Preparing the soil: Adjusting the metabolic health of patients with chronic wounds and musculoskeletal diseases.

In recent years, systemic inflammation has emerged as a pivotal player in the development and progression of various degenerative diseases. This complex, chronic inflammatory state, often undetected, can have far-reaching consequences for the body's physiology. At the molecular level, markers such as C-reactive protein, cytokines and other inflammatory mediators serve as indicators of systemic inflammation and often act as predictors of numerous musculoskeletal diseases and even certain forms of cancer. The concept of 'meta-inflammation', specifically referring to metabolically triggered inflammation, allows healthcare professionals to understand inflammatory responses in patients with metabolic syndrome. Driven by nutrient excess and the expansion of adipose tissue, meta-inflammation is closely associated with insulin resistance, further propagating the metabolic dysfunction observed in many Western societies. Wound persistence, on the other hand, exacerbates the detrimental effects of prolonged inflammation at the local level. Acute inflammation is a beneficial and essential process for wound healing and infection control. However, when inflammation fails to resolve, it can impede the healing process, leading to chronic wounds, excessive scarring and even the activation of fibrotic pathways. This approach significantly reduces the efficacy of regenerative biological therapies. Our review focuses on the vital role of proteins, vitamins and minerals in collagen synthesis and cell proliferation for tissue healing. We also examine hormonal influences on regeneration, noting the negative effects of imbalances, and emphasize glucose regulation's importance in creating a stable environment for chronic wound healing.

Sacral Bioneuromodulation: The Role of Bone Marrow Aspirate in Spinal Cord Injuries.

Spinal cord injury (SCI) represents a severe trauma to the nervous system, leading to significant neurological damage, chronic inflammation, and persistent neuropathic pain. Current treatments, including pharmacotherapy, immobilization, physical therapy, and surgical interventions, often fall short in fully addressing the underlying pathophysiology and resultant disabilities. Emerging research in the field of regenerative medicine has introduced innovative approaches such as autologous orthobiologic therapies, with bone marrow aspirate (BMA) being particularly notable for its regenerative and anti-inflammatory properties. This review focuses on the potential of BMA to modulate inflammatory pathways, enhance tissue regeneration, and restore neurological function disrupted by SCI. We hypothesize that BMA's bioactive components may stimulate reparative processes at the cellular level, particularly when applied at strategic sites like the sacral hiatus to influence lumbar centers and higher neurological structures. By exploring the mechanisms through which BMA influences spinal repair, this review aims to establish a foundation for its application in clinical settings, potentially offering a transformative approach to SCI management that extends beyond symptomatic relief to promoting functional recovery.

The role of orthobiologics in chronic wound healing.

Chronic wounds, characterized by prolonged healing processes, pose a significant medical challenge with multifaceted aetiologies, including local and systemic factors. Here, it explores the complex pathogenesis of chronic wounds, emphasizing the disruption in the normal phases of wound healing, particularly the inflammatory phase, leading to an imbalance in extracellular matrix (ECM) dynamics and persistent inflammation. Senescent cell populations further contribute to impaired wound healing in chronic lesions. Traditional medical management focuses on addressing underlying causes, but many chronic wounds resist to conventional treatments, necessitating innovative approaches. Recent attention has turned to autologous orthobiologics, such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF) and mesenchymal stem cells (MSCs), as potential regenerative interventions. These biologically derived materials, including bone marrow aspirate/concentrate (BMA/BMAC) and adipose tissue-derived stem cells (ADSCs), exhibit promising cytokine content and regenerative potential. MSCs, in particular, have emerged as key players in wound healing, influencing inflammation and promoting tissue regeneration. This paper reviews relevant scientific literature regarding basic science and brings real-world evidence regarding the use of orthobiologics in the treatment of chronic wounds, irrespective of aetiology. The discussion highlights the regenerative properties of PRP, PRF, BMA, BMAC and SVF, showcasing their potential to enhance wound healing. Despite advancements, further research is essential to elucidate the specific roles of each orthobiologic and determine optimal applications for different wound types. The conclusion underscores the evolving landscape in chronic wound management, with a call for more comprehensive studies to refine treatment strategies and maximize the benefits of regenerative medicine.

Platelet-Rich Plasma Power-Mix Gel (ppm)-An Orthobiologic Optimization Protocol Rich in Growth Factors and Fibrin.

