Version May 2024
INTRODUCTION AND DEFINITIONS — Biologic therapies, often referred to as "biologics," are a class of nonpharmacologic treatments being used for a variety of conditions in many areas of medicine. Proponents of biologic therapies in musculoskeletal medicine claim that they improve healing. This topic will review the proposed mechanisms, clinical use, and evidence for biologic therapies that have been the subject of peer-reviewed research and are used in the treatment of tendon and muscle injuries.
TERMINOLOGY AND BACKGROUND — The United States Food and Drug Administration (FDA) states that biologic therapies are "sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities such as cells and tissues." This review will not discuss sugars, proteins, or nucleic acids but will focus rather on cells and substances derived from tissues, as these are the biologic therapies used most often in the treatment of musculoskeletal injuries.
The biologic therapies used to treat muscle and tendon injuries can be divided broadly into two classes:
●Blood-derived therapies, which are reported to deliver cytokines and other substances locally at the site of injury and include injection of autologous whole blood (ABI), platelet-rich plasma (PRP), and extracted blood derivatives
●Cellular therapies, which involve introducing cells directly into local tissue (a process termed engrafting) and can include mesenchymal stem or stromal cells (MSCs), autologous tenocytes, and dermal fibroblasts
The number of clinics offering biologic therapies for muscle and tendon injuries has grown substantially. In Australia, in 2011, a single clinic offered "stem cell" therapy for musculoskeletal conditions but by 2014, over 40 clinics did so [1]. In the United States, the number of "stem cell" clinics has doubled annually over the same period, and it is estimated that 100 new clinics are opening each year [2].
A number of factors have contributed to the growing popularity of biologic therapies despite the dearth of high-quality clinical trials supporting their use. First, few (if any) established treatments improve the healing of musculoskeletal injuries. Biologic therapies are purported to meet this clinical need. Second, biologic therapies are easily administered via local injection by clinicians. In addition, the biotechnology companies that manufacture the equipment used to assist in the production of these therapies in clinics have marketed directly to clinicians and consumers.
Government regulation is another factor. In some countries, clinics have introduced these therapies prior to any regulation, and the resulting variation in geographic availability has led to "stem cell tourism." However, regulation is appearing, and clinicians considering referring patients for biologic therapies and administering such therapies themselves should be aware of national and international regulations regarding their use, including those put forward by the FDA, European Medicines Agency, and Australian Therapeutic Goods Administration.
PROPOSED MECHANISMS AND PRODUCTION OF BIOLOGIC THERAPIES
Blood-derived therapies — Blood-derived therapies involve the local administration of either blood or blood constituents treated to produce supraphysiologic concentrations of cytokines, which are purported to promote the growth and division of host repair cells or mediate the inflammatory process associated with injury.
The first blood-derived therapy used clinically was the local injection of autologous whole blood (ABI), but this has been superseded by platelet-rich plasma (PRP). Platelets are among the earliest cellular elements to be found at the site of tissue injury, where they are activated by exposure to such substances as thrombin and tissue collagen (the major protein in tendons). Once activated, platelets release their intracellular cytoplasmic granules. The platelet alpha-granules contain inflammatory and growth factors, including platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) [3].
PRP is defined as a platelet-rich concentrate with platelet levels greater than the baseline count in whole blood. It is manufactured using centrifugation of blood, which separates the denser red cells from the plasma. The plasma components are divided into a fine (white) buffy coat and an adjacent layer. The buffy coat contains leucocytes and most of the platelets. The adjacent layer of plasma is less rich in platelets and has few leucocytes.
There are a variety of techniques used to harvest the buffy coat, the adjacent plasma layer, or both. Some methods concentrate the buffy coat further using a "double spin." This process involves a second centrifugation of the supernatant obtained from the initial centrifugation and produces a more concentrated sample. Depending on the method, the number of platelets in PRP varies between one and nine times that of whole blood [4]. The techniques that produce lower concentrates of platelets typically produce lower concentrations of leucocytes as well. Conversely, techniques that produce higher platelet concentrations (eg, double spin) typically produce higher leucocyte concentrations. Hence, PRP is often referred to as "leucocyte rich" or "leucocyte poor."
