Search Results (2,249)

Micro-fragmented adipose tissue (mFAT) is a promising autologous biologic in regenerative medicine because it provides a mechanically processed adipose-derived product that preserves native extracellular matrix architecture and a cellular milieu rich in mesenchymal stem cells, pericytes, growth factors, cytokines, and extracellular vesicles. Mechanistically, mFAT is hypothesized to act largely through paracrine signaling that dampens inflammation, supports vascular stabilization, and promotes cartilage and soft-tissue repair; in vitro data suggest modulation of osteoarthritic synovial macrophage signaling, including reductions in chemokines such as CCL2 and CCL3. Preparation involves liposuction harvest followed by closed, sterile mechanical processing without enzymatic digestion or cell expansion, aligning with “minimal manipulation” concepts relevant to regulatory frameworks. Preclinical animal studies generally demonstrate favorable effects on synovial inflammation and cartilage matrix markers (e.g., glycosaminoglycan content) with limited adverse events. Clinically, the strongest body of evidence is in knee osteoarthritis, where multiple prospective and retrospective studies report improvements in pain and function from months to several years after single injections, though response rates vary and study designs are heterogeneous. Evolving data support potential benefit in hip osteoarthritis and select tendon conditions, but cohorts remain small. Overall, mFAT appears safe and potentially effective, yet larger, standardized, long-term randomized controlled trials and comparative studies versus platelet-rich plasma and bone marrow aspirate concentrates are needed to clarify indications, dosing, durability, and mechanisms in vivo. Full article

Engineering multifunctional scaffolds that effectively promote bone regeneration while concurrently mitigating the risk of infection remains a significant challenge in the field of bone tissue engineering. In this study, we present the fabrication of electrospun poly(lactic acid) (PLA) nanofibrous composite scaffold (PLASrCu) incorporating strontium peroxide (SrO₂) and copper-doped hydroxyapatite (CuHA) particles. The resulting composite scaffold exhibited interconnected porous structures and extracellular matrix-like morphologies. Physicochemical characterization confirmed the preservation of PLA chemical structure and the successful incorporation of crystalline SrO₂ and CuHA phases, with the tensile strength increasing from 2.3 to 2.8 MPa. The PLASrCu scaffold exhibited sustained ion release of Sr and Cu (12.2 and 13.3 mg/L, respectively, over 14 days), together with controlled oxygen generation (10.2 mg/L within 30 min), particularly under hypoxic conditions. In vitro biological assessments demonstrated that the PLASrCu scaffold significantly enhanced cell proliferation and viability. Moreover, osteogenic differentiation and mineralization were markedly promoted, as evidenced by upregulated expression of COL1, OPN, and RUNX2 (5.1-, 2.6-, and 1.9-fold increases, respectively) and increased calcium deposition. Importantly, the Cu-containing scaffolds effectively inhibited the growth of Staphylococcus aureus and Pseudomonas aeruginosa, resulting in antibacterial rates above 99.9%. Collectively, these results demonstrate that the PLASrCu nanofibrous scaffold integrates osteogenic, oxygen-generating, and antibacterial functions within a single platform, highlighting its strong potential for the regeneration of infected and oxygen-deficient bone defects. Full article

