The Impact of Regenerative Medicine on Physical Therapy

April 25th, 2019 in  Allied Health
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Regenerative medicine has the power to change the way we provide patient care, and PTs have to prepare for that change now.
The Impact of Regenerative Medicine on Physical Therapy.png

A recent trial use of hematopoietic stem cell transplantation (HSCT) on a man named Roy Palmer in England has resulted in restoring his ability to walk and dance after ten years.1 The 49 year old has spent the last decade in a wheelchair because of the effects of Multiple Sclerosis, but survival rates have increased significantly among patients who received blood stem cell transplants, according to a study published in the Journal of Clinical Oncology.2 The study authors attribute the increase to several factors, including advances in HLA tissue typing, better supportive care and earlier referral for transplantation and/or other regenerative medical techniques. Regenerative medicine is a new field that has evolved through multiple scientific and medical discoveries. The field draws its origins specifically from transplantation medicine. As a result, healthcare is undergoing a paradigm shift in how to treat chronic debilitating conditions.20

Modern rehabilitation is now being catapulted into the future via regenerative medicine. Regenerative rehabilitation is the amalgamation of concepts and techniques from rehabilitation and regenerative medicine with the ultimate goal of repairing and healing degenerated, diseased or damaged tissue, and can help provide solutions for the growing aging population.19

Physical therapy plays a major role in supportive care of these patients. Therefore, it is essential that new grad physical therapists understand how regenerative medicine (ex. Stem cell therapies, platelet rich plasma injections, etc.) affects standard physical therapy practice. A study conducted by Hanh, et. al shows that we are making significant progress, on a national level, in survival after transplantation.2 The procedure conducted in their study, among many others which are still in experimental phases, shows how important regenerative medicine can be for the future of medicine, rehabilitation, and society as a whole.

Regenerative Medicine and Physical Therapy

Regenerative medicine seeks to replace tissue or organs that have been damaged by disease, trauma, or congenital issues This stands as an alternative to the current clinical strategy that focuses primarily on treating the symptoms. The options used to realize these outcomes are tissue engineering, cellular therapies, medical devices and artificial organs.3 Healthcare professionals are now attempting to combine these therapies in order to accelerate and/or increase the natural healing process. Regenerative medicine is a burgeoning area of medicine that combines several scientific approaches in order to address one of the most difficult problems facing humankind: aging.

One of the most important responsibilities that a new grad physical therapist must undertake is the ability to consume knowledge and adapt in response to advances in medical practice and procedure. Regenerative medicine offers a great opportunity for rehab science and PTs to get involved as physical medicine and rehabilitation play a massive role in supportive care and can help improve quality of life and function for those who undergo these new procedures. This article will introduce some of the procedures performed and how it might change the practice of physical therapy.

What is stem cell therapy?

Stem cells are immature cells and depending on their origin can differentiate into many different types of cells. Stem cell therapy transplants these cells into the patient’s body in order to help proliferate new, healthy tissue.

One way regenerative therapy is being used is in helping to abolish the effects of neurodegenerative diseases such as Parkinson’s disease, strokes, ALS, and Huntington’s disease.4 The use of stem cell therapy for neurodegenerative conditions is in its infancy, and there have not yet been many human trials. Studies in animal models, however, have demonstrated that neuronal replacement and partial reconstruction of damaged neuronal circuitry is possible, and beyond that there is evidence from clinical trials that cell replacement in the diseased human brain can lead to symptomatic relief.4

Before clinical trials are initiated, we need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease. It will be paramount for the new grad physical therapists to continue to follow the transition of stem cell research for neurodegenerative disorders from mostly animal-based studies to human-based studies.

Stem cell therapy may dramatically impact the future of PT, but what do PTs think of the industry today? Check out our full 2019 new grad physical therapy report!

Stem Cell Therapy and Cancer

Another type of stem cell therapy, hematopoietic stem cell transplantation (HCT), is a procedure that has evolved over the years to treat different types of blood cancers.5 New insight and research within the discipline has focused on fatigue, inflammation, exercise, and the development of structured rehabilitation programs to improve the musculoskeletal sequelae of HCT.

