Tristan März

Last Name

März

First Name

Tristan

ORCID

0000-0002-4523-6012

Organisational unit

09862 - März, Tristan / März, Tristan

Show all metadata

Search Results

Publications 1 - 10 of 75

siRNA conjugate with high albumin affinity and degradation resistance for delivery and treatment of arthritis in mice and guinea pigs
Colazo, Juan M.; Keech, Megan C.; Shah, Veeraj; et al. (2025)
Nature Biomedical Engineering
Osteoarthritis and rheumatoid arthritis are debilitating joint diseases marked by pain, inflammation and cartilage destruction. Current osteoarthritis treatments only relieve symptoms, while rheumatoid arthritis therapies can cause immune suppression and provide variable efficacy. Here we developed an optimized small interfering RNA targeting matrix metalloproteinase 13 for preferential delivery to arthritic joints. Chemical modifications in a stabilizing zipper pattern improved RNA resistance to degradation, and two independent linkers with 18 ethylene glycol repeats connecting to tandem C18 lipids enhanced albumin binding and targeted delivery to inflamed joints following intravenous administration. In preclinical models of post-traumatic osteoarthritis and rheumatoid arthritis, a single intravenous injection of the albumin-binding small interfering RNA achieved long-term joint retention, sustained gene silencing and reduced matrix metalloproteinase 13 activity over 30days, resulting in decreased cartilage erosion and improved clinical outcomes, including reduced joint swelling and pressure sensitivity. This approach demonstrated superior efficacy over corticosteroids and small-molecule MMP inhibitors, highlighting the therapeutic promise of albumin hitchhiking for targeted, systemic delivery of gene-silencing therapeutics to treat osteoarthritis and rheumatoid arthritis.
Cross-platform transcriptomic data integration of human osteoarthritis synovium
Newton, Michael D.; Swahn, Hannah; Orange, Dana E.; et al. (2025)
Osteoarthritis and Cartilage
Objective Chronic synovitis is associated with osteoarthritis (OA) pain, but the molecular underpinnings remain unclear. Our objective was to characterize the transcriptional phenotype of OA synovium with a focus on signaling relevant to pain. Design Eight publicly-available microarray and RNA-sequencing GEO datasets from human non-OA and OA subjects underwent quality control and re-analysis for differentially-expressed genes (DEGs). Cross-platform statistical integration was performed via a weighted Z-test to combine detection power across datasets. Gene set enrichment, cell type enrichment, and regulon analyses were performed. Human single-cell RNA sequencing data was used to map gene expression to cell types. Ligand-receptor interactions were predicted via multi-omic data from human dorsal root ganglia (DRG). Results Following statistical integration of individual studies (N=153 total subjects, N=139 after quality control), gene set enrichment analysis identified 276 differentially-activated pathway terms in OA synovium, including strong enrichment for pathways related to innate and adaptive immunity (notably MHC Class II) and fibrotic remodeling-relevant extracellular matrix organization. VEGF signaling and angiogenesis-related terms were downregulated. Enriched pain and neuronal pathways primarily related to neuro-immune interactions, including neuroinflammation, and were associated with macrophages, B and T lymphocytes, and synovial fibroblasts. A gene regulatory network comprised of STAT1, FLI1, and VDR putatively governed the expression of 27 genes driving neuro-immune signaling. An unbiased synovium-DRG interactome predicted 76 potential interactions between synovial cells and DRG nociceptors, involving 68 neuronal receptors interacting with 32 ligands overexpressed in OA synovium. Conclusions End-stage OA synovium is markedly enriched for neuroinflammatory and neuro-immune signaling, putatively governed by STAT1, FLI1, and VDR. Introduction Synovitis is an integral component of osteoarthritis (OA) pathogenesis and is recognized as both a downstream consequence of cartilage and bone damage as well as a driver of multiple disease processes, notably cartilage breakdown and pain [1]. Clinically, MRI-based effusion-synovitis scoring has been predictive of future cartilage loss [2], synovitis severity has been associated with overall greater risk of incident OA [3], and multiple studies have demonstrated strong associations between imaging-based synovitis and pain [4], [5], [6], [7]. Despite this evidence linking synovitis to OA symptoms and disease progression, OA treatments targeting inflammatory mediators have been unsuccessful thusfar [8], [9], [10], indicating that the current understanding of the nature of synovitis in OA is insufficient for effective therapeutic development. Synovitis in OA manifests as lining layer hyperplasia, increased immune cell content, fibrosis, increased blood vessel density and vascular damage, and increased nociceptor density and sprouting [1], [11]. The