Musculoskeletal Injections Manual Basics, Techniques and

Injectable Agents

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vi Preface

As ESSKA U45 Committee and ORBIT, we would like to express our

deepest appreciation to the authors for their dedication to advancing the field
of musculoskeletal medicine and for sharing their expertise through this
remarkable publication. We are confident that Musculoskeletal Injections
Manual: Basics, Techniques and Injectable Agents will become an essential
publication for young surgeons who are motivated to deliver the best possible
care in the scene of sports traumatology.

Istanbul, Turkey Baris Kocaoglu

Hadera, Israel  Lior Laver
Milano, Italy  Laura de Girolamo
Milano, Italy  Riccardo Compagnoni
Contents

Part I Basics of Musculoskeletal Injections

1 
Philosophy of Musculoskeletal Injections��������������������������������������   3
Behiç Çelik and Gökhan Meriç
2 
The Evidence-Based Medicine for Injection Therapy������������������   9
Marko Ostojić
3 
Contraindications and Potential Side Effects of Injections���������� 15
Riccardo Compagnoni, Rossella Ravaglia, and Pietro Randelli
4 Informing Patients �������������������������������������������������������������������������� 21
Daniel Pérez-Prieto, Ana Soria, Marta Torruella,
and Narcís Pérez de Puig
5 
Sterilization and Injection Materials �������������������������������������������� 25
F. De Filippo and Maristella F. Saccomanno
6 Things to Take into Consideration in Injection
and Aspiration���������������������������������������������������������������������������������� 29
Thorkell Snaebjörnsson
7 
Postinjection Care and Education�������������������������������������������������� 33
Thorkell Snaebjörnsson

Part II Non Biologic Agents for Injections

8 Corticosteroids and Local Anesthetics ������������������������������������������ 39

Matthieu Ollivier and Ahmed Mabrouk
9 Viscosupplementation Agents �������������������������������������������������������� 45
Camila Grandberg, Svenja Höger, and M. Enes Kayaalp
10 Radiosynovectomy �������������������������������������������������������������������������� 53
Goksel Dikmen, Vahit Emre Ozden, and Kayahan Karaytug
11 Deproteinized Hemoderivative of Calf Blood-Natural
Botanical and Mineral Extracts������������������������������������������������������ 59
Berhan Bayram and Baris Kocaoglu

vii
viii Contents

Part III Ortho-biologic Agents for Injections

12 Orthobiologics: Background���������������������������������������������������������� 67
Paola De Luca, Michela Maria Taiana, and Laura de Girolamo
13 Platelet-Rich
 Plasma for Osteoarthritis���������������������������������������� 73
Trifon Totlis and Angelo V. Vasiliadis
14 Platelet-Rich
 Plasma Treatment for Meniscal Tears�������������������� 81
Yosef Sourugeon, Yaniv Yonai, Yaron Berkovich,
and Lior Laver
15 PRP in Tendinopathy ���������������������������������������������������������������������� 85
Ferran Abat, Ignacio De Rus Aznar, Federico Ibañez,
and Charlotte Raflé
16 Platelet-Rich
 Plasma (PRP) for Rotator Cuff Tears �������������������� 91
Ron Gilat, Ilan Y. Mitchnik, Derrick Knapik, Grant Garrigues,
Nikhil Verma, and Brian J. Cole
17 Platelet-Rich
 Plasma Treatment for Muscle Injuries ������������������ 99
Yosef Sourugeon, Yaniv Yonai, Yaron Berkovich,
and Lior Laver
18 Bone
 Marrow Aspirate Concentrates for Knee OA���������������������� 105
Peter A. Everts, Ignacio Dallo, José Fábio Lana,
and Luga Podesta
19 Fat-Derived
 Orthobiologics for Knee OA�������������������������������������� 117
Peter A. Everts, Raphael Barnabe, Luga Podesta,
and Rowan Paul
20 Autologous
 Conditioned Serum (ACS)������������������������������������������ 127
Tahsin Beyzadeoglu and Onur Cetin
21 Alpha-2-Macroglobulin
 Concentrate as Orthobiologic
in Osteoarthritis ������������������������������������������������������������������������������ 133
Peter A. Everts, Luga Podesta, José Fábio Lana,
Gayan Poovendran, Gabriel Silva Santos,
and Stephany Cares Huber

