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Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox

September 2024
Cureus 16(9):e68487

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Regenerative medicine leverages the body’s inherent regenerative capabilities to repair damaged tissues and address organ dysfunction. In orthopedics, this approach includes a variety of treatments collectively known as orthoregeneration, encompassing modalities such as prolotherapy, extracorporeal shockwave therapy, pulsed electromagnetic field therapy, therapeutic ultrasound, and photobiomodulation therapy, and orthobiologics like platelet-rich plasma and cell-based therapies. These minimally invasive techniques are becoming prominent due to their potential for fewer complications in orthopedic surgery. As regenerative medicine continues to advance, surgeons must stay informed about these developments. This paper highlights the current state of regenerative medicine in orthopedics and advocates for further clinical research to validate and expand these treatments to enhance patient outcomes.

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Review began 08/21/2024

Review ended 08/27/2024

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DOI: 10.7759/cureus.68487

Regenerative Medicine in Orthopedic Surgery:

Expanding Our Toolbox

Ayah Ibrahim , Marco Gupton , Frederick Schroeder

1. Orthopedic Surgery, Burrell College of Osteopathic Medicine, Las Cruces, USA 2. Orthopedic Surgery, Mountainview

Regional Medical Center, Las Cruces, USA

Corresponding author: Marco Gupton, msgupton1021@email.campbell.edu

Abstract

Regenerative medicine leverages the body’s inherent regenerative capabilities to repair damaged tissues and

address organ dysfunction. In orthopedics, this approach includes a variety of treatments collectively known

as orthoregeneration, encompassing modalities such as prolotherapy, extracorporeal shockwave therapy,

pulsed electromagnetic field therapy, therapeutic ultrasound, and photobiomodulation therapy, and

orthobiologics like platelet-rich plasma and cell-based therapies. These minimally invasive techniques are

becoming prominent due to their potential for fewer complications in orthopedic surgery. As regenerative

medicine continues to advance, surgeons must stay informed about these developments. This paper

highlights the current state of regenerative medicine in orthopedics and advocates for further clinical

research to validate and expand these treatments to enhance patient outcomes.

Categories: Orthopedics, Therapeutics

Keywords: ultrasound therapy, extracorporeal shockwave therapy, pulsed electromagnetic field therapy,

photobiomodulation therapy, prolotherapy, regenerative medicine therapies, orthoregeneration

Introduction And Background

Regenerative medicine was popularized by Dr. William Haseltine in the late 1990s and focuses on

therapeutic approaches to harness the body’s regenerative capabilities to repair and regenerate damaged

tissues [1, 2, 3, 4, 5]. In orthopedics, this field features a variety of innovative approaches, including blood-

derived treatments such as platelet-rich plasma (PRP) and autologous protein solutions. Cell-based

therapies utilize cells from bone marrow, fat tissue, and perinatal sources. Other techniques include bone

grafts, 3D-printed biomaterials, and isolates of growth factors such as bone morphogenetic proteins (BMP).

These methods, commonly known as "orthobiologics," comprise a diverse array of substances sourced from

autologous, allogeneic, xenogeneic, or synthetically bioengineered origins [4, 5]. Orthobiologics has

multiple definitions, and although this term does embody most applications of regenerative medicine within

the field of orthopedic surgery, the term orthoregeneration, coined by the Orthoregeneration Network (ON)

foundation, is more encompassing. The ON Foundation is an independent, nonprofit, international

organization committed to advancing research and education in the field of orthopedic tissue regeneration.

Orthoregeneration, as defined by the foundation, includes strategies aimed at addressing orthopedic

conditions by utilizing biological mechanisms to enhance healing, alleviate pain, restore function, and

provide an environment for tissue regeneration [6]. Treatment modalities range from pharmaceutical

interventions and surgical procedures to using scaffolds, cellular biologics, and applying physical or

electromagnetic stimuli [6]. Throughout the paper, the various orthopedic applications of regenerative

medicine will be referred to as orthoregeneration.

The field of regenerative medicine in orthopedic surgery is undergoing rapid evolution and expansion.

Technological advancements have highlighted the potential of biologically sourced materials in enhancing

the healing of musculoskeletal (MSK) tissues, making orthobiologics a focal point of the research [3, 4, 5].

Obona and colleagues [4] reported a significant increase in publications, with 474 articles published in nine

top orthopedic journals from 2009 to 2019, with the greatest increase from 2018 to 2019 [4]. According to

Noback and colleagues [3], a survey conducted among members of the American Orthopaedic Society for

Sports Medicine revealed that out of 165 respondents, 66.1% reported the use of at least one orthobiologic

modality in their practice, with 71.6% intending to increase their usage. Su and colleagues [7], in 2022,

identified over 400 completed or ongoing clinical trials evaluating the use of PRP and more than 1,000 trials

assessing the application of mesenchymal stromal cells across a range of clinical contexts.

The research predominantly focuses on the popular modalities above, but numerous other

orthoregeneration modalities possess significant potential benefits for patients. These include prolotherapy,

extracorporeal shockwave therapy (ESWT), pulsed electromagnetic field therapy (PEMF), therapeutic

ultrasound therapy (TUS), and photobiomodulation therapy (PBMT). Despite the limited education among

orthopedic surgeons regarding these modalities and their limited appearance in top orthopedic journals,

acquiring a foundational understanding could broaden treatment options for patients. Additionally, they can

serve as adjuncts to surgical intervention, potentially enhancing patient outcomes and encouraging future

1 2 1

Open Access Review Article

How to cite this article

Ibrahim A, Gupton M, Schroeder F (Septem ber 02, 2024) Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox. Cureus 16(9):

e68487. DOI 10.7759/cureus.68487

research. As orthopedic surgery evolves, increasing incorporation of orthoregenerative modalities is likely.

Therefore, equipping orthopedic surgeons with this comprehensive knowledge ensures ethical and efficient

navigation of the field, ensuring optimal patient care and outcomes.

Review

Laying the foundation

The following section will briefly discuss a few topics so the reader may understand where the modalities

discussed in this paper fit in the current landscape of orthoregeneration.

Tissue engineering (TE), regenerative engineering, and bioengineering are used synonymously to establish

the foundation of the three principles within the field of orthoregeneration, albeit with slight variations in

definition across sources. According to the ON foundation, TE is defined as a multidisciplinary method that

integrates aspects of cell biology, material science, and engineering to regenerate tissues through an

interplay of cells, biomaterial scaffolds, and signaling factors [6]. Cells serve as the building blocks of TE,

with their manipulation both within and outside the body involving mechanical factors, electromagnetic

stimuli, signaling molecules, and gene mutation.

Category 1: Cells

Cell therapy is the introduction of new cells into a patient's body to treat diseases or repair damaged tissue.

A variety of cell types are used, typically derived from post-natal origins, which can be isolated, expanded, or

utilized as unexpanded cell concentrates [8, 9]. These cells may be of autologous or allogeneic nature, each

with advantages and disadvantages. However, due to regulations by the Food and Drug Administration

(FDA), most cell therapies currently used in orthopedics are unexpanded autologous cell concentrates [5].