Fatigue is the most common (and one of the most devastating) symptoms among patients with cancer, and is also common among patients undergoing HCT.7 Cancer related fatigue (CRF) is a result of many factors including chemotherapy/radiation, side effects from medication, loss of muscle mass, and inherent inactivity, and it’s important for PTs to understand CRF because of the dramatic impact that exercise programs can have on those suffering from it. Exercise has demonstrated significant improvements in multiple areas related to quality of life in addition to fatigue, including mood, bone and sleep health, body composition, functional capacity, and possibly increased chances of survival for certain cancers, including breast and colon.6

Fatigue can be assessed with the Multidimensional Fatigue Inventory (MFI) which is a 20-item, multidimensional self-assessment questionnaire that has been validated for a German-speaking population. It covers five dimensions of fatigue: general fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue. Scores are derived by summing the answers of the appropriate items on a five-stage scale.10

Pre-Transplant Rehabilitation

Pre-transplant rehabilitation is important because the side effects of the procedure can leave individuals debilitated. If the individual can improve in areas of strength, endurance, and mobility then the transplant effects might not be as detrimental.6 Furthermore, it is important to understand the best types of physical therapeutic programming to prepare patients for the side effects of HCT. in particular, there was a recent study introducing treadmill training to those who just underwent bone marrow transplantation and showed that individuals who underwent the six week treadmill training program did not report feeling fatigued by regular daily activities as compared to those who did not. They also did not experience limitations in activities such as stair climbing or shopping due to reduced endurance.6

It is important that a structured exercise program is put in place after evaluating the potential barriers to exercise adherence. Improving exercise adherence involves understanding each patient’s unique barriers and designing a plan to address them. In this synopsis, Sherry Pagoto describes barriers, such as the individual's level of pain, that are important to assess before beginning an exercise-based rehabilitation program. These barriers can also include: lack of sleep, genetics, psychological impairments, social and economic status. As with any rehabilitation program, an analysis of physical activity behaviors must be documented, and the physical therapist has to help the client understand the importance of this period of time.

Post-Transplant Rehabilitation

During the post-transplant period, patients cannot remain in the service of acute care therapists indefinitely. If the patient is unable to safely discharge home, a transfer to another rehabilitation setting may be required. The most significant problem at this juncture can be the infirmity and fatigue of the client, as there is often a significant drop in activity levels after the HCT procedure.8 Rehabilitation during this immediate post-transplant period involves maintaining function, reducing symptom burden, maintaining muscle mass, reducing the risk for pneumonia and atelectasis, and improving aerobic capacity.

The most important aspect of post-transplant rehabilitation is the ability to improve the client’s function. This includes the ability to get in and out of bed, standing up from a seated position, walking, climbing stairs (depending on if the client needs to do this regularly), getting up and down from the floor, and handling instrumental activities of daily living (grocery shopping, cooking, doing laundry, washing dishes, grooming, dressing, etc.).

“Embracing regenerative medical procedures and practices also must come from a marriage between clinician and scientist, clinic and laboratory, and policy and practice.”

Kimberly Presson, PT, DPT, CLT-LANA who works out of MD Anderson Cancer Center, states in this article for PT in Motion, that many of these clients present with low blood count values which can make them rather symptomatic. The most troublesome symptom that limits physical activity is fatigue. Presson emphasizes, "They're so tired from the treatment, we do only as much as they can tolerate, even if it's just a few exercises in the bed." With that in mind, the approach to treatment needs to be individualized.

This process requires a close connection between nurse leaders and the physical/occupational therapists.11 Nursing staff are closely monitoring the patient's physical and mental status and can be a wealth of advice. During the cytopenia phase it may be necessary for the physical therapist to do most of the treatment session in the patient’s room due to their susceptibility to outside viruses and bacteria.13

The approach can be changed by the therapist providing transfer/ADL training, PROM/AAROM/AROM, manual resistance exercises, and education. There are also many patients experiencing depression while in the isolation ward, so having one-on-one physical treatment in those rooms and abiding by all precautions is essential for their physical as well as their mental health. Starting therapy before or just after transplantation seems to be of maximum benefit.18

Exercise in the Cancer and Post-Transplant Population

Physical therapists should include aerobic programming, resistance exercises, and functional training in order to alleviate debilitating symptoms of fatigue, pain, and deconditioning. The rehabilitation team should also perform a pre-exercise assessment to evaluate for any effects of disease, treatments, and comorbidities for all people living with cancer and the post-transplant period. This most importantly includes all pertinent vitals (HR, BP, O2, RR), along with monitoring how the patient’s vitals change with exercise.