understanding of various synovitis “endotypes” in OA, and arthritis as a whole, is rapidly evolving, and recent evidence supports the existence of arthritis subsets with varying degrees of inflammation, structural damage, and extracellular matrix (ECM) and vascular changes [12], [13]. Philpott and colleagues recently showed that histologically-characterized synovial tissue damage score (i.e. lining erosion, fibrosis, vascular damage, and perivascular edema) correlated with patient-reported pain, whereas histological synovial tissue inflammation score (i.e. synovial lining thickness, sub-synovial infiltrate, vascularization, presence of fibrin) did not [11], indicating a high degree of arthritic synovial disease heterogeneity marked by varying patterns of symptoms, imaging findings, and tissue-level phenotypes. Transcriptomic studies have significantly expanded knowledge of the genes and pathways underlying cell- and tissue-level manifestations of OA [14], [15]. Synovial gene signatures indicative of higher fibrosis, myeloid cell content/cytokine expression, senescence, and blood vessel content have been identified [14], [15]; however, these studies also demonstrate the heterogeneous nature of the synovial OA transcriptome arising from disease heterogeneity, biopsy inconsistencies, technical/analytical differences, and other factors. To gain a greater understanding of the human OA synovial transcriptome, meta-analysis presents an opportunity to leverage the combined statistical power of several transcriptomic datasets. Utilizing specialized statistical approaches to integrate data across studies, OA-associated gene and pathway enrichment may be detected with greater statistical confidence and detection power than any individual study, potentially enabling the discovery of previously unidentified genes or pathways. By employing a larger, more diverse subject pool across multiple sites, meta-analyses may also generate a more clinically-representative, generalizable understanding of disease states. To date, no study has performed a cross-platform transcriptomic meta-analysis of OA synovium. Two prior studies reanalyzed microarray datasets in OA synovium: Liu et al. analyzed five microarray datasets encompassing 41 normal and 45 OA synovial tissue samples [16], and seven genes (SLC2A3, CDKN1A, FOXB, TAC1, STMN2, SCRG1, NELL1) were found to be differentially-expressed across datasets. However, this study did not perform formal statistical integration, focusing only on overlapping genes across studies, which limits detection power. Xu et al. merged two microarray datasets encompassing 20 non-OA and 26 OA synovium samples, identifying 46 DEGs [17], but this data represents only a fraction of the more extensive RNA-sequencing data now available from non-OA and OA synovium. Limited information currently exists regarding the neurotrophic and proalgesic mediators overexpressed in OA synovium. Neuro-immune interactions (immune cell-derived ligands interacting with receptors expressed by nociceptors) have received increasing attention in this context [18], [19], and synovial fibroblasts are also emerging as important mediators of proalgesic signaling in arthritis [20], [21], but this has been minimally explored in the context of OA synovium. Given the strong clinical association between OA pain and synovitis, this represents an opportunity to leverage existing transcriptomics datasets to identify pain-relevant transcriptional signatures, providing a robust assessment of overall OA pathogenesis while also identifying potential targets for pain therapeutics. To this end, we conducted a cross-platform transcriptomic meta-analysis to generate a reference atlas for OA synovium, followed by utilization of this dataset to unbiasedly identify OA-associated genes and pathways involved in neuro-immune and pain-relevant pathways as well as synovium-neuron interactions.
Pharmacologic Mobilization and Chemokine-Directed Recruitment of Mesenchymal Stromal Cells to the Surgically Repaired Rotator Cuff
Baker, Kevin C.; Fleischer, Mackenzie; Newton, Michael D.; et al. (2025)
The American Journal of Sports Medicine
Background: Mesenchymal stromal cell (MSC) techniques represent a promising method to enhance the surgical repair of rotator cuff tears. To eliminate the resource-intensive process of cell isolation and culture expansion, a method to recruit endogenous MSCs was investigated in an established rat model of rotator cuff repair. Hypothesis: MSCs can be pharmacologically mobilized from the peripheral blood and recruited to the operative rotator cuff to enhance tendon-bone healing. Study Design: Controlled laboratory study. Methods: The rat model of supraspinatus tendon detachment and acute surgical repair was used to compare the ability of 3 different chemokines (SDF-1β, MIP-3α, and MCP-1) to recruit optically labeled MSCs to the operative shoulder from circulation. Additional experimentation was undertaken to assess the effects of pharmacological MSC mobilization