Stem Cells: Stem cells can be derived from various sources, including bone marrow, adipose tissue, or

embryonic tissue. They are undifferentiated cells with the ability to proliferate, self-renew, and differentiate

into specialized cells. Serving as the body’s natural repair system, renewing and regenerating damaged or

aging tissues [9]. Stem cells are broadly classified into two main categories: embryonic and post-natal, which

are further categorized into totipotent, pluripotent, multipotent, oligopotent, and unipotent. Embryonic

stem cells are totipotent cells that can differentiate into all cell types [9]. Pluripotent stem cells can give rise

to cells of all three germ layers-endoderm, mesoderm, and ectoderm. Multipotent stem cells are often

specific to a tissue or lineage-specific such as mesenchymal stem cells (MSCs), which can develop into a

variety of cell types like bone, cartilage, and fat cells [9, 10]. While MSCs exhibit more restricted

differentiation potential compared to pluripotent cells, they are commonly used for therapeutic purposes.

These multipotent, undifferentiated cells are typically located within specific tissues and are crucial for

tissue maintenance and repair [9].

Mesenchymal stem cells: Mesenchymal stem cells, mesenchymal stromal cells, and medicinal signaling cells

are all commonly used interchangeably and abbreviated as MSC in the literature, leading to ongoing debate

and confusion about their precise definitions [5]. The term “mesenchymal stem cell”, was first introduced

by Caplan in 1991 [11] for orthopedic tissues, and later defined by the International Society for Cell Therapy

with specific criteria for cultured cells. This distinction is critical, as MSCs are often mistakenly applied to

unexpanded cells from bone marrow and adipose tissue. Cell culturing allows for selective growth and

elimination of inhibitory cells, although in the United States (U.S.), such expansion is only allowed under

Investigational New Drug approval. It is important to distinguish these cultured cells from less

characterized, freshly harvested cells used in clinical settings. Most cells currently in clinical use are better

classified as connective tissue progenitor cells (CTP), mesenchymal stromal cells, or medicinal signaling

cells [5]. CTP and mesenchymal stromal cells both describe a varied group of cells capable of proliferation

and differentiation into connective tissues. In more recent years, Kaplan stated the most correct term is

medicinal signaling cells, as they likely produce their effects through paracrine signaling via bioactive

signaling molecules [12]. This signaling, referred to as a secretome, is defined by ON foundation as “cell-

secreted proteins (e.g., growth factors, cytokines, chemokines enzymes, shed receptors, extracellular matrix

constituents) that regulate numerous biological processes through autocrine and paracrine signaling

mechanisms” [6]. This largely explains how the modalities discussed in this paper produce their effects.

Category 2: Growth Factors, Biochemicals, Bioactive Factors

The three categories of TE significantly overlap, with growth factors having already been touched on in the

cell section, given that the source of most signaling molecules originates from the cell. As defined by the ON

foundation, growth factors are “secreted biologically active polypeptides that can affect cellular growth,

proliferation, and differentiation” [6]. Healing and regenerating MSK tissues post-injury or due to

pathological processes involves complex interactions among various cell types and multiple signaling

factors. Bioactive factors refer to signaling molecules that aid in healing and regeneration, whether natural

or engineered substances mimicking natural molecules. Target cells for these factors are those involved in

the cascade of healing and regeneration. Determining the optimal mix of bioactive factors, biomaterials, and

specific target cells for effective tissue repair and restoration of homeostasis is a key challenge and

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opportunity in orthopedic tissue regeneration [5,8]. Recent literature suggests that the biological activity of

transplanted cells is due to a paracrine mechanism via bioactive signaling molecules. Examples of bioactive

molecules are BMP and fibroblastic growth factor 2 (FGF-2) [5, 8]. As stated above, the modalities discussed

in this paper likely exert their effects by influencing the complex regulation of bioactive molecules involved

in repair and regenerative cascades. This is done by altering the cellular environment or cells themselves via

the introduction of biologically active molecules, as well as through the application of mechanical and

electromagnetic stimuli [13, 14].

Category 3: Scaffolds and Biomaterials

Often, these cell and bioactive factors are introduced to the body with the aid of a scaffold, a structure

designed to support cell attachment, growth, and differentiation. Scaffolds provide a three-dimensional

framework mimicking the extracellular matrix of tissues. They can be made from natural sources like dermis

and tendons or synthetic materials such as ceramics and polymers [5, 8]. Engineered to be biodegradable and

biocompatible, some resorbable and some non-resorbable. They can function either as the structural

component or as a vehicle for growth factors to mitigate tissue growth or repair [5, 8].

Other orthoregeneration modalities

Prolotherapy

Introduction: Prolotherapy, or proliferation therapy, involves injecting small amounts of an irritant solution

into specific tissues to stimulate self-repair and healing in MSK conditions [15, 16, 17]. Originating in the

1950s, George Hackett, a U.S. general surgeon, first documented its usage as a treatment for MSK disorders.

Since then, prolotherapy has gained traction, in usage and the literature supporting its efficacy, specifically

over the past two decades [16, 17]. Ankanpar and colleagues published a systematic review in 2016,

analyzing 72 articles, including 30 clinical studies on prolotherapy in orthopedic surgery [15]. Similarly,

Hauser et al. conducted a systematic review in 2016 identifying 14 randomized control trials, one case-

control study, and 18 case series on prolotherapy for chronic MSK pain, providing level-one evidence [16].

Mechanism of Action: Although the mechanism of action is not fully understood, prolotherapy generally

fosters inflammation, proliferation, and tissue remodeling within injured tissues [16]. This is done by

injecting hyperosmolar solutions that incite low-level inflammation. The proposed mechanism of repair and

remodeling revolves around cytokines and other signaling molecules acting through various paracrine

pathways relating to cellular healing. The mechanical disruption provided by needling and hyperosmolarity

works by disrupting cellular membranes and local blood supply causing the release of signaling molecules

[16, 17].

Benefits and Limitations: Compared to other orthoregeneration injections, prolotherapy is cost-effective

and typically avoids undesirable effects like tissue atrophy or depigmentation seen with steroids. While it

may require multiple sessions, they are usually quicker than procedures like PRP injections. However,

significant limitations within the literature include small study populations restricting wider applicability of

results and variations in study protocols, such as injection composition and concentration and frequency of

administration are also notable [16, 17]. Additionally, the inclusion of conservative adjunctive treatments in

these studies could potentially skew the specific impact of prolotherapy.

Technique: Various techniques involve the injection of different hyperosmolar mixtures of dextrose, phenol,

glycerin, or sodium morrhuate across multiple sessions spaced out from 1 to 12 weeks. The most utilized

solution consists of a 10%-25% dextrose solution, sometimes combined with a local anesthetic. These

injections can be administered by palpation or image guidance. Typically, 5-10cc of solution is injected, with

a peppering technique placing small amounts of solution throughout the problematic area. The procedural

details such as obtaining consent and maintaining an antiseptic or sterile technique mirror those of any

office injections, such as corticosteroids. Patients may resume normal activities immediately, including

physical therapy, provided the pain is controlled [15, 16, 17].