Intensity of exercise can be regressed or progressed based on responses to certain variables such as HR, METS, and physiological responses like sweating, getting red or flushed, shortness of breath, and pain. Intensity of the exercise can also be measured subjectively with a self-reported estimate of effort called the “rate of perceived exertion” on a scale of one to ten . Physical therapists can also help the client pick activities that they can enjoy doing at home as part of their home program. Would the client prefer aerobic and resistance training—running, brisk walking, cycling, weight lifting—or body weight elastic band exercises.9

The American College of Sports Medicine (ACSM) published specific recommendations on the frequency, duration, and intensity of exercise required for general fitness. ACSM recommends a goal of 150 minutes of moderate-intensity aerobic exercise spread over three to five days and resistance training at least two days per week. Resistance sessions should involve major muscle groups two to three days per week (eight to ten muscle groups, eight to ten repetitions, two sets). Each session should include a warm-up and cool-down.9

Communication Between Physical Therapist and Patient

For most patients, stem cell therapy is uncharted territory, providing a wholly different healing and recovery experience than traditional treatment approaches or surgeries . It is important for the physical therapist to give adequate time for the patient to ask questions and stress worries. Sometimes physical therapists rely immoderately on the utilization of “hard” clinical skills. Candidly, it requires a combination of “hard” and “soft” clinical skills to allow the client to buy in to the therapeutic program. This is especially important when these clients will be facing the spectrum of symptoms/side effects that can propel most people into inactivity. The physical therapist will be seeing these individuals in their most vulnerable state. A relationship based on acceptance and trust will be beneficial to pushing the client past these barriers and toward activity.

Effective communication skills will help maximize the therapeutic relationship. These benefits include:

  1. Positive clinical outcomes
  2. Higher levels of patient satisfaction
  3. Higher levels of patient compliance with treatment programs
  4. Lower levels of patient frustration and anger.14

New grad PTs should be in constant communication with not only their patients but with the ordering physician. The patient may find solace in knowing their physical therapist and physician are on the same page.

Secondly, the patient will appreciate their therapist explaining their evaluation/assessment process as it can reduce misunderstandings and put them at ease. What your patient hears you communicate is what you communicated, no matter your intent. While it is very important to explain everything that you do with the patient, do not use terminology that can cause confusion such as abbreviations, negative, and/or complex medical vocabulary. Make sure to show that you are actively listening by paraphrasing what the patient has said.

Stem Cell in Orthopedics

Stem cells are now being used in the orthopedic population with mixed results; one area in the population that has seen enormous growth is using stem cells in total knee replacements as a treatment for osteoarthritis. Total joint replacement using artificial components remain the definitive treatment for end-stage OA, but the limited lifespan of these prostheses may be unable to meet the growing demand from younger and more active patients.12 Therefore, physicians and researchers are looking to see if stem cells can treat the pathological process and provide an alternative to surgery. The theory is that stem cells will differentiate into articular cartilage, returning the joint to a healthier, functional state.

Regenerative medicine is intended for certain conditions when the body becomes stuck in phase three of the healing process, remodeling. Due to a wide variety of factors, specific tissue may not have the complete cellular material matrix required to fully remodel. The application of stem cells in combination with physical therapy may be the answer to completing the remodeling phase

Platelet-Rich Plasma Injections (PRP) and their Use in Musculoskeletal Injuries

Platelets are primarily known as cells designated to clot blood, but they also are made up of growth factors that have a role in soft tissue healing. PRP is a blend of plasma and a large number of platelets, many more platelets than those typically found in blood. The concentration of platelets — and, thereby, the concentration of growth factors — can be five to ten times greater than usual. To develop a PRP preparation, blood must first be drawn from a patient. The platelets are then separated from other blood cells and their concentration is increased during a process called centrifugation. Finally, the increased concentration of platelets is combined with the remaining blood.6

Once the PRP is prepared, there are two options for delivery of the injection. The first option is to inject the preparation directly into the injured tissue. This is most commonly performed on patients with achilles tendinosis. Alternatively, injections can be used to increase healing after surgery. For example, the PRP preparation can be stitched into the incision site after an achilles tendon repair.

