastasis and osteolysis [118]. Zeng et al. developed NIR-II responsive nanoplatforms (CuP@PPy-ZOL NPs) to synergize with PTT/PDT/CDT to kill tumors, inhibit osteoclast activity, and disrupt the "vicious cycle" of osteolytic bone destruction, remodeling the bone microenvironment [116]. Under 1064 nm laser irradiation, mild PTT of CuP@PPy-ZOL NPs, together with released Cu²⁺, PO4^3- and zoledronic acid (ZOL), promoted osteogenic differentiation and bone repair, thus inhibiting osteolytic breast cancer bone metastasis (Fig. 9F-I). ZOL, known to preferentially enrich in sites with high osteoclast activity, inhibits osteoclast-mediated bone resorption and is the standard treatment for patients with bone metastasis to reduce the risk of skeletal-related events. Sun et al. developed bone-targeting nanoparticles (Au@MSNs-ZOL) by coupling gold nanorods encapsulated in mesoporous silica nanoparticles with ZOL, effectively treating breast cancer bone metastasis [119]. Au@MSNs-ZOL induced tumor cell apoptosis via PTT under NIR irradiation, inhibited osteoclast differentiation, promoted osteoblast differentiation, and alleviated bone resorption and bone pain.

Osteoarthritis

Osteoarthritis is a degenerative joint disease characterized by the destruction and loss of cartilage in the joints, leading to joint pain, swelling, stiffness, and impaired mobility [120]. Approximately 300 million people worldwide are affected by OA, and this number is expected to rise as the population ages and the prevalence of obesity increases [120, 121]. Currently, common medications used for OA treatment, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticosteroids, primarily aim to alleviate symptoms rather than cure OA and may lead to gastrointestinal and renal adverse effects with prolonged use [122]. Therefore, the search for novel, effective, and highly targeted therapies with minimal side effects to prevent OA progression is crucial. Recently, NIR-responsive drug delivery systems have emerged as promising solutions with advantages such as precise and controllable drug delivery, improved drug stability, prolonged drug residence time, and reduced need for repeated intra-articular drug injections, making them highly promising for OA treatment [123].

Phototherapy strategies for cartilage protection and cartilage regeneration

In progressive OA, cartilage undergoes aberrant metabolic changes characterized by increased chondrocyte apoptosis, reduced synthesis of collagen II and proteoglycans, and enhanced breakdown of cartilage matrix driven by matrix metalloproteinase (MMP). These changes are strongly associated with inflammation, oxidative stress, mitochondrial dysfunction, abnormal mechanical stimuli, and other physicochemical factors [124]. Protecting chondrocytes and restoring the balance between cartilage matrix synthesis and breakdown are essential therapeutic strategies for OA. Recently, Xu et al. constructed NIR-responsive epigallocatechin gallate (EGCG)-modified Au-Ag nanoplatforms [125]. The nanoplatforms utilized the peroxidase (POD) activity in combination with NIR-triggered release of the anti-inflammatory agent EGCG to reduce chondrocyte apoptosis induced by H₂O₂. This approach reversed the trend of decreased type II collagen expression and increased MMP expression, effectively protecting cartilage from damage in OA rats in vivo.

Cartilage defects are an important pathologic feature of OA, and articular cartilage repair is challenging due to the lack of blood vessels, nerves, and lymphatics in the cartilage tissue [126]. MSCs have shown promise for cartilage repair due to their accessibility, self-renewal, and pluripotent nature [127]. Appropriate levels of ROS have been reported to play a role in promoting stem cell growth and chondrogenic differentiation [128, 129]. Recently, Lu et al. constructed collagen-genipin-carbon dots nanocomposite hydrogels loaded with BMSCs (CGN hydrogels) [130]. Incorporating carbon dot nanoparticles (CD NPs) in the hydrogel increased its stiffness by 21-fold, activating the TGF-β/Smad2/3 signaling pathway in BMSCs. Under 808 nm laser irradiation, the CGN hydrogel generated ROS through PDT and activated the mTOR signaling pathway in BMSCs. The synergistic effects of the enhanced hydrogel stiffness and ROS generated by PDT promoted proliferation and chondrogenic differentiation of BMSCs, leading to accelerated cartilage tissue regeneration (Fig. 10A-C). And the new cartilage tissue fused well with the original cartilage, offering hope for long-lasting cartilage repair (Fig. 10D). Although ROS can regulate the proliferation and differentiation of MSCs, however, related studies have found that the viability of MSCs decreases after too high power irradiation, which may be related to excessive ROS production [130, 131]. Hence, further exploration of the optimal ROS level and mechanism for inducing BMSCs chondrogenic differentiation will be essential for future advancements in this field.