Clinical Application: Prolotherapy has exhibited considerable success in treating various chronic

musculoskeletal ailments, including tendinopathies, osteoarthritis, hyperlaxity, back pain, and other

degenerative conditions [15, 16, 17]. It is used more commonly in chronic conditions but there is evidence of

its use in acute injury. Table 1 lists conditions treated with prolotherapy and supporting evidence; however,

this is not all-inclusive of conditions or available evidence.

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Musculoskeletal Condition Supporting Evidence
Achilles Tendinopathy [16, 17, 18, 19, 20, 21]
Chondromalacia Patella [15, 16]
Hand Osteoarthritis [15, 17, 22, 23]
Joint Laxity [15, 16, 17]
Knee Osteoarthritis [15, 16, 17, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]
Lateral Epicondylosis [15, 16, 17, 18, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]
Low back & SI joint [16, 17, 44, 45, 46, 47, 48, 49, 50, 51, 52]
Plantar Fasciopathy [15, 16, 17, 53, 54, 55, 56, 57, 58, 59]
Rotator Cuff Tendinopathy [15, 16, 17, 18, 60, 61, 62, 63]
TABLE 1: Conditions treated with prolotherapy with supporting evidence
SI: sacroiliac
Therapeutic Ultrasound (TUS) Therapy
Introduction: Ultrasound (US) is acoustic energy with a frequency of 1.0 to 5.0 MHz, which is beyond the
threshold of human hearing [64]. While commonly known for diagnostic imaging, it has become a valuable
therapeutic tool for musculoskeletal conditions. TUS has continued to evolve since it emerged in the mid-
1900s in Germany and the U.S. [64]. It can be divided into high or low intensity based on the objective of
treatment, to destroy tissue, or to stimulate physiological processes. Common orthoregeneration
applications use low-intensity pulsed ultrasound (LIPUS), continuous low-intensity ultrasound, and pulsed-
focused ultrasound. On the other hand, extracorporeal high-intensity focused ultrasound is used for tissue
destruction and has limited significance in orthoregeneration [65]. While ESWT is a form of acoustic energy,
it is generally not considered TUS [66]; this is discussed in a later section. 
Mechanism of Action: US waves pass through materials, creating particle oscillations that transfer energy
through compression and refraction. In tissues, US vibrations cause thermal changes, stimulating various
cell types including osteoblasts, chondroblasts, and MSCs, enhancing cellular processes such as
proliferation, differentiation, and maturation [65]. TUS promotes cell adhesion, increases cell adhesion
proteins, and augments MSC migration to target tissues via cytokine and chemokine upregulation [64, 65,
67]. Additionally, ultrasound-generated heat increases blood flow, promoting nutrient delivery and waste
removal [65, 68].
Benefits and Limitations: TUS is a non-invasive option with minimal reported complications, making it an
appealing adjunct to other treatments, including surgery. Its affordability, portability, and accessibility are
advantageous compared to resource-intensive modalities. However, limitations include the need for
standardized treatment protocols, understanding optimal ultrasound parameters for different therapeutic
applications, and translating preclinical findings into clinical practice [64, 65]. Uniform effectiveness can
vary due to operator and patient-dependent variability [69].
Technique: This technique utilizes high-frequency sound waves emitted by a transducer, generating
vibrations beyond human hearing. Treatment outcomes depend on ultrasound parameters such as
frequency, duty cycle, and intensity. The transducer is moved over the treatment area for five to fifteen
minutes, with real-time imaging allowing practitioners to monitor and adjust the application. Treatment
protocols are extremely heterogeneous but usually involve multiple sessions over weeks to months [64,
65]. Patients typically have no restrictions from the treatment itself but often limit activity and participate
in rehabilitation as part of their overall treatment regimen.
Clinical Application: LIPUS has shown success in enhancing bone regeneration and is FDA-approved for the
treatment of accelerated healing of fresh fractures and non-unions. TUS has been successful in the
regeneration of bone, cartilage, tendons, and ligaments. It has also proven to be beneficial in conditions such
as tendinopathies, joint pain, osteoarthritis, and other degenerative disorders [64, 65, 70]. It is noted that US
can be used for phonophoresis which involves the migration of drug molecules through the skin, but this is
typically not considered a regenerative use [64]. Table 2 lists conditions treated with TUS and supporting
evidence; however, this is not all-inclusive of conditions or available evidence.
 
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Musculoskeletal Conditions Supporting Evidence
Ankle sprains [71, 72, 73]
Achilles Tendinopathy [74]
Acute fractures [75, 76]
Back Pain [77]
Carpal Tunnel Syndrome [78, 79, 80]
Calcific tendinopathy of rotator cuff [81]
Chronic Low Back Pain [82]
Chronic calcific shoulder tendinitis [83]
Fracture healing [84, 85, 86]
Femoral head osteonecrosis [87]
General tendinopathies [88, 89]
Iliopsoas hematoma [90]
Knee Osteoarthritis [91, 92, 93, 94, 95, 96]
Lateral epicondylitis [97, 98, 99, 100, 101, 102, 103]
Vertebral Spondylolysis [104, 105, 106]
Myofascial pain syndrome [107, 108]
Non-union healing [109, 110, 111]
Osteoarthritis [112, 113]
Plantar fasciitis [114, 115, 116, 117, 118, 119, 120]
Peripheral Nerve Regeneration [121, 122, 123]
Plantar Fasciopathy [124]
Rheumatoid arthritis [125, 126]
Rotator cuff tendinopathy [127, 128]
Tibial bone stress injuries [129]
TABLE 2: Conditions treated with therapeutic ultrasound with supporting evidence
Extracorporeal Shockwave Therapy
Introduction: Extracorporeal shockwave therapy applies high-energy acoustic waves to stimulate tissue
regeneration and repair, generating pressures 1000 times higher than ultrasound [130]. It includes focused
shockwave therapy (FSWT) and radial shockwave therapy (RSWT), each indicated for different pathologies.
FSWT utilized three techniques-electrohydraulic, electromagnetic, and piezoelectric principles, to generate
shockwaves in water due to similar acoustic impedance with biological tissue. RSWT uses compressed air to
accelerate a projectile within a guiding tube, striking a metal applicator placed on the patient's skin
[131]. ESWT originated in the 1980s for lithotripsy and was expanded to MSK application by Dr. Gerald
Haupt in the 1990s [132]. Since then, ESWT’s presence in orthopedics has continued to grow [133].
Mechanism of Action: The mechanisms of ESWT for the treatment of MSK conditions are not completely
understood. It is hypothesized that ESWT exerts its biological effects through mechanical and biochemical
pathways. Mechanotransduction induces tissue vibrations, triggering changes in cellular functions involved
in repair and regeneration [133]. Shockwaves produce rapid and high-pressure fluctuations, that propagate
energy absorption, reflection, refraction, and transmission within tissues and cells. This process, for
instance, dissolves calcified fibroblasts observed in tendinosis [131, 134].
Benefits and Limitations: This modality is considered a safe and non-invasive therapy that can be combined
 