Platelet- and fibrin-rich orthobiologic products, such as autologous platelet concentrates, have been extensively studied and appreciated for their beneficial effects on multiple conditions. Platelet-rich plasma (PRP) and its derivatives, including platelet-rich fibrin (PRF), have demonstrated encouraging outcomes in clinical and laboratory settings, particularly in the treatment of musculoskeletal disorders such as osteoarthritis (OA). Although PRP and PRF have distinct characteristics, they share similar properties. The relative abundance of platelets, peripheral blood cells, and molecular components in these orthobiologic products stimulates numerous biological pathways. These include inflammatory modulation, augmented neovascularization, and the delivery of pro-anabolic stimuli that regulate cell recruitment, proliferation, and differentiation. Furthermore, the fibrinolytic system, which is sometimes overlooked, plays a crucial role in musculoskeletal regenerative medicine by regulating proteolytic activity and promoting the recruitment of inflammatory cells and mesenchymal stem cells (MSCs) in areas of tissue regeneration, such as bone, cartilage, and muscle. PRP acts as a potent signaling agent; however, it diffuses easily, while the fibrin from PRF offers a durable scaffolding effect that promotes cell activity. The combination of fibrin with hyaluronic acid (HA), another well-studied orthobiologic product, has been shown to improve its scaffolding properties, leading to more robust fibrin polymerization. This supports cell survival, attachment, migration, and proliferation. Therefore, the administration of the "power mix" containing HA and autologous PRP + PRF may prove to be a safe and cost-effective approach in regenerative medicine.

Cannabidiol for musculoskeletal regenerative medicine.

Chronic musculoskeletal (MSK) pain is one of the most prevalent causes, which lead patients to a physician's office. The most common disorders affecting MSK structures are osteoarthritis, rheumatoid arthritis, back pain, and myofascial pain syndrome, which are all responsible for major pain and physical disability. Although there are many known management strategies currently in practice, phytotherapeutic compounds have recently begun to rise in the medical community, especially cannabidiol (CBD). This natural, non-intoxicating molecule derived from the cannabis plant has shown interesting results in many preclinical studies and some clinical settings. CBD plays vital roles in human health that go well beyond the classic immunomodulatory, anti-inflammatory, and antinociceptive properties. Recent studies demonstrated that CBD also improves cell proliferation and migration, especially in mesenchymal stem cells (MSCs). The foremost objective of this review article is to discuss the therapeutic potential of CBD in the context of MSK regenerative medicine. Numerous studies listed in the literature indicate that CBD possesses a significant capacity to modulate mammalian tissue to attenuate and reverse the notorious hallmarks of chronic musculoskeletal disorders (MSDs). The most of the research included in this review report common findings like immunomodulation and stimulation of cell activity associated with tissue regeneration, especially in human MSCs. CBD is considered safe and well tolerated as no serious adverse effects were reported. CBD promotes many positive effects which can manage detrimental alterations brought on by chronic MSDs. Since the application of CBD for MSK health is still undergoing expansion, additional randomized clinical trials are warranted to further clarify its efficacy and to understand its cellular mechanisms.

The Synergistic Effects of Hyaluronic Acid and Platelet-Rich Plasma for Patellar Chondropathy.

Musculoskeletal disorders are increasingly prevalent worldwide, causing significant socioeconomic burdens and diminished quality of life. Notably, patellar chondropathy (PC) is among the most widespread conditions affecting joint structures, resulting in profound pain and disability. Hyaluronic acid (HA) and platelet-rich plasma (PRP) have emerged as reliable, effective, and minimally invasive alternatives. Continuous research spanning from laboratory settings to clinical applications demonstrates the numerous advantages of both products. These encompass lubrication, anti-inflammation, and stimulation of cellular behaviors linked to proliferation, differentiation, migration, and the release of essential growth factors. Cumulatively, these benefits support the rejuvenation of bone and cartilaginous tissues, which are otherwise compromised due to the prevailing degenerative and inflammatory responses characteristic of tissue damage. While existing literature delves into the physical, mechanical, and biological facets of these products, as well as their commercial variants and distinct clinical uses, there is limited discussion on their interconnected roles. We explore basic science concepts, product variations, and clinical strategies. This comprehensive examination provides physicians with an alternative insight into the pathophysiology of PC as well as biological mechanisms stimulated by both HA and PRP that contribute to tissue restoration.