Follistatin (FST) binds to and neutralizes members of the transforming growth factor-beta (TGF-β) superfamily, thereby regulating diverse physiological processes, including regulation of skeletal muscle, adipose, and bone homeostasis. FST also promotes adipose browning and enhances energy metabolism, leading to improved plasma lipid profiles and metabolic health in mice. Given the emerging association between brown adipose tissue (BAT) activation and reduced atherosclerosis, we investigated the anti-atherogenic potential of FST. Transcriptomic and metabolomic analyses of the Hybrid Mouse Diversity Panel (HMDP) revealed that Fst expression was negatively correlated with aortic lesion area and positively correlated with the expression of multiple adipose browning-associated genes. Adeno-associated viral delivery of Fst (AAV1-FST344) in Ldlr^−/− mice significantly reduced aortic lesion area, improved plasma lipid profiles, and decreased expression of adhesion (VCAM1) and inflammatory (iNOS, TNF-α) markers in white adipose tissue (WAT), liver, and heart. Fst gene delivery also markedly increased uncoupling protein 1 (UCP1) expression in WAT, consistent with WAT browning. Integrated correlation analyses of Fst expression with tissue metabolites, together with plasma metabolite–lesion associations identified in the HMDP, implicated the arginase 1 (Arg1)-mediated metabolic pathway as a key regulator of atherogenesis. Consistent with these findings, Arg1 expression was significantly elevated in WAT, liver, and heart of AAV1-FST344-treated mice and in wild-type versus Fst-knockout mouse embryonic fibroblasts (MEFs). Immunostaining localized Arg1 predominantly to CD68⁺ macrophages in heart and liver. Given recent evidence identifying Arg1 as a novel mediator of efferocytosis, these findings suggest that Arg1 may promote macrophage metabolic reprogramming and resolution of inflammation by enhancing the clearance of apoptotic cells. Furthermore, Fst gene delivery increased the expression of fibroblast growth factor 21 (Fgf21) and adiponectin (AdipoQ) in WAT. Collectively, these findings identify Fst as a novel anti-atherogenic regulator that protects against vascular disease by promoting adipose browning, improving lipid metabolism, and activating Arg1-mediated metabolic pathways. Full article

Periodontitis is a chronic inflammatory disease driven largely by dysregulated host responses that lead to destruction of periodontal tissues. Integrins are heterodimeric transmembrane receptors that regulate cell adhesion and bidirectional signaling in epithelial cells, immune cells, periodontal ligament fibroblasts, and osteoclasts. During disease progression, integrin-related responses may shift across overlapping molecular phases. Epithelial integrins such as α3β1 and α6β4 support barrier integrity, whereas α5β1 may facilitate microbial interaction and inflammatory signaling. β2 integrins and α4β1 contribute to leukocyte recruitment and inflammatory amplification, whereas increased α9β1-associated signaling and reduced αvβ6-mediated regulation of transforming growth factor β (TGF-β) may promote inflammatory persistence. Matrix-associated integrins, including α2β1 and α11β1, support extracellular matrix (ECM) organization and mechanotransduction, whereas αvβ3 cooperates with Receptor activator of nuclear factor kappa B ligand (RANKL) to promote osteoclast activity and alveolar bone resorption. Impaired β1 integrin-dependent signaling and potentially reduced αvβ5-associated efferocytosis may contribute to defective resolution and regeneration. Importantly, integrin expression, activation, and downstream signaling are distinct, and the strength of evidence varies among integrin subtypes. This review proposes a conceptual framework in which periodontitis reflects a dynamic imbalance in integrin-mediated processes that link inflammation, bone resorption, and regenerative failure, rather than being a direct equivalent of clinical periodontal stages or grades. Full article

As a traditional element of Chinese medicine, Hippocampus erectus is well known for promoting adolescent growth, yet its active fractions and underlying molecular mechanisms remain unclear. In this study, the aqueous extract of H. erectus was subjected to in vitro simulated gastrointestinal digestion and ultrafiltration to separate three molecular weight fractions (<10 kDa, 10–30 kDa, >30 kDa). Their chemical profiles were characterized, and osteogenic activities were systematically evaluated using cell assays, a juvenile rat model, and integrated transcriptomics and data-independent acquisition (DIA) proteomics. Results revealed that chemical profiling showed the >30 kDa fraction was mainly composed of hemocyanin subunits, and the 10–30 kDa fraction was enriched in growth-related amino acids and steroid derivatives; functionally, the 10–30 kDa fraction promoted preosteoblast proliferation and early differentiation via enhanced alkaline phosphatase (ALP) activity, while the >30 kDa fraction dominated late osteoblast maturation and mineralization. Both fractions significantly increased rat body and bone length by expanding growth plate proliferative zones and elevating serum insulin-like growth factor-1 (IGF-1)/bone morphogenetic protein-2 (BMP-2) levels. Transcriptomic and proteomic analyses identified vascular endothelial growth factor (VEGF), Wingless-related integration site (Wnt), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and extracellular matrix (ECM)–receptor interaction as potential core regulatory pathways. Integrated multi-omics analysis further confirmed Frizzled-related protein B (Frzb) and AKT1 substrate 1 (Akt1s1) as candidate key regulatory targets enriched in the Wnt and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. These findings elucidate the multi-fraction, multi-pathway mechanism of H. erectus in promoting skeletal development, providing scientific evidence for its traditional use and a theoretical basis for growth-promoting functional food development. Full article

