Regenerative Rehabilitation Special Issue Understanding Mechanobiology: Physical Therapists as a Force in Mechanotherapy and Musculoskeletal Regenerative Rehabilitation W.R. Thompson, PT, DPT, PhD, William R. Thompson, Alexander Scott, M. Terry Loghmani, Samuel R. Ward, Department of Physical Therapy, Stuart J. Warden School of Health and Rehabilita- tion Sciences, Indiana University, Indianapolis, Indiana. Achieving functional restoration of diseased or injured tissues is the ultimate goal of both A. Scott, PT, PhD, Department of regenerative medicine approaches and physical therapy interventions. Proper integration and Physical Therapy, Faculty of Med- healing of the surrogate cells, tissues, or organs introduced using regenerative medicine icine, University of British Colum- techniques are often dependent on the co-introduction of therapeutic physical stimuli. Thus, bia, Vancouver, British Columbia, regenerative rehabilitation represents a collaborative approach whereby rehabilitation special- Canada. ists, basic scientists, physicians, and surgeons work closely to enhance tissue restoration by M.T. Loghmani, PT, PhD, Depart- creating tailored rehabilitation treatments. One of the primary treatment regimens that phys- ment of Physical Therapy, School ical therapists use to promote tissue healing is the introduction of mechanical forces, or of Health and Rehabilitation Sci- mechanotherapies. These mechanotherapies in regenerative rehabilitation activate specific ences, Indiana University. biological responses in musculoskeletal tissues to enhance the integration, healing, and restor- ative capacity of implanted cells, tissues, or synthetic scaffolds. To become future leaders in the S.R. Ward, PT, PhD, Departments field of regenerative rehabilitation, physical therapists must understand the principles of of Radiology, Orthopaedic Sur- gery, and Bioengineering, Univer- mechanobiology and how mechanotherapies augment tissue responses. This perspective sity of California–San Diego, La article provides an overview of mechanotherapy and discusses how mechanical signals are Jolla, California. transmitted at the tissue, cellular, and molecular levels. The synergistic effects of physical interventions and pharmacological agents also are discussed. The goals are to highlight the S.J. Warden, PT, PhD, FACSM, critical importance of mechanical signals on biological tissue healing and to emphasize the Department of Physical Therapy need for collaboration within the field of regenerative rehabilitation. As this field continues to and Center for Translational Mus- culoskeletal Research, School of emerge, physical therapists are poised to provide a critical contribution by integrating mech- Health and Rehabilitation Sci- anotherapies with regenerative medicine to restore musculoskeletal function. ences, Indiana University, 1140 W Michigan St, CF-326. Indianapo- lis, IN 46202 (USA). Address all correspondence to Dr Warden at: [email protected]. [Thompson WR, Scott A, Logh- mani MT, et al. Understanding mechanobiology: physical thera- pists as a force in mechanotherapy and musculoskeletal regenerative rehabilitation. Phys Ther. 2016;96:560–569.] © 2016 American Physical Therapy Association Published Ahead of Print: December 4, 2015 Accepted: November 22, 2015 Submitted: April 12, 2015 Post a Rapid Response to this article at: ptjournal.apta.org 560 f Physical Therapy Volume 96 Number 4 April 2016 Physical Therapists and Mechanotherapy egenerative medicine is an emerg- ing field that combines advances in tissue engineering and molecular Rbiology to replace or regenerate human cells, tissues, or organs with the goal of restoring or establishing normal function following loss due to injury, disease, or aging.1 Regeneration in response to injury requires the recapitulation of spe- Figure 1. cific events that occur during embryonic Mechanical forces direct cellular activities to induce tissue adaptation. Extrinsically and and fetal development, as well as a con- intrinsically generated mechanical forces load musculoskeletal tissues, with the characteristics ducive cellular milieu, so that damaged of the resultant tissue forces being dependent on the ability of the tissue to resist those forces. Tissue forces are transmitted to the micromechanical environment of resident cells, with regions are replaced with healthy tissue cellular mechanical properties influencing the characteristics of the cellular forces. Cells can that has exactly the same composition, modify their micromechanical environment via cytoskeletal rearrangement, which feeds back structure, and functional abilities as to alter cellular sensitivity to incoming forces. When cellular forces are sufficient, the cell undamaged native tissue. Unfortunately, initiates a molecular