Platelet-Rich Plasma Gel Matrix (PRP-GM): Description of a New Technique.

Several musculoskeletal conditions are triggered by inflammatory processes that occur along with imbalances between anabolic and catabolic events. Platelet-rich plasma (PRP) is an autologous product derived from peripheral blood with inherent immunomodulatory and anabolic properties. The clinical efficacy of PRP has been evaluated in several musculoskeletal conditions, including osteoarthritis, tendinopathy, and osteonecrosis. When used in combination with hyaluronic acid (HA), a common treatment alternative, the regenerative properties of PRP are significantly enhanced and may provide additional benefits in terms of clinical outcomes. Recently, a new PRP-derived product has been reported in the literature and is being referred to as "plasma gel". Plasma gels are obtained by polymerizing plasmatic proteins, which form solid thermal aggregates cross-linked with fibrin networks. Plasma gels are considered to be a rich source of growth factors and provide chemotactic, migratory, and proliferative properties. Additionally, clot formation and the associated fibrinolytic reactions play an additional role in tissue repair. There are only a few scientific articles focusing on plasma gels. Historically, they have been utilized in the fields of aesthetics and dentistry. Given that the combination of three products (PRP, HA, and plasma gel) could enhance tissue repair and wound healing, in this technical note, we propose a novel regenerative approach, named "PRP-HA cellular gel matrix" (PRP-GM), in which leukocyte-rich PRP (LR-PRP) is mixed with a plasma gel (obtained by heating the plasma up) and HA in one syringe using a three-way stopcock. The final product contains a fibrin-albumin network entangled with HA's polymers, in which the cells and biomolecules derived from PRP are attached and released gradually as fibrinolytic reactions and hyaluronic acid degradation occur. The presence of leukocytes, especially monocytes and macrophages, promotes tissue regeneration, as type 2 macrophages (M2) possess an anti-inflammatory feature. In addition, HA promotes the viscosuplementation of the joint and induces an anti-inflammatory response, resulting in pain relief. This unique combination of biological molecules may contribute to the optimization of regenerative protocols suitable for the treatment of degenerative musculoskeletal diseases.

The Mechanism of Action between Pulsed Radiofrequency and Orthobiologics: Is There a Synergistic Effect?

Radiofrequency energy is a common treatment modality for chronic pain. While there are different forms of radiofrequency-based therapeutics, the common concept is the generation of an electromagnetic field in the applied area, that can result in neuromodulation (pulsed radiofrequency-PRF) or ablation. Our specific focus relates to PRF due to the possibility of modulation that is in accordance with the mechanisms of action of orthobiologics. The proposed mechanism of action of PRF pertaining to pain relief relies on a decrease in pro-inflammatory cytokines, an increase in cytosolic calcium concentration, a general effect on the immune system, and a reduction in the formation of free radical molecules. The primary known properties of orthobiologics constitute the release of growth factors, a stimulus for endogenous repair, analgesia, and improvement of the function of the injured area. In this review, we described the mechanism of action of both treatments and pertinent scientific references to the use of the combination of PRF and orthobiologics. Our hypothesis is a synergic effect with the combination of both techniques which could benefit patients and improve the life quality.

Stromal Vascular Fraction for Knee Osteoarthritis - An Update.

Orthobiologics never cease to cause popularity within the medical science field, distinctly in regenerative medicine. Recently, adipose tissue has been an object of interest for many researchers and medical experts due to the fact that it represents a novel and potential cell source for tissue engineering and regenerative medicine purposes. Stromal vascular fraction (SVF), for instance, which is an adipose tissue-derivative, has generated optimistic results in many scenarios. Its biological potential can be harnessed and administered into injured tissues, particularly areas in which standard healing is disrupted. This is a typical feature of osteoarthritis (OA), a common degenerative joint disease which is outlined by persistent inflammation and destruction of surrounding tissues. SVF is known to carry a large amount of stem and progenitor cells, which are able to perform self-renewal, differentiation, and proliferation. Furthermore, they also secrete several cytokines and several growth factors, effectively sustaining immune modulatory effects and halting the escalated pro-inflammatory status of OA. Although SVF has shown interesting results throughout the medical community, additional research is still highly desirable in order to further elucidate its potential regarding musculoskeletal disorders, especially OA.