Background: Hyaluronan (HA) is a critical extracellular matrix component that we have demonstrated to be important for embryonic endochondral bone formation and postnatal synovial joint formation, supporting normal articular cartilage (AC) architecture and chondrocyte function. Although the embryonic requirement for Hyaluronan Synthase 2 (Has2), the main HA-producing enzyme in skeletal tissues, has been extensively investigated, the cartilage-cell-specific roles of Has2 and HA in maintaining postnatal cartilage and joint integrity are not well-defined. Methods: In this study, we used a tamoxifen-inducible, cartilage-specific Has2 conditional knockout mouse model (AggrecanCreERT2Cre/+; Has2^fl/fl). A total of 20 male mice were collected, followed with tamoxifen administered at 3 weeks of age and tissues analyzed at early and late post-induction time points using histological and matrix-based assessments. Results: Administration of tamoxifen at 3 weeks of age resulted in near-complete absence of HA in AC and growth late (GP) at 4 weeks, one week after the induction, as confirmed by highly specific HA staining Hyaluronan binding protein (HABP) immunohistochemistry. These early changes establish that Has2-dependent HA synthesis is indispensable for maintaining matrix integrity, columnar organization, and postnatal GP maturation. We further extended these findings into later developmental stages, showing that by 11 weeks of age (8 weeks after induction), tibial joints exhibit AC surface irregularity, proteoglycan depletion, disrupted zonal architecture, and changes in the osteochondral unit consistent with early degenerative features. Conclusions: Taken together, these data suggest that HA deficiency triggered in early postnatal life is associated with increased cartilage vulnerability, supporting an important role for Has2 in cartilage maturation and long-term joint integrity. Full article

Bone defects from trauma, tumour resection, infection, and degenerative disease remain a major clinical burden, and autografts face limitations of supply and donor-site morbidity. Three-dimensional (3D) printing offers a route to patient-specific, architecturally defined bone scaffolds, while biopolymers from natural sources provide biodegradability, biocompatibility, and extracellular matrix-mimicking cues consistent with sustainable, green biomaterials science. This review synthesises recent progress in 3D printing of biopolymer-based scaffolds for bone tissue engineering. We first examine the principal feedstocks—alginate, gelatin and gelatin methacryloyl, collagen, chitosan, silk fibroin, cellulose, and microbial polyesters—and their preparation, crosslinking chemistry, and printability. We then compare extrusion, light-based, and indirect printing technologies and the process–property relationships governing resolution, mechanical competence, and cell viability. Composite and functionalisation strategies, including biopolymer–bioceramic hybrids and controlled delivery of growth factors and antimicrobial agents, are analysed as routes to osteoinduction, vascularisation, and infection control. Finally, we evaluate translational performance in preclinical models and outline central challenges of vascularisation, mechanical–degradation matching, scalability, and regulatory standardisation. Biopolymer 3D printing is positioned as a ve rsatile, sustainable platform whose clinical maturation depends on integrated material, structural, and biological design. Full article

Myostatin (MSTN) is a well-established negative regulator of skeletal muscle growth; however, its role in bone metabolism and osteogenic differentiation remains incompletely understood. In this study, untargeted and targeted metabolomic analyses were performed to investigate the metabolic effects of the MSTN^Del73C mutation during osteogenic differentiation of sheep bone marrow mesenchymal stem cells (BMSCs). Metabolomic profiles were analyzed in wild-type and MSTN^Del73C mutant BMSCs at 0, 7, and 14 days of osteogenic induction. During normal osteogenic differentiation, metabolites related to glycerophospholipid metabolism were repeatedly detected among significantly altered features, accompanied by marked increases in multiple lysophospholipid subclasses, including lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), and lysophosphatidylinositol (LPI). In contrast, MSTN^Del73C mutation was associated with significant reductions in several LPC and LPI species (p < 0.01 or p < 0.001), suggesting altered lipid metabolic profiles during differentiation. Targeted metabolomic validation further confirmed the altered abundance pattern of LPC 18:2. Collectively, these findings suggest that MSTN mutation is closely associated with metabolic remodeling during osteogenic differentiation and suggest potential involvement of glycerophospholipid-related metabolites involved in MSTN-related regulation of sheep BMSC osteogenesis. Full article