Phototherapy strategies for regulating joint inflammation

In OA, cartilage destruction and synovial inflammation create a vicious circle where cartilage degradation products activate inflammatory cells, leading to the release of inflammatory factors in large quantities. In turn, these inflammatory signals disrupt chondrocyte metabolism, inhibit cartilage synthesis, and accelerate cartilage breakdown [124]. Therefore, targeting joint inflammation is crucial for slowing the progression of OA. Zhao et al. developed a chitosan-modified molybdenum disulfide platform loaded with dexamethasone (MoS₂@CS@Dex) [134]. After injection into the joints, MoS₂@CS@Dex stayed for more than 48h and released dexamethasone (Dex) upon NIR stimulation. This inhibited the release of TNF-α and IL-1β from activated macrophages, alleviating joint inflammation and protecting cartilage tissue. Similarly, Chen et al. designed a novel nitrogen monoxide (NO) nanogenerator NO-Hb@siRNA@PLGA-PEG (NHsPP) for Notch1-siRNA delivery and promoting near-infrared photothermal conversion-promoted NO gas delivery [135]. Consequently, this activated the AMPK pathway and down-regulated the Notch pathway, inhibiting the release of pro-inflammatory factors from macrophages and mitigating inflammation-induced cartilage erosion and degeneration.

Conventional therapeutic oligonucleotides have limitations in terms of instability and cellular uptake. In a recent study, antisense DNA sequences of IL-1β mRNA were modified onto gold nanorods to create spherical nucleic acids (SNAs) [136]. By modifying hyaluronic acid (HA) with DNA complementary to the SNA sequences, DNA-grafted (^DNAHA) was obtained. HA-SNAs were then formed by base-pairing ^DNAHA with SNAs. HA-SNAs remained in mouse knee joints for more than one month after injection. Under NIR-promoted photothermal conversion, DNA hydrogen bonds in HA-SNAs were broken, releasing SNAs to interfere with IL-1β mRNA molecules, which further down-regulated MMP-1 and MMP-13 whilst up-regulating synthetic components (Col2α, aggregated glycans) in chondrocytes, thus effectively protecting cartilage tissues.

Osteoarthritis analgesia

Chronic pain has long been the predominant symptom of OA, yet the source of its pain is unknown. Joint cartilage lacks nerve innervation, so the synovium and subchondral bone are considered the primary sources of joint pain because they are densely innervated by sensory and sympathetic nerve [137]. Nociceptor nerve terminals in joints express a variety of ion channels that are activated in response to chemical (e.g. nerve growth factor, TNF-α and IL-1β), mechanical or thermal harmful stimuli, resulting in pain signaling (Fig. 10E) [132]. Subsequently, the expressions of chemokine (C-C motif) ligand 2 (CCL2), calcitonin gene-related peptide (CGRP), NLRP3 and Wnt/β-catenin in nociceptor cells bodies were up-regulated [132, 138]. Eventually, secondary neurons within the dorsal horn of the spinal cord are activated by neurotransmitters (glutamate, CGRP, and substance P) and transmit signals to the higher central nervous system to produce nociception. In addition to injurious pain mechanisms, pain in patients with OA involves peripheral and central sensitization [137]. Upon activation of nociceptors, upregulated CGRP and CCL2 are released from activated C-fiber terminals and bind to adjacent Aδ nerve fibers' calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), or chemokine (C-C motif) receptor 2 (CCR2), leading to nerve sensitization, resulting in abnormal mechanical pain and hyperalgesia in the periarticular region of OA patients [138].

Given that pain is a prominent symptom of OA, accurate assessment and effective analgesia are essential to improve the quality of life of patients with OA [139]. Clinically, often a substantial discrepancy between OA pain symptoms and imaging findings can be noted [140]. Therefore, OA pain assessment relies on subjective patient descriptions and semi-quantification of visual analog scores. Recently, Au et al. designed an anti-NGF antibody-coupled MoS₂ nanosheet-coated gold nanorod (anti-NGF-MoS₂-AuNR) for the evaluation and treatment of OA pain [133]. By targeting the OA pain-causing factor nerve growth factor (NGF), anti-NGF-MoS₂-AuNR remained in the OA knee joint after intravenous injection, allowing PAI of NGF-targeted pain for visualization and quantification of pain (Fig. 10F). Furthermore, the nanoplatform achieved joint pain relief for up to 7 days by blocking the binding of NGF to its receptor TrkA and using NIR-promoted localized thermal therapy on the OA knee, as evidenced by improved paw withdrawal threshold and motor coordination in OA mice (Fig. 10G-I). This extended duration of analgesia outperformed the 24-hour efficacy of NSAIDs. Although antagonizing NGF relieves OA pain, recent studies have suggested that this may exacerbate joint damage [141]. Therefore, in subsequent studies, attention should also be paid to whether there is consistency in analgesia and relief of OA progression.