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with other treatment modalities. Major limitations are a lack of standardizations in treatment protocols with
supporting high-level evidence, and expensive equipment. Additionally, coverage limitations from various
insurance providers may pose challenges to patients' access to this therapy. Occasionally there can be some
discomfort following treatment [133].
Technique: Various machine settings and delivery modes are utilized depending on the specific indication.
Multiple parameters can be adjusted including energy flux density (EFD), number of impulses, shockwave
type, and frequency/duration of treatment sessions. EFD, which represents the energy per impulse, is
commonly adjusted [133]. Typically administered by a physician, ESWT involves multiple sessions spanning
weeks to months. During treatment, a transducer is placed on the skin, with sessions lasting between 5 to 25
minutes. Patients typically face no restrictions from the treatment itself but may adjust activity levels and
participate in rehabilitation as part of their overall treatment regimen [130].
Clinical Application: There has been evidence of positive efficacy of ESWT mainly in chronic pathologies
such as tendinopathies like plantar fasciitis and lateral epicondylitis as well as bone disorders such as non-
union. The main contraindication is that air-filled tissue such as the lung cannot be in the path of the
shockwave. Table 3 lists conditions treated with ESWT and supporting evidence; however, this is not all-
inclusive of conditions or available evidence.
Musculoskeletal Condition Supporting Evidence
Adhesive Capsulitis [135, 136, 137, 138, 139]
Achilles Tendinopathy (insertional & non-insertional) [133, 140, 141, 142]
Avascular necrosis of the femoral head [143, 144, 145, 146]
Acute fractures [75, 76, 131, 147, 148]
Bone stress injuries [133, 149, 150, 151, 152]
Bursitis of snapping scapula [153, 154, 155, 156]
Calcific tendinopathy of rotator cuff [81, 157, 158, 159, 160]
Calcifying tendinitis of the shoulder [130, 160, 161, 162, 163]
Foot & Ankle fracture non-unions [164, 165, 166, 167, 168]
Greater trochanteric pain syndrome [133, 169, 170, 171]
Hamstring tendinopathy [133, 172, 173, 174, 175]
Ischial Apophysitis [175, 176]
Lateral epicondylitis [99, 100, 101, 102, 103, 130, 133, 177, 178, 179]
Non-union & delayed union of long bone fractures [130, 180, 181, 182]
Osteoarthritis [183, 184, 185, 186]
Plantar fasciitis [114, 119, 120, 130, 133, 142, 187, 188, 189]
Patellar tendinopathy [130, 142, 190, 191, 192]
Rotator cuff tendinopathy [133, 193, 194, 195, 196]
Subacromial Impingement Syndrome [197, 198, 199, 200]
Supraspinatus Tendinitis [201, 202]
TABLE 3: Conditions treated with extracorporeal shockwave therapy with supporting evidence
Photobiomodulation Therapy
Introduction: PBMT, also known as low-level light therapy (LLLT) or cold laser therapy, offers a non-invasive
and efficacious method for enhancing tissue healing and reducing inflammation through light therapy.
“Cold laser therapy” is derived from the characteristic that low light levels have minimal heat generation,
therefore relying on light’s therapeutic properties. PBMT has gained recognition in orthopedics for its ability
to accelerate tissue repair, alleviate pain, and modulate cellular processes. It encompasses modalities
 
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utilizing specific light wavelengths for healing [203]. PBMT primarily falls into two categories: light

amplification by stimulated emission of radiation (LASER) and light-emitting diodes (LEDs), differing in

light emission and delivery method. Additionally, blue light therapy is another variant used for wound

healing purposes.

Mechanism of Action: PBMT utilizing visible red light and near-infrared radiation operates by interacting

with specific wavelengths of light and cellular chromophores, particularly cytochrome c oxidase (CCO)

within the mitochondria. Upon light absorption, CCO undergoes photochemical reactions stimulating

mitochondrial respiration, thereby increasing adenosine triphosphate (ATP) production and enhancing

cellular metabolism [36]. PBMT may additionally modulate intracellular signaling pathways, gene

expression, nerve cell membrane permeability, and cytokine secretion, promoting tissue repair, reducing

pain transmission and inflammation, and mitigating oxidative stress [204, 205]. In laser therapy, coherent,

monochromatic light, emits a single concentrated wavelength for precise targeting of specific tissues or

cells. In contrast, LED therapy utilizes non-coherent polychromatic light, emitting multiple wavelengths

simultaneously. LEDs produce a broader spectrum of light compared to lasers. Physiological effects have

also been observed with blue and green light [206, 207].

Benefits and Limitations: PBMT is non-invasive and has few complications. Laser therapy devices tend to be

more expensive and may require professional supervision for treatment. LED therapy devices are often more

affordable and may be available for home use, offering convenience and accessibility for regular treatments.

Despite its effectiveness, LLLT has limitations including the biphasic response observed, where lower doses

prove more effective, while high intensities might hinder nerve function. Operator expertise is crucial for

optimal outcomes. There is insufficient evidence on the standardization of treatment.

Technique: Low-power visible or near-infrared light is applied using devices of different sizes and shapes,

emitting specific wavelengths for targeted treatment. Operators customize parameters including

wavelength, intensity, and duration tailored to the patient’s condition. Safety glasses must be worn by both

patient and operator during treatments to protect against harmful effects on the eyes. Treatment duration,

frequency, and target areas vary [203].

Clinical Application: This therapy is versatile in treating various orthopedic conditions, managing pain,

reducing inflammation, and promoting tissue repair. LLLT proves effective for treating acute conditions like

sprains, strains, post-surgical pain, and chronic conditions such as osteoarthritis, rheumatoid arthritis, and

tendinopathy. Clinical targets include injury sites, lymph nodes, nerves, and trigger points.

Contraindications include pregnancy, malignancies, and epilepsy [203]. Laser therapy is typically applied for

targeted healing, focusing on wound care, pain relief, and tissue repair in specific body areas. Conversely,

LED therapy offers more generalized benefits, such as skin rejuvenation, acne treatment, and overall

wellness, due to its broader light spectrum and ability to cover larger areas. Table 4 lists conditions treated

with PBMT and supporting evidence; however, this is not all-inclusive of conditions or available evidence.

