Decoding tissue repair
October 1, 2026
At the AO Research Institute Davos (ARI), researchers are studying physiological joint motion can activate key biological signaling pathways involved in cartilage repair. Their findings shed light on a known principle in regenerative medicine: successful tissue regeneration not only depends on cells and growth factors, but also on the mechanical environment in which healing takes place.
Cartilage is designed for movement. It withstands years of compression, sliding, and shear within load-bearing joints, yet once damaged it has only a limited capacity for self-repair.
For researchers at the ARI, this presents an important challenge and a unique opportunity: Many laboratory models used to study cartilage regeneration are static, while tissue repair in patients takes place within moving joints. Understanding how biological signals respond to mechanical forces is therefore critical to developing more clinically relevant models.
One of the most important signaling molecules involved in cartilage formation is transforming growth factor beta (TGF-beta). Traditionally, TGF-beta has been added to cell cultures in the laboratory in an active form to stimulate cartilage-like tissue formation. However, when cells make TGF-beta in the body it is released in an inactive form (latent TGF-beta) that needs to be switched on. While how much TGF-beta the cells make is a routinely asked question, ARI researchers have been exploring a different problem: How is this latent TGF-beta turned on, and can movement itself activate these pathways?
“We know from treating patients the rehabilitation afterwards is really important. So it made sense to us to mimic the loads in the laboratory to see how it changes the outcome,” said ARI Vice-Director Martin Stoddart, who leads the Regenerative Orthopaedics program.
Recreating joint motion in the laboratory
To investigate this, ARI scientists developed bioreactor systems that expose engineered cartilage constructs to controlled compression and shear forces that mimic key aspects of joint motion.
For its research, the ARI developed a16-sample bioreactor that enables higher-throughput testing under joint-like loading conditions. By loading cell-free scaffolds with latent TGF-beta, the researchers showed that mechanics alone can activate TGF-beta. In a next step, using human mesenchymal stromal cell (MSC) seeded scaffolds, they demonstrated that mechanical loading activated endogenous TGF-beta 1 signaling, increased chondrogenic gene expression, and promoted the formation of cartilage-like matrix tissue without the need to add TGF-beta into the culture medium.
“This was really exciting,” said Stoddart. “It showed that we can turn on a growth factor purely by mechanics and obtain a biologically relevant result. As far as we know, it is the only example of a mechanically activated growth factor, and this links well with what we know about bone and cartilage repair in patients.”
These findings build on more than a decade of ARI mechanobiology research showing that movement is not simply a mechanical stimulus. Under the right conditions, mechanical forces can act as biological signals that influence cell behaviour and tissue development.
Looking beyond growth factor supplementation
In a recent study published in the Journal of Translational Medicine, ARI researchers investigated whether pre-conditioning MSCs with TGF-beta 1 before tissue engineering could improve cartilage formation.
“We previously showed that preconditioning MSCs with TGF-beta1 could boost non-responsive cells and make them able to differentiate into cartilage like cells. Within this study we looked at more detail at how preconditioning affected responder cells and how loading changes the outcome,” Stoddart explained.
While some effects were observed in conventional static culture systems, the approach did not improve outcomes in a three-dimensional mechanically induced cartilage model.
The findings reinforce a key message emerging from the ARI's work: biological responses observed in static laboratory conditions may not necessarily translate to environments that more closely resemble those encountered in patients.
Towards regenerative rehabilitation
The broader significance of this research extends beyond cartilage engineering. Across musculoskeletal regeneration, scientists increasingly recognize that biology and mechanics function together.
For clinicians, the immediate implication is not a new treatment protocol, but a stronger rationale for studying rehabilitation as an integral part of tissue repair. By investigating how mechanical forces influence endogenous signaling pathways such as TGF-beta, ARI researchers are helping build the evidence needed to better understand how rehabilitation, biomaterials, and regenerative therapies may one day be optimized together.
Stoddart is hopeful that the ARI’s bioreactor research can contribute to better patient rehabilitation in the future: “Linking therapies to rehabilitation protocols will be crucial in obtaining the best result possible. Bioreactors offer the opportunity to investigate simple questions such as when should the load be initiated and for how long should the load be applied? Studies such as these a pretty difficult to perform in animal models or clinical trials but we can answer them with human cells.”
Why it matters
- Bridging laboratory research and clinical reality
The ARI's bioreactor systems help recreate the dynamic environment of a joint, reducing the gap between laboratory models and patient conditions. - Understanding endogenous TGF-beta activation
Mechanical loading can activate naturally occurring TGF-beta signaling pathways and support cartilage-like tissue formation without relying solely on externally added growth factors. - Supporting rehabilitation research
The findings strengthen the rationale for studying how postoperative loading and joint motion influence tissue repair and regeneration. - Enabling more scalable preclinical research
The ARI's multi-well bioreactor allows researchers to test cells, biomaterials, and loading protocols more efficiently under clinically relevant mechanical conditions.