While phototherapy has primarily been used to build NIR-responsive drug delivery platforms for modulating inflammation and protecting chondrocytes in OA, it is crucial to note that most of these platforms currently require joint injection, which may increase the risk of joint infections [125]. The lack of vascularization in the joint cavity also limits the entry of antibacterial drugs into the joint, making it challenging to address joint infections [142]. Therefore, exploring PTT and PDT that specifically target OA joints for joint antibacterial therapy and OA treatments holds great significance for enhancing patient outcomes and safety. Further research and development in this direction will pave the way for more effective and comprehensive treatments for OA.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by inflammation of the synovium, pannus formation, and progressive destruction of cartilage and bone [143]. RA affects approximately 1% of the world's population and presents with symmetrical pain and swelling in multiple joints, often affecting small joints in the hands and feet, as well as large joints like knees and shoulders [143, 144]. If left untreated, RA can cause joint deformities, leading to disability, reduced quality of life, and significant healthcare costs [145]. While disease-modifying antirheumatic drugs (DMARDs) (methotrexate, sulfonamides, TNF inhibitors, or inhibitors of Janus kinase) and glucocorticoids are commonly used to control RA progression, and NSAIDs for pain relief, more than 20% of patients experience poor treatment outcomes, in addition to adverse effects associated with the drugs used in the treatment of RA [144, 146].

The pathogenesis of RA remains to be thoroughly elucidated, but genetic and environmental factors, including microbial infections, smoking, and obesity, are thought to play important roles in its development [147]. In RA joints, aberrant autoimmunity activates macrophages, which further activate fibroblast-like synoviocytes (FLS) by releasing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Macrophages and FLS accumulate in large numbers in the synovium, triggering infiltration of mast cells, neutrophils, and lymphocytes via chemokines, exacerbating synovial inflammation and leading to pannus formation [148]. Pannus invades the periarticular bone, causing erosion of bone and cartilage through the release of MMP and induction of osteoclast formation [147, 148].

Conventional organic photosensitizers (photofrin or haematoporphyrin derivatives, benzoporphyrin derivatives) have been used since the 1990s for the destruction of pathologic synovial tissue in RA joints [149]. However, conventional organic photosensitizers have limitations such as skin phototoxicity, poor solubility, and limited tissue penetration of excitation light, which thwart their clinical translation [150]. Encapsulation or modification of photosensitizers can improve their solubility, stability, and selectivity, enhancing their effectiveness for PDT in RA treatment [151, 152]. For example, Gallardo-Villagrán liganded the photosensitizer tetrapyridylporphyrins (TPyP) to dinuclear arene ruthenium(ii) complexes to enhance TPyP solubility for PDT of RA [151]. In another study, Gabriel et al. designed a photosensitizer activated by high levels of thrombin in the RA joints by linking the photosensitizer unit through a thrombin-cleavable peptide, thereby improving its selectivity [153]. In recent years, significant progress has been made in the development of inorganic light-responsive nanomaterials for the treatment of RA. These nanomaterials, including pure metals, metal-organic frameworks, and carbon-based nanomaterials, offer several advantages, such as high ROS productivity, efficient photothermal conversion efficiency, and the ability to tailor their structures and compositions [154]. Leveraging these properties, researchers have successfully constructed light-responsive platforms for targeted and effective phototherapy in RA. Therefore, we herein summarize the advances in the therapeutic strategies and applications of phototherapy in RA.

Phototherapy for FLS and activated macrophage clearance

Currently, the most prominent phototherapy strategy for treating RA involves utilizing PTT or PDT to target and eliminate pathogenic cells in the affected joints, thereby reducing the expression of inflammatory factors and interfering with synovial hyperplasia, as well as bone and cartilage destruction [155, 156]. However, the non-specific nature of heat and ROS generated by PTT and PDT poses a challenge in achieving targeted therapy. Therefore, researchers have actively sought avenues to maximize the selectivity of phototherapy in RA joints.