“...it’s important for PTs working with patients recovering from these new procedures to understand how training protocols...can promote the development of the donor-patient interface.”

PRP can be used to treat multiple conditions. These include chronic tendon injuries at the elbow, heel, knee, and shoulder as well as acute ligament and muscle injuries like hamstring muscle tears; however, there is little to no evidence that PRP is helpful in the latter population. PRP has the most literature in the treatment of chronic tendon injuries, especially at the elbow and heel, but a lack of high level evidence studies and low sample sizes within those conducted show the limitations with PRP injections. Still, there have been few if any side effects identified in using this approach even with so little evidence in support.6

Stephen Clark, PT, DPT, MBA, OCS, president and founder of Athletic Physical Therapy in Los Angeles states “One of the issues with PRP is that there's no single protocol all physicians follow."11 Furthermore, physicians may add other materials or products or include more fenestrations that change the formula of each PRP injection in relation to different body parts. These statements elucidate how important communication between a client’s physical therapist and their primary physician can be. The physical therapist might need to be more conservative with regard to one physicians client than they are with another because of the variance in PRP composition. Research has shown that there is a need for standardization of PRP preparation methods across clinical practice for this very reason.15

Post-PRP Treatment Rehabilitation

Physical therapists must understand the importance of a well-designed rehabilitation program that effectively coordinates an initial phase of protection and healing, does not compromise the tissue, and decreases the effects of immobilization. It is highly recommended that the physical therapist work for a few sessions with the patient before they go in for PRP injections as this gives the PT time to solidify a therapeutic alliance, educate the patient about the procedure, answer any pertinent questions, and find solutions to any barriers the patient might have adhering to the regime.

Most injections, depending on the location, will result in an initial period of immobilization of the affected joint. The physical therapist has an important role in educating the patient on these initial restrictions to activity and the gradual return to higher intensity play or recreation. If the body part is in the lower extremity, weight-bearing status might also change with the addition of assistive devices to help reduce the weight into the affected extremity. Similar to post-surgical rehabilitation, the physical therapist should guide the patient into gentle range of motion and non-resistive exercises to begin the program. Informing the patient that pain might increase in the week or two after the injection can help to ease concern over that pain as well.

The recommended wait time prior to beginning strength exercises and treatments can vary based on the number of injections and the time between these injections. In some programs where PRP injections have been used for tendon problems, patients were allowed to do light activities after a second injection that was given fifteen days after their first injection. The strengthening phase can begin after the fifteen day period or be postponed for another two to three weeks until after the final injection.

Eventually, you should help the client increase their tolerance to load by increasing resistance and time to complete the movement (plyometrics). Lastly, the physical therapist should include a return to sports training regime that emulates the intensity and length of a live game. Along the way, the physical therapist should be monitoring symptoms such as pain, swelling, strength, and endurance in order to continuously improve impairments and ameliorate functional limitations.

Autologous Chondrocyte Implantation (ACI)

In the past thirty years researchers, surgeons, and rehabilitation specialists have looked into new ways of treating individuals with focal defects in their articular cartilage in order to protect from further degeneration. Another goal of this is to reduce the need for knee replacement surgery later in life. As a result of this problem, several techniques have been used to improve the healing potential by implanting chondrocytes into these defects and stimulating normal hyaline cartilage.

The ACI procedure consists of taking a few cartilage cells from the knee, growing them in the lab, and, once millions of cells have been grown, the patient's own cells are implanted into the damaged cartilage. ACI is a two-step procedure, requiring two surgeries several weeks apart: the harvesting of cells and the implanting of them. ACI is a significant procedure, the recovery is lengthy, and patients must be prepared to participate in intensive physical therapy. Again, this is a procedure where pre-operative physical therapy is paramount to successful outcomes.

