Feature PTs on Rehab's Leading Edge: Regenerative Medicine, Robotics, and Genomics Physical therapists are playing key roles in innovative rehabilitation technologies. By Katherine Malmo | April 2019 Corey Kunzer, PT, DPT, often sees patients who've had certain regenerative medicine procedures. He describes the process as helping the body heal itself. "It's like with a paper cut," Kunzer says. "If a person gets a cut, his or her body creates a scab, and, as the scab is working, the skin and tissue below it heals. That's what regenerative medicine is. It's priming the body to heal itself." Kunzer, a board-certified clinical specialist in sports physical therapy, is coordinator of the Mayo Clinic Physical Therapy Sports Residency in Rochester, Minnesota. That's only one of many aspects of regenerative medicine. According to an article in PTJ (Physical Therapy), the term "regenerative medicine" describes anything that helps the body restore biological function lost to age, disease, injury, or congenital abnormality.1 This objective, the National Institutes of Health says, can be accomplished with the help of medical devices and organs, biomaterials, and cellular therapies.2 Cell Therapies and Biologics The regenerative procedures Kunzer describes are cellular therapies that involve a physician removing blood or bone marrow from the patient and, after separating out the platelets or stem cells, using a diagnostic ultrasound to inject the platelet rich plasma (PRP) or bone marrow aspirate concentrate (BMAC) into the targeted tendon, joint, or tissue to stimulate healing. While the injection itself is performed by a physician, a physical therapist (PT) meets with the patient before the procedure. At that time, Kunzer discusses initial restrictions and potential outcomes, reviews rehab protocols, and provides information and guidance on rest, range of motion, and exercise. He also fits patients with slings, crutches, or other assistive devices as needed. These injections are effective for many patients, Kunzer says, and are a good option to explore before seeking a more serious procedure such as a joint replacement. If this type of cellular therapy works for healing muscle and tissue, might it have broader applications? Stem cells can be removed from a person's bone marrow. Because they are unspecialized, they can become tissue, bone, cartilage, or muscle cells. If these cells can help heal any part of the body, why not after paralysis or stroke? "It's an exciting time," says Fabrisia Ambrosio, PT, PhD, MPT. "We're seeing more research and even clinical trials evaluating the potential of stem cell transplantation to promote functional outcomes after stroke. There's a lot of interest in understanding how rehabilitation—which of course is absolutely fundamental for functional recovery after stroke—can synergize with cellular therapy approaches." Ambrosio is an associate professor of physical medicine and rehabilitation at the University of Pittsburgh, director of rehabilitation for UPMC International, and lead author of the previously referenced PTJ article. The PT's role in recovery is crucial because, says Richard Shields, PT, PhD, FAPTA, cells can't be injected into an unhealthy environment and be expected to thrive. He is a professor in and chair of the Department of Physical Therapy and Rehabilitation Science at University of Iowa Health Care. A key concept is the effect of stress on stem cells and the importance of balancing that stress. As one researcher explains: The analysis of stem cell model systems reveals the central importance of stress-response pathways in the maintenance and function of stem cells. Stress is a common mechanism involved in stimulating stem cell division and differentiation in response to tissue needs for normal homeostasis and injury repair. Controlling and responding to intrinsic and extrinsic stress is critical for the long-term maintenance of functional stem cell populations. Oxidative stress in particular has emerged as a common feature that limits stem cell maintenance and disrupts function. As stem cell biology moves into the clinic, controlling stress becomes increasingly important in producing and maintaining functional stem cell reagents and in controlling their differentiation to produce desired cell types for use as interventions in disease and aging.3 "Our lab focuses on the delivery of stress to the cells," Shields explains. "There are various forms of stress. There can be mechanical and unnatural ways that we stress tissues and cells and organs. Then there are natural ways that we deliver stress, in the form of exercise and fatigue. There even may be physiological and environmental stresses, such as heat. We also can have the technology to apply a load for a certain period of time to a joint or a limb, with the understanding that all cells need to see some stress or they die." Too much stress, however, can be harmful. So, Shields continues, "There's a biological bandwidth that's a sweet spot for how we apply these underlying principles of stress to tissue." Shields notes, furthermore, that when skeletal muscle is activated it releases substances into the bloodstream that cross the blood-brain barrier. That, in turn, can influence the health of other tissues, including the brain. Having active muscle likely is a key part of the regenerative process, he suggests, because it delivers these substances into the bloodstream to affect other tissues. "We look at skeletal muscle as much more than a force generator," Shields says. "It's actually a very