One effective strategy involves the enhanced permeability and retention (EPR) effect, which utilizes nanoparticles of specific sizes to cross immature blood vessels in RA tissue and accumulate within the joint [157]. For instance, Dorst et al. constructed liposomes loaded with the photosensitizer IRDye700DX, designed to accumulate in the joints via the EPR effect and phagocytosed by macrophages, thus improving the photosensitizer’s selectivity in vivo [158]. The choice of particle size is crucial for effective targeting, as sizes exceeding endothelial cell gaps cannot penetrate blood vessels, while smaller particles may rapidly diffuse between tissues and blood vessels, leading to reduced retention time [159]. Studies have shown that particle sizes ranging from 100 nm to 220 nm offer optimal RA joint targeting [157, 159].

Another promising approach involves utilizing light-responsive nanomaterials encapsulated with cell membranes from erythrocytes, macrophages, FLS, or hybridized membranes, which can actively target RA tissues through ligand-receptor binding mechanisms. These modified nanomaterials not only enhance their stability in the bloodstream but also exhibit excellent biocompatibility and immunogenicity [152, 160]. Furthermore, recent research has revealed specific molecular expressions in key effector cells activated in RA joints, such as high CD44 expression in FLS and macrophages [160, 161]. Leveraging the antigen-antibody or ligand-receptor specific binding principles, modified photosensitizers and light-responsive nanoplatforms can actively target and eliminate RA key effector cells, thus improving the selectivity of PTT and PDT in RA treatment at both tissue and cellular levels [162]. Herein, we summarize representative studies that have employed PTT or PDT to target RA effector cells, providing valuable insights into the advancement of targeted phototherapy for RA (Table 2).

Table 2 Targeted phototherapy based on molecular expression characterization of RA effector cells

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In healthy joints, FLS produces lubricin and hyaluronic acid to maintain synovial fluid homeostasis [168]. In contrast, in RA joints, FLS accumulates in large numbers in the vascular opacities and exhibits an aggressive phenotype with direct release of MMP mediating cartilage erosion and activation of nuclear factor kappa-β ligand (RANKL) receptor, inducing osteoclast formation and bone erosion [169].

Over the past three years, PTT and PDT-targeted killing of FLS has proven effective in interfering with RA progression in animal models, making it a highly promising therapeutic strategy for RA [170]. Ha et al. constructed MTX-loaded multifunctional nanoparticles, and under NIR irradiation, the combination of 0.13 μM MTX with PTT exhibited a stronger FLS killing compared to 30 μM MTX alone [171]. This reduction in drug dosage helps avoid potential side effects. Huang et al. developed vasoactive intestinal peptide (VIP) and hyaluronic acid-modified Au NR@CuS yolk-shell NPs (VIP-HA-Au NR@CuS NPs) for targeting FLS (Fig. 11A) [170]. The unique yolk-shell structure allowed for multiple light reflection capabilities, resulting in a photothermal conversion efficiency of up to 67% (Fig. 11B, C). The synergistic killing of FLS by PTT, PDT, chemotherapy using MTX, and Fenton-like reaction of copper synergistically inhibited RA progression (Fig. 11D-F). In addition, Yu et al. encapsulated the anti-RA drug schisandra chinensis lactone E (SE) with Prussian blue nanoparticles, further encapsulated with a biomimetic membrane and modified with HA to obtain HRPS NPs [160]. These HRPS NPs targeted FLS, killing about 70% of them through the chemotherapeutic effect of SE and PTT. They also reduced FLS-mediated inflammation by inhibiting the IL-23/IL-17 axis and the NF-κB pathway (Fig. 11G). The oxidative stress state of FLS plays a key role in the hyperinflammatory state and chondrocyte destruction in RA. Antioxidant therapy has been shown to alleviate joint inflammation and treat RA effectively [172]. The rapid proliferation of FLS has been reported to be highly dependent on glycolysis [173]. Therefore, Qiu et al. proposed a dual energy suppression strategy based on respiratory inhibition and starvation therapy to combat RA (Fig. 11H) [163]. Their constructed VIP-ATO-Gox/CuS@HA (V-HAGC) NPs targeted FLS to conserve O₂ by inhibiting the mitochondrial oxidative phosphorylation system (OXPHOS) aerobic metabolism via atovaquone (ATO). Subsequently, glucose oxidase (Gox) in the nanoparticles consumed glucose and O₂ to produce H₂O₂, providing enough substrate for the Fenton reaction to produce •OH. The synergized PTT and enhanced CDT effectively killed more than 80% of FLS and alleviated cartilage and bone destruction in RA mice (Fig. 11I-M).

