Biologic therapies for tendon and muscle injury

INTRODUCTION AND DEFINITIONS — Biologic therapies, often referred to as "biologics," are a class of nonpharmacologic treatments used for a variety of conditions in many areas of medicine. In musculoskeletal medicine, biologics purport to heal tissues and restore function lost due to aging, disease, or injury.

This topic will review the proposed mechanisms, clinical use, and evidence for these therapies in the treatment of tendon and muscle injuries. The use of such agents for rheumatologic diseases and other conditions, and the management of specific tendon and muscle and injuries, are discussed separately, including in the following topics (see "Overview of biologic agents in the rheumatic diseases" and "Overuse (persistent) tendinopathy: Overview of management" and "Rotator cuff tendinopathy" and "Elbow tendinopathy (tennis and golf elbow)" and "Achilles tendinopathy and tendon rupture").

BASIC TENDON AND MUSCLE CELL BIOLOGY AND RESPONSE TO INJURY

Tendon — Healthy tendon is a dense, avascular connective tissue composed of parallel type 1 collagen fibers, elastin, and tendon cells (tenocytes) within an extracellular matrix. Tendons have low cell density, poor vascularity, and low metabolic activity, accounting for their poor healing capacity [1]. Aging tendons and those exposed to repetitive loads can develop tendinopathy, which is typically associated with degeneration that may become symptomatic and possibly progress to intrasubstance tears. Degenerative tendons are characterized by the progressive loss of matrix integrity (eg, collagen disorganization, increase in proteoglycans), thickening, and reduced load capacity [2,3].

Degenerative tendons can rupture but seldom do [4]. Such injury results in bleeding, which causes inflammatory, proliferative, and maturative responses that in turn produce extensive changes in the cells and matrix. These responses result in a tendon that is two to three times thicker than normal and is histologically different from that seen with a chronic, overuse tendon injury. The quality and function of all repaired tendon is inferior to healthy tendon.

Muscle — Skeletal muscle comprises over 40 percent of human body weight. Muscle may be injured by mechanical forces, thermal or metabolic insult (rhabdomyolysis), de-innervation, and ischemia. Muscle contains (relatively) high numbers of satellite cells (2 to 7 percent) [5], which are a heterogenous population of quiescent, undifferentiated stem cells and partially differentiated precursor cells [6].

Unlike tendon, muscle is highly vascular and the fastest repairing of the mesenchyme tissues [5]. Muscle responds to both overuse and load with hypertrophy and probably hyperplasia. Occasionally, acute load causes muscle fiber disruption (ie, tear) that leads to the activation of the quiescent satellite cells. Once activated, these cells differentiate into muscle connective tissue cells and primitive myocytes, which are incorporated into existing muscle fibers.

TERMINOLOGY AND BACKGROUND — The US Food and Drug Administration (FDA) states that biologic therapies are "a diverse category of products and are generally large, complex molecules…that may be produced through biotechnology in a living system." This topic will describe the common autologous (from the same individual) biologics used in clinical practice.

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, for tendon conditions, can include mesenchymal stem or stromal cells (MSCs), autologous tenocytes, and dermal fibroblasts.

Worldwide, the number of medical clinics offering biologic therapies for muscle and tendon conditions has grown substantially over the last 15 years. Several factors have contributed to this phenomenon.

●Limited available treatments – Apart from incremental exercise rehabilitation, few, if any, established treatments improve the healing of musculoskeletal injuries. Biologic therapies are claimed to fulfil this unmet clinical need.

●Ease of production and administration – Biologic therapies are easily manufactured and can be administered as an off-label therapy via local injection at the point of care.

●Marketing by manufacturers – Biotechnology companies that manufacture the equipment used to produce these therapies have marketed directly to clinicians and consumers. This advertising often includes celebrity endorsements and athlete testimonials.

●Minimal regulation – Biologic therapies should be subject to regulation including consumer law for marketers, medical regulation from professional bodies, and manufacturing regulation from government agencies. However, many regulators have been slow to act and have failed to keep pace with the rapidly emerging biologics industry.