Background: Osteochondral lesions of the talus (OLT) remain a challenging condition due to the limited regenerative potential of articular cartilage. Conventional bone marrow stimulation (BMS) techniques often result in fibrocartilage formation with inferior biomechanical properties. This study aimed to evaluate the safety and preliminary clinical efficacy of an arthroscopically assisted, single-stage injection of a heparin-conjugated fibrin hydrogel (HCFH) for OLT treatment. Methods: Twelve patients with symptomatic OLT underwent arthroscopic debridement, microfracturing, and HCFH injection containing autologous mesenchymal stromal cells (MSCs) and growth factors. Safety was assessed through systematic monitoring of adverse events (graded according to Common Terminology Criteria for Adverse Events criteria), wound healing, and serial laboratory inflammatory markers (leukocytes, erythrocyte sedimentation rate, C-reactive protein) during early and late follow-up. Clinical outcomes were evaluated using the Visual Analog Scale (VAS) and American Orthopedic Foot and Ankle Society score (AOFAS) preoperatively and at 6 and 12 months. Morphological assessment was performed using magnetic resonance imaging (MRI) with the modified Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system, evaluated independently by two blinded musculoskeletal radiologists. Results: No serious adverse events (Grade III–IV) were observed during the 12-month follow-up. All adverse events were mild (Grade I) and self-limited. A transient postoperative elevation in inflammatory markers was observed, returning to clinically acceptable levels by day 14. Significant improvements were noted in pain (VAS decreased from 6.0 to 2.0) and ankle function (AOFAS increased from 70.0 to 90.6) (p < 0.001). MRI demonstrated progressive morphological improvement, with the MOCART score increasing from 34.16 ± 17.1 at 6 months to 75 ± 5.43 at 12 months (p < 0.001). This increase corresponded with imaging features consistent with tissue maturation over time. The favorable MOCART outcomes observed in this study may be explained by the regenerative properties of heparin-conjugated fibrin hydrogels; however, larger randomized controlled trials with longer follow-up are needed to confirm the durability of the regenerated tissue. Interobserver agreement was substantial to almost perfect for MOCART scoring (κ = 0.68–0.84), with perfect agreement observed for surface assessment, bony defect/overgrowth, and cysts. Conclusions: Within the limitations of this study, single-stage HCFH injection demonstrated an acceptable safety profile and favorable preliminary clinical and radiological outcomes at 12 months. These findings suggest potential regenerative capability; however, controlled studies with larger cohorts and longer follow-up are required to determine comparative efficacy and long-term durability. Full article

The amniotic membrane is widely recognized in regenerative medicine due to its rich content of extracellular matrix proteins and growth factors that confer anti-inflammatory and pro-regenerative properties. However, its rapid degradation restricts its standalone clinical use. To overcome these limitations, we developed biofilms by incorporating decellularized human amniotic membrane matrix (dHAM) into polycaprolactone (PCL) and polyvinylpyrrolidone (PVP) matrices using spin-coating. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were used to evaluate film biocompatibility through cell viability, proliferation, and wound healing migration assays. Surface characterization was performed using contact angle measurements, Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy, and scanning electron microscopy. Soluble dHAM extracts (4–6 mg/mL) significantly enhanced BM-MSC proliferation at 48 h compared to controls (p ≤ 0.01 and p ≤ 0.0001). Both PCL-dHAM and PVP-dHAM biofilms exhibited high cell viability (>90%) and improved initial adhesion. Notably, dHAM incorporation significantly increased wound closure rates at 24 h, reaching 98.47% for PCL-dHAM and 93.13% for PVP-dHAM, compared to 76.56% and 64.20% for pure polymers (p = 0.0001). All scaffolds maintained hydrophilic surfaces (<90°), favorable for cell interaction. The integration of dHAM into PCL and PVP by spin-coating produces biofilms biocompatible with enhanced regenerative potential, representing promising candidates for wound healing applications. In conclusion, these coatings support BM-MSC adhesion, proliferation, and migration, while significantly accelerating wound closure, underscoring their value as advanced bioactive coatings for regenerative medicine. Full article