Pre-operative ACI Rehabilitation

Physical examination should focus on gait status, knee alignment, and body mass index (BMI). Weight reduction should be an integral component of the preoperative program as it will limit post-operative stress to the healing lesion. If there is a difference in knee flexion or extension range of motion, then that needs to be addressed through physical therapy beforehand as well.

Post-Operative ACI Rehabilitation

Weight-bearing precautions are initiated right after the procedure and progress depending on the size of the focal lesion and how well localized the lesion is. Progressive weight-bearing can start as early as four weeks post-operation with well localized lesions, however, it can take up to twelve weeks for complete weight-bearing in some cases. If the individual undergoes a patello-femoral lesion implantation then protected weight-bearing can start after surgery with a brace locked in extension. However, these lesions will have ROM restrictions due to their location.

Constant communication between the PT and the surgeon/surgical staff is important for improved outcomes. The PT must communicate the progression of weight-bearing, ROM, and strength along with any symptoms of pain, stiffness, and swelling. After three to six months, training can increase in load and intensity. Sport-specific activities can begin about twelve months after surgery. Most athletes do not return to full sport until about sixteen months after surgery.

In Summary

The aging population continues to challenge the healthcare system to improve their quality of life and function. Though great progress has been made in medicine, current evidence-based and palliative treatments are increasingly unable to keep pace with patients' needs. Current projections for the number of joint replacement surgeries continue to skyrocket in the aging population, and it’s estimated that by 2030, the demand for primary total hip arthroplasties will grow by 174% to 572,000. The demand for primary total knee arthroplasties is projected to grow by an even greater amount, 673% to 3.48 million procedures.16 Furthermore, research continues to question the long term outcomes both clinically and financially for recipients of these treatments.17

Regenerative medicine could be the answer to helping the aging population, especially those with osteoarthritis. Regenerative medicine and rehabilitation can be the solution to help decrease the financial burden of all the joint replacement surgeries performed. Unfortunately, there are still technical, clinical, and standardization issues to be resolved before such procedures become routine practice.

Fabrisia Ambrosio, PT, MPT, PhD has seen the increase in studies performed that are trying to dial in on how research can pave the way for regenerative medicine. Gathering this foundational knowledge and the necessary tools starts with education and outreach. To that end, last September, the Alliance for Regenerative Rehabilitation Research and Training (AR3T)—a group Ambrosio founded with colleagues from Pitt's McGowan Institute for Regenerative Medicine and individuals at several other institutions—was awarded a $1.1 million grant by the National Institutes of Health's National Center for Medical Rehabilitation Research.11

Dr. Fabrisia Ambrosio is also the director of rehabilitation for UPMC International and an associate professor in the department of physical medicine & rehabilitation at the University of Pittsburgh. Ambrosio states that physical therapists should learn the basis of regenerative medicine and stem cell biology concurrently with how to cofunction with physicians who practice regenerative medicine.11 Embracing regenerative medical procedures and practices also must come from a marriage between clinician and scientist, clinic and laboratory, and policy and practice. Once this melding occurs, a standard of rehabilitation can be established that can improve healing for millions.

The mission of regenerative rehabilitation is to properly rehabilitate individuals with regard to cell biology and augmented tissue healing. This new practice makes use of physical therapeutics to maximize the intrinsic healing of the patient, so it’s important for PTs working with patients recovering from these new procedures to understand how training protocols (graded movement, functional engagement, resistance training, and endurance exercises) can promote the development of the donor-patient interface.

The future of regenerative medicine still relies on physical therapists understanding operational procedures, changes to tissue healing guidelines, and adapting rehabilitation protocols for the specific tissues affected. Physical therapists play an integral role in the efficacy of these techniques and the future of regenerative medical research.