The role of leucocytes (which contain enzymes such as collagenase) in tendon healing is controversial [5]. However, the results of a meta-analysis of randomized trials that differentiated between leukocyte-rich and leucocyte-poor PRP used to treat tendinopathy suggest that leukocyte-rich PRP may be more effective [4].
Biotechnology companies often provide centrifuges and disposable kits to clinicians; each technique has different preparation protocols (eg, volume of whole blood, plasma, or buffy coat; single or double spin; revolutions per minute; volume and concentration of PRP produced). Some practitioners add exogenous calcium salts to the PRP just prior to administration with the intention of ensuring platelet activation, while others assume that contact with tendon collagen will suffice. Administration protocols vary, but for tendon conditions, one to four intratendinous injections over two weeks is common [6]. There are no accepted exercise protocols or return-to-sport guidelines following PRP treatment.
As reflected in the discussion above, PRP is a general term describing a therapy with no gold standard of preparation or administration technique. This heterogeneity and the small number of controlled trials make it difficult to assess the efficacy of PRP for tendon and muscle injuries and disorders.
Cell-based therapies — Cell-based therapies for tendon and muscle conditions include the administration of undifferentiated stem cells, differentiated tenocytes, and nonhomologous dermal fibroblasts. Stem cell biology and the use of these products in other areas of medicine are reviewed separately. (See "Overview of stem cells".)
Unlike blood-derived therapies, cellular therapies are purported to produce a regenerative effect via their direct incorporation into injured tissue and adjacent tissue (ie, cellular engraftment). However, stem cells can remain unengrafted and produce cytokines that may contribute to tissue regeneration by promoting growth and differentiation of local cells.
There are several different types of stem cells, but they all possess the properties of proliferation and differentiation into adult cell lines. The mesenchymal stem or stromal cell (MSC) is a rare, undifferentiated multipotent stem cell considered to be the body's repair cell. It is relatively mature with less capacity for differentiation and proliferation compared with pluripotent stem cells. By definition, MSCs must demonstrate in vitro differentiation into fat, bone, and cartilage [7]; however, MSCs are also capable of differentiation into muscle, tendon, and ligament to varying degrees [8].
Importantly, undifferentiated MSCs receive local paracrine signals (cytokines), leading to proliferation and differentiation into the surrounding host tissue. Hence, if MSCs are placed within normal healthy bone, cartilage, or adipose tissue, they differentiate into that particular tissue. This property probably applies to all mesenchyme tissues, including muscle, tendon, and fibrous tissues. However, MSCs demonstrate little capacity for differentiation into nonmesenchymal tissue (eg, neural or hepatic cells).
MSCs are immunosuppressive and do not appear to initiate host rejection, so allogeneic cells may be used [9]. Even though allogeneic cells are highly cost effective, there are complex regulatory frameworks governing their use. MSCs appear to be a safe therapy, and published clinical trials involving local implantation to treat orthopedic conditions have not shown a significant risk of tumor formation, unintended differentiation, or other serious adverse events [10,11].
Bone marrow aspirate has been the traditional source for MSCs, although they comprise only 0.01 to 0.001 percent of nucleated marrow cells. Adipose tissue is a richer source of MSCs, and harvesting is less invasive [12]. However, in all tissue sources, the number of MSCs declines with age.
The manufacture of MSCs involves several distinct processes:
●Harvesting of cells by bone marrow- or lipoaspirate
●Isolation of MSCs by plastic adherence
●Proliferation of MSCs in a culture medium (termed "expansion by passage"; up to five passages may be performed safely, and each requires up to a week)
●Storage, usually by cryopreservation
(By definition, stem cells are harvested but not expanded, while stromal cells are expanded.)
These processes are costly, time consuming, and subject to considerable regulatory oversight.
