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Abstract

Dramatic changes in the health care landscape over the next few decades undoubtedly will affect rehabilitation specialists' practice. In the multidisciplinary field of regenerative medicine, cell, tissue, or organ substitutes are used to enhance the healing potential of the body. Given that the restoration of normal functioning of injured or diseased tissues is expected to be the ultimate goal of these therapies, the future of regenerative medicine is, undeniably, tightly intertwined with that of rehabilitation. Rehabilitation specialists not only must be aware of cutting-edge medical advances as they relate to regenerative medicine but also must work closely with basic scientists to guide the development of clinically relevant protocols. The purposes of this article are to provide a current perspective on biological approaches to the management of musculoskeletal disorders and to highlight the needed integration of physical therapeutics with regenerative medicine.

Physical rehabilitation optimizes the quality of life for people with limitations imposed by functional loss resulting from disease or trauma. The practice of physical therapy has continued to change as scientific and technological innovations have guided clinical practice. As early as 300 bc, there was evidence of the development of orthotic and prosthetic devices to compensate for the function of an amputated limb.1 The design of prostheses has changed dramatically over time, and rehabilitation specialists now commonly work closely with prosthetists to maximize the reacquisition of limb function.

Physical therapist practice continues to evolve, and the regeneration of an amputated limb, much in the same way that a salamander regrows a limb after amputation, someday may replace the prosthetic approach. As has been our tradition, basic scientists must work in partnership with scientists to develop cutting-edge medical advances for the treatment of musculoskeletal disorders. Here we highlight recent advances in regenerative medicine and suggest an immediate need for the consideration of physical therapeutics in the development of biological therapies for the management of musculoskeletal diseases and injuries.

Regenerative Medicine: Medicine of the Future Is Now in the Present

The goal of regenerative medicine is to help the body heal itself more effectively. When tissue healing is significantly impaired, because of aging or disease or because an injury is so extensive, regenerative medicine approaches may be indicated. In regenerative medicine, cellular, tissue, and organ substitutes are developed to restore biological function that has been lost to age, disease, injury, or congenital abnormalities.2 This definition is so broad that subdividing the field into clusters to bring together scientists with overlapping backgrounds is important. Here we describe relevant advances in medical devices and artificial organs, material therapies and biomaterials, and cellular therapies.

Medical Devices and Artificial Organs

In cases of end-stage organ failure, transplantation of the entire organ may be indicated. An artificial organ is a manufactured device that replaces the natural organ to restore system function. The development of artificial organs is becoming increasingly important because the number of patients on waiting lists for organ transplantation far exceeds the number of donors. As of December 2009, there were 107,869 candidates on waiting lists for organ transplantation; as of May 28, 2010, there were 2,221 donors.3

To address this growing need, considerable efforts have been dedicated to designing optimal materials for the development of artificial organs. Several considerations ultimately will determine therapeutic efficacy. For example, if the host perceives the transplanted device to be a foreign surface, it will rapidly initiate the coagulation or inflammatory cascade; this situation could place the patient at risk for serious complications, such as an embolus or even organ rejection. Moreover, the device must not readily degrade in the body, subsequently releasing artificial particles into the bloodstream. The ability of the device to respond to physiological stressors also is important. How well an artificial device, such as a heart, can work together with the body in response to physical activity, for example, may dictate the patient's return to daily activities. Along these lines, the administration of graded exercise tests may become important in the assessment of artificial device integration into the host.

A concern about replacement therapies is that the underlying regenerative potential of organs being considered for excision may be overlooked. With this concern in mind, we propose that the development of organ assistive devices that facilitate resident organ regeneration by enhancing the intrinsic self-renewing ability of the damaged tissue or organ system is necessary and important. Perhaps a large number of patients burdened with a wide variety of organ insufficiencies may be better served by the development of treatment modalities that embrace a historic principle of medicine: optimization of the regenerative potential intrinsic to many organ systems. Such an approach must include a detailed characterization of the disease process and organ failure, the design of organ-supportive devices and techniques and, finally, the implementation of quantitative models to guide and inform the management of organ healing.

