Advances in regenerative rehabilitation in the rehabilitation of musculoskeletal injuries

Abstract

In the rapidly advancing field of regenerative medicine, relying solely on cell transplantation alone may be insufficient for achieving functional recovery, and rehabilitation before and after transplantation is crucial. Regenerative rehabilitation functions by synergizing the therapeutic effects of regeneration and rehabilitation to maximize tissue regeneration and patient function. We used the keywords “regenerative rehabilitation” to search across the database for published works; this review discusses the development of regenerative rehabilitation for the treatment of musculoskeletal injuries. Rehabilitation has become a crucial component of regenerative medicine because it can enhance patients’ functional activity and facilitate their early return to society. Experimental data increasingly demonstrates that rehabilitation interventions support the regeneration of transplanted tissues.

Plain Language Summary

Regenerative medicine concepts can be incorporated into rehabilitation to help patients achieve a better functional recovery outcome. Rehabilitation therapy can help patients return to society sooner following an injury. Regenerative medicine concepts can also be integrated into regenerative therapy to maximize its benefits when compared with traditional rehabilitation or regenerative therapy alone. The development of regenerative rehabilitation for the treatment of skeletal muscle, bone and bone junction injuries is reviewed in this article.

Plain language summary

Executive summary.

Background introduction

• Regenerative medicine focuses mostly on healing bodily damage, whereas traditional rehabilitation solely considers how a physical intervention affects a person's ability to function.

What is regenerative rehabilitation?

• Regenerative rehabilitation is an interdisciplinary field that aims to restore and repair impaired organ function by integrating the viewpoints of both standard rehabilitation treatment and regenerative medicine.

Development of regenerative rehabilitation in the musculoskeletal system

• Whereas rehabilitation therapy seeks to restore functional activity, regenerative medicine seeks to repair loss of function. Improving patients’ functionality to enable them to resume their social lives is the aim of both disciplines.

Fracture healing & repair of articular cartilage & skeletal muscle repair & other growth factors at the cellular level vs. the tissue level

• Regenerative rehabilitation is being used more often to improve the success rate of regenerative therapy by restoring the tissue to its optimal operational state before regeneration therapy and by encouraging the restoration of the body's function after regeneration. This is in addition to single injections of stem cells or specific growth factors.

Conclusion

• Bone, bone connection and bone muscle make up the musculoskeletal system; the therapeutic impact can be enhanced by rehabilitation intervention when regeneration material is implanted. PRP, interfilling stem cells, mechanical stimulation, in vitro digital red light and other treatments are incorporated into the research and clinical treatment process in addition to the musculoskeletal system at the tissue-cell level.

1. Background

The rapid progress of regenerative medicine and its increasing application in clinical settings have significantly improved the care provided to patients with various acute and chronic disorders. Regenerative medicine, a multidisciplinary field that combines scientific and clinical components, employs theoretical approaches from biology and engineering to repair and regenerate damaged tissues, organs and cells [1]. The best way to treat patients while facilitating their swift return to their social lives requires immediate attention. Rehabilitation medicine aims to enhance all functional aspects, including prevention, diagnosis, assessment, treatment, training and handling of dysfunctions. It strives to eliminate and reduce patient dysfunctions and compensate for and rebuild functional deficiencies. Regenerative rehabilitation is a new cross-disciplinary field designed to meet these needs. It helps patients recover from regenerative treatments such as nerve regeneration and organ or cell transplantation by providing the necessary rehabilitation support to expedite their return to their social lives and functional activities.