using a combination of a β₃ adrenoreceptor agonist (BRL37344) and a CXCR4 antagonist (AMD3100) on chemokine-directed recruitment to the shoulder. Finally, the effects of this therapeutic strategy on tendon-bone healing were assessed. Results: MCP-1-loaded hydrogels recruited the greatest number of MSCs from circulation. MCP-1-driven MSC recruitment was significantly enhanced by a regimen of subcutaneous BRL37344 and AMD3100. Postmortem micro-computed tomography imaging performed at a 6-week endpoint revealed that local MCP-1 delivery was associated with significant reductions in trabecular spacing and apparent mineral density, and a significant increase in trabecular number, while pharmacological MSC mobilization had no significant effects. MCP-1 delivery was associated with a lower tendon cross-sectional area and a significant increase in percent relaxation (P = .006). Pharmacological MSC mobilization was associated with significantly increased peak stress (P = .039), significantly increased elastic modulus (P = .037), and a nonsignificant increase in both equilibrium stress (P = .057) and ultimate stress (P = .058). Local MCP-1 delivery was associated with significant improvements in tenocyte morphology. Conclusion: Endogenous MSCs can be pharmacologically mobilized into peripheral blood and recruited to the site of rotator cuff repair via local delivery of MCP-1. This therapeutic strategy was associated with improvements in the static and dynamic mechanical properties of the tendon-bone interface. Clinical Relevance: The healing of rotator cuff repairs represents an ongoing clinical challenge in orthopaedic surgery. This study demonstrates a method to use endogenous MSCs to enhance healing of the rotator cuff.
CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis
Lammlin, Lindsey; Redding, Stephen; Knights, Alexander J.; et al. (2025)
bioRxiv
Abstract This study investigates the role of the chemokine CXCL16 and its receptor, CXCR6, in post-traumatic osteoarthritis (PTOA) and joint nociception, highlighting the potential of targeting the CXCL16-CXCR6 axis for therapeutically managing joint inflammation and pain. Following joint injury in mice, the CXCL16-CXCR6 signaling axis is activated in synovium, driven by synovial fibroblasts and macrophages. Human OA synovium also exhibited increased CXCL16 and CXCR6 gene expression. CXCL16 stimulated a pro-inflammatory response in fibroblasts and macrophages, contrasting with an anti-inflammatory response observed in mesenchymal progenitor cells. In mice, repeated intra-articular CXCL16 injections induced histological synovitis and sex-dependent activation of inflammatory and fibrotic transcriptional programs in synovium. Repeated CXCL16 joint injections also induced knee hyperalgesia, which was mitigated by co-administration of the CXCR6 antagonist, ML339. A single intra-articular injection of CXCL16 induced acute knee hyperalgesia as early as 30 minutes post-injection, which was completely abrogated by ML339 co-treatment, suggesting direct CXCL16 binding to nociceptor-expressed CXCR6. In a murine PTOA model, systemic CXCR6 antagonism with ML339 alleviated knee hyperalgesia and altered circulating immune cell profiles. Direct stimulation of mouse dorsal root ganglion-derived nociceptive neurons with CXCL16 induced rapid calcium signaling, which was abolished by co-treatment with ML339. These findings establish CXCL16 as a regulator of joint inflammation and identifies the CXCL16-CXCR6 binding mechanism as key in mediating pain-related behaviors and nociceptor activation, offering a therapeutic target for PTOA-related inflammation and pain management.
Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis
Knights, Alexander J.; Farrell, Easton C.; Ellis, Olivia M.; et al. (2025)
eLife
Synovium is home to immune and stromal cell types that orchestrate inflammation following a joint injury; in particular, macrophages are central protagonists in this process. We sought to define the cellular and temporal dynamics of the synovial immune niche in a mouse model of post-traumatic osteoarthritis (PTOA), and to identify stromal-immune crosstalk mechanisms that coordinate macrophage function and phenotype. We induced PTOA in mice using a non-invasive tibial compression model of anterior cruciate ligament rupture (ACLR). Single-cell RNA-sequencing and flow cytometry were used to assess immune cell populations in healthy (Sham) and injured (7 and 28 days post-ACLR) synovium. Characterization of synovial macrophage polarization states was performed, alongside computational modeling of macrophage differentiation, as well as implicated transcriptional regulators and stromal-immune communication axes. Immune cell types are broadly represented in healthy synovium, but experience drastic expansion and speciation in PTOA, most notably in the macrophage portion. We identified several polarization states of macrophages in synovium following joint injury, underpinned by distinct transcriptomic signatures, and regulated in part by stromal-derived macrophage colony-stimulating factor signaling. The transcription factors Pu.1, Cebpα, Cebpβ, and Jun were predicted to control differentiation of systemically derived monocytes into pro-inflammatory synovial macrophages. In summary, we defined different synovial macrophage subpopulations present in healthy and injured mouse synovium. Nuanced characterization of the distinct functions, origins, and disease kinetics of macrophage subtypes in PTOA will be critical for targeting these highly versatile cells for therapeutic purposes.