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Musculoskeletal Condition Supporting Evidence
Achilles Tendinopathy [208, 209]
Back pain [77, 209]
Bone healing [210]
Bone Tumors [211, 212, 213]
Carpal Tunnel Release/Syndrome [214, 215, 216, 217, 218]
Frozen Shoulder (Adhesive Capsulitis) [219, 220, 221]
General tendinopathy [209, 222, 223]
Lateral elbow tendinopathy [224]
Lateral Epicondylitis [179, 225, 226, 227, 228, 229]
Musculoskeletal Pain Management [203, 205, 230]
Osteoarthritis [205, 209, 231, 232, 233, 234, 235, 236]
Peripheral Nerve Regeneration [122, 237]
Plantar fasciitis [120, 223, 238, 239]
Rheumatoid Arthritis [209, 233, 240, 241]
Subacromial Impingement Syndrome [242, 243, 244, 245, 246]
Vertebral Disc Hernias [247]
TABLE 4: Conditions treated with photobiomodulation therapy with supporting evidence
Pulsed Electromagnetic Field Therapy
Introduction: PEMF is a non-invasive, painless therapy where electromagnetic fields are used to promote
healing and regeneration. Utilizing low-frequency electromagnetic fields, PEMF therapy is recognized for its
unique biological effects without causing ionization or heat [248]. During World War II, the development of
electromagnetic signals led to their use in medical treatments. In the 1950s, research by Yasuda and others
revealed that bones exhibit electric potentials, sparking interest in using electrical stimulation for bone
growth and healing [249]. This interest resulted in the creation of devices designed to stimulate bone
formation through electromagnetic fields. In 1964, Bassett and colleagues demonstrated the beneficial
effects of electric currents on bone growth, leading to the clinical adoption of PEMF for treating bone issues
[250]. The FDA approved PEMF therapy for nonunion fractures in 1979, and numerous studies have since
supported its effectiveness in bone repair and other MSK Pathologies [248, 251, 252].
Mechanism of Action: Despite extensive study, PEMFs are still considered an empirical treatment with a
mechanism of action that remains largely undefined. The PEMF field affects tissues by firstly exerting a
magnetic force on molecules based on their magnetic properties, and secondly by creating an electrical force
on ions, leading to the movement of ions and charged molecules like proteins [13]. It is suggested that the
effects on tissues occur via amplification processes linked with transmembrane coupling, particularly at
transmembrane receptor sites. This is thought to affect various signaling pathways involved in growth,
repair, regeneration, and inflammation [248, 253, 254].
Benefits and Limitations: PEMF, approved by the FDA for various MSK pathologies, is a non-invasive
treatment with minimal side effects. It offers a simple therapeutic applicability and potential for home use
under the direction of a physician. Unlike many biophysical therapies such as PBMT and ESWT, magnetic
fields can penetrate the body with minimal resistance. However, consensus on treatment regimens for PEMF
therapy is lacking, necessitating further research on session duration, frequency, and intensity [13, 248,
255].
Technique: During the treatment, the patient either sits or lies down, and the PEMF device-varying in forms
like mats, pads, or rings-is positioned appropriately based on the treatment area. The device settings,
including frequency, intensity, and pulse duration, are customized to the individual's needs and the specific
condition being treated. Treatments can last from a few minutes to an hour, with the number of sessions
needed varying by condition. There's no discomfort during therapy, and patients can resume normal
 
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activities immediately afterward [13, 248].

Clinical Application: PEMF therapy is widely utilized in treating MSK conditions due to its pain relief and

healing properties. It is FDA-approved for accelerating the healing of nonunion bone fractures,

demonstrating effectiveness in bone regeneration. PEMF is also beneficial for individuals with

osteoarthritis, helping to reduce pain and potentially slow cartilage degeneration. The therapy supports

recovery from acute and chronic conditions like tendonitis and tendinosis [13, 248]. Table 5 lists conditions

treated with PEMF and supporting evidence; however, this is not all-inclusive of conditions or available

evidence.

Musculoskeletal Condition Supporting Evidence

Achilles Tendinopathy [255, 256, 257, 258, 259]

Chronic mechanical neck pain [260, 261, 262, 263]

Fibromyalgia [261, 264, 265, 266, 267]

Knee osteoarthritis [235, 261, 268, 269, 270, 271, 272]

Lateral Epicondylitis [179, 273, 274, 275, 276]

Low Back Pain [261, 277, 278, 279, 280]

Osteoarthritis [255, 269, 281, 282, 283]

Shoulder Impingement Syndrome [196, 261, 284, 285, 286]

Supraspinatus tendon tear [287, 288, 289, 290]

Subacromial Impingement Syndrome [284, 291]

TABLE 5: Conditions treated with pulsed electromagnetic field therapy with supporting evidence

Other Orthoregeneration Techniques

Several other modalities, including cryotherapy, heat therapy, ozone therapy, blood flow restriction, dry

needling, and interferential current therapy, likely operate within the realm of regenerative medicine and

align with the principles discussed above. However, they typically fall beyond the traditional scope of

physicians. The specifics of these modalities exceed the scope of this review, but a foundational

understanding could help orthopedic surgeons offer more informed guidance to their patients. Additionally,

incorporating these modalities as adjuncts may enhance surgical outcomes.

Challenges of orthoregeneration

Regenerative medicine has emerged as a promising avenue for enhancing outcomes in orthopedics, offering

numerous advantages for patients with diverse pathologies. However, the optimism surrounding its

potential often outpaces the available evidence. A lack of standardization throughout orthoregeneration,

from terminology to outcome measures, leads to no consensus in defining biological targets and the

specifics of each treatment modality. There is an absence of agreement regarding best practices for the

formulation, origin, administration, and dosage of orthoregeneration therapies [5, 7, 292, 293]. Future

studies must prioritize improved reporting standards to monitor efficacy and enhance collaboration among

scientists, the commercial sector, and regulatory agencies such as the FDA. This collaborative approach is

essential for accelerating the development of safe and effective therapies that benefit patients [5, 7, 292,

293].

Regenerative medicine therapies, while holding promising, do carry risks. The true incidence of

complications remains difficult to determine due to the largely unregulated nature of this field. Despite

these uncertainties, driven by the desire for improved outcomes, patients and providers may be inclined to

explore these treatments despite any risks involved. Ethical considerations also arise regarding the informed

consent process for patients undergoing regenerative procedures. Patients must be adequately informed

about the nature of treatment, potential risks, and uncertainties associated with orthoregeneration

interventions [5, 7, 292, 293]. Transparent communication and comprehensive informed consent protocols

are crucial for upholding patient autonomy and ensuring their understanding of these treatments. As

clinicians, it is our responsibility to be well-versed in the costs, efficacy, and risks of orthoregeneration

modalities, enabling us to counsel patients effectively on the discrepancies between available evidence and

industry claims [5, 7, 292, 293].

2024 Ibrahim et al. Cureus 16(9): e68487. D OI 10.7759/cureus.68487 9 of 21

Orthoregeneration holds significant promise for enhancing patient outcomes across a wide spectrum of MSK

conditions. To fully grasp its potential, it is essential to grasp the regulatory requirements, logistical

challenges, and ethical considerations involved in its clinical application. Many orthoregenerative

treatments are minimally invasive with low associated risks, making them valuable adjuncts to traditional

methods, including surgery. Ongoing research and the development of standardized data collection

protocols and treatment guidelines are vital to generating high-level evidence, which will help identify the

most suitable candidates for these therapies. As evidence-based practice grows, it could also reduce barriers

to insurance coverage. Additionally, increasing orthopedic surgeons’ education and familiarity with

orthoregenerative modalities will empower them to offer patients the most effective treatment options in a

variety of clinical situations. Further information can also be explored through the resources in the

Appendices section.