2. What is regenerative rehabilitation?

Bioengineering, genomic medicine, telemedicine and regenerative rehabilitation are the four advanced technologies that constitute the Frontiers in Rehabilitation Science and Technology (FiRST) program, proposed by Steve Wolf of Emory University in 2002 at the Asia-Pacific Rehabilitation Association annual meeting. The initiative was formally established 4 years later (https://timeline.apta.org/timeline/three-new-councils-created-first-health-systems-and-prevention-and-wellness/).The first annual Symposium on Regenerative Rehabilitation was held at the University of Pittsburgh in 2011. In 2013, the University of Pittsburgh and eight other universities established the International Regenerative Rehabilitation Consortium. As of 2018, seventeen universities, including Kyoto University, had joined the consortium. The alliance is expanding rapidly, uniting research clinics with education programs to increase the number of specialists in regenerative rehabilitation.

The International Consortium for Regenerative Rehabilitation (ICRR) was founded in 2014 to advance this new multidisciplinary subject. Currently, it comprises 17 institutions globally (https://ar3t.pitt.edu/icrr/). The ICRR describes regenerative rehabilitation as “the integration of principles and methods from the fields of regenerative medicine and rehabilitation science”. Regenerative medicine involves exogenous stem cell transplantation or endogenous stem cell enhancement to replace or repair tissues lost due to disease, injury, or aging [1]. Rehabilitation science primarily focuses on promoting tissue regeneration and functional recovery through mechanical or other physical stimulation [2]. The combination of these two strategies aims to maximize patient autonomy and participation.

In the case of cell therapy, which is commonly used in regenerative medicine, success depends on the microenvironment of the graft site: providing space for the cells to survive through tissue engineering; providing sufficient nutrients, such as growth factors; adjusting the gas concentration, pH and temperature; and providing the appropriate mechanical stress [2,3]. The pretransplantation in vitro environment has been extensively explored in regenerative medicine and has proven to be very controllable, if not maximized, in order to increase transplantation success rates. The optimization of the cellular milieu post-transplantation has also been studied in tissue engineering and biochemistry, ensuring a more conducive space with adequate nutrient availability for transplanted cells. However, relying solely on cell treatment may not be sufficient for restoring the body to its normal state, which is why the ICRR developed regenerative rehabilitation. Regenerative rehabilitation employs physical therapy and noninvasive quantitative physical stimulation applied to the patient's body, triggering neurophysiological and chemical reactions. This approach is used in rehabilitation both before and after transplantation to enhance regenerative medical effects, inhibit pain and promote healing in the injured area [4].

Regenerative healing sites can benefit from rehabilitation therapies such as promoting secreted regenerative factors, facilitating stem cell entry into the circulation, guiding stem cell differentiation and mechanically and chemically modifying the local stem cell microenvironment [5,6]. Standard exercise regimens, focused mechanical therapies and external stimulation (such as electrical stimulation, low-intensity pulsed ultrasound and pulsed electromagnetic field therapy) are a few examples of these rehabilitative methods. Using these rehabilitation measures after regenerative medical procedures may improve biomechanical impacts and functional activities [7]. As a result, this multidisciplinary integration of techniques has gained increasing recognition [8], as indicated by a search of the PubMed database for “Regenerative Rehabilitation” revealing that regenerative rehabilitation has received increasing attention from 2013 to 2023 (Figure 1). In the last 5 years, the number of connected articles has climbed to 210, 294, 383, 402 and 330, correspondingly, from just 41 in 2013. The process of developing regenerative rehabilitation for musculoskeletal injuries has been outlined in this review by searching for the terms “regenerative rehabilitation” and “musculoskeletal injuries” as well as after analyzing and discussing the degree to which rehabilitation of various aspects of musculoskeletal injuries has been integrated with regenerative medicine.

Figure 1.

Annual number of publications in the field of regenerative rehabilitation.

3. Development of regenerative rehabilitation in the musculoskeletal system

Regenerative rehabilitation is increasingly being used to increase the success rate of regenerative therapy by stimulating tissues to their ideal state before the treatment and to aid in the body's functional recovery following treatment [2]. This includes applying moderate physical stimulation in addition to single injections of stem cells or specific growth factors.