The Association between Gut Microbiota and Osteoarthritis: Does the Disease Begin in the Gut?

Some say that all diseases begin in the gut. Interestingly, this concept is actually quite old, since it is attributed to the Ancient Greek physician Hippocrates, who proposed the hypothesis nearly 2500 years ago. The continuous breakthroughs in modern medicine have transformed our classic understanding of the gastrointestinal tract (GIT) and human health. Although the gut microbiota (GMB) has proven to be a core component of human health under standard metabolic conditions, there is now also a strong link connecting the composition and function of the GMB to the development of numerous diseases, especially the ones of musculoskeletal nature. The symbiotic microbes that reside in the gastrointestinal tract are very sensitive to biochemical stimuli and may respond in many different ways depending on the nature of these biological signals. Certain variables such as nutrition and physical modulation can either enhance or disrupt the equilibrium between the various species of gut microbes. In fact, fat-rich diets can cause dysbiosis, which decreases the number of protective bacteria and compromises the integrity of the epithelial barrier in the GIT. Overgrowth of pathogenic microbes then release higher quantities of toxic metabolites into the circulatory system, especially the pro-inflammatory cytokines detected in osteoarthritis (OA), thereby promoting inflammation and the initiation of many disease processes throughout the body. Although many studies link OA with GMB perturbations, further research is still needed.

The regenerative mechanisms of platelet-rich plasma: A review.

Orthobiologics continue to gain popularity in many areas of medical science, especially in the field of regenerative medicine. Platelet-rich plasma derivatives are orthobiologic tools of particular interest. These biologic products can be obtained via centrifugation of a patient's whole blood and the components can then be subsequently isolated, concentrated and ultimately administered into injured tissues, particularly in areas where standard healing is disrupted. The elevated concentration of platelets above the basal value enables accelerated growth of various tissues with minimal side effects. The application of autologous orthobiologics is a relatively new biotechnology undergoing expansion which continues to reveal optimistic results in the stimulation and enhanced healing of various sorts of tissue injuries. The local release of growth factors and cytokines contained in platelet alpha granules accelerates and ameliorates tissue repair processes, mimicking and supporting standard wound healing. This effect is greatly enhanced upon combination with the fibrinolytic system, which are essential for complete regeneration. Fibrinolytic reactions can dictate proper cellular recruitment of certain cell populations such as mesenchymal stem cells and other immunomodulatory agents. Additionally, these reactions also control proteolytic activity in areas of wound healing and regenerative processes of mesodermal tissues including bone, cartilage, and muscle, which makes it particularly valuable for musculoskeletal health, for instance. Although many investigations have demonstrated significant results with platelet-rich plasma derivatives, further studies are still warranted.

Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine.

The rise in musculoskeletal disorders has prompted medical experts to devise novel effective alternatives to treat complicated orthopedic conditions. The ever-expanding field of regenerative medicine has allowed researchers to appreciate the therapeutic value of bone marrow-derived biological products, such as the bone marrow aspirate (BMA) clot, a potent orthobiologic which has often been dismissed and regarded as a technical complication. Numerous in vitro and in vivo studies have contributed to the expansion of medical knowledge, revealing optimistic results concerning the application of autologous bone marrow towards various impactful disorders. The bone marrow accommodates a diverse family of cell populations and a rich secretome; therefore, autologous BMA-derived products such as the "BMA Matrix", may represent a safe and viable approach, able to reduce the costs and some drawbacks linked to the expansion of bone marrow. BMA provides -it eliminates many hurdles associated with its preparation, especially in regards to regulatory compliance. The BMA Matrix represents a suitable alternative, indicated for the enhancement of tissue repair mechanisms by modulating inflammation and acting as a natural biological scaffold as well as a reservoir of cytokines and growth factors that support cell activity. Although promising, more clinical studies are warranted in order to further clarify the efficacy of this strategy.

Nebulization of glutathione and N-Acetylcysteine as an adjuvant therapy for COVID-19 onset.