response, which ultimately alters synthesis or degradation of the extra- most musculoskeletal tissues in adults cellular matrix. The latter alters tissue mechanical properties, which feeds back to influence lack the ability to regenerate, with injury tissue forces. resulting in a repair response whereby fibrous connective tissue is laid down, forming a scar with inferior mechanical, physiologic, and functional properties. individuals who receive regenerative The success of therapies in regenerative therapies will require rehabilitation to medicine at repairing or regenerating Regenerative medicine has opened the make best use of their restored anatomy musculoskeletal tissues ultimately possibility for full healing of injured or and newly regained abilities. Physical depends on the therapies being accepted degenerated musculoskeletal tissues, therapists are specifically trained to and incorporated into the native tissue thereby offering hope for people who assess and manage musculoskeletal (eg, in the case of ex vivo grown tissues have conditions that traditionally have pathologies and thus are well positioned or bioengineered scaffolds) and creating had limited recovery potential. Examples to be important allies in musculoskeletal a musculoskeletal tissue with optimized of musculoskeletal conditions that may regenerative medicine. However, the mechanical characteristics (eg, in the benefit from regenerative medicine role of physical therapists extends case of biologic or pharmaceutical approaches include: (1) injury-related beyond the serial approach of simply agents). One group of therapies that conditions that use repair processes to reestablishing function at the organism physical therapists have in their reper- heal, such as muscle strains, ligament level following tissue healing.2,3 In par- toire that have great potential of having sprains, tendon ruptures, and integu- ticular, physical therapists have the additive, or even synergistic, effects ment wounds; (2) injury-related condi- potential to become the leaders in mus- when introduced in conjunction with tions that exhibit compromised healing, culoskeletal regenerative rehabilitation. regenerative medicine treatments is such as osteochondral defects and non- mechanotherapies. united bone fractures; (3) injury-related Musculoskeletal regenerative rehabili- conditions that have little prospect of tation can be defined as the integration Mechanotherapy healing, such as volumetric muscle loss of principles and approaches from reha- Musculoskeletal tissues are critical for and segmental bone defects; and (4) bilitation and regenerative medicine, load bearing but also generate, absorb, disease-related conditions, such as sar- with the ultimate goal of promoting the and transmit force, thereby enabling copenia, osteoporosis, and osteoarthro- restoration of function through musculo- functional movement. Given their sis. Examples of some regenerative ther- skeletal tissue regeneration and repair.4 mechanical role, it follows teleologically apies currently being used or developed This definition does not confine the role that musculoskeletal tissues are capable for these conditions include the intro- of physical therapists to restoring func- of responding and adapting to their duction of stem cells, progenitor cells, or tion after tissue regeneration or repair mechanical environment. Mechanical biologically active molecules and the but also enables therapists to play an forces direct cellular activities influenc- implantation of bioengineered scaffolds active role by facilitating regeneration ing the tissue-level processes of growth, or ex vivo grown tissues. In this article, and repair at the tissue level during heal- modeling, remodeling, and repair, with we provide a perspective of how mech- ing. In addition, the definition encour- the ultimate outcomes being altered tis- anotherapies influence the development ages therapists to contribute to the con- sue mass, structure, and quality (Fig. 1). and healing of various tissues, with a par- ception and development of novel Nearly every physical therapy interven- ticular emphasis on bone. regenerative therapies by working col- tion in musculoskeletal rehabilitation laboratively with other disciplines introduces mechanical forces, regardless As the goal of regenerative medicine is to involved in regenerative medicine in a of whether the forces are generated restore or establish normal function, team-based approach to optimize func- extrinsically via therapist intervention tional outcomes.2,3 (eg, during joint or tissue mobilization or April 2016 Volume 96 Number 4 Physical Therapy f 561 Physical Therapists and Mechanotherapy apy on the tissue-level processes respon- sible for the development, maintenance, healing, and regeneration