Michael P. Grant

Articular cartilage has a limited capacity for self-repair due to its avascular nature, dense extracellular matrix, and low cellularity. Current treatments for cartilage injury and osteoarthritis (OA) often provide temporary symptom relief but do not restore native tissue structure or function. Intra-articular (IA) administration enables localized delivery of therapeutic agents; however, its effectiveness is limited by rapid clearance from the joint, poor cartilage penetration, and insufficient tissue retention. Controlled-release systems, including scaffolds, hydrogels, nanoparticles, and stimuli-responsive platforms, have been developed to address these barriers by prolonging local therapeutic exposure and enabling sustained or targeted delivery. Preclinical studies have demonstrated the potential of these systems to reduce inflammation and support cartilage protection and repair. However, clinical evidence remains limited, and further studies are required to determine whether these delivery advantages translate into sustained disease-modifying or regenerative outcomes in patients. This review discusses the biological barriers that limit effective IA delivery and summarizes recent advances in controlled-release strategies, with particular attention to their ability to improve joint retention, cartilage penetration, and sustained therapeutic exposure. The advantages and limitations of the different delivery platforms are critically discussed, together with the translational challenges that currently limit their progression from preclinical studies to clinical application.

Osteoarthritis (OA) is now widely recognized not merely as a cartilage-centric disease but as a multifactorial disorder affecting the entire joint as an organ, including the articular cartilage, subchondral bone, synovium, ligaments, menisci, and the innervating neural elements. This review explores the complex pathophysiology of OA with a focus on the emerging mechanisms of pain and inflammation that extend beyond articular cartilage degradation. Joint inflammation driven by immune activation in response to cellular stress signals promotes the release of pro-inflammatory mediators and catabolic enzymes. Key signaling pathways such as NF-κB, MAPKs, and JAK/STAT amplify these responses, and pain is sustained through peripheral and central sensitization, contributing to exacerbating symptoms even in the absence of visible joint damage. This review also integrates molecular and cellular mechanisms to highlight innovative therapies aimed at modifying both the structural damage and neurosensory drivers of pain. These approaches offer the potential to not only alleviate symptoms but also alter disease progression, signaling a move toward personalized, mechanism-based treatments. Given the intricate interactions among joint tissues, immune activation, and sensory processing, a comprehensive strategy that targets both structural degeneration and neuroinflammation is essential for the future of OA management. Emphasizing the joint as an integrated organ, we advocate for translational research linking molecular pathology with clinically meaningful outcomes.

Intervertebral disc (IVD) disease is typically characterized by the degradation of IVD tissue, secretion of inflammatory and painful factors, and hyperinnervation of the disc. The pro-inflammatory cytokine interleukin-1β (IL-1β) has been regarded as a principal factor in orchestrating disc degeneration. Link N (LN) is a peptide derived from the link protein that has been shown to promote extracellular disc regeneration even in an inflammatory milieu; however, no mechanism(s) has been described for their behaviour to date. Building on prior studies on LN, we hypothesize that LN directly inhibits IL-1β. IVD degeneration was experimentally induced in New Zealand white rabbits, followed by the injection of either sLN or saline as the vehicle control. To determine the expression of markers of pain, histology was performed. Cultured human Nucleus Pulposus disc cells (hNP) were used to determine the effects of LN on IL-1β-induced changes in gene expression, including the effects on IL-1β, TNFα, and IL6 signalling. Isolated murine dorsal root ganglia (DRG) neurons were used to assess the effect of LN on IL-1β-induced neuronal hyperactivity. LN significantly reduced IL-1β-induced NF-κB activation in a dose-dependent manner in disc cells and was further able to modulate IL-1β-induced gene expression, inflammatory mediators, and neurotrophic factors. Peptide docking simulations revealed that LN could interact with IL-1β. A direct interaction of LN and IL-1β was revealed through co-immunoprecipitation experiments. Although IL-1β was able to hypersensitize DRG neurons following a seven-day exposure, as demonstrated by Ca²⁺ imaging, this effect was significantly blunted when co-treated with LN. LN demonstrates a novel mechanism of action by directly inhibiting IL-1β, in addition to mitigating IL-1β-induced hypersensitivity in DRG neurons. These data suggest a potential role for LN in reducing discogenic pain.