Conclusions

The integration of regenerative medicine into orthopedic surgery is a pivotal advancement in the field,

offering innovative approaches to repair and restore MSK tissues. As this discipline continues to evolve, the

potential to improve patient outcomes through orthoregeneration becomes increasingly evident. However,

there are also significant challenges to overcome, including the need for standardized treatment protocols,

rigorous clinical evidence, and a comprehensive understanding of the mechanisms underlying these

therapies. Orthoregeneration therapies, such as prolotherapy, therapeutic ultrasound, extracorporeal

shockwave therapy, photobiomodulation, and pulsed electromagnetic field therapy, among others, present

promising alternatives or adjuncts to conventional treatments. These modalities are generally minimally

invasive, with fewer complications, making them attractive options for a wide range of MSK conditions.

Nevertheless, the lack of standardization and the variability in outcomes underscore the need for further

research and the development of clear clinical guidelines.

Appendices

Orthoregeneration resources

Here is a list of resources to aid orthopedic surgeons in safely and ethically incorporating orthoregeneration

into their practice or at least gaining knowledge of the field.

- Orthobiologics: Scientific and Clinical Solutions for Orthopaedic Surgeons by the American Academy of

Orthopaedic Surgeons (AAOS)

- AAOS Biologics Dashboard

- AAOS Biologics Symposium

- AAOS Biologics Initiative

- Arthroscopy Association of North America

- Hype, Promise, and Reality: Orthopaedic Use of Biologics by the American Orthopaedic Society for Sports

Medicine

- Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal

Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff

- Orthoregeneration Network Foundation

- Interventional Orthobiologics Foundation

- Biologics Association

Additional Information

Author Contributions

All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the

work.

Concept and design: Ayah Ibrahim, Marco Gupton

Acquisition, analysis, or interpretation of data: Ayah Ibrahim, Marco Gupton, Frederick Schroeder

Drafting of the manuscript: Ayah Ibrahim, Marco Gupton, Frederick Schroeder

2024 Ibrahim et al. Cureus 16(9): e68487. D OI 10.7759/cureus.68487 10 of 21

Critical review of the manuscript for important intellectual content:  Ayah Ibrahim, Marco Gupton
Supervision:  Marco Gupton
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
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Advancements in Regenerative Therapies for Orthopedics: A Comprehensive Review of Platelet-Rich Plasma, Mesenchymal Stem Cells, Peptide Therapies, and Biomimetic Applications

Article

Full-text available

Mar 2025

Background/Objectives: Regenerative therapies have gained interest in orthopedic applications for their potential to enhance tissue regeneration, functional recovery, and pain modification. This review evaluates the clinical efficacy of platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), peptide-based treatments, and biomimetic materials in orthopedic care, with a focus on pain reduction and functional outcomes. Methods: A structured literature search in PubMed (January 2009–January 2025) identified 160 studies. After applying inclusion criteria prioritizing randomized controlled trials (RCTs) and clinical trials, 59 studies were included: 20 on PRP, 20 on MSCs, 10 on peptide therapies, and 7 on biomimetics. Data extraction focused on pain reduction and functional recovery, with risk of bias assessed using the Cochrane Risk of Bias (RoB) tool and ROBINS-I tool. A random-effects meta-regression analysis was conducted to evaluate the impact of therapy type, sample size, and risk of bias on reported pain reduction outcomes. Results: Meta-regression analysis identified MSC therapy as the most effective intervention for pain reduction (β = 8.45, p < 0.05), with PRP and peptide-based therapies showing moderate improvements, and biomimetic therapies demonstrating the lowest effect. PRP provided short-term pain relief, particularly in acute injuries and tendon repair, though inconsistencies in preparation methods limited success in chronic conditions. MSC therapies demonstrated cartilage regeneration and early osteoarthritis improvement, but high costs and ethical concerns remain barriers to widespread adoption. Peptide-based therapies and biomimetic materials, including engineered scaffolds and autologous protein solutions, showed promise for infection control and wound healing, though further research is needed to optimize dosing, delivery methods, and long-term safety. Conclusions: Regenerative therapies offer significant potential in orthopedic care, with MSC therapies demonstrating the most reliable regenerative effects, PRP providing short-term symptomatic relief, and peptide-based and biomimetic treatments emerging as promising adjuncts. However, standardized protocols and large-scale clinical trials are needed to establish long-term efficacy and improve clinical translation for broader adoption.

Biologic Strategies for Shoulder Injuries

Chapter

May 2025

Dynamics of the level of endogenous intoxication during stimulation of osteogenesis by direct electric current

Article

May 2025

The aim of the study . To study the dynamics of changes in endogenous intoxication products in the blood serum of rabbits during leg bone lengthening according to Ilizarov under the influence of direct electric current on the regenerate zone. Materials and methods . The study was performed on 49 male rabbits, which underwent leg bone lengthening according to Ilizarov. In both experimental groups, the procedure of electrical action on the bone was performed six times, repeating it after 48 hours. The current strength was 150 μA. The exposure time was 60 seconds. In the first group, the anode (+) of the device was connected to the spokes-electrodes distal to the osteotomy zone, the cathode (-) – proximal to the osteotomy. In the second group, the anode (+) was attached to the spokes-electrodes proximal to the osteotomy, the cathode (-) – distal to the osteotomy zone. Within the groups, the animals were divided into subgroups depending on the time of the onset of electrical exposure: immediately after surgery (subgroup 1.1, n = 11; subgroup 2.1, n = 9) and from 10 days after surgery (subgroup 1.2, n = 10; subgroup 2.2, n = 8). In the control group (n = 11), no electrical exposure was performed. Endogenous intoxication was assessed by the level of oligopeptides and substances of low and medium molecular weight (SLMM) in the blood serum. Results . A significant increase in SLMM during the experiment was found only in the rabbits of the control group. The percentage of the catabolic pool among SLMM during the experiment was significantly increased in the animals of group 1.1 on the 5th day of distraction, for group 1.2 – from the 15th to the 20th day of distraction; in group 2.1 – on the 10th day of distraction; in group 2.2 – at the end of fixation. In all groups with electrical exposure, in contrast to the control, a decrease in the level of oligopeptides was noted during the period of fixation and up to 30 days after the removal of the device. Conclusion . The effect of direct electric current on the distraction regenerate did not cause a significant increase in the products of endogenous intoxication in the blood of laboratory animals under the studied application modes.