Periodontal disease remains one of the leading causes of tooth loss worldwide, highlighting the need for effective regeneration of alveolar bone, periodontal ligament, and cementum. The structural complexity and unique biological behavior of these tissues have historically posed significant challenges for clinical regeneration strategies. The primary therapeutic approach used is guided bone regeneration; however, it has certain limitations, such as morbidity, low structural integrity and dimensional stability. Recent advances in 3-dimensional (3D) bioprinting have made it possible to fabricate customized scaffolds with precise architecture and spatial organization that closely mimic normal periodontal structures. The incorporation of multifunctional nanocomposite biomaterials and nanoparticles further enhances the performance of the scaffolds by increasing mechanical strength, bioactivity and controlling degradation rates. These advanced scaffolds function as dynamic microenvironments that support cell adhesion, proliferation and differentiation, ultimately promoting tissue regeneration. Furthermore, their multifunctional properties allow for the controlled release of growth factors, anti-inflammatory and antimicrobial agents, as well as the incorporation of stem cells and bioactive molecules that facilitate angiogenesis. This review investigates and critically evaluates modern approaches for the regeneration of periodontal tissues through scaffolds, biomaterials and 3D bioprinting technologies, as well as to assess their effectiveness compared to established clinical practices. Full article

Astragalus membranaceus, a medicinal plant used in traditional Chinese medicine for centuries, has attracted growing scientific attention for its potential anti-aging and anticancer properties, particularly for skin and bone health. Its key bioactive compounds like astragalosides, cycloastragenol, and its commercial derivative TA-65, have been associated with telomerase activation and telomere maintenance, suggesting a possible role in modulating cellular senescence and tissue repair processes. In addition to the claimed telomere maintenance, A. membranaceus exhibits antioxidant, anti-inflammatory, and DNA-protective activities, properties that contribute to its anti-aging effects. Emerging evidence also suggests that telomerase modulation by A. membranaceus influences cancer cell dynamics, either suppressing tumor progression through immune regulation and apoptosis induction or, in some contexts, potentially promoting tumor growth. This duality highlights the importance of dose, formulation, and targeted application. Clinically, TA-65 has been reported to improve vascular health, bone mineral density, and skin elasticity in aging individuals. Preclinical studies further support its protective effects against osteoporotic bone loss and photoaging-induced dermal degeneration. This review summarizes the phytochemical composition of A. membranaceus and critically evaluates the mechanistic and therapeutic evidence underlying its anti-aging and anticancer actions on skin and bone tissues. It also discusses the pharmacokinetic properties of A. membranaceus, including its absorption, bioavailability, and safety profile. The integration of A. membranaceus into evidence-based senile therapeutic strategies holds promise, but further mechanistic and clinical studies are required to optimize its safety and efficacy. Full article

The development of multifunctional biomaterials for bone repair requires precursors that combine bioactivity, moderate antimicrobial growth-inhibitory effect, and imaging. This study demonstrates the multifunctional versatility of a single family of rare-earth-doped β-tricalcium phosphates (β-TCPs), Ca₉Eu(PO₄)₇ and Ca₉Dy(PO₄)₇, across three distinct formats: bioactive thin films (for implant coatings), brushite cements (for injectable bone fillers), and radiopaque PMMA bone composites (for load-bearing applications). This work serves as a proof-of-concept that the same doped phosphate precursors can address different clinical needs while retaining bioactivity, antimicrobial properties, and radiopacity. The phosphate precursors were synthesized via solid-state reaction. Pulsed laser deposition (PLD) was used to form amorphous, dense, and crack-free coatings, which exhibited excellent in vitro bioactivity through the rapid dissolution–reprecipitation of a carbonated apatite layer in simulated body fluid. The brushite-based bone cements were produced from doped β-TCPs. These cements demonstrated high cytocompatibility with mesenchymal stromal cells (>89% viability) and significantly enhanced osteogenic differentiation with antimicrobial activity against common pathogens (S. aureus, E. coli, P. aeruginosa). Furthermore, incorporation of these phosphates as fillers into PMMA bone cement resulted in a homogeneous particle distribution with reduced agglomeration compared to undoped β-TCPs, achieving clinically relevant radiopacity values (913 ± 22.4 HU for Dy-doped sample). Post-mortem studies by the CT method were performed on the vertebrae with PMMA–phosphate composites and brushite cements. It was shown that brushite cement in ovine lumbar vertebrae defects exhibited the highest radiopacity (1450–1550 ± 25 HU). The findings establish rare-earth-doped β-TCP as a unified multifunctional precursor that imparts bioactivity, the ability to support in vitro mineralization, antimicrobial properties, and enhanced radiopacity to thin films, phosphate cements, and polymer composite materials. Full article