Emerging evidence indicates periostin (POSTN) is upregulated in patients with OA, and studies have shown that it can induce the activation of inflammatory cytokines and catabolic enzymes, making it a potential therapeutic target. Link N (LN) is a peptide fragment derived from the link protein and has been demonstrated as an anabolic-like factor and anti-catabolic and anti-inflammatory factors both in vitro and in vivo. This study aims to determine if LN can regulate POSTN expression and function in OA cartilage. Articular cartilage was recovered from donors undergoing total knee replacements to isolate chondrocytes and prepare osteochondral explants. Cells and explants were treated with POSTN and LN (1 and 100 μg) and measured for changes in POSTN expression and various matrix proteins, catabolic and proinflammatory factors, and signaling. To determine the effects of POSTN expression in vivo, a rabbit OA model was used. Immunoprecipitation and in silico modeling were used to determine peptide/POSTN interactions. Western blotting, PCR, and immunohistochemistry demonstrated that LN decreased POSTN expression both in vitro and in vivo. LN was also able to directly inhibit POSTN signaling in OA chondrocytes. In silico docking suggested the direct interaction of LN with POSTN at residues responsible for its oligomerization. Immunoprecipitation experiments confirmed the direct interaction of LN with POSTN and the destabilization of its oligomerization. This study demonstrates the ability of a peptide, LN, to suppress the overexpression and function of POSTN in OA cartilage.

Intervertebral disc degeneration and pain are associated with the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome activation and the processing of interleukin-1 beta (IL-1β). Activation of thehm inflammasome is triggered by Toll-like receptor stimulation and requires the cofactor receptor cluster of differentiation 14 (CD14). Short Link N (sLN), a peptide derived from link protein, has been shown to modulate inflammation and pain in discs in vitro and in vivo; however, the underlying mechanisms remain elusive. This study aims to assess whether sLN modulates IL-1β and inflammasome activity through interaction with CD14. Disc cells treated with lipopolysaccharides (LPS) with or without sLN were used to assess changes in Caspase-1, IL-1β, and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Peptide docking of sLN to CD14 and immunoprecipitation were performed to determine their interaction. The results indicated that sLN inhibited LPS-induced NFκB and Caspase-1 activation, reducing IL-1β maturation and secretion in disc cells. A significant decrease in inflammasome markers was observed with sLN treatment. Immunoprecipitation studies revealed a direct interaction between sLN and the LPS-binding pocket of CD14. Our results suggest that sLN could be a potential therapeutic agent for discogenic pain by mitigating IL-1β and inflammasome activity within discs.

Purpose: Self-inflicted facial gunshots (SIGSWs) typically result in a spectrum of severe injuries to facial structures, including the orbit and globe. Roughly three-quarters of those who arrive to the hospital will survive their injuries, and recidivism is typically low. Therefore, effective management is paramount to preserve vision, and long-term quality of life. The objective of this study is to characterize the common injuries to the orbit, globe, and periocular structures following SIGSWs, their management, and their eventual visual and reconstructive outcomes. Methods: Retrospective review of trauma registry records at a Level 1 trauma center for patients who presented alive following SIGSWs involving the globe and/or orbit from 2007 to 2016. Results: Of the 47 patients who presented with SIGSWs to the orbit, 33 (70%) were discharged alive from the hospital. Management strategies for these patients fell into 3 groups, based on the involved structures: i) Open globe injuries (Type I: n = 12, 34%) ii) Orbital fractures with preserved globe and optic nerve (Type II: n = 15, 43%), and iii) Optic nerve injuries with preserved globe (Type III: n = 8, 23%). Compared with Type II and III injuries, patients who had Type I injuries were more likely to die prior to hospital discharge (46% vs. 20% vs. 12%, p = 0.04), undergo ophthalmologic intervention (73% vs. 6% vs. 11%, p = 0.01), and more surgery (6 vs. 3 vs. 0.5 mean surgeries, p < 0.001). Type II injuries most frequently underwent debridement and reconstruction of the bony orbit. Type III and Type I injuries were associated with worse initial and final visual acuity, with the majority (100% and 75%, respectively) having No Light Perception (NLP) on initial exam, and no visual recovery during the follow-up period (median follow up= 25 months). Conclusions: Management and visual outcomes of orbital injuries from SIGSWs is determined by whether the globe and optic nerve are preserved. Open globe injury by itself is associated with higher mortality and significant permanent vision loss.

INTRODUCTION: Osteoarthritis (OA) is a degenerative joint disease characterized by a slowly progressive degradation of articular cartilage, Incre |