Editorial for Special Issue: Effect of Mechanical Loading on the Tendon for Tissue Engineering Approaches

Clemens Gögele^1*Herbert Tempfer^2,3Mersedeh Tohidnezhad⁴Florien Jenner⁵Denitsa Docheva⁶

• ¹Institute of Anatomy and Cell Biology, Paracelsus Medical University Nuremberg, Germany, Nuremberg, Germany
• ²Institute of Tendon and Bone Regeneration, Paracelsus Medical University Salzburg, Salzburg, Austria
• ³Austrian Cluster for Tissue Regeneration, Vienna, Austria, Vienna, Austria
• ⁴Faculty of Medicine, Health and Medical University, Campus Düsseldorf/Krefeld, Düsseldorf, Germany
• ⁵Veterinary Tissue Engineering and Regenerative Medicine Vienna (VETERM), Equine Surgery Unit, University of Veterinary Medicine Vienna, Vienna, Austria
• ⁶Department of Musculoskeletal Tissue Regeneration, Orthopaedic Hospital König-Ludwig-Haus, University of Würzburg, Würzburg, Germany

The papers included in the Frontiers Research topic 'Effect of mechanical loading on the tendon for tissue engineering', collectively update and refine the agenda in four ways: (1) mechanobiological principles should be mapped to biofabrication workflows; (2) there is a need for smarter in vivo models and integration of AI and 3D-bioprinting; (3), strain-dependent inflammatory and fibrotic signaling must be elucidated in human tendon and ligament cells; and (4), tissue engineering benchmarks must be grounded in in vivo loading metrics should be proposed. Together, these studies argue for an integrated translational pipeline that couples physiology-inspired loading, immune-aware constructs, and rigorous functionally-relevant preclinical metrics.A short synopsis of each article published in this special issue is given bellow: Gögele and colleagues (2025) propose the central hypothesis that mechanostimulation-guided biofabrication can yield structurally and functionally superior tendon constructs. The authors concluded that successful translation of tendon mechanobiology into biofabrication requires scaffolds and bioreactors that mimic physiological cyclic stretch, frequency, and anisotropic cues that drive tenogenic differentiation and hierarchical matrix assembly. Their review synthesizes mechanosensitive pathways, cell-matrix feedback loops, and examples of cyclicstretch regimens, arguing that precise, tunable mechanostimulation should be a core design parameter of any tendon biofabrication platform. Without incorporating dynamic mechanical loading (not solely biochemical cues), engineered tendons will inevitably fail to recapitulate the mechanics and function of native tissue (Goegele et al., 2025). Aykora et al. (2025) propose the systems-level integration of harmonized in vivo models coupled with artificial intelligence (AI) and three-dimensional bioprinting to reduce the current gap between research and translation and expedite clinically significant tendon regeneration. They contend that current preclinical paradigms are fragmentated, and often limited by inconsistent loading conditions and poorly standardized endpoints. By contrast, AI-assisted analytics applied to standardized models can extract mechanophenotypes from multimodal datasets, while 3D bioprinting will provide sophisticated control over spatial cell-matrix architecture, including tendon/ligament-like tissues. The integration of modeling, computation and fabrication offers a path beyond incremental, device-centric development toward adaptive data-driven tissue engineering (Aykora et al., 2025). Heidenberger et al. (2024) demonstrate that ligamentocytes' response to mechanical strain is context-dependent, shaped by both the magnitude of loading and the surrounding biochemical environment. Physiologic dynamic strain can attenuate pro-inflammatory and profibrotic signaling, whereas excessive strain promotes inflammation and maladaptive remodeling. Moreover, the transcriptional and matrix responses to strain are modulated by cytokine context, underscoring that mechanical and biochemical cues interact rather than act in isolation. Together, these findings establish that mechanotransduction is not a passive background process but an active determinant of ligamentocyte fate. Consequently, anti-inflammatory or anti-fibrotic strategies that disregard the mechanical context may prove ineffective or even counterproductive (Heidenberger et al., 2024). Muscat and Nichols (2024) argue that in vivo tendon loading metrics should define success criteria for engineered constructs. Their review describes animal models of tendon loading and compiles reproducible mechanical and structural readouts, including strain magnitudes, loading regimens, and extracellular matrix organisation, that correlate with functional recovery in animal models. The authors emphasize that isolated molecular markers or single tensile tests are insufficient; engineered constructs must be assessed against the same loading performance and criteria for matrix alignment, stiffness, fatigue resistance and biologic integration expected of native tendons. The calls for physiologic benchmarking and preclinical pipelines that test engineered tissues under loading regimes that mirror the target biology, sets a new translational standard for tendon tissue-engineering (Muscat and Nichols, 2024). Taken together, the papers in this collection map a rational research roadmap for the next phase of tendon research and engineering: i: embed physiologic mechanostimulation into biofabrication approaches, ii: integrate AI and advanced printing to produce engineered, multiscale constructs, iii: account for immuno-mechanical crosstalk and strain-dependent cytokine responses in therapeutic development, and iv: benchmark engineered tissues against in vivo-derived mechanical and structural metrics.The next frontier is not conceptual but operational: To ensure that engineered tendons can meet the demands exerted upon native tissues, the field must standardize loading protocols, share open datasets, and couple mechanobiology with immune modulation and high-fidelity preclinical testing. Only through such integration can we ensure that engineered tendons are not merely biological imitations but functional, mechanocompetent tissues capable of enduring the demands of life.Keywords: tendon, mechanical loading, mechanostimulation, mechanosensation, biofabrication, in vitro and in vivo modeld, inflammation