Part IV Injections of Anatomical Regions and Diseases

22 Injections
 of Anatomical Regions and Diseases: Shoulder���������� 143
Mocini Fabrizio, Candura Dario, Proietti Lorenzo,
Ciolli Gianluca, Brancaccio Vincenzo, and Cerciello Simone
23 Injections
 of Anatomical Regions and Diseases: Elbow �������������� 155
Eduard Alentorn-Geli and Jorge Ramírez Haua
Contents ix

24 Injections of Anatomical Regions and Diseases:

Wrist and Hand�������������������������������������������������������������������������������� 167
Gamlı Alper and Gereli Arel
25 Injections of Anatomical Regions and Diseases: Hip�������������������� 183
Bruno Capurro, Francesco Vecchi,
Beatriz Álvarez de Sierra, Alex Ortega,
Laura Gimeno-Torres, and Eva Llopis
26 
Injections of Anatomical Regions and Diseases: Knee ���������������� 201
Sarper Gursu, Ahmet Sukru Mercan, Anıl Erbas,
Serda Duman, and Ozgur Ismail Turk
27 Injections of Anatomical Regions and Diseases:
Ankle and Foot �������������������������������������������������������������������������������� 211
Tekin Kerem Ulku and Berhan Bayram
 Part I
Basics of Musculoskeletal Injections
 Philosophy of Musculoskeletal
Injections
1
Behiç Çelik and Gökhan Meriç

1.1 Introduction musculoskeletal system to relieve pain, inflam-

mation, and other symptoms. Musculoskeletal
While providing orthopedic healthcare services, injections can be used to treat a variety of condi-
various invasive interventions are applied to tions, including arthritis, tendonitis, bursitis, and
patients according to their clinical status. other inflammatory or degenerative diseases like
Injection, which is an invasive procedure, is one osteoarthritis. The common use of injections,
of the most commonly used medical procedures their use for preventive, therapeutic, or recre-
in the world. Many other invasive procedures ational purposes, and their varied routes of
also require injections. In addition, injections are administration make one forget that the person
also applied to healthy individuals for the pur- credited with inventing the method over a century
pose of maintaining health and protection apart years ago was merely looking to treat the agony
from its therapeutic purpose. According to the of neuralgia. The goal is to provide targeted relief
2002 data of the World Health Organization to the affected area while minimizing systemic
(WHO), it is estimated that 16 billion injections side effects that can occur with oral medications.
are made annually in developing countries, 95% Modern medicine followed the footsteps of
of which are therapeutic in purpose [1]. Providing nature, just as in any other field which has techno-
health care without injections through needles is logical aspects that have to stay up to date. Sharp
merely possible. And here is how to paint this as objects which were necessary for hunting and
a theme; the needle represents the ability to heal piercing through thing were always necessary in
through pain. As Brokensha portraits in 1999, the the ancient times. Snake bites and arrows loaded
needle, like the hollow teeth of the serpent that with poison were fine examples. Even though
wraps around Aesculapius’ staff, penetrates and many references were present in nature, it still
reinforces doctors’ authority [2]. took several centuries for the syringe and the nee-
The philosophy of musculoskeletal injections dle, which are the current must-have devices for
in medicine is based on the idea of delivering modern medicine, to be developed. Before any
therapeutic agents, such as medications or local medical subdivision even occurred, invasive pro-
anesthetics, directly into the affected area of the cedures such as dissections, injections, etc. were
all part of the general medical practice in countries
that were forerunners of science and research. It is
B. Çelik · G. Meriç (*) no coincidence that these developments took place
Department of Orthopedics and Traumatology, in Europe, where medicine took its modern turn
Yeditepe University Medical Faculty, via experimentations arising from its ancient roots.
Istanbul, Turkey