Where does the field of rehabilitation fit into this process? Physical therapeutics has foundations in the application of targeted mechanical stimuli designed to enhance intrinsic healing potential. Therefore, to maximize a functional interaction between hosts and donor devices, rehabilitation programs should similarly be positioned to play an important role in the optimization of posttransplant recovery. To maximize the intrinsic healing of the host and to help integrate donor transplants in a useful and functional way, the application of training protocols or graded exercise programs may help to recapitulate normally occurring developmental sequences at the donor-host interface.

Material Therapies and Biomaterials

In cases of large tissue defects, the application of extracellular matrixes, or scaffolds, may guide the healing process of the host. Such tissue engineering approaches provide support for the body to heal itself using a biologically inductive, 3-dimensional construct. For example, in the case of a peripheral nerve injury, large gap defects result in an inability of the residual nerve buds to rejoin and regenerate into a functional structure (reviewed by Ide4). The application of a scaffold or channel provides a conduit for communication between the nerve ends; in animal models, this technique has resulted in significantly improved healing (reviewed by Subramanian et al5). Important attributes of a scaffold are its inherent biologically inductive properties, which facilitate better healing by the host, and its capability for rapid degradation within the host.68

Badylak et al9,10 designed a tissue engineering construct comprising the same structure as the body's naturally occurring scaffold material, extracellular matrix (ECM). In the case of a large tendon defect, the ECM provides a supportive medium for vessel and collagen growth,9,10 and degradation of the scaffold over time triggers the formation of natural tissue in its place.6,9,11 The time course of tendon regenerative events after the application of an ECM scaffold obtained from the small intestinal submucosa has been well characterized6 and is illustrated in the Figure. The presence of donor ECM also appears to promote the infiltration of progenitor cells and bone marrow stem cells into the site of injury,11,12 a phenomenon associated with an enhanced regenerative response after injury.

Figure.

Demonstration of tendon gap injury repair after the application of a small intestine submucosal (SIS) extracellular matrix scaffold. bFGF=basic fibroblast growth factor, TGF-β1=transforming growth factor β1, VEGF=vascular endothelial growth factor. Based on Gilbert et al.6

Early mobilization after the application of an ECM scaffold appears to play an important role in the beneficial effect of scaffold remodeling on tendon tissue regeneration13 and may assist in the recruitment of circulating growth factors and progenitor cells to the injury site. Given that revascularization of the treated area is critical to promote tissue healing, scaffolds offer the further advantage of possessing angiogenic properties,1416 which also are related to mechanical loading.13 This fact begs the question of whether the application of a targeted rehabilitation modality, such as a chronic, low-intensity electrical stimulation protocol designed to target therapeutic angiogenesis,1719 may work synergistically with an ECM scaffold to further enhance treatment efficacy. Investigations of such possibilities should be conducted early in the development of these biological therapies to hasten clinical translation and optimize functional relevance.

Cellular Therapies

Cellular therapies traditionally involve the introduction of cells into a targeted system or tissue to promote a desired response. The overarching goal is to replace or restore tissue reparative functions that have been lost because of injury, the aging process, or disease. Transplanted cells may act as pharmacological agents, exerting paracrine influences or stimulating the cytokine secretion of donor cells to modulate the host's regenerative response.20 Alternatively, transplanted donor cells themselves may regenerate host tissue. Aged skeletal muscle serves as an example. Aged muscle is characterized by a significant decrease in both the local secretion of critical growth factors, such as vascular endothelial growth factor (VEGF),21,22 and the number of cells responsible for muscle regeneration (muscle stem cells).23,24 Together, these deficits result in a considerably diminished healing potential of aged muscle. Cell-based strategies hold promise. The transplantation of cells may restore the regenerative potential of aged muscle, either by enhancing the local secretion of critical growth factors or by restoring the reservoir of regenerating cells.

In particular, interest in the clinical use of stem cells (the basic building blocks of the body's regenerative processes) to enhance the regenerative potential of tissue has grown. Stem cells have the capacity to repair or replace tissue that has been damaged because of injury or disease. Stem cells are distinguished, in part, by the fact that they are not specialized, but have the capacity to become specialized tissue, such as bone, cartilage, or muscle. Moreover, stem cells can undergo many cell division cycles in an undifferentiated state. Although stem cells are commonly associated with embryonic tissue, advances in the field of stem cell biology have determined that there are populations of stem cells that persist throughout adult life.20,25,26 Such cells offer the advantages of eliminating many of the ethical concerns about embryonic stem cells and being readily accessible from bone marrow, muscle, and other tissue.