Use of extracorporeal shockwave therapies for athletes and physically active individuals: a systematic review

Article

Full-text available

Jan 2024
BRIT J SPORT MED

Objective To determine the efficacy of extracorporeal shockwave therapy (ESWT) and investigate outcomes following the use of ESWT for athletes and physically active individuals. Design Systematic review. Data sources We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and searched four databases: PubMed (NLM), Embase (Elsevier), CINAHL Complete (EBSCO) and Web of Science (Clarivate). Eligibility criteria for selecting studies Included studies were randomised controlled trials, cohort and case–control studies, cases series and reports that evaluated outcomes following ESWT for athletes, physically active individuals and occupational groups requiring regular physical activity such as military cadets. Results 56 studies with 1874 athletes or physically active individuals were included. Using the Oxford level of evidence rating, included studies were 18 level I (32.1%), 3 level II (5.4%), 10 level III (17.9%), 13 level IV (23.2%) and 12 level V (21.4%). Based on the level I studies, ESWT may be effective alone in plantar fasciitis, lateral epicondylitis and proximal hamstring tendinopathy and as an adjunct to exercise treatment in medial tibial stress syndrome and osteitis pubis in athletes or physically active individuals. In most studies, athletes were allowed to continue activities and training and tolerated ESWT with minimal side effects. Conclusion ESWT may offer an efficacious treatment alone or as an adjunct to concurrent exercise therapy in selected sports-related injuries and without major adverse events. Further high-level research is needed to better define the role and clinical outcomes of ESWT.

The Beneficial Effects of High-Intensity Laser Therapy and Co-Interventions on Musculoskeletal Pain Management: A Systematic Review

Article

Full-text available

Jan 2020

Introduction: High-intensity laser therapy (HILT) has been used more recently in the therapeutic protocols of pain managements. Adding therapeutic interventions to laser therapy is usual in clinical practice. This study aimed to evaluate the efficacy of HILT and beneficial effects of adding co-interventions to HILT in musculoskeletal pain management. Methods: The following databases were searched up to August 2018: Medline, PubMed, EMBASE, Cochrane, Google Scholar, Springer and ISI. The keywords of pain, HILT, high power laser therapy, laser therapy, photobiomodulation, physical therapy and rehabilitation were searched. The quality of the articles was assessed using the PEDro scale. The primary measure was pain severity expected to be reported in all studies. Effect size was calculated as standardized mean differences divided by the standard deviation of either the treatment or other group. Results: Initially 52 potential studies were found. Eighteen of these studies were excluded based on title and abstract. The full text of 34 remaining articles was screened and 15 of the studies were excluded. All included studies had high quality (PEDro ≥7). Approximately, 94% of included articles (n=18) revealed positive effects of HILT on pain. The effect sizes for HILT and placebo/comparator groups were 0.9-9.11 and 0.21-11.22 respectively. Also, the differences of effect size between two groups were between 0.03 to 5.85. Conclusion: It is early to determine that HILT may be an effective non-invasive agent in the management of musculoskeletal pain, as few studies have shown its clinical efficacy. Adding related co-interventions to HILT may enhance the beneficial effects of laser therapy. The variability of the study methods and outcomes suggests that further long-term follow-up, randomized controlled clinical trials with appropriate methodological design are needed regarding the effectiveness of HILT on pain.

Impact of Blue Light Therapy on Wound Healing in Preclinical and Clinical Subjects: A Systematic Review

Article

Full-text available

Dec 2022

Introduction: While a wound caused by a minor cutaneous incision routinely heals in a short time, wounds from major surgical operations might need numerous days to heal and may leave an obvious cicatrix. The use of blue light therapy (BLT) to destroy infectious microorganisms and disrupt biofilm formation could be an efficient method for healing ulcers. This systematic review focused on the effects of BLT in different preclinical in vivo studies and clinical models of skin wound healing. Furthermore, this study attempted to determine what main light parameters should be tested in preclinical and clinical studies. Methods: The online databases PubMed.gov, Google Scholar, Scopus, Web of Science, and Cochrane were searched using the keywords “blue light” and “wound healing” according to PRISMA guidelines. No publication time limit was enforced. Results: A total of 858 articles were identified, and 17 articles in three distinct categories were included for review. They comprised two articles on humans, fourteen articles on healthy animals, and one article on diabetic animals. Conclusion: Some studies have shown that the application of BLT on preclinical and clinical models of wound healing in vivo is able to significantly accelerate the healing process. Few studies, however, have explored the bactericidal effect of BLT on skin injury repair in burn patients. Further preclinical investigations designed to provide a better understanding of the bactericidal effect of BLT using standardized protocols, different BLT wavelengths, and different stages of the wound-healing process of infected wounds and ulcers in healthy and diabetic animals should be carried out before clinical trials can be considered. BLT could eventually be a good option for treating infected chronic wounds, including those in diabetic patients.

Low-Level Laser Therapy for Rheumatoid Arthritis: A Review of Experimental Approaches

Article

Full-text available

Dec 2022

Introduction: Rheumatoid arthritis (RA) is an inflammatory and autoimmune disorder that is characterized by joint inflammation, pain, physical disability, and morning stiffness. In the present study, the effect of low-level laser therapy (LLLT) on RA was reviewed. Methods: “Low-level laser therapy”, “rheumatoid arthritis disease”, and “photobiomodulation” keywords were searched in Google Scholar, PubMed, and Medline. Results: A literature survey led to a discussion about the immunology of the RA, laser therapy, mechanism of LLLT action, and anti-inflammatory and immunomodulatory properties of LLLT. Conclusion: It was concluded that LLLT could improve RA patients’ quality of life, reduce pain, and enhance physical movement.

Effectiveness of high-intensity laser therapy in the treatment of patients with frozen shoulder: a systematic review and meta-analysis

Article

Full-text available

Nov 2023
LASER MED SCI

The purpose of this study is to evaluate the effects of high-intensity laser therapy (HILT) in patients with frozen shoulder. PRISMA guidelines were adhered to, and a systematic search was conducted in the PubMed, Web of Science, Scopus, CINAHL, Science Direct, and PEDro databases (last update: September 4, 2023; search period: December 2022-Septem-ber 2023). The inclusion criteria encompassed RCTs comparing HILT with other physical therapy interventions in frozen patients with frozen shoulders, with or without sham HILT, assessing pain intensity, shoulder ROM, and disability outcomes. The quality of the RCTs was assessed with the Cochrane Risk of Bias tool, and evidence was assessed using the GRADE approach. Five trials met the eligibility criteria and were included in the review and meta-analysis, which pooled results from the visual analog scale (VAS), goniometry, and the shoulder pain and disability index (SPADI). Mean differences (MDs) for pain intensity and disability show a pooled effect in favor of HILT both for VAS (MD = − 2.23 cm, 95% CI: − 3.25, − 1.22) and SPADI (MD = − 10.1% (95% CI = − 16.5, − 3.7), changes that are statistical (p < 0.01) and clinical. The MD for flexion (MD = 9.0°; 95% CI: − 2.36°, 20.3°; p = 0.12), abduction (MD = 3.4°; 95% CI: − 6.9°, 13.7°; p = 0.51), and external rotation (MD = − 0.95°; 95% CI: − 5.36°, 3.5°; p = 0.67) does not show statistical and clinical differences between groups after treatment. PI and disability changes were graded as important due to their clinical and statistical results. HILT into a physical therapy plan reduce pain and disability, but it does not outperform conventional physical therapy in improving shoulder ROM. It is suggested that future RCTs compare the effects of HILT and LLLT to assess their possible differences in their analgesic effects.