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 3

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
https://doi.org/10.1007/978-3-031-52603-9_1
4 B. Çelik and G. Meriç

1.2 Philosophy Pravaz, and Luer resulted in increased utilization,

of Musculoskeletal safety, and accuracy. As a result, the Luer syringe
Injections was designed for aseptic heating and a sharp nee-
dle that could easily pierce the skin. Pasteur,
Physicians have experimented with a multitude Chamberland, and Koch created autoclave steril-
of strategies to get medications into the body over ization after regulating aseptic conditions.
the decades. Rubbing of ointments and oils onto Another invention, Limousin’s ampoule, intro-
the skin, one of the earliest procedures, was duced in 1886, provided a secure technique for
described in the Old Testament, Homer’s storing sterile injectates, followed by the advent
Odyssey, and by Aristotle and was employed by of multi-dose containers. Nowadays, with the
practically all ancient physicians. However, emergence of transdermal drug delivery via
severe adverse effects and questionable results micron-scale needles and monitored drug deliv-
prompted the search for alternate treatments. ery, the evolution of the syringe and its needle
According to our knowledge, the earliest intrave- goes on [5].
nous injection trials were conducted in 1642 in Considering all the historical processes and
eastern Germany and in 1656 in England by developments that took place, just as there is a
Christopher Wren [3]. need for improvement, management and keeping
The philosophy of injections, just as any other things up-to-date in any practice in medical sci-
invention that ever took place in the history of ence, the practice of injection depends on the
mankind, got his origin idea from nature. In purpose, the right indication, the dose, the mate-
1628, William Harvey presented fresh knowl- rial and sterility, the right patient selection, and
edge about human blood circulation, which the right agent. It is a clear fact that research and
spurred these studies. According to our knowl- inventions under appropriate conditions must be
edge, the earliest intravenous injection trials were done, keeping things up to date, and while doing
conducted in 1642 in eastern Germany and in that, all the following must be taken into account:
1656 in England by Christopher Wren. the right place and timing, the right method and
Subcutaneous injection was also one of the new circumstance of application, the right follow-up,
methods; predecessors of this application either ideal doctor and patient communication, the
used a vaccination-lancet to introduce the medi- patients’ expectation, and all that might affect the
cation beneath the epidermis or they’d remove outcome in terms of improvement of the patients’
the epidermis before introducing the medication condition and well-being. An understanding of
to the stripped epidermal layer. Lafargue, the determinants of current injection practices in
Lembert, and Lesieur reported these procedures the sociocultural-economic context is necessary
starting early in the 1800s, and they remained in in order to plan relevant and effective
use until the discovery of subcutaneous injection interventions.
in the second half of the century. From a doctor’s perspective, we use injections
The syringe for subcutaneous injection was with various application methods in cases that do
invented by Alexander Wood of Edinburgh and not respond to conservative treatment, with the
Charles-Gabriel Pravaz of Lyon. In Lyon in 1853, logic of transitioning to a higher-level treatment.
the French surgeon C. Pravaz devised a miniature At the same time, various injection techniques
syringe, the piston of which could be moved by a can be used in advanced cases where surgery is
screw, allowing precise dosage. Using a sharp not considered, in patients who do not want sur-
needle with a trocar, he eliminated the need for a gery but need an outpatient invasive procedure
dissection. Pravaz used his syringe to obliterate that does not require surgery. From a patient’s
artery aneurysms with ferric chloride injections. perspective, there are several reasons why injec-
His device sparked the development of calibrated tions may be necessary. Injections are often
syringes made of glass or metal coupled with required when oral medications or alternative
glass [4]. The gradual steps introduced by Wood, treatments are not as effective or suitable for a
1 Philosophy of Musculoskeletal Injections 5