In the United States, the FDA has attempted to increase oversight of stem cell use, but this has not prevented an increase in such clinics from 315 in 2016 to 2754 in 2021 [7,8]. The Australian Therapeutic Goods Administration (TGA) introduced more restrictive stem cell regulation in 2019, resulting in a dramatic reduction in stem cell clinics outside of hospital settings. However, geographic regulatory variation persists and has led to cross-border marketing of biologic therapies and the emergence of "stem cell tourism."

Due to the factors described above, commercial interests have successfully promoted biologic therapies, sometimes without sufficient evidence of improved clinical outcomes. Many published studies of biologics are unblinded and uncontrolled. When assessing the evidence for biologics, clinicians should be aware that placebo effects may play a role in the purported effectiveness of expensive, ritualistic, and emerging therapies [9,10].  

The assessments in this topic are based primarily on evidence from systematic reviews and high-quality, peer-reviewed, controlled clinical trials.

Clinicians considering referring patients for biologic therapies or 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 TGA.

PROPOSED MECHANISMS AND PRODUCTION OF BIOLOGIC THERAPIES

Blood-derived therapies, including platelet-rich plasma — Blood-derived therapies involve the local administration of either blood or blood constituents resulting in 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 largely 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 local proteins including thrombin and tissue collagen. 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) [11].

PRP is defined as a platelet-rich concentrate with platelet levels greater than the baseline count in whole blood. It is manufactured using differential centrifugation of blood, which separates the denser red cells from the plasma. Between these two components is a fine (white) buffy coat, which contains the leucocytes and most of the platelets. The "adjacent layer" of plasma, located just above the buffy coat, is less rich in platelets and has very few leucocytes. Above the adjacent layer is the platelet-poor plasma (PPP).

A variety of techniques are used to harvest the buffy coat, the adjacent layer, or both. Depending on the method of preparation and supernatants extracted, the number of platelets in prepared PRP varies between one and nine times that of whole blood [12]. The techniques that produce higher concentrates of platelets are typically from the buffy coat and contain large numbers of leucocytes. Hence, PRP is often referred to as leucocyte rich (LR), with higher concentrations of both leucocytes and platelets, or leucocyte poor (LP). The role of leucocytes (which contain enzymes such as collagenase) in soft tissue healing is controversial [13].

Biotechnology companies market their centrifuges and disposable kits to clinicians and health care institutions. Each manufacturing technique has different preparation protocols, including volume of whole blood extracted, LR or LP, single or double spin, and 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 tissue collagen will suffice. Administration protocols vary, but for tendon conditions, most call for between one and four intra-tendinous injections over a two- to four-week period [14]. There is no consensus about exercise protocols or return-to-sport guidelines following PRP treatment.

PRP should be viewed as a general term describing a therapy with no gold standard of preparation, administration guidelines, or post-procedural exercise rehabilitation program. The heterogeneity of possible approaches allows some proponents to claim the superiority of one technique over another. Furthermore, the small number of well-controlled trials using similar administration and rehabilitation protocols makes it difficult to assess the efficacy of any individual preparation technique for tendon and muscle disorders.

Cell-based therapies, including mesenchymal stem cells — Cell-based therapies for tendon and muscle conditions include the administration of undifferentiated mesenchymal stem cells (MSCs), differentiated tenocytes, and dermal fibroblasts. Cellular therapies are purported to produce a regenerative effect at an injury site via two pathways. The first involves cells (tenocytes, dermal fibroblasts, differentiated MSCs) engrafting directly into local tissues, while the second involves undifferentiated cells (MSCs only) producing cytokines that may facilitate tissue regeneration by promoting growth and differentiation of local precursor cells.

While there are several types of stem cells, all are capable of proliferation and differentiation into adult cell lines. Stem cell biology and the use of these products in other areas of medicine are reviewed separately. (See "Overview of stem cells".)

Mesenchymal stem cells are an undifferentiated, multipotent cell and are the body's repair cell for mesenchyme tissues. By definition, MSCs must demonstrate in vitro differentiation into fat, bone, and cartilage [15]; however, most MSCs are also capable of differentiation into muscle, tendon, and ligament to varying degrees [16].