Some clinicians, with assistance from biotechnology companies, are offering an alternative method of "stem cell manufacturing" that is less costly and less regulated but "nonquantitative." With this low-tech manufacturing procedure, there is no cellular isolation or proliferation, and the resulting number of MSCs is unknown. The final product is a solution of mononuclear cells, which contain relatively few MSCs (ie, less than 10 percent of the number found in adipose tissue or 3 percent in bone marrow) [13,14]. Technically, these aspirates should be termed "adipose stromal vascular fraction" or "bone marrow mononuclear cell concentrates," but they are often referred to as MSCs when described or marketed to patients and clinicians [15]. Clinicians should be aware of the difference between expanded MSCs (often used in research) and the nonexpanded heterogeneous stem cell therapies offered by most stem cell providers (table 1).
In some countries, it is permitted to administer differentiated cells, which are not stem cells and therefore do not possess the potential to proliferate. These include autologous tenocytes (tendon cells), which have been expanded in vitro after harvesting a small piece of autologous tendon; and dermal fibroblasts, which form a scar tissue in tendons and are an example of a nonhomologous therapy. There is insufficient high-quality evidence of these cell-based therapies to justify further discussion. We believe they should be used only as part of well-designed research trials.
INDICATIONS AND CONTRAINDICATIONS FOR BIOLOGIC THERAPIES
Indications — We believe that there is insufficient high-quality evidence to justify the use of biologic therapies for the treatment of tendon or muscle injuries outside of well-designed clinical trials. Despite the dearth of quality evidence, the manufacturers of biologic therapies claim that platelet-rich plasma (PRP), (nonexpanded) stem cell therapies, and combinations of these can be used for multiple clinical indications [16].
PRP is safe, relatively inexpensive, subject to minimal regulation, and easy to administer. Consequently, it is widely used to treat osteoarthritis and tendinopathy refractory to standard conservative therapy, rotator cuff tears, ligament injuries, and muscle tears [16].
Conversely, the manufacture of mesenchymal stem or stromal cells (MSCs) is costly, prolonged, and requires assistance from specialized biotechnology companies. Because MSCs are multipotent cells, they have been subjected to more rigorous government oversight than PRP and are considered investigational. A search of the National Institutes of Health clinical trial database reveals that the majority of registered trials of MSC for the treatment of tendon injuries are either phase 1 or 2, and few have been completed or published. These trials include both expanded and nonexpanded MSCs for the treatment of a range of conditions, including isolated Achilles or lateral epicondyle tendinopathy and tissue scaffolding following surgical repair of rotator cuff injury.
Contraindications — Biologics are not recommended for patients with an allergy to any manufacturing components (eg, dimethyl sulfoxide), serious intercurrent illness (eg, acute infection causing fever), or local infection at or near the site of injection. PRP and MSCs are contraindicated in any patient with a malignancy or recent remission from a malignancy, with the exception of nonmetastasizing skin tumors such as squamous cell carcinoma or basal cell carcinoma. This is because of the risk of injecting malignant cells or growth factors that theoretically could accelerate a malignancy.
Local anesthetics may adversely affect platelet and stem cell function and should not be injected into the same location as the biologic therapy [17,18]. However, local anesthetics can be used in adjacent tissues and to block peripheral nerves, provided they do not mix with the biologic injection.
PRP therapy is not recommended in patients with thrombocytopenia or those who use nonsteroidal anti-inflammatories in the two weeks prior to bloodletting due to the effect on platelet numbers and function [19].
MSC therapies are not recommended in pregnant patients. While there is no research in this area, the proscription stems from theoretical risks to the fetus.
In theory, nonexpanded (same-day) MSC concentrates are relatively contraindicated for tendon disorders due to the low number of MSCs and the resulting larger volumes that must be injected intratendinously. This increases the risk of tendon damage and may lead to MSC extravasation, which could be harmful. Extravasated MSCs could potentially differentiate into undesired tissues, depending on signals from local adipose, osseous, or synovial tissues.
Biologic therapies and doping in sport — Many elite athletes must abide by the World Anti-Doping Agency (WADA) regulations and are subject to drug testing requirements. According to the 2019 WADA Prohibited List, autologous PRP by local injection for the treatment of soft tissue injury is permitted. Systemic injection of blood products, including PRP, is not permitted. Local or systemic injection of individual purified growth factors derived from PRP is not permitted. Cellular products can be administered only if they are not used to enhance sports performance. Doping in sport and substances used for performance enhancement are discussed in detail separately. (See "Use of androgens and other hormones by athletes" and "Prohibited non-hormonal performance-enhancing drugs in sport" and "Prescription and non-prescription medications permitted for performance enhancement".)
