Gabriel Ohana Marques Azzini

Hyaluronan-based materials are widely described as hydrogels, yet the term is applied without distinction to preparations that differ fundamentally in structure. This review addresses that imprecision by separating three material states of hyaluronan and by stating the criteria under which each may be called a gel: native linear hyaluronan, which forms a viscoelastic solution; the hexadecylamide derivative (HYADD-4), which self-assembles into a transient physical network through hydrophobic interactions; and hyaluronan cross-linked with 1,4-butanediol diglycidyl ether (BDDE), which forms a covalent three-dimensional network. A material is treated as a gel here only where both a percolated network and a solid-like mechanical response are documented. On that basis the covalent network qualifies; the derivative is elastic-dominated across the walking-to-running frequency band of the knee but has not been subjected to a formal Winter–Chambon analysis and is therefore described as gel-like; and the linear solution does not qualify at the molecular weights and concentrations used in marketed viscosupplements. We review the chemistry of network formation, the comparative physicochemical and rheological behavior, including viscosity, the storage and loss moduli, boundary lubrication, and resistance to enzymatic and oxidative degradation, and the receptor-mediated and anti-inflammatory mechanisms of action involving CD44 and molecular-weight-dependent signaling. Clinical and regenerative applications in osteoarthritis viscosupplementation and in scaffolds and carriers for cells and growth factors are summarized for each state. The networked materials show higher viscoelasticity and greater resistance to degradation than the linear solution, which provides a rationale for longer residence; the evidence for a clinical advantage over conventional hyaluronan, however, rests largely on preclinical and rheological data. A three-state framework is proposed, pending validation, to support clearer interpretation of the literature and more rational material selection.

Knee osteoarthritis is commonly managed with intra-articular therapies that differ widely in composition, mechanism, and clinical persistence, yet the duration of their benefit is discussed inconsistently, which limits practical comparison between ozone, hyaluronic acid, platelet-derived products, and cell-rich orthobiologics. In this narrative review we examine the mechanism-driven temporal behavior of these therapies, focusing on the physicochemical, biomechanical, biological, and regenerative factors that influence how long a clinical response persists. By temporal hierarchy we mean the mechanistically informed pattern by which therapies differ in the duration of their physicochemical presence, biological activity, and clinical benefit, not a ranking of efficacy or a claim of equivalence. Read against this definition, ozone occupies the shortest end of the spectrum; conventional hyaluronic acid shows intermediate persistence; modified hyaluronic acid hydrogels may extend activity through improved rheology and enzymatic resistance; platelet-rich plasma and injectable platelet-rich fibrin provide more sustained biological signaling; and bone marrow aspirate concentrate and stromal vascular fraction may act over longer periods through trophic and paracrine pathways. Heterogeneity in study design, patient selection, and outcome reporting still limits firm conclusions, and standardized reporting of product characteristics and time-related endpoints will be essential to validate or refine the proposed framework.

Knee osteoarthritis (KOA) is a degenerative joint condition characterized by progressive cartilage deterioration and chronic pain, leading to functional im

Type 2 diabetes mellitus (T2DM) affects approximately 10–25% of patients undergoing orthopedic procedures and is associated with impaired tissue healing, increased complication rates, and reduced responsiveness to orthobiologic therapies, including platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and mesenchymal stem cell (MSC) preparations. The underlying mechanisms include advanced glycation end-product accumulation, NF-κB-driven chronic inflammation, Nrf2 pathway impairment, mitochondrial dysfunction, and epigenetic diabetic memory, collectively compromising both orthobiologic product quality and the tissue microenvironment. Emerging, predominantly mechanistic evidence suggests that targeted nutritional interventions, including bioactive compounds targeting mitochondrial biogenesis pathways, anti-inflammatory dietary patterns, and specific micronutrients, may modulate these pathological processes and potentially improve orthobiologic outcomes. This narrative review synthesizes evidence from diabetic pathophysiology, orthobiologic outcomes research, and nutritional science to propose a conceptual clinical framework for regenerative medicine optimization in T2DM patients. Critical knowledge gaps are identified, and a research agenda is proposed. The proposed framework, based primarily on mechanistic and preclinical evidence, should be interpreted as a foundation for research prioritization and hypothesis generation rather than as a clinical protocol. Rigorous randomized trials directly evaluating nutritional optimization in orthobiologic therapy for diabetic patients are required before evidence-based recommendations can be established.

The evolving paradigm of precision medicine is redefining the landscape of orthobiologic therapies by moving beyond traditional diagnosis-driven approaches toward biologically tailored interventions. This review synthesizes current evidence supporting precision orthobiologics, emphasizing the significance of individualized treatment strategies in musculoskeletal regenerative medicine. This narrative review synthesized literature from PubMed, Embase, and Web of Science databases (January 2015–December 2024) using search terms, including ‘precision medicine,’ ‘orthobiologics,’ ‘regenerative medicine,’ ‘biomarkers,’ and ‘artificial intelligence’. Biological heterogeneity among patients with ostensibly similar clinical diagnoses—reflected in diverse inflammatory states, genetic backgrounds, and tissue degeneration patterns—necessitates patient stratification informed by molecular, genetic, and multi-omics biomarkers. These biomarkers not only enhance diagnostic accuracy but also improve prognostication and monitoring of therapeutic responses. Advanced imaging modalities such as T2 mapping, DTI, DCE-MRI, and molecular PET offer non-invasive quantification of tissue health and regenerative dynamics, further refining patient selection and treatment evaluation. Simultaneously, bioengineered delivery systems, including hydrogels, nanoparticles, and scaffolds, enable precise and sustained release of orthobiologic agents, optimizing therapeutic efficacy. Artificial intelligence and machine learning approaches are increasingly employed to integrate high-dimensional clinical, imaging, and omics datasets, facilitating predictive modeling and personalized treatment planning. Despite these advances, significant challenges persist—ranging from assay variability and lack of standardization to regulatory and economic barriers. Future progress requires large-scale multicenter validation studies, harmonization of protocols, and cross-disciplinary collaboration. By addressing these limitations, precision orthobiologics has the potential to deliver safer, more effective, and individualized care. This shift from generalized to patient-specific interventions holds promise for improving outcomes in degenerative and traumatic musculoskeletal disorders through a truly integrative, data-informed therapeutic framework.