In RA joints, circulating monocytes migrate to synovial membrane under the action of chemokines and transform into pro-inflammatory macrophages, exacerbating synovial inflammation. Under the stimulation of RANKL from FLS and osteoblasts, they can even differentiate into osteoclasts, directly participating in bone erosion [174]. Depletion of these macrophages is undesirable, as they are the first responders of the immune system. Instead, researchers are exploring targeted nanoplatforms based on the antigenic expression characteristics of activated macrophages to selectively eliminate them through combination therapy [164, 175]. Recently, Li et al. developed PEG-FA functionalized semiconducting polymer quantum dots (SP) hybrid mesoporous silica nanoparticles (SMPFs) targeting macrophages via folate (FA) [176]. The SMPFs depleted local oxygen via PDT and activated the hypoxia-activated prodrug tirapazamine, resulting in the synergistic elimination of macrophages and alleviation of RA progression through PTT, PDT, and chemotherapy. Additionally, ameliorating macrophage oxidative stress and reversing the pro-inflammatory phenotype of macrophages can alleviate local inflammation in RA [174]. Zheng et al. constructed Pd@Se-HA NPs that target macrophages, and through ROS scavenging and PTT, they synergistically inhibited the expression of multiple pro-inflammatory factors in macrophages, preventing joint degeneration [161]. RA joints are hypoxic due to a highly dysfunctional microvascular system and over-infiltrated heterogeneous cells [177]. Reversing the localized hypoxic microenvironment in inflammatory joints reduces ROS accumulation and alleviates joint inflammation, proving to be an effective strategy for RA treatment [178]. One study encapsulated oxygen-saturated perfluoro-n-pentane (PFP) by biodegradable poly(dl-lactide-co-glycolic acid) phase-transition nanoparticles aiming to oxygenate the joints and improve the hypoxic microenvironment using NIR-responsive mode [179]. Wang et al. constructed polyethylene glycol-modified cerium dioxide shell-coated gold nanorods (Au@CeO₂), which scavenge ROS and oxygenate by catalyzing H₂O₂ to produce oxygen. This improved the joint hypoxic microenvironment and down-regulated the expression of hypoxia-inducible factor-1 (HIF-1) in the joints. PTT, on the other hand, ablated inflammatory cells, alleviating inflammation and strengthening the catalytic oxygen-producing ability of CeO₂. In vivo, this combined PTT, ROS scavenging, and oxygen therapy effectively suppressed synovial inflammation and cartilage destruction, demonstrating excellent RA treatment outcomes [178].

Overall, direct delivery of oxygen is limited in its ability to relieve joint hypoxia. Instead, the nanozyme-based oxygen production through H₂O₂ consumption shows promise in simultaneously reversing oxidative stress and hypoxic microenvironments, as well as increase the catalytic rate under photothermal modulation, presenting a more promising modality for the treatment of RA [180].

Light-responsive diagnostic and treatment platform

Early diagnosis of RA is crucial to treat the joint before it becomes irreversible. MRI and ultrasound (US) imaging are used for early inflammation detection in the joints. However, MRI is time-consuming, costly, and potentially contraindicated, while US imaging is dependent on the experience of the operator [181]. PAI has gained attention as a non-invasive, low-cost, high-contrast, real-time continuous imaging technique for early diagnosis of RA [182]. PAI utilizes light absorption by hemoglobin and the difference in the absorption spectra of oxygenated and deoxygenated hemoglobin to detect local neovascularization, blood flow, and hypoxia in joints without the need for exogenous imaging agents [183, 184]. For RA diagnosis, integrated nanoplatforms using exogenous contrast agents have been developed. Recently, TNF-α and IL-6 silencing siRNA (siRNA^T/I) and Prussian blue nanoparticles (PBNPs) encapsulated by macrophage membrane vesicles (MMVs) have been used to develop biomimetic nanoparticles M@P-siRNAs^T/I which target RA joints (Fig. 12A) [185]. PBNPs allowed PAI to assess joint targeting of M@P-siRNAs^T/I and also mimicked peroxidase, catalase, and superoxide dismutase activities, scavenging of ROS and production of oxygen, which synergized with the inhibitory effects of siRNA^T/I on inflammatory factor expression, inhibited joint inflammation and alleviated hypoxia, as well as ameliorated joint erosion (Fig. 12B, C). In another study, nanoparticles consisting of dextran sulfate (DS)-modified thermosensitive molecular poly (lactic-co-glycolic acid) (PLGA) as a shell and quadrilateral ruthenium (QRu) as a core, QRu-PLGA-RES-DS NPs, with photothermal and PAI capabilities were developed [166]. PAI of QRu provided information on the in vivo distribution of nanoparticles, and photothermal functional modulation of resveratrol (RES) release increased the M2/M1 macrophage ratio, enabling PAI-guided RA therapy. NIR-II PA imaging has higher spatial resolution and deeper tissue penetration (i.e., more than 10 cm) compared to NIR-I PA imaging [186]. Recently, Chen et al. constructed the first NIR-II PAI nanoprobes utilizing tocilizumab (TCZ)-coupled polymeric nanoparticles (TCZ-PNPs) for the diagnosis and treatment of RA [187]. A signal-to-noise ratio of up to 35.8 dB has been reported for TCZ-PNPs, allowing them to monitor the RA condition by displaying swelling in cartilage tissues. After one month of treatment with TCZ-PNPs, the progression of RA was observed to be inhibited in mice.

