Ronald J. Kulich

Micro-fragmented adipose tissue (mFAT) is a promising autologous biologic in regenerative medicine because it provides a mechanically processed adipose-derived product that preserves native extracellular matrix architecture and a cellular milieu rich in mesenchymal stem cells, pericytes, growth factors, cytokines, and extracellular vesicles. Mechanistically, mFAT is hypothesized to act largely through paracrine signaling that dampens inflammation, supports vascular stabilization, and promotes cartilage and soft-tissue repair; in vitro data suggest modulation of osteoarthritic synovial macrophage signaling, including reductions in chemokines such as CCL2 and CCL3. Preparation involves liposuction harvest followed by closed, sterile mechanical processing without enzymatic digestion or cell expansion, aligning with “minimal manipulation” concepts relevant to regulatory frameworks. Preclinical animal studies generally demonstrate favorable effects on synovial inflammation and cartilage matrix markers (e.g., glycosaminoglycan content) with limited adverse events. Clinically, the strongest body of evidence is in knee osteoarthritis, where multiple prospective and retrospective studies report improvements in pain and function from months to several years after single injections, though response rates vary and study designs are heterogeneous. Evolving data support potential benefit in hip osteoarthritis and select tendon conditions, but cohorts remain small. Overall, mFAT appears safe and potentially effective, yet larger, standardized, long-term randomized controlled trials and comparative studies versus platelet-rich plasma and bone marrow aspirate concentrates are needed to clarify indications, dosing, durability, and mechanisms in vivo.

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.

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.

Platelet-rich plasma (PRP) is a commonly used intra-articular therapy for knee osteoarthritis (OA), yet substantial heterogeneity in PRP preparation and delivery limits comparability across trials and complicates clinical translation. We conducted a scoping review in accordance with PRISMA and PRISMA-ScR guidance. MEDLINE and Embase were searched from inception to 15 November 2025 for English-language randomized controlled trials comparing PRP with non-regenerative comparators (e.g., hyaluronic acid, corticosteroids, radiofrequency ablation, or saline placebo) in adults with knee OA. Data were charted on study characteristics, OA severity, injection guidance, centrifugation protocols, injected PRP volume and platelet concentration, dosing regimens, follow-up, adverse events, and overall conclusions (superior/non-inferior/inferior). Twenty-one studies (2012–2025) were included, spanning multiple regions and enrolling 21–288 participants per study with follow-up from 12 weeks to 60 months. PRP protocols varied widely, including single- versus double-spin centrifugation, spin rates and durations, injected volumes (approximately 1.4–8 mL), and platelet enrichment (approximately 1.15x to 9.85x baseline when reported). The most common regimen was three injections, typically weekly. Across studies, major adverse events were not reported, and post-injection pain or transient synovitis/effusion were the most frequent events. PRP for knee OA is generally safe and frequently demonstrates comparable or improved outcomes versus standard injectables, but marked protocol heterogeneity persists. Standardized reporting and consensus parameters for PRP preparation and administration are needed to improve reproducibility and guide evidence-based practice.

Micro-fragmented adipose tissue (mFAT) is a promising autologous biologic in regenerative medicine because it provides a mechanically processed adipose-derived product that preserves native extracellular matrix architecture and a cellular milieu rich in mesenchymal stem cells, pericytes, growth factors, cytokines, and extracellular vesicles. Mechanistically, mFAT is hypothesized to act largely through paracrine signaling that dampens inflammation, supports vascular stabilization, and promotes cartilage and soft-tissue repair; in vitro data suggest modulation of osteoarthritic synovial macrophage signaling, including reductions in chemokines such as CCL2 and CCL3. Preparation involves liposuction harvest followed by closed, sterile mechanical processing without enzymatic digestion or cell expansion, aligning with “minimal manipulation” concepts relevant to regulatory frameworks. Preclinical animal studies generally demonstrate favorable effects on synovial inflammation and cartilage matrix markers (e.g., glycosaminoglycan content) with limited adverse events. Clinically, the strongest body of evidence is in knee osteoarthritis, where multiple prospective and retrospective studies report improvements in pain and function from months to several years after single injections, though response rates vary and study designs are heterogeneous. Evolving data support potential benefit in hip osteoarthritis and select tendon conditions, but cohorts remain small. Overall, mFAT appears safe and potentially effective, yet larger, standardized, long-term randomized controlled trials and comparative studies versus platelet-rich plasma and bone marrow aspirate concentrates are needed to clarify indications, dosing, durability, and mechanisms in vivo.