Ever since its emergence, the highly transmissible and debilitating coronavirus disease spread at an incredibly fast rate, causing global devastation in a matter of months. SARS-CoV-2, the novel coronavirus responsible for COVID-19, infects hosts after binding to ACE2 receptors present on cells from many structures pertaining to the respiratory, cardiac, hematological, neurological, renal and gastrointestinal systems. COVID-19, however, appears to trigger a severe cytokine storm syndrome in pulmonary structures, resulting in oxidative stress, exacerbated inflammation and alveolar injury. Due to the recent nature of this disease no treatments have shown complete efficacy and safety. More recently, however, researchers have begun to direct some attention towards GSH and NAC. These natural antioxidants play an essential role in several biological processes in the body, especially the maintenance of the redox equilibrium. In fact, many diseases appear to be strongly related to severe oxidative stress and deficiency of endogenous GSH. The high ratios of ROS over GSH, in particular, appear to reflect severity of symptoms and prolonged hospitalization of COVID-19 patients. This imbalance interferes with the body's ability to detoxify the cellular microenvironment, fold proteins, replenish antioxidant levels, maintain healthy immune responses and even modulate apoptotic events. Oral administration of GSH and NAC is convenient and safe, but they are susceptible to degradation in the digestive tract. Considering this drawback, nebulization of GSH and NAC as an adjuvant therapy may therefore be a viable alternative for the management of the early stages of COVID-19.

Bone marrow aspirate clot: A feasible orthobiologic.

Musculoskeletal disorders are one of the major health burdens and a leading source of disability worldwide, affecting both juvenile and elderly populations either as a consequence of ageing or extrinsic factors such as physical injuries. This condition often involves a group of locomotor structures such as the bones, joints and muscles and may therefore cause significant economic and emotional impact. Some pharmacological and non-pharmacological treatments have been considered as potential solutions, however, these alternatives have provided quite limited efficacy due to the short-term effect on pain management and inability to restore damaged tissue. The emergence of novel therapeutic alternatives such as the application of orthobiologics, particularly bone marrow aspirate (BMA) clot, have bestowed medical experts with considerable optimism as evidenced by the significant results found in numerous studies addressed in this manuscript. Although other products have been proposed for the treatment of musculoskeletal injuries, the peculiar interest in BMA, fibrin clot and associated fibrinolytic mechanisms continues to expand. BMA is a rich source of various cellular and molecular components which have demonstrated positive effects on tissue regeneration in many in vitro and in vivo models of musculoskeletal injuries. In addition to being able to undergo self-renewal and differentiation, the hematopoietic and mesenchymal stem cells present in this orthobiologic elicit key immunomodulatory and paracrine roles in inflammatory responses in tissue injury and drive the coagulation cascade towards tissue repair via different mechanisms. Although promising, these complex regenerative mechanisms have not yet been fully elucidated.

Metabolic syndrome and subchondral bone alterations: The rise of osteoarthritis - A review.

Metabolic syndrome (MS) has become one of the top major health burdens for over three decades not only due to its effects on cardiovascular health but also its implications in orthopedics. Extensive research has shown that MS is tightly linked to osteoarthritis and inflammation, a process which appears to primarily occur in the subchondral bone via the incidence of bone-marrow lesions (BMLs). Numerous studies identify obesity, dyslipidemia, insulin resistance and hypertension as the top metabolic risk factors, the so-called "deadly quartet". These factors are responsible for the disruptive physiological processes that culminate in detrimental alterations within the subchondral bone, cartilage damage and, overall, the predominant pro-inflammatory joint microenvironment. Although it has long been thought that osteoarthritis was limited to the cartilage component of the joint, other studies indicate that the disease may originate from the harmful alterations that occur primarily in the subchondral bone, especially via means of vascular pathology. Since metabolic risk factors are manageable to a certain extent, it is therefore possible to decelerate the progression of OA and mitigate its devastating effects on the subchondral bone and subsequent articular cartilage damage. METHODS: Literature was reviewed using PubMed and Google Scholar in order to find a correlation between metabolic syndrome and osteoarthritic progression. The investigation included a combination of nomenclature such as: "metabolic syndrome", "obesity", "insulin resistance", "hypertension", "dyslipidemia", "low-grade systemic inflammation", "osteoarthritis", "subchondral bone", "cartilage" and "inflammatory biomarkers". CONCLUSION: Based on several studies, there seems to be a significant association between The Deadly Quartet (metabolic syndrome), dysregulation of both pro- and anti-inflammatory biomarkers, and osteoarthritic progression arising from unbridled systemic inflammation.