important organ that plays a metabolic role by taking up a lot of glucose. If you don't have enough skeletal muscle to take up glucose after a meal, you may become functionally diabetic. Metabolic instability makes for a very poor environment for cells to survive." Michael Boninger, MD, a professor and vice chair for research in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh School of Medicine, agrees that stem cells need to be trained and programmed through motion. For instance, he says, "If we really want to cure paralysis, we probably need to make sure stem cells understand the electrical signaling they need to do. So, there might need to be a brain-computer interface moving the arm as the person intended to move, so that the right connections are made." This piece of the puzzle—making sure the body receives the proper signal and motion to help regeneration—is where advancements in wearable technology and exoskeletons play a critical role. Wearable Technology Craig Hospital in Englewood, Colorado, was one of the first centers to obtain an Ekso exoskeleton. Candy Tefertiller, PT, DPT, director of physical therapy at Craig Hospital, says the facility installed the device in 2012 in its community fitness and wellness center. She is a board-certified clinical specialist in neurologic physical therapy. "Using an exoskeleton is similar to going to the gym and using the treadmill," Tefertiller says. "This is a specialized piece of technology that allows individuals who otherwise would be unable to do so to walk over ground on their own. People really like it. Those who have motor-complete injuries especially want the opportunity to stand upright, bear weight, and move. Many report that walking helps them manage their spasticity, assists them with their bowel and bladder programs, and reduces the number of infections they get. They describe an overall sense of well-being." Today, Craig Hospital primarily uses the Ekso and the Indego exoskeletons in its wellness facility to enable individuals to walk within the facility after a neurologic injury. The facility also has the ReWalk and the Indego in its outpatient program for individuals interested in purchasing a device for home use. Kaitlin Hays, PT, DPT, who's also at Craig Hospital, has experience working with each of those exoskeleton models. "At first glance, they all look the same," Hays says. "It's a robot helping somebody walk. But when you get in the device, when you're using it, when you're trained on it, they all function very differently and feel very different. The way a patient initiates a step, the amount of control the patient has, and the way the PT spots the patient are very different on each device." One of the ways therapists and patients can customize the amount of assistance is through the devices' software. The software suites of the Indego and the Ekso devices, for example, allow patients who already are ambulatory to work on a specific aspect of their gait. "You can layer on the assistance that you need," Hays says. "If you need help pulling your leg up or extending it at the end of the gait cycle, or if you need to step faster or to focus on any more-specific aspects of gait, the software suite can be adjusted to facilitate that. If one leg can do everything without assistance and you're unable to control your other leg, you can have 'full assist' on one leg and be completely responsible yourself for the other one." The PT's role typically includes conducting a full evaluation of range of motion and upper body strength, consulting with a physician, fitting the device, providing initial instruction and education on what to expect, then spotting patients while they're walking. Hays says the devices aren't effective for all of her patients who are ambulatory, but they offer benefits to many. "After 1 or 2 sessions in the device with just patterning and repetitive stepping, their gait often is improved even outside the device," he says. "Many patients are walking more symmetrically. They report feeling better and more balanced, with gait that's more normal. As with any intervention, though, it's not for everybody." Sujay Galen, PT, DPT, an associate professor and the chair of physical therapy at Georgia State University, researches wearable robotics. He's a board-certified clinical specialist in sports physical therapy. "Currently, wearable robots tend to be bulky," Galen notes. "The future is soft robotics—devices made with flexible materials that can be individualized and incorporated into clothing or worn under clothing. They're not heavy or bulky. They're flexible and may use mechanical pulleys and cords that can assist a patient's movement and be integrated into clothing." Next: Training the Stem Cells With the movement piece of the puzzle likely being provided by an exoskeleton or robotics, Boninger discusses cell therapies, explaining that stem cells need to be trained to become the functional cells that rebuild muscle or tissue. "For 30 or 40 years, people have been talking about using stem cells or other means of reconnecting a broken spinal cord," he says. "There has not been much success. One problem may be that the stem cells don't know what to do when they're implanted in a nonfunctioning cord." However, Boninger says, if the stem cells are given a "mechanical cue," they're much more likely to know how to differentiate themselves and become a functional stem cell that can turn into muscle or tissue. "If we can decode the signals for movement from the brain and plant stem cells, then move the