There are potential risks of unintended differentiation with all stem cell therapies. To minimize these, MSCs can be pre-differentiated in vitro into the intended unipotent precursor cells, which serves to reduce risks. However, the cell biology of tendons is the least well understood of the major mesenchyme tissues, and tenogenic pre-differentiation factors are not yet known [17].  

MSCs are rare, and their numbers decrease with age. In response to tissue injury, it is thought that undifferentiated MSCs receive local paracrine activation signals (cytokines), resulting in activation and modulation of local cells, proliferation, and/or differentiation into the surrounding host tissue. Hence, MSCs are sometimes referred to as "the conductor of the orchestra." MSCs are also immunosuppressive and do not appear to initiate host rejection, so allogeneic cells may be used [18].

MSCs are found in every tissue of the body. While bone marrow remains the most common harvesting source, MSCs comprise only 0.01 to 0.001 percent of the nucleated cells in bone marrow aspirate concentrate (BMAC) [19]. Adipose tissue contains 2500 more MSCs per gram, and harvesting is less invasive [20]. Adipocytes can be removed by dissolving in collagenase, and the resulting supernatant is termed the stromal vascular fraction (SVF), which contains between 0 and 10 percent MSCs amongst the nucleated cells.

The manufacture of expanded or cultured MSCs (typically used in research and hematology) involves several distinct steps performed in vitro:

●Harvesting of cells (eg, BMAC or SVF)

●Isolation of MSCs by plastic adherence

●Proliferation/expansion of MSCs; termed "expansion by passage," a culture process that takes days to weeks and produces large numbers of MSCs

●MSC storage, usually by cryopreservation

This manufacturing process is costly, time consuming, and subject to considerable government regulation. Hence, it is more cost effective to manufacture by expansion high numbers of allogeneic MSCs, which can be then administered to multiple patients without immunologic rejection.

Due to the disadvantages associated with the manufacturing of expanded MSCs, an alternative therapeutic technique without expansion has been used that involves injecting BMAC or SVF directly into the patient on the day of treatment [21,22]. This circumvents much of the current stem cell regulation, as there is minimal cellular manipulation. However, MSC yields vary enormously among providers, and cells can be damaged during harvesting, meaning the actual number of viable MSCs cannot be qualitatively or quantitatively measured. Clinicians should be aware of the difference between pure expanded MSCs and the nonexpanded heterogeneous cell population in SVF or BMAC marketed as a stem cell therapy (table 1).

In some countries, it is permitted to administer differentiated unipotent 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 autologous 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 clinical trials.

Differences between biologic and glucocorticoid injection therapy — Glucocorticoid remains the most common injection therapy for tendon injury. There are several important differences between glucocorticoid and biologic injection. Typically, glucocorticoid is administered adjacent to the tendon with optional radiologic guidance. Biologics must be administered directly into the tendon or muscle, and radiologic guidance is strongly recommended. Other possible differences include claims that biologics are regenerative, as opposed to glucocorticoids, which are potentially degenerative. Onset and duration of action differ, as proponents claim that PRP produces regeneration after approximately three months [12], while glucocorticoid relieves pain within days and has anti-inflammatory effects that last for one to two months. (See "Major adverse effects of systemic glucocorticoids".)

INDICATIONS AND CONTRAINDICATIONS FOR BIOLOGICS IN MUSCLE AND TENDON CONDITIONS

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.

The proponents of biologic therapies claim that platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) accelerate recovery from acute sporting injury and may be used for multiple clinical musculoskeletal indications [23].

PRP is safe, easy to administer at the point of care, and subject to minimal regulation. While PRP is relatively inexpensive to produce, fees are often exorbitant (around $1000 per injection in the United States in 2019 [24]). espite its cost, PRP is widely used to treat soft tissue conditions, including tendinopathy and tears of tendons, muscles, and ligaments. PRP is sometimes used as an adjunct to surgical repair of tendons, menisci, and ligaments. (See 'Studies of PRP for tendon injuries' below and 'Studies of PRP for muscle injury' below.)

