Clinical application of regenerative medicine is steadily advancing nowadays, and some cell therapies have already reached patients in need. However, in many cases, there are issues due to which patients were not able to adequately restore their function by just cell transplantation.Recently, the importance of rehabilitation is being revealed in the field of regenerative medicine; therefore, a new research field, Regenerative Rehabilitation, has emerged. A factor in the success of cell therapy is optimization of microenvironments both at the site of cell transplantation and around it. Rehabilitative approaches will be able to optimize one of the microenvironments such as the environment of mechanical stress and temperature. To put this into practice, we need to verify the effects of physical therapy on transplanted and endogenous cells and its mechanisms, safety, economics, and possibility for clinical application. These are the fields that physical therapists can apply their specialty and experiences on adding or modifying mechanical stress. We hope that many physical therapists will join the field of Regenerative Rehabilitation.

Autograft is a gold standard for regeneration after peripheral nerve defect but leads to donor-site dysfunction. Cell transplantation offers an alternative treatment for peripheral nerve injuries. Rehabilitation, such as ultrasound stimulation and exercise, could accelerate peripheral nerve regeneration. Therefore, a combination of rehabilitation and cell transplantation is expected to be a new strategy for peripheral nerve regeneration. In this paper, we review studies that describe rehabilitation after cell transplantation in animal models of peripheral nerve injuries. Ten studies on the combination of cell transplantation and rehabilitation were identified from PubMed. They transplanted Schwann or stem cells and conducted physical or exercise therapies as methods of rehabilitation. Either cell transplantation or rehabilitation could increase neurotrophic factors and promote nerve regeneration and functional recovery, which are better enhanced by their combination. However, there are some limitations. Compared with autograft, the effect of combination therapy is inadequate. Furthermore, differentiation of stem cells into Schwann cells is insufficient in vivo. For further advances of cell therapy to facilitate peripheral nerve regeneration, a study on optimal intensities of rehabilitation is required.

Articular cartilage injury affects many people in the world. However, the articular cartilage tissue is difficult to restore because it has not blood vessels and neurons. Recently, cell therapy has been shown to affect cartilage regeneration. Autologous chondrocyte implantation （ACI） is one of the most common therapies and also performed in Japan under the medical insurance coverage. It is reported that ACI for cartilage defects relieves pain, improves function, and restores the cartilage. Mesenchymal stem cell （MSC） therapy is also performed worldwide. MSC therapy also relieves pain, improves function, restores the cartilage like ACI. However, both ACI and MSC therapy are limited to cartilage restoration and functional recovery. Mechanical stress is an important key factor that facilitates cartilage regeneration, so rehabilitation involving mechanical stress could have synergistic effects. However, evidence on the rehabilitation program after cell therapy is still insufficient. Further verification will be necessary in the future.

Damage to the central nervous system leads to motor dysfunction and a loss of coordination, often resulting in long-lasting nursing care. Current therapeutic options include surgery, drug administration and rehabilitation as a physical therapy for central nervous system diseases, but their effects are limited, and an alternative option, such as a cell-based therapy, is desired. Previous studies suggest that cell transplantation can improve the motor dysfunction that follows central nervous system diseases such as stroke, traumatic brain injury and Parkinson’s disease. The cell survival and neuronal formation, however, are not sufficient for substantial behavioral recovery, suggesting that an additional treatment is needed. It has been shown that rehabilitation for brain damage reduces the impairment of motor function and promotes compensatory functional recovery. The therapeutic effect of a combined therapy of cell transplantation and rehabilitation is an expected novel therapeutic strategy for central nervous system diseases because rehabilitation has positive effects on graftted cells. Here, we review studies about cell transplantation, rehabilitation and their combination in animal models of stroke, traumatic brain injury and Parkinson’s disease.