arm—possibly with an exoskeleton," he continues, "all of these efforts together might actually create a better environment for the stem cells to work. That's the regenerative medicine component. The pathways would be recreated by having a better understanding of which signals want to get through, then providing the milieu that enables them to work." This is another area in which physical therapy plays an important role. "The hard work that physical therapists have been pushing people to do keeps being proven important," Boninger says. "What physical therapists do has great scientific basis." "Regenerative medicine and rehabilitation likely will need to go hand in hand," Shields says. "We can't take that client who needs more nerve cells, leave him or her inactive in a room, just do the cellular therapy, and expect everything to respond without tying it to stimuli related to stress induced by general systemic activity, exercise, or localized load placed on target tissues." Cells need a healthy environment and stress to work properly, but how much? What is this sweet spot for each tissue and procedure? The answer depends largely on the person and varies based on his or her genetics. Genetics "Every physical therapist knows that a '1-size-fits-all' approach to patients doesn't work," Boninger notes. "And you know what? We're finding the basis for why there must be variation in how medical science cares for individual patients." Mapping of the human genome has shown that approximately 99.9% of all people's DNA sequences are the same. However, the 0.1% that differs is critically important—influencing a person's risk for diseases and conditions such as stroke, arthritis, diabetes, heart disease, and cancer. All the diseases and conditions that PTs see on a regular basis, and the way individuals respond to treatment of them, are influenced by that person's DNA.4 "What we're learning across every area of medicine is that genetics have a profound impact on how we respond to treatment, Boninger says. "Some drugs might work in certain people and not in others. One major factor is genetic variation." Understanding a patient's DNA can be vital to physical therapy treatment, researchers say, and reveal more about how the disease presents itself, the types of medication to which it responds, and how the condition responds to various types of exercise.5 Shields maintains that PTs always are manipulating regulation of genes through their interventions. When a person adapts to a stress, such as exercise, that naturally regulates the expression of genes. So, in a very real way, physical therapy is a form of gene therapy. Shields sees the work that he and his team are doing in the lab as a form of genetic tagging. "When we apply a dose of stress—let's say it's using electrical stimulation to activate the skeletal muscle of a client who is paralyzed—we use those signaling pathways to help us learn the best way to introduce stress to the skeletal muscle of those clients," Shields says. "So, 3 hours after an exercise activity we literally can look at which genes are being regulated. Then, based on those findings, we can make some determinations as to whether our dose is targeting the intended pathways to promote muscle growth or muscle endurance." Shields explains that this analysis is done by taking a biopsy of skeletal muscle after exercise and analyzing the signaling pathways of the entire genome. Twenty years ago, this process would have cost more than $1 million per subject. It's now down to about $100 to $200. "What this does," he continues, "is offer us an opportunity to learn how cells are responding to our interventions almost in real time." "If you look well into the future, tailored medicine will be based on genetic information," Boninger forecasts. "And not only your baseline genes, but how your genes have been influenced by other factors. The environment that you live in will be something that's part of the practice of medicine. That won't happen tomorrow or 5 years from now. Probably not even 10. But I do think that's the future." That prediction may be accurate, but current obstacles to genetic testing include the following: Screening is not always sensitive enough. The clinical significance of some results can be unclear. There are too few professionals with relevant knowledge. Some medical providers face the dilemma of choosing whether to disclose other incidental findings that are inherent in whole genome sequencing. There is potential for discrimination or stigmatization based on a patient's genetic information. Legal safeguards under the 2008 Genetic Information Nondiscrimination Act (GINA) and the 2010 Patient Protection and Affordable Care Act (ACA) ensure confidentiality and deter discriminatory practices related to insurance coverage or employment. Some argue, however, that these laws have not been fully tested.4 If for any reason genetic testing is not possible, practitioners still can compile a thorough family history, as individuals share approximately 50% of their genetic variation with first-degree relatives.4 The Future The summary description of "Personalized Physical Therapy: The Time Is Now," a presentation from APTA's 2019 Combined Sections Meeting, noted the importance of PTs in the genetic landscape of the future: "With greater access to consumer genetic testing services, more and more clients will be arriving in clinics with genetic data in hand. It is imperative that physical therapists, as integral members of the health care team, become prepared to guide patients