3.1. Fracture healing

According to Wolf's law, “bone affects and adapts to changes in loading”. Therefore, in the context of regenerative rehabilitation for fractures or severe bone defects, the issue becomes more complicated, necessitating consideration of not only the bone itself but also the defects associated with instability, the repair tissues that bridge the defects and the vascularization necessary for effective healing [9]. Stem cell transplantation or immobilization are no longer the only options available. Previous research indicates that dynamic loading facilitates fracture healing [10] and post-transplantation, modulation promotes angiogenesis [11]. The inter-fragmentary movement (IFM) size, the loading conditions and the progenitor cells’ degree of differentiation influence the local cellular response to mechanical loading, thereby dictating the amount and caliber of the healing tissue that is generated. Thus, the production of healing tissue will be restricted if the IFM's hard fixation is minimized, but healing tissue will grow larger if the IFM's flexible fixation is increased. Although shear loading is harmful, an equivalent amount of axial pressure promotes fracture repair [12]. Therefore, the design of load-shifting fixation strategies [13] and exercise programs to promote regeneration and accelerate the patient's full recovery and return to functional activity would be made possible if the axial load that does not span the bone defect could be tracked and determined [14], as well as correlated with vascularization and repair [15].

The mechanical environment, which is influenced by the stiffness of the implant used to support and stabilize the fracture, is crucial for bone healing in fractures. If fixation is too flexible or rigid, it may lead to bone nonunion. To enhance the mechanical environment and support cartilage development, Vaida et al. suggested implementing a greater IFM during the first healing phase. This can be accomplished by stabilizing defects under low axial stiffness conditions, a concept referred to as ‘reverse dynamization’, which addresses bone flaws at low initial stiffness. By modeling the rat femur, researchers examined the impact of fixator stiffness on the healing of critical size, diaphyseal and segmental defects treated with recombinant human bone morphogenetic protein-2 (BMP-2) [16]. They discovered that stiffness modulation during the early healing stages was most beneficial. In the rat model, tissue within the defect underwent flexible or rigid fixation during the inflammatory stage of healing (3 days), at the time of cartilage scab formation (7 days) and at the time of hard bone scab emergence (14 days) to gain insights into fixation dynamics during the early stages of healing. Gene expression analysis demonstrated that the best time for applying reverse dynamization was during the early phases of inflammation and cartilage production, which is also the essential period for modifying the axial stiffness of fixation to modulate bone healing in this rat model. Subsequently, Vaida et al. [17,18] repaired all abnormalities resulting from a 1-mm mid-trochanteric osteotomy in the rat femur initially with low axial stiffness and applied reverse dynamization – involving increased stiffness – at varying intervals ranging from 3 days to 3 weeks. It was observed that increased stiffness in the fixation 7 days following surgery yielded the best results. In comparison to the other test groups, forward dynamization at day 7 had a detrimental effect on bone repair. By 3 weeks, the effect of reverse dynamization vanished, yielding identical outcomes to those under standard forward dynamization. Consequently, the study demonstrated that Wolf's law of bone adaptation is more closely followed by forward dynamization during the post healing phase and reverse dynamization for compression fixation during the pre-healing phase. In other words, improved fracture healing may be achieved through the use of regenerative scaffolds implanted during surgery, continuous passive motion during rehabilitation and healing external fixation following arthroplasty [12].

3.2. Repair of articular cartilage

The low-cellular substance known as cartilage coats the ends of the long bones in joints, facilitating painless, friction-free movement. Cartilage damage primarily occurs through two major mechanisms: trauma and osteoarthritis (OA) [19].