Macrophage-mediated PDGF Activation Correlates With Regenerative Outcomes Following Musculoskeletal Trauma
Chowdary, Ashish R.; März, Tristan; Henn, Dominic; et al. (2023)
Annals of Surgery
Objective: Our objective was to identify macrophage subpopulations and gene signatures associated with regenerative or fibrotic healing across different musculoskeletal injury types. Background: Subpopulations of macrophages are hypothesized to fine tune the immune response after damage, promoting either normal regenerative, or aberrant fibrotic healing. Methods: Mouse single-cell RNA sequencing data before and after injury were assembled from models of musculoskeletal injury, including regenerative and fibrotic mouse volumetric muscle loss (VML), regenerative digit tip amputation, and fibrotic heterotopic ossification. R packages Harmony , MacSpectrum , and Seurat were used for data integration, analysis, and visualizations. Results: There was a substantial overlap between macrophages from the regenerative VML (2mm injury) and regenerative bone models, as well as a separate overlap between the fibrotic VML (3mm injury) and fibrotic bone (heterotopic ossification) models. We identified 2 fibrotic-like (FL 1 and FL 2) along with 3 regenerative-like (RL 1, RL 2, and RL 3) subpopulations of macrophages, each of which was transcriptionally distinct. We found that regenerative and fibrotic conditions had similar compositions of proinflammatory and anti-inflammatory macrophages, suggesting that macrophage polarization state did not correlate with healing outcomes. Receptor/ligand analysis of macrophage-to-mesenchymal progenitor cell crosstalk showed enhanced transforming growth factor β in fibrotic conditions and enhanced platelet-derived growth factor signaling in regenerative conditions. Conclusion: Characterization of macrophage subtypes could be used to predict fibrotic responses following injury and provide a therapeutic target to tune the healing microenvironment towards more regenerative conditions.
Patient-Perceived Outcomes Improve Faster Than Hip Strength in Recovery After Surgical Correction for Symptomatic Femoroacetabular Impingement
Konnaris, Maxwell A.; Junginger, Lucas M.; Sibilsky Enselman, Elizabeth R.; et al. (2023)
HSS Journal: The Musculoskeletal Journal of Hospital for Special Surgery
Background: Patients with symptomatic femoroacetabular impingement (FAI) have hip strength deficits, instability, and increased risk for concomitant injury. While surgical intervention is an effective method of treatment for FAI, more information is needed about the recovery process. Purposes: We sought to understand how patients with FAI recover from surgical correction in the short term. Do patients' perceptions of improvement correspond with measured improvements in hip strength? Methods: We conducted a prospective cohort study of 17 patients (11 male, age range: 16-38 years) who were diagnosed with symptomatic FAI at a single surgeon's practice. Hip strength (flexion, extension, and abduction) was measured preoperatively and at 14, 26, and 52 weeks postoperatively. Patient-reported outcomes using the modified Harris Hip Score (mHHS) and Hip Outcome Osteoarthritis Score (HOOS) subscales were measured at the same time points and at 2 weeks postoperatively. Results: Compared with preoperative values, there was a significant increase in postoperative values at 26 and 52 weeks in normalized isokinetic hip extension (29% and 38%, respectively) and normalized hip abduction (48% and 55%, respectively). No differences in strength were observed at 14 weeks. Modified Harris Hip Score and all HOOS subscales were decreased by 2 weeks postoperatively, and by 14 weeks mHHS improved by 21%, and HOOS subscales improved as well (activities of daily living by 18%, pain by 34%, quality of life by 69%, sport and recreation by 36%, and symptoms by 28%). Conclusion: We observed that patient-reported outcomes including symptoms, function, and satisfaction improved at 14 weeks, while objective measures of hip strength improved at 26 weeks following surgical correction of FAI. More rigorous study is indicated.
Arthroscopic suture bridge rotator cuff repair: functional outcome, repair integrity, and preoperative factors related to postoperative outcome
Rimmke, Nathan; März, Tristan; Cooper, Ross; et al. (2016)
The Physician and Sportsmedicine