particular condition. Injections allow medica- for pain and inflammation, facilitate healing, and
tions to be delivered directly into the body, ensur- enhance performance. Here are some ways in
ing quicker and more potent effects. which injections are important in sports medi-
Musculoskeletal injections are an important cine. Injections can be used to provide rapid pain
diagnostic and therapeutic technique for orthope- relief to athletes who have sustained injuries or
dist. Some medical conditions require ongoing are experiencing chronic pain. Platelet-rich
treatment and management. While regular injec- plasma (PRP) injections, for instance, contain
tions may be inconvenient, they can significantly growth factors that can stimulate the repair and
improve the patient’s quality of life and overall regeneration of damaged tissues. Injections of
health outcomes (Fig. 1.1). Injections are some- hyaluronic acid can also help improve the health
times used as part of diagnostic procedures to of damaged joint cartilage by lubricating and
help identify or evaluate certain medical condi- cushioning the joint [7]. In some cases, injections
tions. It can help with pain management and can be used to enhance athletic performance. For
overall function [6]. The choice of injection tech- example, erythropoietin (EPO) injections can
nique and medication depends on the specific increase the production of red blood cells, which
condition being treated, as well as the patient’s can improve an athlete’s endurance by delivering
individual needs and preferences. Overall, the more oxygen to the muscles [8].
philosophy of musculoskeletal injections is to Musculoskeletal pain is a prevalent problem
provide safe, effective, and minimally invasive that many primary care physicians, orthopedic
treatments for musculoskeletal conditions, with surgeons, and pain specialists identify and try to
the goal of improving patients’ quality of life and treat on a daily basis. Treating pain with a multi-
functional outcomes while minimizing the use of modal strategy is critical to provide patients with
more invasive interventions, such as surgery. safe and effective results. In addition to this com-
Injections play a crucial role in sports medi- mon ground of application, each specialty has its
cine as they can provide targeted and rapid relief own particular aspects. When we take a look at
the top of the specialties which use musculoskel-
etal injections in their practice routine, we see
orthopedics, physical therapy and rehabilitation,
algology, and anesthesia. It is possible to extend
the list depending on the application of some
regimes of therapy. Physicians should compre-
hend the target anatomy and injection indica-
tions. Injections can be used to both identify the
source of discomfort and reduce pain to allow for
a more thorough evaluation. Aspiration may be
used in injections to aid in diagnostics, provide
pain relief, and restore joint motion. It is critical
to explain activity restrictions, postinjection pain
expectations, and the planned treatment course,
and as always, just before any other medical
intervention, informed consent should always be
acquired prior to the procedure [9, 10]. Injections
could be performed blind or through guiding.
When compared to landmark guiding, ultrasound
guidance has been shown in numerous trials to be
more accurate and effective [6].
Musculoskeletal injections also differ accord-
Fig. 1.1 Injection for peroneal tendon synovitis ing to the specific agent that is used and its spe-
6 B. Çelik and G. Meriç