3.2.1. OA of the knee

The World Arthritis Association, in its 2014 guidelines, stated that exercise, together with patient education, weight loss and strength training, is the preferred rehabilitation treatment for knee OA. Mechanical stress exercise has been shown to protect the knee against articular cartilage wear and degradation in animal models of OA [20]. The joint fluid (synovial fluid) within the joint cavity determines the degree of cellular metabolism of articular cartilage, which is a nonvascular tissue. Past reports have indicated the severity of traumatic knee OA due to meniscal instability is reduced by a lack of chondrotrophic enzymes released by chondrocytes or by cell death (rather than by metabolic breakdown) of cartilage surface cells [21–23]. Consequently, mesenchymal stem cells (MSCs) are used in regenerative medicine to regenerate articular cartilage. It has been demonstrated that knee traction with extracapsular fixation enhances MSC regeneration of articular cartilage by enhancing the pericellular microenvironment and optimizing the mechanical stress environment within the joint through rehabilitative therapies such as exercise guidance and mechanical traction [19,24,25]. A study described the surgical induction of medial meniscus instability in a mouse model of OA, followed by allowing the mice to engage in running table exercise (30 min per day, 5 days per week) under various conditions for 4 weeks. The analyses included histological, immunohistochemical and micro-computed tomography analyses. The findings demonstrated that while high-intensity (21 m/min) mechanical stress accelerated proteoglycan loss and the knee OA process, moderate-intensity mechanical stress (12 m/min) decelerated the loss and delayed the knee OA process [20]. Furthermore, strength training is a crucial part of the rehabilitation process for individuals with OA, and its benefits are well known. However, it is unknown how precisely muscle strengthening might lessen pain and activity restrictions. Various mechanisms have been proposed, including neuromuscular control changes, peri-articular, intra-articular and psychosocial mechanisms or via general health [26–29]. Exercise therapy typically focuses on training muscles intrinsic to the knee, but recent research has shown strengthening hip and pelvis musculature can produce positive results in this population [30]. As a result of biochemical signals produced by physiologic mechanical stimulation of the articular cartilage, chondrocyte anabolic activity is increased. This implies that certain exercise regimens can support the regeneration or healing of cartilage in both regeneratively treated tissues and during rehabilitation.

3.2.2. Post-traumatic OA

Post-traumatic OA (PTOA), also known as traumatic arthritis and injurious osteoarthritis, is a disease resulting from trauma accompanying degenerative degeneration of articular cartilage and secondary cartilage hyperplasia and ossification as the main pathological changes, and joint pain and activity dysfunction as the main clinical manifestations. It can affect individuals of any age group, but is more common a young adults; it most often occurs in the joints that are post-traumatic, weight-bearing imbalanced and overloaded with activities. Joint replacement is the gold standard surgical procedure for PTOA, and pain control is the recommended course of treatment. Current rehabilitation treatments and strategies have not been successful in preventing or treating PTOA. Trauma is frequently associated with fractures, particularly when the fracture occurs on the articular surface or inside the joint, which potentially harms the nearby articular cartilage. For this reason, ongoing research is focused on combining articular cartilage regeneration with rehabilitative treatments.

Regenerative medicine, which uses cells and/or biologics with or without scaffolding materials to restore tissue that has been lost or destroyed as a result of trauma or illness, forms the basis of regenerative rehabilitation. Preclinical models must consider post-transplant rehabilitation because the medical process extends beyond cell transplantation or tissue construction. In contrast, post-transplant motor activity can help cells integrate and make the right connections with host tissues to enhance post-transplant success. Rehabilitation before regenerative therapies can also improve post-treatment recovery by preconditioning the individual, influencing functional activity and enhancing neural pathway conduction by promoting neuronal plasticity and improving neural synapses at the graft site [31–33]. As a result, cyclic loading is necessary for maintaining proper cartilage homeostasis [34,35]. Research has also demonstrated that this process depends on matrix transformation-associated growth factor β, a surface mechanical influence and deeper regional enzymatic regulation [36].