Hydrogel scaffolds have emerged as instructive microenvironments for craniofacial tissue regeneration, moving beyond passive cell carriers toward platforms that regulate cell fate, vascularization, immune remodeling, and tissue-specific architecture. This review synthesizes hydrogel-associated strategies across dental pulp, periodontal ligament, gingival, bone marrow, jawbone, endothelial, oral mucosal, induced pluripotent stem cell (iPSC), extracellular vesicle (EV), exosome, secretome, and acellular systems. The evidence indicates that craniofacial hydrogel performance is governed by reciprocal interactions among biological source, scaffold composition, matrix mechanics, spatial architecture, mineral or ionic signaling, growth factor delivery, vesicle-mediated communication, and inflammatory niche modulation. Mineralized and ion-releasing hydrogels most consistently supported osteogenesis and bone repair, whereas extracellular matrix (ECM)-mimetic, peptide, collagen, fibrin, gelatin methacryloyl (GelMA), alginate, hyaluronic acid (HA), and chitosan-based systems enabled pulp–dentin, periodontal, peri-implant, oral mucosal, and soft-tissue reconstruction. Responsive, antimicrobial, antioxidant, conductive, and immunomodulatory hydrogels further expanded the field by targeting diseased microenvironments rather than regeneration alone. Despite strong preclinical evidence, translation remains limited by heterogeneity in scaffold formulations, biological sources, analytical endpoints, defect models, and long-term functional validation. Future progress will require standardized characterization, tissue-specific design criteria, clinically relevant large-animal models, scalable cell-free technologies, and integrated assessment of regeneration, immunity, vascularization, innervation, mechanics, and safety. Full article

Objectives: Distraction osteogenesis (DO) is an established technique for bone regeneration but is associated with prolonged consolidation time and extended external fixation. Biophysical and biologic adjuncts have been proposed to accelerate regenerative maturation. This systematic review aimed to comparatively evaluate the available clinical evidence regarding low-intensity pulsed ultrasound (LIPUS) and biologic augmentation strategies in distraction osteogenesis. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD420251125456). MEDLINE, Embase, Scopus, and Google Scholar were searched from inception to October 2025. Randomized controlled trials and cohort studies evaluating LIPUS, platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), culture-expanded mesenchymal stem cells, or hyperbaric oxygen therapy in distraction osteogenesis were included. Risk of bias was assessed using RoB 2 for randomized trials and structured domain-based criteria for observational studies. Due to substantial clinical and methodological heterogeneity, findings were synthesized narratively. Results: Nine studies involving 304 participants met the inclusion criteria, including randomized controlled trials and cohort studies across multiple anatomical sites and fixation techniques. Randomized trials evaluating LIPUS demonstrated inconsistent reductions in healing index and consolidation time, with no consistent effect on complication rates. Biologic adjuncts such as PRP, BMAC, and cell-based therapies showed signals of improved consolidation parameters in selected studies; however, evidence was limited by small sample sizes and methodological heterogeneity. Hyperbaric oxygen therapy lacked sufficient high-quality evidence to support routine use. Overall, the certainty of evidence was constrained by variability in study design, outcome definitions, and risk of bias. Conclusions: Although both biophysical and biologic adjuncts demonstrate compelling biological rationale, current clinical evidence in distraction osteogenesis remains heterogeneous and inconclusive. Biologic strategies may offer theoretical advantages through direct cellular and growth factor supplementation, whereas LIPUS provides non-invasive mechanotransductive stimulation; however, neither approach can currently be recommended for routine clinical use. High-quality, adequately powered trials with standardized outcome reporting are required to define their true clinical role. Level of Evidence: Level III (Systematic review of Level I–III studies). Full article