Franzes Anne Z. Liongson

As the population ages, the incidence and prevalence of musculoskeletal degeneration, such as osteoarthritis, increase. While the currently accepted treatment options provide symptomatic and functional improvement, they do not halt the progression of osteoarthritis. This results in the eventual need for surgery for many patients with advanced osteoarthritis. Due to the seemingly inevitable progression of OA, many clinicians and researchers have shifted their focus to regenerative therapies. Orthobiologics, a specific type of regenerative therapy designed to treat orthopedic conditions, has been gaining traction in recent years due to the utilization of autologous biological substances and synthetic peptides in healing musculoskeletal injuries and degenerative conditions. Orthobiologics can be distinguished into one of four classes: cell-based, biologic fluids-based, matrix-based, molecular-based, and based on their composition. In this review, key examples of each class, mechanism of action, and current clinical data for each agent are examined. Limitations of current orthobiologics involve a lack of standardization in the preparation and administration of each agent, as well as uniformity in assessment endpoints across different clinical studies. Lastly, we will discuss future directions of orthobiologics as a therapy for the treatment of osteoarthritis.

Opioids remain central to managing moderate to severe pain, yet they also produce significant and often under-recognized effects on the immune system. In this narrative review, we synthesize evidence from 1994 to 2025 across preclinical, translational, observational, and limited interventional studies in adults to examine how different opioid classes modulate immunity and the clinical relevance of these effects. Opioids act directly on immune cells via mu-opioid receptors (MORs), nociceptin/orphanin FQ receptors (NOR), and Toll-like receptor 4 (TLR4), and indirectly through neuroendocrine, autonomic, neuroinflammatory, and gut microbiota-mediated pathways. Immunologic consequences are drug specific: Morphine, fentanyl, and to a lesser extent methadone exhibit pronounced immunosuppressive profiles; oxycodone appears comparatively less suppressive; and buprenorphine and tramadol generally preserve, and may in some contexts enhance, immune function. Clinically, chronic or intensive opioid exposure is associated with increased risk of infection and sepsis-related mortality, potential facilitation of tumor progression or recurrence, impaired perioperative and transplant outcomes, and contributions to tolerance and opioid-induced hyperalgesia, with convergent data indicating these immune effects are intrinsic to opioid pharmacology. Framing opioid-induced immunomodulation as a clinically meaningful, agent-specific phenomenon argues for incorporating immunologic risk into analgesic selection—prioritizing less immunosuppressive opioids where appropriate, considering rotation and tapering strategies, using peripherally acting antagonists, and implementing multimodal analgesia—while underscoring the need for standardized immunologic endpoints, rigorously controlled clinical studies, and development of next-generation analgesics that maintain effective pain relief while minimizing detrimental immune effects.

Craniofacial and corneal neuropathic pain are disabling conditions characterized by persistent pain that is frequently refractory to conventional pharmacologic and interventional therapies. These disorders arise from complex interactions between peripheral nerve injury, neuroinflammation, and maladaptive central sensitization within trigeminal pathways, features that span neuropathic and nociplastic pain mechanisms as defined by the International Association for the Study of Pain, thus emphasizing the need for mechanism-based, patient-stratified treatment strategies. Regenerative medicine offers a paradigm shift from symptom suppression toward structural nerve repair and functional restoration. This narrative review examines the pathophysiological mechanisms underlying craniofacial and corneal neuropathic pain and critically evaluates emerging regenerative therapies, including autologous biologics (autologous serum tears and platelet-rich plasma), mesenchymal stem cells and their derivatives, exosomes and extracellular vesicles, and neurotrophic peptides. Particular emphasis is placed on corneal neuropathic pain as a translational model, given the cornea’s dense sensory innervation and the ability to non-invasively quantify nerve regeneration using in vivo confocal microscopy as an objective biomarker of treatment response. Clinical evidence across regenerative modalities varies by indication: cenegermin has demonstrated robust efficacy and regulatory approval for neurotrophic keratitis, while platelet-rich plasma shows growing evidence in temporomandibular disorders, myofascial pain, and occipital neuralgia. Cell-based and cell-free therapies demonstrate strong preclinical promise but remain limited by heterogeneous protocols and a paucity of large-scale randomized trials. Key barriers to translation include regulatory uncertainty, lack of standardized outcome measures, and workforce and implementation challenges. Advancing regenerative therapies for craniofacial and corneal neuropathic pain will require rigorous clinical trials, biomarker-driven patient selection, and multidisciplinary collaboration. Sex as a biological variable remains underexplored across all regenerative modalities and represents a priority for future research.

As the population ages, the incidence and prevalence of musculoskeletal degeneration, such as osteoarthritis increases. While the currently accepted treatment options provide symptomatic and functional improvement, they do not halt the progression of osteoarthritis. This results in eventual need for surgery for many patients with advanced osteoarthritis. Due to seemingly inevitable progression of OA, many clinicians and researchers have shifted their focus to regenerative therapies. Orthobiologics, a specific type of regenerative therapy designed to treat orthopedic conditions, have been gaining traction in recent years due to utilization of autologous biological substances and synthetic peptides in healing in musculoskeletal injuries and degenerative conditions. Orthobiologics can be distinguished into one of four classes: cell-based, biologic fluids-based, matrix-based and molecular-based, and based on its composition. In this review, key examples of each class, mechanism of action, and current clinical data for each agent are examined. Limitations of current orthobiologics involve lack of standardization in preparation and administration each agent as well as uniformity in assessment end points across different clinical studies. Lastly, we will discuss future directions of orthobiologics as a therapy for treatment in osteoarthritis.