NIR persistent luminescence nanoparticles (NIR-PLNPs) continuously emit NIR persistent luminescence (PersL) after stop** excitation light irradiation [189]. Recently, Wang et al. constructed mZMI@HA nanoprobes targeting activated macrophages for guided therapy and therapeutic evaluation in RA (Fig. 12D) [188]. After mZMI@HA was injected into the body, PersL imaging showed distinct signals in the paws of RA mice, suggesting that mZMI@HA accumulated at the site of RA onset (Fig. 12E). To scavenge activated macrophages and inhibit synovial proliferation and cartilage destruction, mZMI@HA also released MTX via NIR and pH-responsive forms. After complete treatment, PersL imaging with mZMI@HA was again administered intravenously, and low luminescent signal intensity was found in the paws of RA mice, which were consistent with joint morphology and histology, suggesting that PersL imaging with mZMI@HA can also be used for treatment monitoring and efficacy assessment (Fig. 12F-I). Fluorescence imaging is also used for in vivo distribution detection of nanomaterials. Recently, Pan et al. constructed Pt-MOF@Au@QDs/PDA for hydrothermal therapy targeting FLS, emitting fluorescent signals under 640 nm light excitation to determine joint distribution [190]. Further, Pt-MOF@Au acted as a visible light-activated H₂ generator to produce H₂ to scavenge •OH in FLS to alleviate cellular oxidative stress. Under NIR irradiation, Pt-MOF@Au@QDs/PDA induced FLS death via PTT. In vivo, H₂ therapy synergized with PTT to alleviate joint inflammation and inhibit synovial proliferation as well as bone and cartilage erosion in RA mice.

Skeletal muscle injury

Skeletal muscles constitute approximately 30-40% of the body's weight and are necessary for voluntary movement [191]. Minor injuries to skeletal muscle, such as strains and contusions, can be repaired through the proliferation and differentiation of muscle satellite cells, the stem cell population of skeletal muscle [192]. However, severe muscle injuries may lead to fibrosis, scarring, and loss of muscle function [193].

Heat therapy shows significant potential in the treatment of muscle injuries by alleviating muscle pain, promoting satellite cell proliferation, and reducing collagen fiber formation [194, 195]. Recently, Zhang et al. recently developed a microneedle patch (CW-PGE₂-MN) containing carbonized wormwood and prostaglandin E₂ (PGE₂) for damaged muscle repair [196]. NIR-induced photothermal therapy for 20 minutes three times daily, combined with PGE₂, promoted the proliferation and differentiation of muscle stem cells. After three weeks of treatment, muscle strength and myogenic fiber counts improved in muscle-damaged mice, indicating effective muscle repair.

It is essential to note that the muscle repair effect in this study was achieved through heat transfer from the skin patch to the deeper tissues. The skin temperature reached as high as 60°C after 5 minutes of NIR (808 nm, 3 W/cm²) irradiation, which may be harmful to the skin. Currently, research on photothermal therapy for muscle injuries is scarce, but previous studies have suggested that heat therapy at 40°C may promote muscle repair [196]. In the future, the construction of photothermal materials with high photothermal conversion efficiency capable of accurately targeting injured muscles for localized photothermal therapy will improve therapeutic efficacy and reduce damage to other tissues [197].

Conclusion and outlook

In recent years, nanotechnology has advanced the development of multifunctional nanoplatforms based on PTT and PDT, showing great promise in addressing medical challenges related to musculoskeletal disorders. This article outlines the progress in strategies and applications of PTT and PDT for treating MSDs, considering the characteristics of different diseases. Specifically, for MSDs involving tissue damage, phototherapy directly modulates several key processes in tissue repair, such as promoting angiogenesis, modulating immune homeostasis, and promoting stem cell differentiation, thereby accelerating tissue repair. Meanwhile, synergistic therapies based on PTT and PDT have demonstrated a powerful clearance effect on bacteria and biofilms, which is essential for creating a microenvironment suitable for tissue regeneration. For bone tumors and RA, the intravenously administered light-responsive nanoplatforms can be accurately localized to the corresponding pathological tissues based on the EPR effect, modified targeting ligands. Therefore, phototherapy can be performed on the tumor or the affected joint without invasive procedures on the patient, which helps reduce the pain. In addition, for bone tumors, the construction of a multifunctional phototherapy nanoplatform can combine PTT and PDT with chemotherapy, CDT, gene therapy, immunotherapy, or starvation therapy to achieve precise and efficient tumor cell killing and even overcome tumor drug resistance. As for joint diseases, the light-responsive drug delivery nanoplatform can not only relieve pain symptoms through hyperthermia, but also extend the retention time of the loaded drug in the joint, and achieve light-responsive active drug delivery to delay disease progression.