Gremlin-1 was injected in one study [20], which used the previously described animal model of knee OA to investigate the impact of BMP signaling on the development of PTOA following moderate exercise. In superficial chondrocytes, moderate exercise was found to increase the expression of BMP-2, BMP-4, BMP-6, pSmad-5 and DNA-binding protein-1 inhibitors. It was also found to inhibit bone redundancy growth, subchondral bone (SB) injury, osteoclast-mediated SB resorption and cartilage degradation. Thereafter, the daily amount of intense activity was increased from 30 to 60 min, and it was discovered that time had no impact on the accelerated development of PTOA. This shows that the degree of exercise intensity, rather than the duration of the activity, may affect PTOA development following surgically induced medial meniscal instability. The moderate exercise regimen adopted in this investigation (12 m/min, 30 min/day, 5 days/week) is compatible with physiological exercise loads (12–18 m/min, 30–60 min/day, 3–7 days/week) that have been demonstrated to upregulate anti-inflammatory genes and inhibit chondrocyte apoptosis [37,38]. At the same time, studies have shown that the whole body vibration (WBV) may slow the progression of cartilage loss potentially due to modulation of skeletal tissue, increasing oscillation of chondrocytes and augmenting thickness of the chondrocyte layer [39]. The amplitude is varied while the patient is either positioned orthostatically [40]. Therefore, regenerative rehabilitation programs that combine WBV exercise with regenerative medicine may lead to better treatment outcomes.

In conclusion, regenerative rehabilitation can be used in this direction to improve treatment outcomes by performing moderate exercise therapy, i.e., mechanical compression of articular cartilage, both before and after regenerative medicine interventions.

3.3. Skeletal muscle repair

The skeletal muscle is a highly malleable and dynamic tissue that reacts quickly to exercise and inactivity.

3.3.1. Skeletal muscle disuse atrophy

Skeletal muscle disuse atrophy (SMDA) refers to biochemical, morphological and functional changes in skeletal muscle due to hypokinesia or hyperfixation. For instance, bone and cartilage regeneration and rehabilitation following fracture surgery is a major topic, and the previous section provided a summary of the discussion in this regard. Recent advancements in bioreactor designs that enable multiaxial displays have provided new insights into the response of chondrocytes, chondroprogenitor cells and bone to different loading conditions, particularly shear forces. Current research on the mechanobiology of bone healing has demonstrated that healing is much accelerated when the mechanical environment of experimental bone lesions is modulated through the process of “reverse dynamization” soon after injury [12].

Conversely, muscle atrophy associated with bone is also caused by fractures or other orthopedic surgeries. Thus, histological examination, histomorphometric analysis and fluorescent labeling have been used in experimental investigations employing mouse and running table models to show that exercise protects atrophied skeletal muscle and promotes hypertrophic development of muscle fibers. Rats were familiarized with the equipment 1 week before surgery through 5 min per day at a speed of 10 m/min (interval training, between light and moderate intensity). The exercise aimed to stimulate the limbs’ bones, joints and muscles in both flexion and extension. Rats were subjected to exercise three-times a week, and the speed and duration were increased gradually from 10–15 m/min for 5 min to 20–30 m/min for 15 min (1–4 weeks), from 10–15 m/min for 5 min to 30–40 m/min for 20 min (1–8 weeks), and from 10–15 m/min for 5 min to 40–50 m/min for 25 min (1–16 weeks) to adjust the rats’ time-dependent ability to perform exercise. Rats were trained to run on a treadmill tilted gradually between 2° and 6°. Rats receiving more than five shocks during a training session were removed from the exercise. Minimal shocks (0.2 mA) were used to keep the rats from stopping when distracted. All of these procedures were closely monitored in real-time via data acquisition software. Exercise training [41] protects against sedentary-induced atrophy, although not by sustaining muscle remodeling, as indicated by an analysis of muscle fiber diameters through optical densitometry counts of double immunostaining on muscle tissue.