Purpose: Chronic orofacial pain (COP) is associated with substantial pain interference and emotional distress. Psychosocial treatments for COP are scarce, rely on talking, which is often painful for this population, and require intensive resources. There is a clear need for a novel, scalable, accessible, “talk free” intervention to reduce pain interference and emotional distress among individuals with COP. This study explored people with COP’s perceptions of a novel mind-body web-based intervention targeting pain interference and emotional distress (Face-Forward-Web) to inform its development and optimization. Patients and Methods: We conducted semi-structured focus groups (N=4 groups, 22 participants; 77% female; mean age 47 (SD = 15.9)) and used Rapid Data Analysis (RDA) to gauge perceptions of the intervention’s content structure, format, and barriers and facilitators to participation. Results: Perception of the intervention was largely positive, and participants perceived its value for increasing engagement in life activities. They emphasized the importance of tailoring the intervention to the unique characteristics of COP. They expressed that the self-paced web-based format was ideal given unpredictable pain flares and variable needs. Concurrently, they desired social connection. They perceived the content and skills as helpful and relaxing. They identified barriers and facilitators to participation, including technical considerations, reminders and incentives, and providers setting up realistic expectations for outcomes. Conclusion: This study elucidates insights that can inform psychosocial and mind-body interventions for people with COP. Findings give voice to the needs and perceptions of people with COP, guiding the development of tailored, patient-informed treatment approaches such as Face-Forward-Web.

Background: Chronic orofacial pain (COP) is common, costly, and associated with substantial pain interference and emotional distress. Psychosocial treatments for COP are scarce and limited (eg, rely on talking, which is often painful for this population; require intensive resources, limiting scalability). Here, we describe the study protocol for developing Face-Forward-Web, a “talk-free” web-based mind-body intervention for patients with COP. Objective: We aim to (1) develop Face-Forward-Web with the aid of live-video focus groups with adults with COP and (2) optimize Face-Forward-Web and our study protocol through beta testing followed by an open feasibility trial. Methods: We will accomplish these aims in 2 phases, incorporating user-centered design principles. For phase 1, we conducted semistructured focus groups (n=4 groups, 22 participants) with individuals with COP. We are using rapid data analysis followed by thematic analysis to gauge treatment needs, preferences, and perceptions of the proposed platform and skills. This information will inform session structure and content as well as development of a wireframe followed by a prototype. For phase 2, we will conduct beta testing (up to n=10) followed by a feasibility trial (up to n=20) with exit interviews to gather feedback. The primary outcomes are feasibility benchmarks such as recruitment (≥70% of the eligible participants will participate), acceptability (≥70% of the participants complete ≥4 or 5 sessions), credibility, expectancy (≥70% above the Credibility and Expectancy scale’s midpoint), and satisfaction (≥70% above the User Experience Questionnaire’s midpoint). Results: Recruitment for phase 1 began in October 2024 and concluded in January 2025. Data analysis for phase 1 will conclude in fall 2025 and for phase 2 in 2026. Results will iteratively guide the development of the intervention. Conclusions: Face-Forward-Web will be the first talk-free web-based intervention tailored to the needs of adults with COP. Results will inform a future efficacy trial. Trial Registration: ClinicalTrials.gov NCT06754917; https://clinicaltrials.gov/study/NCT06754917 International Registered Report Identifier (IRRID): DERR1-10.2196/71839

BACKGROUND Chronic orofacial pain (COP) is common, costly, and associated with substantial pain interference and emotional distress. Psychosocial treatments for COP are scarce and limited (eg, rely on talking, which is often painful for this population; require intensive resources, limiting scalability). Here, we describe the study protocol for developing Face-Forward-Web, a “talk-free” web-based mind-body intervention for patients with COP. OBJECTIVE We aim to (1) develop Face-Forward-Web with the aid of live-video focus groups with adults with COP and (2) optimize Face-Forward-Web and our study protocol through beta testing followed by an open feasibility trial. METHODS We will accomplish these aims in 2 phases, incorporating user-centered design principles. For phase 1, we conducted semistructured focus groups (n=4 groups, 22 participants) with individuals with COP. We are using rapid data analysis followed by thematic analysis to gauge treatment needs, preferences, and perceptions of the proposed platform and skills. This information will inform session structure and content as well as development of a wireframe followed by a prototype. For phase 2, we will conduct beta testing (up to n=10) followed by a feasibility trial (up to n=20) with exit interviews to gather feedback. The primary outcomes are feasibility benchmarks such as recruitment (≥70% of the eligible participants will participate), acceptability (≥70% of the participants complete ≥4 or 5 sessions), credibility, expectancy (≥70% above the Credibility and Expectancy scale’s midpoint), and satisfaction (≥70% above the User Experience Questionnaire’s midpoint). RESULTS Recruitment for phase 1 began in October 2024 and concluded in January 2025. Data analysis for phase 1 will conclude in fall 2025 and for phase 2 in 2026. Results will iteratively guide the development of the intervention. CONCLUSIONS Face-Forward-Web will be the first talk-free web-based intervention tailored to the needs of adults with COP. Results will inform a future efficacy trial. CLINICALTRIAL ClinicalTrials.gov NCT06754917; https://clinicaltrials.gov/study/NCT06754917 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/71839

The Lyceum for Pain Education: Providing Accessible Education on Chronic Pain and Headaches to a Global Audience