cific mechanism of action. Anesthetic drugs are peutic purpose in which the underlying principle
mostly used in injections to reduce pain and help is the promotion of health and the alleviation of
to diagnose the medical condition [10]. suffering; secondly, the autonomy and informed
Corticosteroids are effective immune suppres- consent, which ensures that individuals under-
sants and pain relievers. Intra-articular cortico- stand the potential benefits, risks, and alternatives
steroid injections might reduce pain temporarily, before agreeing to undergo an injection; and
especially when used to treat osteoarthritis [11]. thirdly, and maybe most importantly, beneficence
Hyaluronic acid (HA) is a naturally occurring and non-maleficence which emphasizes the duty
polysaccharide chain that the synovium secretes to promote benefit and avoid harm at all costs.
into the joint area. In the mid- to long-term treat-
ment of knee osteoarthritis, higher molecular
weight formulations seem to be more helpful and 1.3 Conclusion
efficient [12, 13]. Trigger point injections are a
treatment option for myofascial trigger points, In conclusion, musculoskeletal injections can
particularly in symptomatic individuals. Chronic provide a safe and effective treatment option for
or episodic headaches, temporomandibular joint a variety of conditions affecting the bones, joints,
pain, back pain, restricted range of motion due to and muscles. Whether it be corticosteroids for
trigger points, and groin pain are common con- inflammation, hyaluronic acid for joint lubrica-
current symptoms. Trigger point injections can tion, or platelet-rich plasma for tissue regenera-
produce meaningful results and should be con- tion, there are a variety of injection therapies that
sidered as a therapy option in the right circum- can help alleviate pain and improve mobility.
stances [14]. Dry needling is a procedure that However, it is important to note that these injec-
uses a small needle which pierces the epidermis, tions should only be administered by qualified
subcutaneous tissues, and muscle in order to healthcare professionals and that patients should
mechanically disrupt tissue without the use of an be thoroughly evaluated beforehand to ensure
anesthetic. The physiological mechanism under- that they are suitable candidates for the proce-
lying the effects of dry needling is still unknown. dure. Overall, with careful consideration and
Dry needling, on the other hand, has been hypoth- appropriate use, musculoskeletal injections can
esized to elicit both local and central neural be a valuable tool in the management of muscu-
responses to restore homeostasis at the site, loskeletal conditions. Overall, our chapter
resulting in a reduction in both peripheral and emphasizes the critical role that injections play in
central sensitivity to pain [15]. Prolotherapy, also modern medicine and underscores the impor-
known as regenerative injection therapy, is a tance of ongoing research and education in this
medical procedure used to treat chronic musculo- area. By continually striving for safer, more
skeletal pain and promote tissue healing. It effective injection techniques, we can improve
involves the injection of a substance, typically a patient outcomes and advance the field of health
proliferant solution, into damaged or weakened care as a whole.
ligaments, tendons, or joints to stimulate the
body’s natural healing response [16].
It is important to note that the philosophy of
injections is a broad topic that encompasses vari- References
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1. WHO. Injection safety. World Health Organization
sions. Philosophers, medical professionals, and revised April 2002. DSÖ Fact Sheet No:231.
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our understanding of these issues and inform InjectionFactSheet2002.pdf
2. Brokensha G. The hollow needle: inappropriate injec-
ethical decision-making in medical practice.
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mentioned key aspects of this topic are the thera- cal technology: a review of the literature on injection
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 The Evidence-Based Medicine
for Injection Therapy
2
Marko Ostojić

2.1 Introduction beneficial effects. Approaches to injection ther-

apy as a field of treatment have been known for a
As a therapeutic modality, injections have been lack of standardization. A more evidence-based
widely used in treating musculoskeletal disor- approach to this field is necessary to oppose some
ders, usually in an outpatient clinic setting. This well-established dogmas with the final goal of
treatment modality is defined as a method delivering the best available care to patients. For
whereby therapeutical agents are delivered to the future studies, it is of outmost importance to
selected location with the use of a syringe and define the outcome measures leading to clinical
hypodermic needle. It is common practice that improvement, with a special focus on “respond-
injection therapy, in terms of treatment sequence, ers” and “nonresponders.” The remission of
finds a place between the conservative first-line symptoms and the deceleration of disease pro-
treatment (physical therapy, lifestyle modifica- gression are not the sole objectives of an optimal
tion, pain management, etc.) and the surgical injectable. A scientific research perspective
intervention. The type and timing of injections would pronounce the importance of developing
depend on many factors: from the pathology that an injectable agent with disease-modifying prop-
is being treated and the patient’s functional erties. In other words, an agent that reverses dis-
demands to the modus operandi of the attending ease progression, by breaking the vicious circle
physician. Regarding the latter, some physicians of tissue deterioration and leads to tissue healing
are prone to deliver conservative treatment, while [1, 2]. Since orthobiologic agents show a pro-
others favor the operative approach. Some physi- nounced healing potential, it is not a surprise that
cians are quick to adopt new emerging tech- some people see it as the holy grail of nonsurgical
niques, yet others are skeptical and require hard treatment.
clinical evidence to be convinced. A plethora of Let us briefly go through the available options
different factors affect the type of treatment that in an evidence-based and critical manner. First, it
patients will receive. During medical training, is of paramount importance to make a clear dis-
doctors gain a lot of anecdotal knowledge in this tinction between intra-articular and extra-­
field, mostly concerning corticosteroids and their articular injections.