Given the inherent ability of stem cells to differentiate into multiple tissue lineages, the potential of stem cell therapy to be the “ultimate repair toolbox” for spinal cord repair after injury, recovery from a traumatic brain injury, or even severe skin wounds and burns is promising. As investigators venture into these exciting areas, new questions undoubtedly will arise. Can we ensure that the delivery of these cells will not heighten the risk for tumor formation, as has been suggested?27 How can we ensure that these cells behave in the intended manner and result in functional tissue recovery after transplantation?

These examples illustrate the many approaches and considerations in the development of clinically relevant regenerative medicine strategies. There is substantial evidence that exercise, mechanical stimulation, or both will play a critical role in the success of neurogenerative and musculoskeletal regenerative therapies. For the remainder of this review, we concentrate on the potential use of physical therapeutics in the application of cellular therapies.

Common Barriers in the Development of Cellular Therapies

Some key features determining the success of stem cell therapy, once introduced into the host, include the abilities of stem cells to survive and divide after transplantation, migrate to the site of interest, and effectively differentiate into the targeted tissue of interest (reviewed by Bongso et al28). Donor stem cell regenerative potential is affected by sex,29 age,25,30 and disease state.3133 Deasy et al29 found that muscle stem cells isolated from male mice had a significantly decreased myogenic capacity compared with those from their female counterparts, a difference largely attributed to the male cells' relatively decreased resistance to stress. The upregulation of cellular resistance to stress enhances the transplantation efficiency of donor cells.34 In a study by Urish et al,34 the antioxidant levels of muscle stem cells obtained from mice were upregulated, resulting in a significantly increased myogenic engraftment of donor cells after transplantation. Similarly, in individuals with diabetes, endothelial progenitor cells display a significantly decreased capacity for angiogenesis compared with counterparts without diabetes.33,35 This impaired angiogenic response also was linked to decreased endothelial progenitor cell resistance to stress.36 Fortunately, these changes are reversible, and modulation of the critical pathways determining progenitor resistance to stress restores cellular functionality and results in the attenuation of diabetes.37,38

Many of the critical factors determining the success of cell transplantation in murine models have been linked to the host microenvironment, or niche. For example, mouse embryonic stem cells, which typically demonstrate exquisite regenerative potential and resistance to stress, rapidly assume an aged phenotype once transplanted into an aged muscle environment.39 This occurrence is evidenced by increased scar tissue formation and decreased myogenic differentiation of the embryonic donor cells.39 On the other hand, modulation of the aged muscle environment by exposure to a young systemic environment actually rejuvenates the regenerative potential of very old cells.30,40 Niche modulation of aged, injured, or diseased tissue has long been thought to be a prerequisite for successful stem cell transplantation.31,41 Although traditional approaches have involved gene therapy or direct growth factor injection to modulate the niche, these approaches have cost, safety, or feasibility issues that may limit their clinical application. Noninvasive, inexpensive methods to enhance the stem cell microenvironment are clearly of clinical importance.

Can Stem Cells and the Stem Cell Environment Be Rehabilitated?

Evidence from recent studies4244 has suggested that many of the characteristics dictating cellular function, including cellular division, survival, resistance to physiological stress, and the microenvironment, are modifiable through the application of targeted loading approaches. Mechanical stimulation modulates the cellular niche, and the use of forces can help the donor cells integrate into the body in a useful and functional way. Although the traditional approach to stem cell transplantation has been to introduce the cells into the host and hope for the best response, the application of targeted mechanical stimuli provides a means for communication with the cells after transplantation. Such an approach allows scientists to direct the cells to perform in vivo in the intended manner. Both in vitro and in vivo, stem cells are amenable to modulation by external mechanical forces (G. Distefano, C.M. Weiss, R.J. Ferrari, et al, unpublished data, 2010).4345 The application of exercise helps both to recruit the donor cells to the site of interest44 and to stimulate the activity of endogenous stem cells4648; these effects may be the result of increased growth factor secretion within the exercised area. A few tissue-specific examples of how the integration of rehabilitation may be beneficial in the development of regenerative medicine strategies are provided below.