Robert et al. employed hydrogel dynamic fluid loading of blood vessels with loading intensities of 5, 10 and 30%. They demonstrated that functional loading has a time-dependent effect on muscle remodeling and vascular growth, with early loading being detrimental but delayed loading enhancing results [42]. This implies that after starting muscle regeneration treatments, a break is advisable before determining the type of activity to engage in. In order to locate and mark ‘motor points’ (nerve fibers that run in the muscular belly just below the surface electrical stimulation points), Naichi Chino's research used methylene blue staining and electrical stimulators on the epidermis. Specimens of intramuscular nerve fibers are analyzed using this marking method [43]. Besides the aforementioned exercise loads, electrical stimulation is often employed in the rehabilitation of disuse atrophy. The labeling method serves as a pathology search and monitors therapeutic targets, enabling a more intuitive visualization of motor unit movement and muscle fiber regeneration.

3.3.2. Volumetric muscle loss

Volumetric muscle loss (VML) is a complex issue resulting from major trauma or surgically removed skeletal muscle tissue. In military medicine, where some traumatic injuries cause severe trauma to extremities and typically involve severe soft tissue injuries that frequently result in chronic disability and persistent functional deficits, regenerative rehabilitation for VML is a primary focus. The most crucial factor in long-term function is the volumetric loss of skeletal muscle, which can result from the initial trauma (such as a blast-related to a strike or a ballistic trauma) or surgical procedures performed later in the posttraumatic care continuum (such as a fasciotomy and debridement secondary to fascial compartment syndrome). Because mammalian skeletal muscle cannot regenerate muscle fibers from scratch after a major VML injury, volumetric muscle defects constitute an especially severe type of injury [44].

Thus, studies have explored the use of extracellular matrix (ECM) in medicine to treat VML regeneration. The initial application of an extracorporeal magnetic field involved a Marine who sustained injuries from an improvised explosive device blast, resulting in chronic quadriceps VML due to an open femur fracture [45]. For soft tissue loss, a latissimus dorsi flap was used to repair the open fracture. Approximately 3.5 years after the incident, the patient showed a 72% loss of isometric knee extensor strength, despite receiving traditional physical therapy for more than 1.5 years. 4 months after the accident, knee extensor strength improved by 13% owing to the ECM implant and recovery physical therapy program, which included weight-bearing activities to restore knee function. This improvement was assessed using a Biodex isokinetic dynamometer. Nevertheless, compared with preoperative contralateral control values, 68% of strength was retained [46]. VML injuries, commonly occurring in the quadriceps or anterior region of the lower leg, lead to 60%–90% muscle tissue loss [47].

Only a small number of specialized tests have thus far adhered to a rehabilitation paradigm designed to address skeletal muscle function following VML. To eliminate about 20% of muscle mass, Aurora et al. [48] employed random wheel running in a rat model of VML in the calf triceps (CT) muscle. After 2 or 8 weeks, the animals were examined for function, with half of them starting to use the running wheel 1 week following their VML lesion. Running lengths of approximately 1.7 km/day within 7 weeks increased the foreleg muscle torque by 17% and the CT muscle mass by 13%. However, measurements of the cross-sectional area or the number of muscle fibers did not indicate any promotion of hypertrophy or hyperplasia. A distinct dystrophy-like phenotype in the muscle was demonstrated by a marked increase in the number of centrally positioned nuclei in muscle fibers. Furthermore, an experiment involving a 20% loss of muscle mass revealed a 20% loss of pseudo-synergy between the CT and extensor digitorum longus muscles. This suggests that running after VML affects the muscles’ ability to transmit force but not hypertrophy or force production.

In order to address the disease, George et al. [49] proposed a multiscale biomechanical approach, which includes imaging, kinematics, kinetics, computer modeling and muscle function testing. This approach is currently employed to study the disease and develop new medicines and rehabilitation techniques to reverse it [50]. It can be applied to population healthcare and more effectively combined with ECM regeneration therapies to increase healing rates and expedite the return of soldiers to active duty.

3.4. Other growth factors at the cellular level versus the tissue level

The approach toward musculoskeletal injury rehabilitation is increasingly utilizing regenerative treatments at the cellular and tissue levels.