Although phototherapy, as a non-invasive, highly selective, and controllable technique, has demonstrated significant therapeutic potential in MSDs, it is still subject to various limitations in the treatment of MSDs. First, the musculoskeletal system is often covered by skin and subcutaneous tissues, and there is inevitable energy scattering and absorption as light propagates through these tissues, which may reduce the efficacy of phototherapy. Secondly, for certain MSDs involving tissue damage, such as bone defects, the repair process is dynamic and complex, and phototherapy's regulation of cellular functions may not align well with this process. Furthermore, in the case of bone infections, bacteria can easily hide within the complex anatomical structures of the bone, leading to a risk of infection recurrence even after phototherapy. Moreover, the uneven distribution of photothermal agents and photosensitizers in tumors may lead to suboptimal tumor clearance. It's worth noting that bone fracture sites, tumor tissues, as well as joints affected by OA and RA often exhibit hypoxia, which could limit the effectiveness of highly oxygen-dependent PDT. Therefore, before phototherapy can be widely applied in the clinical treatment of MSDs, several challenges need to be addressed:

(i)
Choice of light source: Most light sources currently used for the treatment of MSDs focus on NIR-I, although they have been shown to be effective in activating phototherapy in animals. In humans, however, the thickness of the skin and subcutaneous tissue is much greater than in animal models, which may hinder phototherapy. Currently, NIR-II lasers with deeper tissue penetration, lower tissue light absorption and scattering, and higher maximum permissible exposure (MPE) (1 W/cm² at 1064 nm versus 0.33 W/cm² at 808 nm) are believed to help reduce adverse tissue reactions and improve treatment outcomes. NIR-II-based imaging has superior imaging depth, spatiotemporal resolution, and signal-to-noise ratio, which helps to build more accurate diagnostic systems. In the future, studies need to further investigate the interaction between light and tissue to guide the selection of light for MSDs phototherapy.
(ii)
Disease microenvironment: Develo** phototherapy nanoplatforms must consider the disease microenvironment, such as low pH, hypoxia, high ROS, high GSH or specific enzyme expression. Considering the limitations of hypoxia in PDT, constructing nanoplatforms for oxygen supply or oxygen self-generation, combined with PTT to enhance blood circulation for improved oxygen supply, can enhance the efficacy of PDT. In addition, the design of multiple stimulus-responsive drug delivery systems with light- and microenvironment-responsiveness and various combination therapies can help to achieve on-demand drug delivery, increase drug utilization efficiency, improve the disease microenvironment and enhance therapeutic efficacy.
(iii)
Biosafety: Ensuring the biosafety of phototherapy in MSDs treatment is of paramount importance. Phototherapy toxicity can arise from the light absorption by skin tissue, heat from PTT and ROS from PDT. Selecting light sources with larger wavelengths, improving photothermal conversion efficiency, shortening the irradiation time, controlling temperature and ROS production, and constructing targeted nanomaterials through ligand modification will help overcome these challenges. Further, long-term biotoxicity and metabolic pathways of nanomaterials in vivo need to be systematically studied prior to clinical translation.
(iv)
Molecular and cellular mechanisms: Phototherapy has been demonstrated to modulate cellular functions, such as PTT promoting the osteogenic differentiation of MSCs and PDT promoting the chondrogenic differentiation of MSCs. Although some signaling pathways have been shown to be involved through traditional methods, researchers still need to utilize cutting-edge technologies such as single-cell transcriptomics, proteomics, and metabolomics to uncover more molecular regulatory mechanisms by which phototherapy influences cellular functions. In addition, MSDs often involve complex cellular mechanisms. For bone defect repair, current phototherapy strategies overemphasize anti-inflammation and ignore the benefits of appropriate levels of inflammation early in bone injury (e.g., removal of pathogens and damaged tissues). In the case of RA and OA, the complexity and incomplete understanding of pathogenesis make this a challenge for the application of phototherapy techniques. Therefore, emphasizing interdisciplinary collaboration and in-depth basic research to deepen the understanding of the molecular mechanisms of MSDs and phototherapy on cellular function will be key to advancing the development of new therapeutic strategies for MSDs.