Duchenne muscular dystrophy (DMD) is one of the most severe forms of muscle disorders. Muscle in DMD patients is extremely fragile and can be damaged even during normal daily activity. The disease is caused by mutations in the DMD gene that result in the loss of dystrophin protein expression. There is little in the way of treatment for the disease and no cure. Some investigators have been developing cell therapies for DMD by generating muscle stem cells from human induced pluripotent stem (iPS) cells and other progenitor/stem cells. Although reports have shown the effects of cell transplantation therapy in DMD, optimal methods that maximize the efficacy of the transplantation are still needed. Exercise is expected to enhance the effect of cell therapy for DMD, acting as a form of “regenerative rehabilitation”. We evaluated the efficacy of transplanting human myogenic progenitor cells that can express dystrophin into the skeletal muscle of DMD model mice by histological and functional analysis. We found that optimized muscle contraction training programs enhance the effect of the cell transplantation therapy. Regenerative rehabilitation could be a basis for effective cell therapy towards DMD patients.

Increasing excitability of the pathway between the primary motor cortex and the skeletal muscles might play an important role in promote functional motor recovery after central nervous system (CNS) damage. Peripheral nerve electrical stimulation (PES) effectively increases the excitability of this pathway in patients with CNS damage. Furthermore, PES combined with voluntary contraction or motor imagery is more effective than each intervention alone. However, the modulatory effect of PES on corticospinal excitability varies with the type of voluntary contraction performed. In healthy people, shortening contraction with PES increases corticospinal excitability, whereas isometric contraction with PES has no effect on excitability. On the other hand, PES parameter is a crucial factor for determining the extent of modulation of corticospinal excitability after PES. The application of train PES is a new method and is more effective than conventional PES in increasing excitability. In summary, both PES combined with voluntary contraction or motor imagery and train PES may promote functional motor recovery after CNS damage more than conventional PES does. However, further verification of the optimal parameter is necessary.

Motor imagery and imitation have been widely used in physical therapy. However, all of their neural mechanisms have been not always clarified. Understanding of their neural substrates leads to not only enhancement of the scientific evidence of physical therapy but also development in new neurorehabilitation. In this review, I would like to introduce achievements of our MEG study focused on motor imagery and imitation. Motor imagery: The relationship between M1 activity representing motor information in real and imagined movements have yet to be fully elucidated. We investigated the similarities and differences in M1 activity during real and imagined movements using MEG. Imitation: Imitation is a complex process that includes higher-order cognitive and motor function. This process requires an observation-execution matching system that transforms an observed action into an identical movement. Although recent studies have demonstrated the relationship between the neural substrate of imitation and the mirror neuron system, few studies have focused on the mechanisms of imitation from the aspect of neural oscillation. We examined oscillatory neural activities associated with imitation.

Afferent somatosensory information is modulated before the afferent input arrives at the primary somatosensory cortex during voluntary movement. We investigated the changes in gating effect by muscular contraction strength and innervated and non-innervated muscles in human using 306-channel magnetoencephalography. SEFs were recorded following the right median nerve stimulation in a resting condition and during isometric muscular contractions from 10% electromyographic activity (EMG), 20% EMG, and 30% EMG of the right extensor indicis muscle and abductor pollicis brevis muscle. Our results showed that the equivalent current dipole (ECD) strength for P35m decreased with increasing strength of muscular contraction of the right abductor pollicis brevis muscle. However, changes were observed only at 30% EMG contraction level of the right extensor indicis muscle, which was not innervated by the median nerve. There were no significant changes in the peak latencies and ECD locations of each component in all conditions. The ECD strength did not differ significantly for N20m and P60m regardless of the strength of muscular contraction and innervation.Therefore, we suggest that the gating of SEF waveforms following peripheral nerve stimulation was affected by the strength of muscular contraction and innervation of the contracting muscle.