References

  1. https://www.cbsnews.com/news/after-stem-cell-transplant-man-with-ms-able-to-walk-and-dance-for-first-time-in-10-years/
  2. Theresa Hahn, Philip L. McCarthy Jr, Anna Hassebroek, Christopher Bredeson, James L. Gajewski, Gregory A. Hale, Luis M. Isola, Hillard M. Lazarus, Stephanie J. Lee, Charles F. LeMaistre, Fausto Loberiza, Richard T. Maziarz, J. Douglas Rizzo, Steven Joffe, Susan Parsons, and Navneet S. Majhail. Significant Improvement in Survival After Allogeneic Hematopoietic Cell Transplantation During a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors. JCO, May 28, 2013
  3. http://www.mirm.pitt.edu/about-us/what-is-regenerative-medicine/
  4. Lindvall, O., Kokaia, Z., & Martinez-Serrano, A. (2004). Stem cell therapy for human neurodegenerative disorders–how to make it work. Nature medicine, 10(7s), S42.
  5. Steinberg, A., Asher, A., Bailey, C., & Fu, J. B. (2015). The role of physical rehabilitation in stem cell transplantation patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 23(8), 2447-60.
  6. https://orthoinfo.aaos.org/en/treatment/platelet-rich-plasma-prp/
  7. Challenge of managing cancer-related fatigue. Bruera E, Yennurajalingam S. J Clin Oncol. 2010 Aug 10; 28(23):3671-2.
  8. Danaher EH, Ferrans C, Verlen E, Ravandi F, van Besien K, Gelms J, Dieterle N. Fatigue and physical activity in patients undergoing hematopoietic stem cell transplant. Oncol Nurs Forum. 2006;33(3):614–624. doi:10.1188/06.ONF.614-624.
  9. Segal, R., Zwaal, C., Green, E., Tomasone, J. R., Loblaw, A., Petrella, T., Exercise for People with Cancer Guideline Development Group (2017). Exercise for people with cancer: a clinical practice guideline. Current oncology (Toronto, Ont.), 24(1), 40-46.
  10. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995;39(3):315–25. doi: 10.1016/0022-3999(94)00125-O.
  11. http://www.apta.org/PTinMotion/2016/3/Feature/RegenerativeMedicine/
  12. Diekman, B. O., & Guilak, F. (2013). Stem cell-based therapies for osteoarthritis: challenges and opportunities. Current opinion in rheumatology, 25(1), 119-26.
  13. Morishita S, Kaida K, Setogawa K, S. Ishii, Kajihara K, et al. (2013) Safety and feasibility of physical therapy in cytopenic patients during allogeneic haematopoietic stem cell transplantation. Eur J Cancer Care (Engl) 22:289-299.
  14. Wanzer, M. B., Booth-Butterfield, M. & Gruber, K. (2004). Perceptions of health care providers’ communication: Relationships between patient-centered communication and satisfaction. Health Care Communication, 16(3), 363-384.
  15. Cochrane Database of Systematic Reviews Platelet-rich therapies for musculoskeletal soft tissue injuries (Review). Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JCMoraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC.Platelet-rich therapies for musculoskeletal soft tissue injuries.Cochrane Database of Systematic Reviews 2014, Issue 4. <https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010071.pub3/epdf/full>
  16. The Epidemiology of Primary and Revision Total Hip Arthroplasty in Teaching and Nonteaching Hospitals in the United States. Journal of the American Academy of Orthopaedic Surgeons 2016; 24(6): 393–398.
  17. Ferket Bart S, Feldman Zachary, Zhou Jing, Oei Edwin H, Bierma-Zeinstra Sita M A, Mazumdar Madhu et al. Impact of total knee replacement practice: cost effectiveness analysis of data from the Osteoarthritis Initiative BMJ 2017; 356 :j1131
  18. Kuba et al. (2017). Depression and anxiety following hematopoietic stem cell transplantation: a prospective population-based study in Germany. Bone Marrow Transplantation, volume 52, pages 1651–1657.
  19. http://www.apta.org/RegenerativeRehab/
  20. Perez-Terzic, C., & Childers, M. K. (2014). Regenerative rehabilitation: a new future?. American journal of physical medicine & rehabilitation, 93(11 Suppl 3), S73-8. rences