M. Ostojić (*)
Department of Orthopaedics and Traumatology,
University Hospital Mostar,
Mostar, Bosnia and Herzegovina

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 9

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
https://doi.org/10.1007/978-3-031-52603-9_2
10 M. Ostojić

2.2 Intra-Articular Injections short-term effect is beneficial concerning pain

relief, but, unfortunately, their long-term positive
Intra-articular injections are used for the treat- effect has not been observed [10, 11]. As men-
ment of osteoarthritis and other degenerative dis- tioned before, corticosteroids are often given
eases on one hand and for fresh injuries where we with local anesthetics, which are proven to be
strive for faster tissue healing and pain manage- chondrotoxic, causing the apoptosis of the chon-
ment on the other. A joint is an enclosed organ drocytes [12]. Corticosteroids also have a time-
possessing its equilibrium. The synovial mem- and dose-­dependent negative effect on hyaline
brane of a joint acts as a barrier that holds in any cartilage, being beneficial at low doses and detri-
injected substance for a defined period. Any kind mental at high doses [13]. In combination with
of arthritis or fresh injury affecting a part of the local analgesics, the chondrotoxicity of cortico-
joint causes an inflammatory reaction that leads steroids is more pronounced due to the synergis-
to a vicious circle that leads to further tissue dam- tic effect these two injectables possess [14, 15].
age [3, 4]. This induces the release of ­inflammatory Hyaluronic acid, a large molecule that binds
factors in the synovial fluid that promote further water and that is naturally produced by the syno-
synovial inflammation [5, 6]. There is a (proba- vial membrane, has anti-inflammatory and shock
bly oversimplified) rule that any intra-­articular absorption effects and acts as a lubricant during
injection that is given in a conventional medicine joint motion, with possible disease-modifying
setting leads to the improvement of clinical effects [16]. Theoretically, it has all the necessary
symptoms in osteoarthritic joints. For example, qualities to be a highly successful intra-articular
in hip osteoarthritis, the injection of saline into an injectable agent. Indeed, meta-analyses have
osteoarthritic hip joint resulted in symptomatic shown the superiority of hyaluronic acid as com-
relief that was comparable to some of the com- pared to corticosteroids. However, HA falls
mercially most often used treatments [7]. Many behind when compared to orthobiologic agents
studies evaluating the treatment of osteoarthritis [17, 18]. Orthobiologic therapies that have gained
use saline as a placebo, which is a methodologi- popularity in the last two decades, including
cally questionable procedure. Saline, the isotonic platelet-­
rich plasma (PRP) and cellular-based
solution of sodium chloride and water, has the products (e.g., stem cells), show the most promis-
effect of diluting the synovial fluid and “washing ing results in the middle- and the long-term
out” inflammatory factors. It does not have a results in the treatment of early osteoarthritis.
long-term effect, but it does bring on the tempo- The main difference to the previously mentioned
rary improvement in clinical function and pain agents is that, due to their biological origin, they
[8]. A true placebo for this kind of trials should are autotransplants that possess more disease-
be a “sham procedure” in which the joint capsule modifying effects. Meta-analyses have demon-
is not penetrated and where the injectable pla- strated the superiority of orthobiologic agents to
cebo agent is given subcutaneously [9]. other injectables. However, some controversies
Corticosteroids are naturally produced in the cor- exist due to the diversity of the products and a
tex of adrenal glands. Synthetic variants have lack of high-quality randomized control trials
been used for over 70 years, and they still are one [17]. PRP is the most widely used blood-derived
of the most widely used anti-inflammatory medi- product, and therefore, details on other blood-
cines. In orthopedics, long-releasing (depo) prod- derived products are not going to be discussed
ucts are routinely used in the form of injections, (e.g., alpha-2 macroglobulin, autologous condi-
both intra- and extra-articularly. In combination tioned serum). Let’s try to clarify how PRP works
with local analgesics, they are a potent injectable practically. After most injuries, bleeding occurs,
agent. This combination has a quick effect and and blood is the first source of healing agents.
brings on short-term pain relief. This translates to With PRP, the fraction of venous blood from
patients walking out of their physician’s office which we expect the strongest healing potential
satisfied. Studies have indeed shown that their (serum with growth factors and platelets) is
2 The Evidence-Based Medicine for Injection Therapy 11