Cell transplantation, survival and differentiation into mature cells are typically necessary for cellular therapies. Furthermore, transplanted cells must be further functionalized into tissues or organs and reconstituted in tissue form [3]. However, there is a dearth of clinical knowledge and research on post-transplantation therapy, or rehabilitation, which is necessary to promote post-transplantation survival, differentiation and functionalization.

Recent advancements in cell transplantation therapy have achieved significant cellular protection, functional compensatory promotion and inflammation suppression. Achieving true regeneration of lost function based on these methods is the next objective. A key aspect of achieving this objective will be finding ways to stimulate endogenous neural stem cells and transplanted cells to regenerate brain circuits.

Regenerative rehabilitation research requires interdisciplinary cooperation focused on regenerative medicine, rehabilitation medicine and engineering. As a result, the subject of connecting these fields has to be covered in the future.

3.4.1. Application of platelet-rich plasma

Newer autologous cell therapies that employ platelet-rich plasma (PRP) applications show promise in supplementing various therapy regimens in regenerative medicine. The term ‘platelet-rich plasma’ was coined by Kingsley in 1954. Many years later, Ehrenfest et al. [51] established the first categorization scheme that divided numerous PRP products into four basic categories: leukocyte poor PRP (P-PRP), leucocyte-rich, PRP (LR-PRP), pure platelet-rich fibrin (P-PRF) and leukocyte-rich PRF (L-PRF). The approach was based on three primary variables: platelet, leukocyte and fibrin content. Current studies suggest that P-PRP is more successful in treating intra-articular OA, while LR-PRP is more successful in treating tendons, ligaments and fibrous tissue.

Several high-quality systematic reviews, meta-analyses and randomized controlled trials have demonstrated the efficacy of PRP biotechnology in various medical fields, including orthopedic surgery, pain management, spinal disorders and sports medicine [52–56]. The effectiveness of PRP biotechnology has been shown in numerous medical fields, including orthopedic surgery, pain treatment, spinal problems and sports medicine, by several excellent systematic assessments, meta-analyses and randomized controlled studies. The foundation of PRP therapy lies in the observation that platelet growth factor promotes the three stages of the wound healing and repair cascade, namely inflammation, proliferation and remodeling [57,58]. When combined with other physiotherapy treatments such as ultrashort wave therapy (utrashort wave therapy is the application of ultra-high frequency alternating current to the human body with a frequency of 30 – 300MHz and a wavelength of 1 – 10 meters for therapeutic reasons. It is also known as ultra-high frequency electric field therapy or ultra-short wave electric field therapy because of the employment of capacitive electrodes in the treatment process and the primary function of the capacitive field in the treatment of continuous waves.), laser therapy and ultrasound, PRP therapy can further enhance the patient's prognosis.

3.4.2. Tryptophan, kynurenine & MSCs

In a study conducted by Pham et al. [59], L-tryptophan was injected intramuscularly into the middle of the median femur in a mouse model. The results demonstrated that L-tryptophan in vivo enhanced the migration, colony formation and osteogenic differentiation of mouse bone marrow MSCs (mBMSCs). These findings support a new function for L-tryptophan and L-kynurenine in enhancing the phenotype of BMC stem cells, potentially contributing to bone homeostasis maintenance. Therefore, L-tryptophan and/or L-kynurenine could be considered useful targets for developing novel materials and therapeutic strategies to address bone loss in tissue-specific stem/progenitor cells and the aging-related deterioration in stem cell capabilities.

Another experiment highlighted the significance of the kynurenine pathway in the osteogenic development of human mesenchymal stromal cells (hMSCs) [60]. The study emphasized the role of granulocytes as harmful cells, while monocytes were identified as being rich in growth factors. Additionally, the research demonstrated that mild mechanical stress can enhance cartilage regeneration in a prior regenerative treatment of MSCs for knee OA [18], suggesting a progressive effect.