Goal-directed movements involve representative sensorimotor control, planning, and execution, both sequentially and cyclically. An optimal motor control is necessary to minimize jerk, torque change, variance, interaction torques. Disturbance of optimal motor control may cause or exacerbate pathological pain in patients with complex regional pain syndrome (CRPS). The present review article demonstrated abnormal kinematic feature in CRPS indicating sensorimotor disturbance and pain-related fear. Then, we also demonstrated rehabilitation strategy for them based on analyzing kinematic data. While, phantom limb pain is exacerbated through altered movement representations of their phantom limb, for example, ‘my phantom limb is frozen in one or more peculiar positions’. Previously study hypothesized that visual feedback using a mirror restored the voluntary movement representation of such a ‘paralysed’ phantom limb and simultaneously improved phantom limb pain. This observation generated a working hypothesis ‘distorted movement representation of a phantom limb induces pathological pain as the alarm sign of the limb abnormality'. In the present review article, we demonstrated process of verifying the working hypothesis by using the bimanual circle-line coordination task and rehabilitation with virtual reality system. We suggest the importance of evaluating the movement representations in a quantitative way, and that structured movement representations of the phantom limb are necessary for alleviating phantom limb pain.

The purpose of this study was to clarify the safety and the effects of thermal therapy on skeletal muscle atrophy with leukemia by using model rats. Thirty Wistar rats (4 weeks old; male) were used. The rats were divided randomly into three groups; Control (n = 10), leukemia (L, n=10), and leukemia plus thermal therapy groups (L+T, n = 10). Leukemia was induced by injection of 7,12-dimethylbenz-[a]anthracene in the L and L+T groups, injection was carried out 4 times with 10 days interval. Infrared therapy device was used for thermal therapy on hindlimbs in the L+T groups. Thermal therapy was begun after end of the injection and was performed for 4 weeks (40min/day, once per 2 days). Weight, erythrocyte sedimentation rate (ESR), hematocrit, and number of white blood cell (WBC), plasma concentrations of tumor necrosis factor alpha (TNFα), plasma concentrations of LDL receptor related with 11 binding repeats (LR11), muscle RING fiber protein 1 (MuRF1), heat shock protein 72 (HSP72) and muscle fiber diameter were measured. As the result, although HSP72 level was increased in the L+T group compared with the L group, MuRF1 level and muscle fiber diameter were not changed after thermal therapy. The change of progress of leukemia by thermal therapy was not observed from the results of weight, ESR, he matocrit, WBC, TNFα, LR11. In conclusion, thermal therapy on skeletal muscle might not prevent and recover the muscle atrophy with leukemia, though thermal therapy on skeletal muscle do not affect a progress of leukemia.

Although shear wave elastography (SWE) has been used to indirectly measure passive force in muscle tissues, it is unknown whether SWE can be utilized to evaluate passive force in capsule tissues. This study investigated the relationship between the shear elastic modulus and passive force in posteroinferior shoulder capsules using SWE. Six posteroinferior shoulder capsules were dissected from six fresh-frozen cadavers; then, humeral head–capsule–glenoid specimens were created from each capsule. The humeral head and glenoid were each immobilized with clamps of a custom-built device. Passive force (0-400 g in 25 g increments) was applied to each capsule via a pulley system, and elasticity was measured simultaneously using SWE. Our data revealed that the relationship between the shear elastic modulus and passive capsule force was highly linear for all six tested capsules (p < 0.01). The mean (± standard deviation) coefficient of determination was 0.933 (±0.030; range 0.883 and 0.963). Our study demonstrated that SWE is a valid and useful method for indirectly and noninvasively evaluating the passive force of the posteroinferior shoulder capsule.

The vestibular sensory plays an important role in coordinated movement of postural stability; however, there have been few studies evaluating the vestibular function related to standing postural stability. The purposes of this study were to clarify the relationship between the modified Clinical Test of Sensory Interaction and Balance (mCTSIB) and the Galvanic Body Sway Test (GBST), and to quantitatively evaluate whether aging would have synergic effects on mCTSIB and GBST among healthy subjects. Forty-four healthy subjects underwent the mCTSIB and the GBST to examine the vestibular information related to standing postural control function. There were no significant differences between the mCTSIB and the GBST. Aging showed no significant correlated with the mCTSIB; however, aging was significantly correlated with the sway velocity in GBST (ρ = －0.413, p = 0.005). The GBST was used to assess the vestibulo-spinal reflex (VSR). This study suggested that aging might diminish the VSR function by the middle-age.