Skeletal Muscle

Duchenne muscular dystrophy is an X-linked disease that affects 1 in 3,500 boys. The absence of a functional dystrophin protein, which provides support to muscle fibers,49,50 renders the skeletal muscle of children with this disease incapable of withstanding loads typical of everyday activities. This decreased loading capacity triggers a continuous degeneration-regeneration cycle of dystrophic muscle and eventually exhausts the muscle stem cell pool. Gradually, the skeletal muscle becomes replaced with noncontractile scar and adipose tissue. Failure of the heart or diaphragm typically results in death by the second or third decade of life.

Cellular therapy has been proposed as a means both to deliver dystrophin to dystrophin-deficient fibers and to restore the muscle stem cell pool.51,52 Unfortunately, the clinical translation of this therapy has been limited by massive cell death after transplantation53,54 and by minimal functional improvements in the contractile capacity of transplanted muscle.54,55 In the laboratory, to recruit and stimulate increased participation of donor cells in host tissue, scientists commonly induce an in vivo muscle injury, for example, through a myotoxin injection. This approach is clearly not desirable for use in patients. Research in our laboratory has demonstrated that the application of a muscle loading protocol elicits a similar increase in the myogenic contribution of transplanted donor cells.42,43 Coupling the intramuscular injection of donor cells with mechanical stimulation has been shown to significantly increase the contribution of transplanted cells to muscle regeneration and to increase engraftment efficiency.4446 More importantly, this enhanced engraftment is functionally relevant; transplantation of muscle stem cells into dystrophic mouse muscle resulted in increased resistance to overloading-induced muscle weakness.43

Future studies should investigate how the application of targeted mechanical stimulation protocols can further refine the integration of donor and host components toward the restoration of normal skeletal muscle behavior. Just as the success of orthopedic surgery is largely reliant on effective rehabilitation programs after surgery, the need to implement targeted rehabilitation programs soon after stem cell transplantation to maximize functional outcomes is clear.

Cardiac

For the application of cellular therapies to myocardial infarction, the secretion of VEGF, the most potent stimulator of angiogenesis, is critical in determining the functional contribution of transplanted cells.56,57 Accordingly, scientists have worked to genetically engineer donor cells to overexpress the growth factor of interest before transplantation into the host.56,58 In fact, stem cells engineered to secrete higher levels of VEGF have been associated with increased restoration of cardiac function and decreased scar tissue formation.56 However, caution must be taken with such approaches because, once the stem cells are transplanted into the body, the excessive secretion of VEGF has been shown to result in hematoma formation.56 Therefore, growth factor expression must be carefully adjusted to minimize adverse events. Moreover, although the genetic modulation of transplanted cells to overexpress VEGF does result in a significant increase in blood vessel formation,58 the resulting vessels have been shown to be “leaky” and may not elicit the same functional response as physiological angiogenesis.59

Physical therapeutics, on the other hand, offer a clinically relevant and physiologically appropriate model for stimulating VEGF secretion and may increase donor cell participation in cardiac regeneration. Wu et al60 demonstrated that the addition of exercise after a myocardial infarction in mice significantly increased VEGF expression and improved angiogenesis. In cell cultures, mechanical stimulation significantly increased the stem cell secretion of VEGF.56 Therefore, a combination of stem cell therapy and a cardiac exercise program may hasten the return of function after a myocardial infarction. Future studies should investigate how, when administered together, exercise and stem cell transplantation may maximize cardiovascular function after a myocardial infarction.

Bone

The beneficial effects of loading on bone healing and remodeling are well documented and date back to the 19th century, when Julius Wolff first described the ability of bone to adapt to various loading conditions.61 More recently, the ability of mechanical loading to initiate an anabolic cascade and stimulate not only stem cell proliferation but also osteogenic differentiation was demonstrated.62 Duty et al63 recently found that the application of cyclic mechanical compression significantly increased the mineralization of a scaffold seeded with osteogenic cells, further suggesting a role for applied external stimuli in guiding terminal stem cell fate. Driving donor cell differentiation toward an osteogenic lineage by coupling stem cell transplantation with loading protocols may have important implications for the development of novel approaches for the treatment of conditions such as osteoporosis and nonunion fractures.