The use of both PRP and MSCs is addressed on the WADA "Q&A" website [20].
BIOLOGIC THERAPIES FOR TENDON INJURIES
Types of tendon injuries treated
Degenerative overuse tendon injury — Tendon injuries commonly occur from overuse, particularly overuse involving energy-storage-and-release (spring) loads (eg, jumping) and compressive loads (eg, squatting with weight) [21]. The cumulative effects of overuse can produce tendon pathology, usually degeneration, that may become symptomatic and possibly progress to rupture. Sometimes, intrasubstance tendon tears develop, although the clinical diagnosis of these is problematic and they may not be clinically meaningful [22].
Degenerative tendon is characterized by a progressive loss of matrix integrity (eg, collagen disorganization, increase in proteoglycans) [23,24] and leads to a thickened tendon with a matrix that cannot transmit load, an important stimulus for tissue repair. As no acute injury is involved, and there is no inflammation, important stimuli for tendon repair are missing. The result is that overuse tendon pathology does not heal.
Tendon rupture — Tendons that rupture have degenerative pathology that is often asymptomatic [25]. Tendons rupture when the load placed on the tendon exceeds the capacity of the remaining normal part of the tendon. Hence, a profoundly degenerative tendon can rupture with little load (stepping off a curb); conversely, a gymnast can rupture a minimally degenerative tendon due to the high landing loads (up to 17 times body weight) that their sport entails. The injury results in bleeding, which causes an inflammatory, proliferative, and maturative response that in turn produces extensive change to the cells and matrix. This response results in a tendon that is two to three times thicker than the original and is completely different from that seen with an overuse tendon injury.
Studies of PRP and ABI for tendon injury
Medical therapy — The results of studies of autologous whole blood injection (ABI) and platelet-rich plasma (PRP) for the treatment of tendon injuries are contradictory, but most show no clear benefit. A 2014 systematic review of 19 randomized and quasi-randomized trials of PRP for musculoskeletal soft tissue injuries, involving 1088 participants, noted the following [26]:
●"The evidence for all primary outcomes was judged as being of very low quality."
●Methods for preparing and quantifying PRP therapies lack standardization.
●Evidence to support the use of PRP therapies for treating muscle and tendon injuries is lacking, both overall and for specific conditions.
The authors' review of 16 randomized trials (four published after the 2014 systematic review) assessing the effectiveness of ABI or PRP for overuse tendinopathy found that 11 reported no difference in clinically important outcomes [27-42]. Subsequent studies have reported similar findings [43,44]. A small, well-performed trial comparing leukocyte-rich PRP with leukocyte-poor PRP and saline for the treatment of patellar tendinopathy (in addition, all participants completed the same rehabilitation program) found no difference in outcome at 12 weeks and 12 months [45].
As reported in the systematic review, the quality of many of the clinical studies of PRP is limited, and many are at high risk of bias. The following are among the common methodologic problems noted:
●Small number of participants
●Blinding of participants and/or outcome assessors not performed or not described
●Treatment preparation not standardized among trials
●Outcome measures often focused on pain; healing of tendon tissue not considered
Tendon injuries are not monolithic but involve a number of considerations not accounted for in many trials that may be a source of some of the contradictory outcomes reported. Such considerations include whether the injury involves an upper or lower extremity, a mid-tendon or entheseal tendon, an intact collagen scaffold or tendon tear, and bursal involvement or not. Additional problems may be related to specific treatments. For therapies that are "innovative," expensive, and ritualistic, the placebo effect must be considered carefully [46,47].
Adjunct to surgical repair — The great majority of randomized trials have reported no clinically significant benefit at long-term follow-up from the addition of PRP therapy to surgical repair of injured rotator cuff or Achilles tendons [48,49]. Heterogeneity among studies and poor methodologic quality limit much of the available evidence [50]. Therefore, we do not recommend that PRP be used as adjunctive therapy for tendon surgery outside of well-designed clinical trials.