3.4.3. Physical stimulation of the injured epidermis

Robert et al.’s translational mechanobiology research delved into strategies for promoting cell migration to wound sites and enhancing factor delivery through mechanical activation to support the production and repair of musculoskeletal tissue [61]. This includes various techniques such as electrical stimulation, manual therapy (such as joint mobilization and traction), ultrasound, stress application through tugging, the application of heat or cold to modify tissue temperature, and prescribed exercise to manage tissue loading and conditioning. Furthermore, DC electrical stimulation, in addition to mechanical pressure, has long been employed to promote stem cell migration and epidermal wound healing. In patients with peripheral nerve damage, low-frequency electrical nerve stimulation promotes targeted innervation and functional recovery [6].

4. Conclusion

Conventional rehabilitation treatment ignores the changes occurring at the cellular and molecular levels, concentrating on the body's response to physical interventions. Conversely, researchers in regenerative medicine employ sophisticated methods to induce changes at the molecular, cellular and tissue levels, frequently overlooking clinical approaches that can accomplish the same goals. Regenerative rehabilitation has emerged as a new field that integrates both perspectives.

Regenerative rehabilitation research is an interdisciplinary topic dedicated to the functional recovery and repair of injured organs. Collaboration between basic science researchers, doctors and rehabilitation specialists is crucial from the early stages of research to develop clinically applicable regenerative medicine that can effectively and efficiently maximize the restoration of patient function.

To sum up, regenerative medicine was designed to restore lacking functions, while rehabilitation medicine was developed to restore functional activity. Both fields aim to improve patient function and enable them to resume their social lives.

Regenerative rehabilitation is also expected to become popular in the future due to the use of capsule-wrapped 3D printable biomaterials, targeted injections into the disability site and in vitro digital red light-directed quantitative irradiation to stimulate the growth of specific tissues in research.

5. Future perspective

The future development of regenerative rehabilitation holds great potential and is expected to make advancements in various aspects. Here are some possible trends: Research is now being done to determine the significance of adipose granulocytes in regenerative rehabilitation. Adipose granulosa cells, which are adult stem cells abundant in adipose tissue, possess pluripotency, which enables them to develop into many cell types such as osteoblasts, chondrocytes and adipocytes. Apart from their ability to regenerate, they also possess anti-inflammatory characteristics. They release a range of growth factors, cytokines and anti-inflammatory proteins that aid in reducing inflammatory reactions and encouraging the restoration and renewal of injured tissues. Furthermore, because adipose tissue is extensively dispersed throughout the human body, obtaining adipose granulocytes doesn't need difficult or invasive surgery. Instead, it may be collected by procedures like fat adsorption or extraction. Adipose granulocytes may also be used for cell multiplication and cryopreservation, which makes regenerative rehabilitation convenient and feasible. As a result, using adipose granulocytes for regenerative rehabilitation is certain to become popular in the future. The medical profession has also benefited from advances in 3D printing technology. In the future, 3D printing will make it possible to create biomaterials that are more suited for patient customization, leading to improved regenerative rehabilitation options. Neural interfaces, which link computers to the human brain without the need of sensors and electrodes, are another hot issue in brain-computer interfaces right now. More sophisticated brain interfaces could be available in the future to aid in the restoration of motor and sensory capabilities in transplanted bodies.

Funding Statement

Shanghai Science and Technology Commission “Science and Technology Innovation Action Plan” Biopharmaceutical Support Project (19441908400).

Author contributions

Z Zhang: conceptualization, writing-original draft, investigation, search literature and analyze results. P Yao: supervision, writing, review & editing. S Fan: project administration, writing, review & editing.

Financial disclosure

Shanghai Science and Technology Commission “Science and Technology Innovation Action Plan” Biopharmaceutical Support Project (19441908400).

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data availability statement

This is a review paper with no experimental data.