MSCs are a multipotent cell, capable of regenerating any of the mesenchyme tissues. However, few clinical trials have been performed to assess the effectiveness of MSCs for the treatment of tendon and muscle injuries. (See 'Studies of MSC for tendon injury' below and 'Studies of MSC for muscle injury' below.)

Contraindications — Biologics are not recommended for patients with any of the following conditions:

●Allergy to any manufacturing components (eg, dimethyl sulfoxide [MSC preservative])

●Serious intercurrent illness (eg, acute infection causing fever)

●Local infection at or near the site of injection

In addition, PRP and MSCs are contraindicated in any patient with a malignancy or recent remission from an active malignancy (apart from nonmetastasizing skin tumors) due to the potential of injecting malignant cells accompanied by growth factors.

Local anaesthetics may adversely affect platelet and stem cell function and should not be injected into the same location as the biologic therapy [25,26]. However, local anaesthetics can be used in adjacent tissues to block skin or peripheral nerves.

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 effects on platelet numbers and function [27].

MSC extravasation from tendon or muscle could potentially result in ectopic production of osseus, adipose, or synovial tissues. Hence, MSCs must only be administered in small volumes directly into the site of pathology via a radiologically guided injection. If MSCs are being administered into partial-thickness tendon tears, scaffolds such as fibrin glue are sometimes mixed with the MSCs to reduce risks from extravasation.

Cellular therapies of any type are not recommended in pregnant patients. While there is no research in this area, the contraindication is due to theoretical risks to the fetus.

The US Food and Drug Administration (FDA) has published warnings about the therapeutic use of unregulated stem cells that describe cases of tumor formation, blindness, and infection [6]. Evidence published to date suggests that MSCs are safe for the treatment of musculoskeletal conditions. The few published clinical trials involving local implantation do not report a significant risk of tumor formation, unintended differentiation, or other serious adverse events [28,29].

Biologic therapies and doping in sport — Elite, international athletes must abide by the World Anti-Doping Agency (WADA) regulations and are subject to drug testing requirements. According to the 2024 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 also not permitted. Cellular products can be administered only if they are not used to enhance sports performance [30]. 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".)

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) [31]. 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 [32].

Degenerative tendon is characterized by a progressive loss of matrix integrity (eg, collagen disorganization, increase in proteoglycans) [2,3] 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 [4]. 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 autologous whole blood for tendon injuries — Overall, controlled trials investigating autologous whole blood (ABI) for the treatment of tendon conditions show no clear benefit [33-35]. The results of small trials comparing ABI versus glucocorticoid injections for lateral elbow tendinopathy have been mixed, but glucocorticoid appeared to provide greater short-term reduction in pain while ABI led to greater benefit after 6 to 12 weeks [36-38].

In clinical practice, ABI has largely been overtaken by platelet-rich plasma (PRP) for treatment of tendon conditions. A 2021 systematic review and meta-analysis of 32 studies (n = 2337) of ABI and PRP for treatment of lateral epicondylitis concluded that "these injections probably provide little or no clinically important benefit for pain or function" [39].

Studies of PRP for tendon injuries — We do not support the use of PRP as a first-line treatment for tendinopathy or acute tendon injury. Too often in clinical practice, PRP is administered for tendon conditions before patients have participated in a well-designed physical rehabilitation program for an appropriate period. We believe this approach is incorrect.

Systematic reviews of studies of PRP for the treatment of tendon conditions do not demonstrate clear, clinically significant benefits in terms of pain reduction, strength gain, or radiologic evidence of tissue healing [40-46]. As examples, a systematic review and meta-analysis of 29 randomized trials of treatment for Achilles tendinopathy found no evidence of additional, clinically significant benefit from injection therapies over exercise therapy alone at either 3- or 12-month follow-up [47]. In another meta-analysis limited to randomized trials comparing PRP versus placebo for the treatment of tendinopathy, there was no statistically or clinically significant difference in pain relief or functional improvement at any follow-up point [43]. (See "Achilles tendinopathy and tendon rupture".)  