In conclusion, phototherapy technology holds exciting potential for the treatment of MSDs. Continued research and optimization of phototherapy nanoplatforms towards versatility, precision, and efficiency for the treatment of bone, cartilage, and bone tumor diseases, along with exploring other MSDs therapies, will ultimately pave the way for clinical translation and benefit patients.

Availability of data and materials

Not applicable.

Abbreviations

MSDs:: Musculoskeletal disorders
RA:: Rheumatoid arthritis
PTT:: Photothermal therapy
PDT:: Photodynamic therapy
ROS:: Reactive oxygen species
CDT:: Chemodynamic therapy
PAI:: Photoacoustic imaging
NIR:: Near-infrared
OA:: Osteoarthritis
MSCs:: Mesenchymal stem cells
HSP:: Heat shock protein
Runx-2:: Runt-related transcription Factor-2
ALP:: Alkaline phosphatase
BMP:: Bone morphogenetic protein
Col-I:: Collagen I
PDGF:: Platelet-derived growth factor
TGF:: Transforming growth factor
VEGF:: Vascular endothelial growth factor
BP:: Black phosphorus
PLGA:: Poly (lactic acid-glycolic acid copolymer)
SMPs:: Shape memory polymers
3D:: Three-dimensional
4D:: Four-dimensional
CT:: Computed tomography
RGD:: Arginylglycylaspartic acid
ER:: Endoplasmic reticulum
ERS:: Endoplasmic reticulum stress
ALN:: Alendronate
PDA:: Polydopamine
MRI:: Magnetic resonance imaging
NSCLC-SM:: Spinal metastasis of non-small cell lung cancer
ICD:: Immunogenic cell death
DAMPs:: Damage-associated molecular patterns
PD-1:: Programmed cell death protein 1
PD-L1:: Programmed cell death ligand 1
ZOL:: Zoledronic acid
MMP:: Matrix metalloproteinase
NGF:: Nerve growth factor
FLS:: Fibroblast-like synoviocytes
EPR:: Enhanced permeability and retention
HA:: Hyaluronic acid
RANKL:: Nuclear factor kappa-β ligand
VIP:: Vasoactive intestinal peptide
FA:: Folate
US:: Ultrasound

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Acknowledgements

Figures 1, 2 and 5 are created with BioRender.com.

Funding

This work was supported by the Wuhan Science and Technology Bureau (2022020801020464) National Key R&D Program of China (2021YFA1101500), National Natural Science Foundation of China (No. 82202676), China Postdoctoral Science Foundation (2021M701333).

Author information

Zhenhe Zhang, Rong Wang, Hang Xue and Samuel Knoedler contributed equally to this work.

Authors and Affiliations

Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
Zhenhe Zhang, Hang Xue, Yongtao Geng, Yuheng Liao, Bobin Mi & Guohui Liu
Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Zhenhe Zhang, Hang Xue, Yongtao Geng, Yuheng Liao, Bobin Mi & Guohui Liu
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
Rong Wang & Jie Ming
Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02152, USA
Samuel Knoedler & Adriana C. Panayi
Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377, Munich, Germany
Samuel Knoedler
Division of Hand, Plastic and Aesthetic Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
Michael Alfertshofer
Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071, Ludwigshafen, Rhine, Germany
Adriana C. Panayi

Authors

Zhenhe Zhang
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Rong Wang
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Hang Xue
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Samuel Knoedler
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Yongtao Geng
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Yuheng Liao
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Michael Alfertshofer
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Adriana C. Panayi
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Jie Ming
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Bobin Mi
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Guohui Liu
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Contributions

ZZ, RW, HX, and KS conceived the conceptualization and wrote the manuscript. YL, YG, MA, and AP collated and produced relevant figures for the manuscript. JM, BM and GL revised the manuscript. All authors have read and approved the manuscript.

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Correspondence to Jie Ming, Bobin Mi or Guohui Liu.

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Zhang, Z., Wang, R., Xue, H. et al. Phototherapy techniques for the management of musculoskeletal disorders: strategies and recent advances. Biomater Res 27, 123 (2023). https://doi.org/10.1186/s40824-023-00458-8

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Received: 15 August 2023
Accepted: 28 October 2023
Published: 28 November 2023
DOI: https://doi.org/10.1186/s40824-023-00458-8

Phototherapy techniques for the management of musculoskeletal disorders: strategies and recent advances

Abstract

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