On the Horizon From the ORS
Regenerative rehabilitation is the convergence and integration of regenerative medicine and physical rehabilitation sciences.1 Physical therapy (PT) is essential to support the return to function of a damaged or repaired tissue. However, the specific effects of PT down to the cellular level of regeneration are largely unexplored.2 Conversely, when thinking of regenerative approaches, the mechanical environment that cells and scaffolds must withstand in orthopaedic repair is often regarded as a challenge that needs to be endured or overcome rather than as an opportunity that can be leveraged. In tissue engineering, cellular mechanobiology is more often studied to promote the maturation and the three-dimensional organization of engineered constructs, ranging from aligned muscled fibers to the zonal organization of chondrocytes. Regenerative rehabilitation can then be appreciated as an approach to translational mechanobiology, in which the mechanical cues driving cell differentiation and function are directed by rehabilitation routines to promote repair and regeneration.3,4
Bone is well known to respond and adapt to changes in load (Wolff's law). However, during regeneration after fracture or critical bone defects, the picture becomes more complex, as there is not just the bone to account for but also a defect with associated instability, the repair tissue that bridges the defect, and vascularization that is required for effective healing. Ambulatory loads have been found to promote fracture repair5 and to regulate angiogenesis,6 so if the axial loads across bone defects can be monitored7 and related to vascularization and repair,8 this would allow us to design fixation strategies that transfer loads9 and ambulatory exercises so as to promote regeneration and ideally accelerate a full patient recovery. The stability of the fracture fixation has a direct influence on whether fracture repair is achieved by way of endochondral ossification or direct intramembranous healing, and this can be modulated by the loads applied during the rehabilitation period.
When stem cells are used to support healing of muscle injury, exercise-driven mechanical activation supports proliferation of the transplanted stem cells and their effective repair of the injured muscle.4 For larger volumetric muscle loss, in which scaffolds are combined with stem cells for repair, exercise regimens enhance both force production and innervation of the engineered construct.10 Robotic platforms could then be developed to monitor muscle impairment and administer tailored training during the recovery process to enhance repair and overall motor performance.11
Normal cartilage homeostasis is reliant on cyclical loading, and this has been associated in part with mechanical activation of matrix-associated transforming growth factor-β. Within native cartilage, this is thought to be strongly influenced mechanically at the superficial zone12 but enzymically regulated in the deeper zones.13,14 Chondrogenic differentiation of human bone marrow–derived mesenchymal stromal cells, such as those that would be present during microfracture, can be induced in vitro by mechanical forces alone,15 and a similar response has been observed in human articular chondroprogenitor cells.16 This is due to the production and activation of endogenous transforming growth factor-β, a process that, in part, is regulated by the application of shear.17-19 Such mechanistic knowledge at the protein and cellular level provides the opportunity to devise rehabilitation protocols based on a strong underlying scientific rationale.
The joint as a whole, however, consists of more than just articular cartilage. In fact, the joint is an organ comprising multiple tissues—bone, cartilage, synovium, meniscus, ligaments, and infrapatellar fat pad—all of which interact and influence each other.20,21 More generally, in considering the musculoskeletal system, one should not approach it as evaluating each tissue in isolation, but rather should regard it as a continuum of components, all tightly connected and transitioning from one to the next via the osteochondral junction, the enthesis, and so on.22 The development of proregenerative rehabilitation regimens should then account for load transduction across tissue interfaces20 and for the different mechanobiological responses of each tissue.
Overall, PT has been used for years in orthopaedics to promote tissue repair and return to function. However, the cellular signaling and mechanistic relation between exercise and cellular responses are still far from being fully appreciated. Better understanding of these underlying mechanisms would allow us to design the rehabilitation protocol based on empirical data, focusing on the integration with regenerative medicine to enhance patients' outcomes.3,23 The development of assistive devices to monitor the progression of tissue repair and guide accordingly the delivery of proregenerative mechanoactivation stimuli could greatly enhance the research in regenerative rehabilitation and the delivery of personalized regenerative treatments.
Dr. Gottardi acknowledges support from the Ri.MED Foundation and Alliance for Regenerative Rehabilitation Research & Training (AR3T) through NIH Grant no. P2CHD086843. Dr. Stoddart acknowledges support from the AO Foundation and Swiss National Science Foundation Grant 31003A_179438/1.
References printed in bold type are those published within the past 5 years.
1. Ambrosio F, Boninger ML, Brubaker CE, et al.: Guest editorial: Emergent themes from second annual symposium on regenerative rehabilitation, Pittsburgh, Pennsylvania. J Rehabil Res Dev 2013;50:vii-xiv.