In addition to published systematic reviews, the authors assessed 13 randomized trials comparing rotator cuff or Achilles tendon repair with or without adjunctive treatment using PRP [51-63]. Only one of the trials reported a clinically important improvement in tendon healing and functional outcome at long-term follow-up in patients given PRP [57].
Studies of stem cell therapy for tendon injury — Additional research is needed to determine whether mesenchymal stem or stromal cells (MSCs) are an effective treatment for tendinopathy in humans and, if found to be effective, to establish the best MSC-harvesting source and the number of MSCs to inject.
The potential benefits of MSC therapy in tendon disorders was first described in the equine thoroughbred industry. Racehorses are prone to developing superficial digital flexor tendinopathy, and the intratendinous implantation of 10 to 20 x 106 expanded autologous bone marrow MSCs suspended in 2 mL of solution has been reported to be beneficial. The equine reinjury rate after MSC therapy was 27.4 percent, which is nearly one-half the rate of alternative nonsurgical treatments [64]. Subsequent postmortem studies have shown minimal evidence of tendinopathy after MSC implantation.
Clinical evidence supporting the use of MSCs in humans is limited and unconvincing. A systematic review identified four published clinical trials with a total of 79 patients [65]. All four trials describe positive results without serious adverse outcomes, but only one trial used expanded (allogeneic) MSCs, and none of the trials involved contemporaneous controls. The authors found that all trials were at high risk of bias, and evidence did not support the use of stem cells to treat tendon disorders.
BIOLOGIC THERAPIES FOR MUSCLE INJURIES
Types of muscle injuries treated — Skeletal muscle is frequently injured due to load-related strains during activity. Proponents of biologic therapies claim they are effective treatments for such injuries. Skeletal muscle is also susceptible to tears, contusions, lacerations, crush injury, and age-related atrophy (sarcopenia).
Muscle strains (commonly referred to as "pulls" or "tears") occur when the load placed on the muscle exceeds the muscle's capacity to resist the load. This causes acute injury of the muscle fibers at the muscle-tendon junction (MTJ). Strains occur at the MTJ within the muscle belly or involve the intramuscular connective tissue. Muscle strain results in bleeding from the injured tissue that initiates an inflammatory, proliferative, and maturative (regenerative) response. Many cytokine growth factors are released, and cellular responses occur during a complex healing process.
The established treatment of muscle-strain injuries emphasizes active recovery, including exercise-based interventions [66]. An important consideration with muscle-strain injuries is recurrence or reinjury.
Studies of PRP use for muscle injury — Muscle injuries are heterogeneous, varying in the mechanism, site of injury, extent of injury, and the presence or absence of connective tissue involvement. Depending on the nature of the injury, a range of therapies may be of potential use. Nevertheless, few randomized trials of platelet-rich plasma (PRP) for the treatment of muscle injuries have been performed, and results have been mixed. Thus, no conclusions can be drawn about the effectiveness of PRP therapy for acute muscle injury.
The limited evidence available includes the following [67-69]:
●A meta-analysis of five randomized trials of moderate overall quality involving 268 patients with grade I or II acute muscle injury reported that treatment with PRP led to earlier return to sport (mean difference -5.57 days; 95% CI -9.57 to -1.58) but no statistically significant difference in reinjury rates [67]. The large majority of patients were men, and hamstring strains were the most common injury treated.
●Perhaps the best trial included in the meta-analysis described above was a multicenter randomized trial of 80 competitive and recreational athletes with acute hamstring strains. In this trial, patients treated with PRP injection did not return to play more quickly and did not experience lower rates of reinjury at either two months or one year (hazard ratio [HR] 0.89; 95% CI 0.38-2.13) compared with those treated with placebo [69].
●In a randomized trial of 75 athletes with acute grade II muscle strains, patients treated with physical therapy plus PRP injection returned to play sooner than those treated with physical therapy alone (21 versus 25 days) and experienced less pain throughout the study, but the rate of reinjury at two years was not statistically different [68].