The Mechanisms and Efficacy of Photobiomodulation Therapy for Arthritis: A Comprehensive Review

Article

Full-text available

Sep 2023
INT J MOL SCI

Rheumatoid arthritis (RA) and osteoarthritis (OA) have a significant impact on the quality of life of patients around the world, causing significant pain and disability. Furthermore, the drugs used to treat these conditions frequently have side effects that add to the patient’s burden. Photobiomodulation (PBM) has emerged as a promising treatment approach in recent years. PBM effectively reduces inflammation by utilizing near-infrared light emitted by lasers or LEDs. In contrast to photothermal effects, PBM causes a photobiological response in cells, which regulates their functional response to light and reduces inflammation. PBM’s anti-inflammatory properties and beneficial effects in arthritis treatment have been reported in numerous studies, including animal experiments and clinical trials. PBM’s effectiveness in arthritis treatment has been extensively researched in arthritis-specific cells. Despite the positive results of PBM treatment, questions about specific parameters such as wavelength, dose, power density, irradiation time, and treatment site remain. The goal of this comprehensive review is to systematically summarize the mechanisms of PBM in arthritis treatment, the development of animal arthritis models, and the anti-inflammatory and joint function recovery effects seen in these models. The review also goes over the evaluation methods used in clinical trials. Overall, this review provides valuable insights for researchers investigating PBM treatment for arthritis, providing important references for parameters, model techniques, and evaluation methods in future studies.

Outcomes Using Focused Shockwave for Treatment of Bone Stress Injury in Runners

Article

Full-text available

Jul 2023

Bone stress injury (BSI) is a common overuse injury that can result in prolonged time away from sport. Limited studies have characterized the use of extracorporeal shockwave therapy (ESWT) for the treatment of BSI. The purpose of this study was to describe the use of ESWT for the management of BSI in runners. A retrospective chart review was performed to identify eligible patients in a single physician’s clinic from 1 August 2018 to 30 September 2022. BSI was identified in 40 runners with 41 injuries (28 females; average age and standard deviation: 30 ± 13 years; average pre-injury training 72 ± 40 km per week). Overall, 63% (n = 26) met the criteria for moderate- or high-risk Female or Male Athlete Triad categories. Runners started ESWT at a median of 36 days (IQR 11 to 95 days; range 3 days to 8 years) from BSI diagnosis. On average, each received 5 ± 2 total focused ESWT treatments. Those with acute BSI (ESWT started <3 months from BSI diagnosis) had an average return to run at 12.0 ± 7.5 weeks, while patients with delayed union (>3 months, n = 3) or non-union (>6 months, n = 9) had longer time for return to running (19.8 ± 14.8 weeks, p = 0.032). All runners returned to pain-free running after ESWT except one runner with non-union of grade 4 navicular BSI who opted for surgery. No complications were observed with ESWT. These findings suggest that focused ESWT may be a safe treatment for the management of BSI in runners.

The effectiveness of shockwave therapy on patellar tendinopathy, Achilles tendinopathy, and plantar fasciitis: a systematic review and meta-analysis

Article

Full-text available

Aug 2023

Background Tendinopathy is a growing global concern affecting many people, like athletes, workers, and the elderly. Despite its commonality among the sporting population, there is no practical clinical guideline for patellar tendinopathy (PT). Furthermore, there is conflicting evidence between clinical guidelines on shockwave therapy’s application and clinical utility for Achilles tendinopathy (AT) and plantar fasciitis (PF). Thus, our aim of this study is to evaluate the evidence for shockwave therapy; to provide a Grading of Recommendation, Assessment, Development and Evaluation (GRADE) level of the evidence and effectiveness of shockwave therapy for patellar tendinopathy, Achilles tendinopathy, and Plantar fasciitis. Method Medical Literature Analysis and Retrieval System Online (Medline), Embase, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Physiotherapy Evidence Database (PEDro) and China National Knowledge Infrastructure database (CNKI) were searched to find relevant studies published before December 14th, 2022. Results Our study showed that for PT in the short term, extracorporeal shockwave therapy (ESWT) or ESWT + eccentric exercise (EE) has a negligible effect on pain and function compared to a placebo or placebo + EE. On the contrary, ESWT significantly affects pain compared to conservative treatment (CT). For AT, ESWT has a small inconclusive effect on pain and function in the short term compared to EE. On the other hand, a placebo outperformed ESWT in improving function for AT but not pain outcomes. PF showed that ESWT significantly affects short- and long-term pain and function. When ESWT was compared to other interventions such as low laser therapy (LLLT), corticosteroid injection (CSI), or CT, there was a small inconclusive effect on pain and function in the short term. Conclusion There is low-moderate evidence that ESWT has a negligible effect on pain and function for PT and AT. However, high-quality evidence suggests ESWT has a large effect on pain and function for PF. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023396835, identifier CRD42023396835.

Effectiveness of Pulse Electromagnetic Field Therapy in Patients With Subacromial Impingement Syndrome: A Double-Blind Randomized Sham Controlled Study

Article

Oct 2023
ARCH PHYS MED REHAB

Recent advances and pathological mechanisms in photodynamic and sonodynamic therapy in the treatment of bone tumors (Review)

Article

Sep 2023

Given the recent advances that have been made with photodynamic therapy (PDT) combined with sonodynamic therapy (SDT) (PDT/SDT; also known as SPDT), the application of this combination therapy in the clinic has provided another major breakthrough in the medical field, especially with regard to the treatment of deep tumors. Concerning its application in the treatment of bone tumors, numerous pathological mechanisms have been taken advantage of to overcome the barrier of tissue hypoxia, and SPDT is expected to achieve radical effects, with high penetration depth and low aggressiveness. In the present review, it is comprehensively shown how, according to the histoanatomy of bone tumors, PDT and SDT target cells in a coordinated manner, affecting such processes as necrotizing apoptosis, pyroptosis, autophagy and ferroptosis on the macroscopic level, and crucially, thrombosis at the vascular level, which leads to the triggering of immunogenic cell death in local and distant locations. Additionally, PDT and SDT have been shown to have roles in: i) degrading the extracellular matrix; ii) influencing the receptor activator of nuclear factor‑κB (RANK)/RANK ligand signaling pathway; iii) disrupting the equilibrium between glutathione peroxidase 4 and reactive oxygen species (ROS); and iv) destroying the microscopic structure of the bone tumor. Upon PDT/SDT stimulation, several mechanisms act in concert to ensure that the targeted bone tumor is eliminated. Furthermore, widely distributed ROS have been revealed to promote osteoclast formation and osteogenic mineralization through the regulation of macrophages, processes that greatly improve the effects of postoperative repair. Finally, the developmental prospects of bone tumor engineering in the future are discussed in the present review.

Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox

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