and their families, or make referrals to other health professionals. Clinicians with awareness of the effects of genetic variants on health and disease will be distinctly prepared to devise individualized lifestyle interventions." In Shields's vision of the future of regenerative medicine, practitioners will regrow tissue—for example, articular cartilage on the femoral head of the hip joint—well before a hip replacement is needed. He sees regenerative medicine as a preventive measure in which treatment starts at grade 1 or 2 osteoarthritis instead of waiting for grade 4 bone-on-bone situations that require joint replacement. Then, using careful placement of a patient's own stem cells and applying the appropriate mechanical stress, as Shields sees it implanted cells will proliferate and differentiate into the desired smooth articular cartilage tissue—offering a natural healing process. PTs will be crucial to this process. "As the field of medical regenerative medicine progresses, so, too, will physical therapy," Shields says. "It must, because we already know that the kind of stresses applied to these joints and tissues is critical to the health and survival of cells. When I talk about a cell and getting it to start dividing, that's genetics, because you're turning on the genes that up-regulate the production of daughter cells to become another type of tissue. How are you going to manipulate the genetics? You're likely going to do it through various forms of technology that allow us to apply loads and movement, whether through robotics or just plain exercise. Understanding how to dose for cellular response is going to be the new frontier." Ambrosio agrees that the field needs PTs trained in regenerative medicine in order to create protocols. "We can't afford to take a trial-and-error approach," she says, "because advances in regenerative medicine are moving very quickly. We can't be reactive and wait until these patients are regularly in our clinics before starting to identify optimal protocols." But where will that training and education come from? And how will work done in the laboratory get to the clinic? Steve Wolf, PT, PhD, FAPTA, is a professor in the Department of Rehabilitation Medicine, Medicine, and Cell Biology at the Emory University School of Medicine, and associate director for training at the Atlanta VA Center for Visual and Neurocognitive Rehabilitation. He was a member of the APTA steering committee that developed the Physical Therapy and Society Summit (PASS) in 2009, which was charged with determining the extent to which the profession was aligned with its "Vision 2020." Among the committee's findings was that physical therapy education was deficient in 4 key areas—telehealth, sensors and robotics, regenerative rehabilitation, and genomic-rehabilitation interfaces. By 2012, APTA had established the Frontiers in Rehabilitation Science and Technology (FiRST) working group. This alliance of PTs and interdisciplinary colleagues created information bases to be continuously updated and posted on the APTA website. Within the past 2 years, FiRST was designated an APTA council, with representation from all the association's sections. Meanwhile, a fifth important content area—imaging—was added to its portfolio. "These content areas were deemed important yet underserved and underutilized in our educational preparation," Wolf says. "We have developed fairly extensive groups of folks to put this information base together. It now appears on the APTA website. Using its hub, any PT or non-PT can gain access with permission." Ambrosio also has been working to bridge this gap between PTs and rapidly advancing technology and science as codirector of the Alliance for Regenerative Rehabilitation Research and Training (AR3T) . AR3T is a National Institutes of Health-funded resource center "supporting the expansion of scientific knowledge, expertise and methodologies across the domains of rehabilitation science and regenerative medicine."6 It is a multi-institutional network of laboratories that includes those at the University of Pittsburgh, Stanford University, the Mayo Clinic, and the University of Texas at Austin. With help from a $5 million grant from the National Institutes of Health, the organization provides funding for what its website calls the "development of novel lines of research" and education through webinars, sabbatical experiences, and research design consultations. Every year, it also hosts the Annual International Symposium on Regenerative Rehabilitation, with the goal of bringing scientists and clinicians together. "For some time," Ambrosio says, "basic scientists have used devices such as bioreactors to apply stimuli to stem cells at the laboratory bench, with the goal of promoting stem cell function. The next logical step is to evaluate how clinically-relevant mechanical, thermal, or electrical stimulation protocols, such as via exercise or modalities, might elicit similar stem cell benefits in vivo. The Symposium on Regenerative Rehabilitation allows basic scientists to gain increased exposure to cutting-edge rehabilitation technologies and approaches. It also exposes rehabilitation clinicians to advances in regenerative biology. "This is important," she continues, "because insights into stem cells and their role in tissue healing after injury or in the setting of disease has the potential to help inform the rational design of rehabilitation protocols. Our symposium is intended to be a mashup between the two fields." Katherine Malmo is a freelance writer.