2. Ambrosio F, Wolf SL, Delitto A, et al.: The emerging relationship between regenerative medicine and physical therapeutics. Phys Ther 2010;90:1807-1814.
3. Rando TA, Ambrosio F: Regenerative rehabilitation: Applied biophysics meets stem cell therapeutics. Cell Stem Cell 2018;22:306-309.
4. Ambrosio F, Ferrari RJ, Distefano G, et al.: The synergistic effect of treadmill running on stem-cell transplantation to heal injured skeletal muscle. Tissue Eng A 2010;16:839-849.
5. Glatt V, Evans CH, Tetsworth K: A concert between biology and biomechanics: The influence of the mechanical environment on bone healing. Front Physiol 2017;7:678.
6. Ruehle MA, Krishnan L, LaBelle SA, Willett NJ, Weiss JA, Guldberg RE: Decorin-containing collagen hydrogels as dimensionally stable scaffolds to study the effects of compressive mechanical loading on angiogenesis. MRS Commun 2017;7:466-471.
7. Klosterhoff BS, Ghee Ong K, Krishnan L, et al.: Wireless implantable sensor for noninvasive, longitudinal quantification of axial strain across rodent long bone defects. J Biomech Eng 2017;139:111004.
8. Boerckel JD, Uhrig BA, Willett NJ, Huebsch N, Guldberg RE: Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc Natl Acad Sci U S A 2011;108:E674-E680.
9. Pobloth AM, Checa S, Razi H, et al.: Mechanobiologically optimized 3D titanium-mesh scaffolds enhance bone regeneration in critical segmental defects in sheep. Sci Transl Med 2018;10:eaam8828.
10. Quarta M, Cromie M, Chacon R, et al.: Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss. Nat Commun 2017;8:15613.
11. Lai S, Panarese A, Lawrence R, Boninger ML, Micera S, Ambrosio F: A murine model of robotic training to evaluate skeletal muscle recovery after injury. Med Sci Sport Exerc 2017;49:840-847.
12. Albro MB, Nims RJ, Cigan AD, et al.: Accumulation of exogenous activated TGF-β in the superficial zone of articular cartilage. Biophys J 2013;104:1794-1804.
13. Madej W, van Caam A, Blaney Davidson EN, van der Kraan PM, Buma P: Physiological and excessive mechanical compression of articular cartilage activates Smad2/3P signaling. Osteoarthr Cartil 2014;22:1018-1025.
14. Albro MB, Nims RJ, Cigan AD, et al.: Dynamic mechanical compression of devitalized articular cartilage does not activate latent TGF-β. J Biomech 2013;46:1433-1439.
15. Li Z, Kupcsik L, Yao S-J, Alini M, Stoddart MJ: Mechanical load modulates chondrogenesis of human mesenchymal stem cells through the TGF-β pathway. J Cel Mol Med 2010;14:1338-1346.
16. Neumann AJ, Gardner OFW, Williams R, Alini M, Archer CW, Stoddart MJ: Human articular cartilage progenitor cells are responsive to mechanical stimulation and adenoviral-mediated overexpression of bone-morphogenetic protein 2. PLoS One 2015;10:e0136229.
17. Gardner OFW, Fahy N, Alini M, Stoddart MJ: Joint mimicking mechanical load activates TGF-β1 in fibrin-poly(ester-urethane) scaffolds seeded with mesenchymal stem cells. J Tissue Eng Regen Med 2017;11:2663-2666.
18. Schätti O, Grad S, Goldhahn J, et al.: A combination of shear and dynamic compression leads to mechanically induced chondrogenesis of human mesenchymal stem cells. Eur Cel Mater 2011;22:214-225.
19. Albro MB, Cigan AD, Nims RJ, et al.: Shearing of synovial fluid activates latent TGF-β. Osteoarthr Cartil 2012;20:1374-1382.
20. Lozito TP, Alexander PG, Lin H, Gottardi R, Cheng AW-M, Tuan RS: Three-dimensional osteochondral microtissue to model pathogenesis of osteoarthritis. Stem Cel Res Ther 2013;4 suppl 1:S6.
21. Nichols DA, Sondh IS, Litte SR, Zunino P, Gottardi R: Design and validation of an osteochondral bioreactor for the screening of treatments for osteoarthritis. Biomed Microdevices 2018;20:18.
22. Alexander PG, Gottardi R, Lin H, Lozito TP, Tuan RS: Three-dimensional osteogenic and chondrogenic systems to model osteochondral physiology and degenerative joint diseases. Exp Biol Med 2014;239:1080-1095.
23. Ambrosio F, Kleim JA: Regenerative rehabilitation and genomics: Frontiers in clinical practice. Phys Ther 2016;96:430-432.