Studies of MSC use for muscle injury — Stem cell therapies for skeletal muscle injuries and disorders remain investigational and have yet to be studied sufficiently in clinical trials. These therapies are the subject of research for a range of uses.
Skeletal muscle has the capacity to repair and regenerate due to the presence of muscle satellite cells, which are unipotent differentiated cells capable of proliferation and engraftment. Skeletal muscle is also a source of multipotent mesenchymal stem cells and has been used as a harvesting source to treat other pathologies.
Most muscle-strain injuries heal well, but an exception is injury complicated by muscle fibrosis. In this condition, local mesenchymal stem or stromal cells (MSCs) differentiate into myofibroblasts rather than myoblasts/satellite cells, and this is thought to be due to the production of local cytokines [70,71]. Therefore, in theory, stem cells injected into such tissue could differentiate into additional scar rather than muscle.
Ongoing research is investigating the use of MSCs combined with tissue-engineering scaffolds to treat massive posttraumatic muscle loss and postdenervation muscle injury. In some of these trials, MSCs are predifferentiated into myoblasts/satellite cells so that inappropriate differentiation does not occur.
Research is ongoing into the use of MSCs in reversing nonskeletal muscle pathology, including fibrosis following myocardial infarction and urinary incontinence due to detrusor instability. There are a number of medical conditions associated with systemic skeletal muscle wasting, including disuse atrophy, cancer cachexia, muscular dystrophy, and sarcopenia [72]. Theoretically, systemic MSCs could be useful for these conditions, but methods of stem cell delivery to peripheral muscle have not yet been established. If this problem is overcome, any such therapy would have a significant potential for sport doping.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General issues in muscle and tendon injury diagnosis and management".)
SUMMARY AND RECOMMENDATIONS
●Basic types of biologic therapies – The biologic therapies used to treat muscle and tendon injuries are described in greater detail in the text but can be divided broadly into two classes (see 'Terminology and background' above):
•Blood-derived therapies include injection of autologous whole blood (ABI), platelet-rich plasma (PRP), and extracted blood derivatives. They are injected at the site of injury and are purported to deliver supraphysiologic concentrations of cytokines and other substances that promote growth and repair and mediate the inflammatory process. (See 'Blood-derived therapies' above.)
•Cellular therapies include mesenchymal stem or stromal cells (MSCs), autologous tenocytes, and dermal fibroblasts; and involve introducing cells directly into local tissue (a process termed "engrafting"), where they purportedly have regenerative effects. (See 'Cell-based therapies' above.)
●Contraindications – Biologic treatments are generally regarded as low risk, but they are not recommended for patients with an allergy to any manufacturing components (eg, dimethyl sulfoxide), serious intercurrent illness (eg, acute infection causing fever), or local infection at or near the site of injection. PRP and MSCs are contraindicated in any patient with a malignancy or recent remission from a malignancy, with the exception of nonmetastasizing skin tumors such as squamous cell carcinoma or basal cell carcinoma. (See 'Indications and contraindications for biologic therapies' above.)
●Platelet-rich plasma (PRP) treatments – PRP therapy describes a treatment without standardization of manufacturing methodology, administration schedules, or return-to-exercise guidelines, meaning efficacy is hard to assess. The preponderance of the evidence does not support the efficacy of PRP for treating tendon disorders. There is virtually no high-quality evidence to support the use of PRP in association with surgical treatments, and there have been insufficient clinical trials to determine if PRP has any role in muscle healing. (See 'Biologic therapies for tendon injuries' above and 'Biologic therapies for muscle injuries' above.)
●Mesenchymal cell treatments – MSCs remain an investigational therapy for tendon and muscle injuries that has yet to be studied in well-performed randomized trials. (See 'Studies of stem cell therapy for tendon injury' above and 'Studies of MSC use for muscle injury' above.)
●Safety and lack of proven effectiveness – Evidence from clinical trials suggests that biologic therapies, including PRP and MSCs, are safe and do not cause significant adverse effects in tendon or muscle tissue. However, evidence for their efficacy is sparse and limited in quality, and we do not recommend their use outside of well-designed clinical trials.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