Studies of PRP often have methodologic limitations. In many studies, evidence of efficacy is based largely on patients' self-reported outcomes with minimal consistent benefit noted [48-53]. Other problems, such as inconsistency, imprecision, and significant risk of bias, may stem from the following:

●Small number of participants

●Blinding of participants and/or outcome assessors not performed or not described

●Nonstandardized controls used, including placebo injections, exercise rehabilitation, or both

●Treatment preparations not standardized

●Outcome measures often focused on pain; radiologic signs of healing and clinical assessment of strength not described

●Multivariate analysis of potential confounders not performed

While a few studies have reported trends towards greater pain reduction, these findings are statistically fragile, as slight alterations in the results would change the conclusion [54].

In systematic reviews of studies comparing PRP versus glucocorticoid injection for the treatment of tendinopathy, injection of the latter is consistently associated with reduced symptoms during the first 6 to 12 weeks, after which patients treated with PRP report fewer symptoms [55-57]. This is consistent with studies of ABI and may be due to the short-term anti-inflammatory and long-term catabolic effects of glucocorticoid. (See 'Differences between biologic and glucocorticoid injection therapy' above.)

The results of studies comparing leukocyte-rich (LR) PRP and leukocyte-poor (LP) PRP for treatment of tendon conditions are contradictory, and no firm conclusions can be drawn [12,58]. As examples, two controlled trials that directly compared LR PRP, LP PRP, and normal saline for patellar tendinopathy or lateral epicondylitis found no significant difference in outcomes among groups [13,59].

One author of this topic occasionally suggests a trial of percutaneous PRP therapy in refractory tendinopathy, but only when established treatments have been exhausted, and only as part of shared decision-making, including education about the treatment and informed consent [60,61].

Adjunct to surgical repair — Due to the lack of evidence of efficacy, we do not support the use of PRP as a therapy to augment surgery for tendon conditions outside of well-designed clinical trials. Most randomized trials have reported no clinically significant benefit at long-term follow-up from treatment with PRP following surgical repair of the rotator cuff or Achilles tendons [62,63]. Heterogeneity among studies and methodologic limitations affect much of the available evidence [64].

Studies of MSC for tendon injury — We do not support the use of mesenchymal stem cell (MSC) therapy for the treatment of tendon injury and believe such use should be restricted to well-designed clinical trials.

While the results of systematic reviews of clinical trials of MSC therapy for tendon conditions suggest possible benefit, researchers have noted a high risk of bias among included studies [65-68]. Many studies were small, observational, and otherwise methodologically limited. Problems included the absence of a preferred harvesting site and inconsistency in the manufacturing process and quantity of MSCs administered. Published clinical trials have used MSCs harvested from bone marrow or adipose tissue with minimal manipulation (bone marrow aspirate concentrate; stromal vascular fraction) or expanded MSCs. No major adverse effects relating to MSC treatment have been noted. (See 'Cell-based therapies, including mesenchymal stem cells' above.)

The potential benefits of MSC therapy were first described in the equine thoroughbred industry where implantation of autologous bone marrow MSCs was reported in observational studies to improve tendon healing in racehorses, which are prone to developing superficial digital flexor tendinopathy [69]. Several small trials in humans have suggested benefit. As an example, in a randomized trial of 20 patients with proximal patellar tendinopathy, both treatment groups experienced reductions in pain but only those treated with expanded, adipose-derived MSCs had normalization of tendon tissue on ultrasound [70].

BIOLOGIC THERAPIES FOR MUSCLE INJURIES

Types of muscle injuries treated — Acute muscle fiber strains and tears are common in sport and responsible for approximately 30 percent of time lost for participation [71,72]. Injury recurrence rates can be as high as 40 percent, especially if return to sport is accelerated or proper rehabilitation is not performed. Hence, acute muscle injury is a common reason for treatment with platelet-rich plasma (PRP), as it can be prepared immediately and administered at the point of care shortly after an injury is confirmed.