extracted and applied to the desired site. Platelets

that has the least adverse effects on the surround-
comprise several growth factors, which play cru- ing tissues. It is known that corticosteroids can
cial roles in tissue repair and regeneration mecha-cause weakening of the tendon tissue. For exam-
nisms [2]. To put it in a nutshell, a fresh injury is
ple, using corticosteroids is effective in the treat-
mimicked to start the healing cascade. The litera- ment of tendovaginitis, but potentially negative
ture supporting the use of PRP is growing, with side effects can occur, iatrogenic tendon rupture
meta-­analyses and ESSKA “ORBIT Delphi con- being of the most disastrous one [21]. Hyaluronic
sensus” supporting its use for knee osteoarthritis acid can be used as an extra-articular injection
[18]. The injectable agents, which the orthopedic but preferably delivered inside the space that is
community is putting most hopes in recently, are encircled by a tendon sheath. This space partially
cellular-­based products, which show promising resembles the intra-articular milieu and has hyal-
long-term effects. Mesenchymal stem cells uronic acid produced naturally in small quanti-
(MSCs) are multipotent cells that are usually ties. Again, orthobiologic agents, particularly
derived from fat tissue or bone marrow and can PRP, show the most promising results with their
be used as autotransplant or homotransplant. anti-inflammatory properties that oppose extra-­
They can be given immediately after the explan- articular inflammation. For acute injuries, like
tation process, in a minimal manipulation man- muscle and tendon rupture, corticosteroid and
ner, or they can also be expanded in vitro for hyaluronic acid use does not have a biological
application at a later date. New insights show thatrationale, and PRP is advised to be first option as
most of their therapeutic potency is due to their injection therapy [22]. The other therapy modal-
paracrine effect. Hence it is suggested that the ity that is commonly used for extra-articular tis-
MSC abbreviation should stand for medicinal sue disorders is prolotherapy. It is a modality that
signaling cells [19]. In vivo studies have shown uses irritative agent (like hyperosmotic dextrose
that there is a scarce chance of these cells surviv-
or saline) causing a local inflammatory response
ing for a longer period of time after intra-articular
that leads to fibrosis and potential healing of the
injection and, afterward, transforming to the diseased tissue. It is mostly used in tendinopa-
desired missing chondrocyte cells in the diseased thies, where it shows successful results [23]. The
joint. More hope is put in their exosome, which is use of botulinum toxin is common in neuromus-
expected to have a healing potential, through the cular disorders, where spastic muscles are relaxed
previously mentioned paracrine effect. Due to the by intramuscular application. Botulinum toxin
heterogeneity of MSCs products, the results, blocks the neuromuscular junction thus paralyz-
although promising, have some confronting con- ing the muscle. It has shown clinical improve-
clusions, with high-quality randomized con- ment in patients with the spastic type of cerebral
trolled studies still needed to support long-lasting
palsy.
effects of this therapeutic agent [20]. The most important factor in getting a suc-
cessful outcome in this type of treatment is care-
ful selection of the adequate injectable agents for
2.3 Extra-Articular Injections a certain patient. All of the beforementioned have
their advantages and disadvantages. It is there-
Extra-articular injections are most commonly fore crucial to choose an agent that brings on an
used in inflammatory conditions, degenerative improvement and minimizes iatrogenic harm.
conditions (e.g., tendinopathies), and acute inju- The primum nil nocere rule is of headmost impor-
ries. Some of the chronic overuse injuries have tance in this field, where paramedical factors
characteristics of chronic inflammation and often influence the physician’s decision-making
degenerative conditions, so they are treated where the desire for a lucrative practice can cloud
accordingly. In the case of inflammatory condi- her/his judgment. Also, we have to outline that
tions, it is crucial to seek benefit of anti-­ placebo effect could be encountered, but we can-
inflammatory potential of the therapeutic agent not, in any instance, rely on it.