  21. https://www.cbsnews.com/news/after-stem-cell-transplant-man-with-ms-able-to-walk-and-dance-for-first-time-in-10-years/
  22. Theresa Hahn, Philip L. McCarthy Jr, Anna Hassebroek, Christopher Bredeson, James L. Gajewski, Gregory A. Hale, Luis M. Isola, Hillard M. Lazarus, Stephanie J. Lee, Charles F. LeMaistre, Fausto Loberiza, Richard T. Maziarz, J. Douglas Rizzo, Steven Joffe, Susan Parsons, and Navneet S. Majhail. Significant Improvement in Survival After Allogeneic Hematopoietic Cell Transplantation During a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors. JCO, May 28, 2013
  23. http://www.mirm.pitt.edu/about-us/what-is-regenerative-medicine/
  24. Lindvall, O., Kokaia, Z., & Martinez-Serrano, A. (2004). Stem cell therapy for human neurodegenerative disorders–how to make it work. Nature medicine, 10(7s), S42.
  25. Steinberg, A., Asher, A., Bailey, C., & Fu, J. B. (2015). The role of physical rehabilitation in stem cell transplantation patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 23(8), 2447-60.
  26. https://orthoinfo.aaos.org/en/treatment/platelet-rich-plasma-prp/
  27. Challenge of managing cancer-related fatigue. Bruera E, Yennurajalingam S. J Clin Oncol. 2010 Aug 10; 28(23):3671-2.
  28. Danaher EH, Ferrans C, Verlen E, Ravandi F, van Besien K, Gelms J, Dieterle N. Fatigue and physical activity in patients undergoing hematopoietic stem cell transplant. Oncol Nurs Forum. 2006;33(3):614–624. doi:10.1188/06.ONF.614-624.
  29. Segal, R., Zwaal, C., Green, E., Tomasone, J. R., Loblaw, A., Petrella, T., Exercise for People with Cancer Guideline Development Group (2017). Exercise for people with cancer: a clinical practice guideline. Current oncology (Toronto, Ont.), 24(1), 40-46.
  30. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995;39(3):315–25. doi: 10.1016/0022-3999(94)00125-O.
  31. http://www.apta.org/PTinMotion/2016/3/Feature/RegenerativeMedicine/
  32. Diekman, B. O., & Guilak, F. (2013). Stem cell-based therapies for osteoarthritis: challenges and opportunities. Current opinion in rheumatology, 25(1), 119-26.
  33. Morishita S, Kaida K, Setogawa K, S. Ishii, Kajihara K, et al. (2013) Safety and feasibility of physical therapy in cytopenic patients during allogeneic haematopoietic stem cell transplantation. Eur J Cancer Care (Engl) 22:289-299.
  34. Wanzer, M. B., Booth-Butterfield, M. & Gruber, K. (2004). Perceptions of health care providers’ communication: Relationships between patient-centered communication and satisfaction. Health Care Communication, 16(3), 363-384.
  35. Cochrane Database of Systematic Reviews Platelet-rich therapies for musculoskeletal soft tissue injuries (Review). Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JCMoraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC.Platelet-rich therapies for musculoskeletal soft tissue injuries.Cochrane Database of Systematic Reviews 2014, Issue 4. <https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010071.pub3/epdf/full>
  36. The Epidemiology of Primary and Revision Total Hip Arthroplasty in Teaching and Nonteaching Hospitals in the United States. Journal of the American Academy of Orthopaedic Surgeons 2016; 24(6): 393–398.
  37. Ferket Bart S, Feldman Zachary, Zhou Jing, Oei Edwin H, Bierma-Zeinstra Sita M A, Mazumdar Madhu et al. Impact of total knee replacement practice: cost effectiveness analysis of data from the Osteoarthritis Initiative BMJ 2017; 356 :j1131
  38. Kuba et al. (2017). Depression and anxiety following hematopoietic stem cell transplantation: a prospective population-based study in Germany. Bone Marrow Transplantation, volume 52, pages 1651–1657.
  39. http://www.apta.org/RegenerativeRehab/
  40. Perez-Terzic, C., & Childers, M. K. (2014). Regenerative rehabilitation: a new future?. American journal of physical medicine & rehabilitation, 93(11 Suppl 3), S73-8.