Platelet-rich plasma (PRP) is widely used in regenerative medicine, yet clinical outcomes remain inconsistent. While traditional strategies have focused on platelet concentration and activation methods, emerging evidence suggests that the biological age of platelets, especially platelet senescence, may be a critical but overlooked factor influencing therapeutic efficacy. Senescent platelets display reduced granule content, impaired responsiveness, and heightened pro-inflammatory behavior, all of which can compromise tissue repair and regeneration. This review explores the mechanisms underlying platelet aging, including oxidative stress, mitochondrial dysfunction, and systemic inflammation, and examines how these factors influence PRP performance across diverse clinical contexts. We discuss the functional consequences of platelet senescence, the impact of comorbidities and aging on PRP quality, and current tools to assess platelet functionality, such as HLA-I–based flow cytometry. In addition, we present strategies for pre-procedural optimization, advanced processing techniques, and adjunctive therapies aimed at enhancing platelet quality. Finally, we challenge the prevailing emphasis on high-volume blood collection, highlighting the limitations of quantity-focused protocols and advocating for a shift toward biologically precise, function-driven regenerative interventions. Recognizing and addressing platelet senescence is a key step toward unlocking the full therapeutic potential of PRP-based interventions.

Red blood cells (RBCs) have traditionally been excluded from orthobiologic formulations due to inflammation, oxidative stress, and hemolysis concerns. However, emerging evidence suggests that RBCs may play an active role in regenerative medicine, contributing to immune modulation, vascular support, and oxidative balance. Their interactions with macrophages, involvement in nitric oxide signaling, and release of extracellular vesicles suggest they may influence tissue repair more than previously assumed. Despite these potential benefits, RBC retention in orthobiologic preparations like platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) remains controversial, with most protocols favoring their removal in the absence of robust translational clinical data. This review explores the biological functions of RBCs in regenerative medicine, their potential contributions to PRP and BMAC, and the challenges associated with their inclusion. While concerns about hemolysis and inflammation persist, controlled studies are needed to determine whether selective RBC retention could enhance musculoskeletal healing in some scenarios. Future research should focus on optimizing RBC processing techniques and evaluating their impact on clinical applications. Addressing these gaps will clarify whether RBCs represent an overlooked but valuable component in regenerative therapies or their exclusion remains justified.

Upper Crossed Syndrome (UCS), described by Vladimir Janda, is characterized by postural changes involving the cervical spine and trunk, leading to biomechanical limitations and cervicoscapulobrachial pain. This study proposes a mesotherapy protocol, termed the 8:1 block, to address cervicoscapulobrachialgia by targeting the scapulae and associated musculature. The scapula, central to shoulder girdle kinematics, often exhibits dyskinesis and muscular imbalances, notably the pattern referred to as scapular upper trapping (SUT). SUT involves scapular elevation, medial rotation, and shoulder protraction, contributing to cervicobrachial pain. The protocol includes a comprehensive assessment of muscle tone changes and biomechanical considerations, highlighting the importance of the scapula in upper limb movement and posture. Key anatomical changes involve tightened upper trapezius, levator scapulae, and pectoralis minor muscles, with weakened middle trapezius and serratus anterior. The mesotherapy approach targets these imbalances through specific injection points to alleviate muscle tension and correct postural deviations. Case studies from our clinic demonstrate the protocol’s effectiveness in reducing pain and restoring scapular biomechanics. Patients reported significant improvements in pain relief and functional outcomes, underscoring the clinical utility of the 8:1 block in treating cervicoscapulobrachialgia. This protocol offers a feasible, cost-effective intervention that enhances the efficacy of traditional therapeutic exercises by addressing underlying muscular and biomechanical dysfunctions. In conclusion, the 8:1 block mesotherapy protocol provides a novel approach to managing cervicoscapulobrachial pain by focusing on scapular biomechanics and muscle tension. Further studies are needed to validate these findings and refine the protocol for broader clinical application.

SDIMMMER is an acronym intended for use in both clinical practice and medical research. It facilitates a comprehensive evaluation of a patient’s metabolic profile and serves as a mnemonic for the following key assessment areas: Sleep, Diet, Microbiome, Metabolism, Medications, Exams, and Rehabilitation. In the clinical setting, SDIMMMER’s primary objective is to monitor and manage the patient’s metabolic status, particularly targeting low-grade chronic systemic inflammation, a hallmark of metabolic syndrome (MS). This inflammatory condition is characterized by elevated levels of circulating inflammatory cytokines and increased macrophage infiltration in peripheral tissues. SDIMMMER aims to enhance the effectiveness of ortho biological treatments by elevating growth factor levels, thereby enhancing patient outcomes. Additionally, SDIMMMER emphasizes guiding patients toward positive lifestyle changes to improve overall quality of life and foster a healthier metabolism. SDIMMMER introduces a patient metabolic profile quantification tool comprising 7 domains, totaling 35 items. Additionally, an instructional guide is provided to facilitate the application process. Its versatility spans various clinical and research domains, showcasing its potential to positively influence multiple fields.