Studies of PRP for muscle injury — We do not support the use of PRP as a first-line treatment for acute muscle injury. Published trials do not demonstrate clear improvements in the time needed to return to sport following such injury or in rates of injury recurrence among those treated with PRP.

While multiple retrospective case series report accelerated return to sport following treatment with PRP, few well-controlled trials have been published. A meta-analysis of five randomized trials of moderate quality, involving 268 patients with high-grade, acute muscle injury reported that treatment with PRP led to a slightly earlier return to sport (mean difference -5.57 days, 95% CI -9.57 to -1.58) but no statistically significant difference in reinjury rates [73].

Most trials of PRP for muscle injury have involved athletes with acute hamstring strains and a primary outcome of time to return to sport [74-77]. In two such trials (n = 170), no significant differences were noted in either time to return to sport or reinjury rates in patients treated with leukocyte-rich (LR) PRP compared with those given placebo [74,76]. Two unblinded trials (n = 103) reported slightly shorter times to return to sport among those treated with PRP but no difference in reinjury rates [75,77].

Studies of MSC for muscle injury — The use of mesenchymal stem cells (MSCs) for treatment of acute skeletal muscle injury is not well studied, and such use remains investigational. In most cases, healing of such injuries occurs relatively quickly, and thus, the cost and regulatory hurdles of manufacturing MSCs are not justified. In addition, appropriate physical rehabilitation exercises are a potent stimulator of muscle satellite cells. A few preliminary studies of MSCs for rotator cuff and gluteal muscle tears are underway, including one clinical trial of allogenic MSCs for treatment of arthroplasty-associated tears of the gluteus medius [78].

Rare complications to muscle healing include fibrosis, myositis ossificans, and fatty infiltration. In such cases, it is thought that MSCs and satellite cells are exposed to local cytokines and inappropriately differentiate into myofibroblasts, osteocytes, and adipocytes [79,80]. There are theoretical benefits to treatment with MSCs in these conditions, but pre-differentiation into myocyte lineages would be preferred. Little research into the clinical application of such potential therapy has been performed [81].

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, including platelet-rich plasma' above.)

•Cellular therapies include mesenchymal stem or stromal cells (MSCs), differentiated tenocytes, and dermal fibroblasts. Treatment involves introducing cells directly into local tissue (a process termed "engrafting"), where they purportedly have regenerative effects. (See 'Cell-based therapies, including mesenchymal stem cells' above.)

●Contraindications – Biologic treatments are generally regarded as low risk, but they are not recommended for patients with an allergy to any manufacturing components, 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, except for non-metastasizing skin tumors (eg, squamous cell carcinoma, basal cell carcinoma). (See 'Indications and contraindications for biologics in muscle and tendon conditions' above.)

●PRP treatments – PRP therapy describes a treatment without standardization of manufacturing methodology, administration schedules, or return-to-exercise guidelines, making efficacy difficult to assess. We suggest against the use of PRP for treating tendon disorders (Grade 2B), as an adjunct to tendon surgical repair (Grade 2C), or for treating acute muscle injury (Grade 2C).

Clinical trials evaluating PRP in patients with tendinopathy do not report clinical benefits in terms of pain reduction, strength gain, or radiologic evidence of tissue healing. Clinical trials evaluating PRP as an adjunct to surgery are mixed, though most reported no clinical benefit. There is little high-quality evidence to assess the efficacy of PRP for acute muscle injury. Use of PRP for any of the above conditions should be limited to well-designed clinical trials. (See 'Biologic therapies for tendon injuries' above and 'Biologic therapies for muscle injuries' above.)

●Mesenchymal cell treatments – We suggest against the use of MSCs for tendon and muscle injuries (Grade 2C). The available clinical trials investigating MSC therapy have important methodologic limitations, and its efficacy remains uncertain. Use of MSCs should be limited to well-designed clinical trials. (See 'Biologic therapies for tendon injuries' above and 'Biologic therapies for muscle injuries' above.)

●Safety – 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.