Targeted Steps Toward Regenerative Rehabilitation

The clinical translation of regenerative medicine approaches to the enhancement of musculoskeletal functioning presupposes the existence of a critical mass of basic scientists working in close collaboration with rehabilitation clinicians. Rehabilitation professionals must contribute their expertise in physiological responses to timed stress toward the development of noninvasive approaches to harnessing intrinsic tissue-healing capacity.

Accordingly, the field of regeneration must not advance at a pace that exceeds the readiness of rehabilitation professionals. To avoid this gap, rehabilitation training programs should now incorporate the latest research into their core curricula and increase the exposure of students in these programs to relevant orthobiological strategies in development or in clinical trials. Such course work introduced into physical therapy education programs might include a course on mechanotransductive principles, highlighting how the application of mechanical forces affects not only whole-body and tissue functioning but also cellular and molecular functioning. An overview of the latest research findings relating to artificial devices, tissue engineering, and the development of cellular therapies, with a special emphasis on ongoing clinical trials, also might be included.

A better understanding of underlying principles guiding the development of these approaches will better position prospective clinicians to refine interventions to achieve a targeted physiological response. For example, in the near future, a percentage of patients with cardiac conditions referred for physical therapy are likely to have a diagnosis of cardiac infarction with subsequent stem cell transplantation into the ischemic heart tissue. Rehabilitation care plans designed to enhance cellular survival and engraftment after transplantation may play a critical role in maximizing the efficacy of these cellular therapies. Finally, to further promote a symbiotic relationship between the 2 fields, rehabilitation professionals should seek resources within their academic or geographical communities, such as scientists performing orthobiological research, to inform both students and faculty about the latest regenerative medicine approaches through course lectures or consultations.

To achieve this goal effectively in training programs, educators, practitioners, and researchers in the rehabilitation field need to be more involved in basic science research projects extending beyond the laboratory bench to the design of clinical trials. As an example of just such an initiative, we plan to hold a symposium in regenerative rehabilitation that will bring together respected scientists working in multidisciplinary fields. The overarching goal of this symposium will be to design a foundation for the future development of targeted rehabilitation approaches designed to maximize the benefit of biological therapies.

Key researchers working at the forefront of the fields of rehabilitation and regeneration must increasingly interact with rehabilitation program directors and rehabilitation students. The development of forums that foster these collaborations and identify specific future research directions and attitudinal changes for rehabilitation students, program directors, and scientists is long overdue.

Conclusions

Undoubtedly, progress in the field of rehabilitation will increase proportionally with the pace at which rehabilitation professionals keep up with innovations in medical practice. Russell stated, “the greatest advances in medical practice are occurring at the interface between disciplines.”64(p ix) The goal of rehabilitation is to use the body's innate healing potential to maximize tissue functioning. The goal of regenerative medicine is the same. These 2 approaches, applied together, will hasten the attainment of desired improvements in musculoskeletal outcomes. Understanding the latest basic science findings will reduce trial-and-error approaches, a major source of frustration in the field of rehabilitation. More effective use of the information gleaned from basic science discoveries is needed to guide the development of targeted and specific rehabilitation programs. Similarly, an increased integration of rehabilitation approaches with regenerative medicine strategies will accelerate the science underlying tissue restoration after injury and disease. In the immediate future, rehabilitation will likely play as critical a role in the comprehensive care plan of regenerative medicine treatments of musculoskeletal disorders as it now does in the delivery of prosthetic devices or postoperative care. Rehabilitation specialists, in particular, physical therapists, should assume a far more proactive role in the development of regenerative medicine approaches.

Footnotes

  • All authors provided concept/idea/project design. Dr Ambrosio, Dr Wolf, and Dr Boninger provided writing. Dr Delitto provided fund procurement and institutional liaisons. Dr Fitzgerald and Dr Boninger provided consultation (including review of manuscript before submission).

  • This work was supported by funding from NIH K12 for Physical and Occupational Therapists, Comprehensive Opportunities in Rehabilitation Research Training (K12 HD055931) (to F.A.), the Pittsburgh Claude D. Pepper Older Americans Independence Center (1 P30 AG024827), and the Foundation for Physical Therapy.

  • Received January 21, 2010.
  • Accepted August 2, 2010.

References

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