Using load to improve tendon/ligament tissue engineering and develop novel treatments for tendinopathy

New research according to Tam and Baar (2025) highlighting tendons and ligaments are among the many most frequently occur- ring but poorest-healing injuries in the body, and standard treatments—e.g., immobilisation, which remains unchanged for centuries—often lead to degeneration not regeneration of functional tissue. Scars exhibit disorganised collagen, more narrow fibre with decreased cross linking compared to the two populations of fibrils present in healthy tendons (35 nm and 150 nm in diameter). Molecular factors such as

TGFβ, EGR1 and MMPs influence development and pathology and mechanical forces (tension, compression, shear) are also critically important for tissue remodelling. In development, tendons and ligaments remodel according to mechanical stimuli, becoming transcriptionally and functionally differentiated. Transcription factors including scleraxis (Scx) start collagen production (Col1a1) and after birth it is load-activated mohawk (Mkx) that pushes fibrils through their maturation. Neonatal tendons regenerate, but following injuries in adults, the tissue is structurally aberrant and exhibits degenerative, hyper cellular

features that do not resemble normal tendon or developing tendon. It is interesting to note that healing process in MRL mice is hypertrophied decadency due to reactivation of developmental programs, implying that, if the same system can be harnessed in humans, then regeneration in humans can also be achieved.

Challenges in tissue engineering include that auto grafts result in donor site morbidity, whereas allografts are at risk for rejection. Tissue fabrication technology is not yet at the point of producing similar tissue to this mature, functional kidney. Efficient methods should mimic the physical environment, which controls developmental paths, mechanically applying loading to induce collagen to align, (e.g., to suppress scar formation).

Early mobilisation leads to the best results including joint motion and tendon gliding, but immobilisation remains common clinically.

Key challenges include:

1. Mechanical Signalling: Load dependent pathways (e.g., Mkx) are critical for maturation but are less well understood in healing.

2. Scar vs. Regeneration Embryonic tendon (small fibrils, high cellularity) in Scar cannot mature. COLIII, which is rich in scars, is an end product of unsuccessful repair, rather than the cause of the failure of repair.

3. Environmental Adaptation: Tendons differ by function (e.g., energy storing vs position holding), and need tissue-specific strategies to modify healing. Whereas fibrocartilage is created at compression-vulnerable enthuses, lubricin is associated with shear-prone gliding surfaces.

4. Intervention: Early deep loading may facilitate healing; dynamic loads may be initiated later. DE tensioning or stress-shielding (e.g., from abnormal cross links) is a cause of degeneration.

   
   

Future Directions

1. Targeted Loading: Replace immobilization with staged mechanical signals (creep, and then dynamic loads) to direct regeneration.

2. Developmental Recapitulation: Use Scx/Mkx pathways to shift scar in the direction of regenerative programs.

3. Engineered Tissues: Minic native mechanical environment to promote maturation.

4. Translational Studies: Provide the bridge between MRL mechanism and humans therapies.

   
   

Overall, breaking down these barriers could revolutionise tendon and ligament repair, bridging biomechanics, molecular biology and tissue engineering to restore function in millions.

Reference

Tam, K. T., & Baar, K. 2025. Using load to improve tendon/ligament tissue engineering and develop novel treatments for tendinopathy. Matrix biology : journal of the International Society for Matrix Biology, 135, pp. 39–54. https://doi.org/10.1016/j.matbio.2024.12.001