Objectives: To assess the retear rate, retear size and location, the clinical impact of a retear, and preoperative patient factors related to postoperative outcome after arthroscopic suture bridge rotator cuff repair. Methods: Fifty six patients with an isolated, full-thickness supraspinatus tendon tear who underwent arthroscopic suture bridge rotator cuff repair were retrospectively identified. Patients were evaluated and rotator cuff integrity was assessed using ultrasonography. Visual analog score (VAS), the American Shoulder and Elbow Surgeon (ASES) score, shoulder range of motion and strength were used for clinical evaluation. Retears were assessed for size and location on ultrasonography. Results: Forty two patients (75%) aged a mean 59.7 ± 8.6 years (range 41-79 years) were available for follow-up at a mean 13.5 months. Postoperative evaluation indicated significant improvements in ASES score (49.76 ± 18.2 to 86.57 ± 13.4, P < 0.001), VAS pain score (4.69 ± 2.17 to 0.63 ± 1.29, P < 0.001), forward elevation range of motion (144.1° ± 29.9 to 159.69° ± 13.9, P = 0.002), and internal rotation ROM (44.13° ± 12.0 to 52.09° ± 12.0, P = 0.003). The retear rate was 14.28% (6/42). Patients with retears were not older (P = 0.526) but had a larger preoperative tear size (3.25 cm ± 0.5 vs. 2.05 cm ± 0.48, P < 0.001). Preoperative tear size was significantly associated with a postoperative retear (P < 0.001). The duration of preoperative symptoms was significantly associated with pain (P = 0.029), pain improvement (P = 0.013), internal rotation ROM (P = 0.002), and internal rotation strength (P = 0.004). Conclusions: Arthroscopic suture bridge repair provides good clinical results with a low retear rate. The duration of preoperative symptoms was associated with postoperative outcome, indicating that delaying surgery may result in inferior outcomes. Level of Evidence: IV, Case Series.
Strength of ulnar fixation in ulnar collateral ligament reconstruction: a biomechanical comparison of traditional bone tunnels to the tension-slide technique
Jackson, Atiba; März, Tristan; Koueiter, Denise M.; et al. (2012)
Journal of Shoulder and Elbow Surgery
Background: Surgical reconstruction of the ulnar collateral ligament after rupture has evolved substantially since the original description. Reconstruction techniques vary significantly at the ulnar and humeral interface. The purpose of this study was to develop a model to isolate, test, and compare the ulnar fixation of the traditional bone tunnel technique and a new technique, the tension slide. Materials and methods: Six matched pairs of cadaveric arms were dissected to isolate the ulna. Pairs were randomized to the bone tunnel or tension-slide ulnar fixation technique, and consistent tendon grafts were used for each reconstruction. A specialized tendon clamp was used to grip the grafts. Specimens were preloaded with a valgus force to 1 Nm and tested to failure in torsion at 4.5°/s. Statistical analysis was performed with 1-way analysis of variance with the Tukey post hoc test (α = .05). Results: The bone tunnel technique exhibited higher initial and total stiffness, as well as higher torsional torque at 10° and 30° of valgus angulation and at ultimate failure. The tension-slide technique exhibited significantly higher angular displacement at 3 Nm but not at ultimate failure. The bone tunnel technique exhibited higher work at 10° and 30° of valgus angulation. Conclusion: In this model, traditional bone tunnels performed superior to the tension-slide construction in terms of both strength and stiffness. Whether there is a kinematic benefit to the tension slide, which moves the ulnar fixation to within the native ulnar collateral ligament footprint, is yet to be determined. Further study is needed to assess the clinical benefit of a stronger ulnar fixation.
Biomechanical properties of the repaired and non-repaired rat supraspinatus tendon in the acute postoperative period
Kurdziel, Michael D.; Davidson, Abigail; Ross, David; et al. (2019)
Connective Tissue Research
Purpose: The rat rotator cuff (RC) model is used to study RC pathology and potential treatment; however, native scar-mediated healing allows the rat RC to recover at 4-6weeks but little is known about acute healing. This study characterized the properties of the repaired and non-repaired rat RC following surgical detachment. Materials and Methods: Forty-eight rats underwent surgical RC detachment and received surgical repair (Repair) or left unrepaired (Defect) to either 12 or 19 days. Healthy controls were obtained from contralateral limbs. Biomechanical properties were assessed using stress relaxation and failure testing and mechanical modeling performed using quasilinear viscoelastic (QLV) and structurally based elastic models. Histology and micro-magnetic resonance imaging were used to qualitatively grade tendon-to-bone healing. Results: Repair and Defect exhibited significantly inferior mechanical properties compared to Healthy at both time points. Repair had significant increases in peak, equilibrium, and ultimate stress, modulus, and stiffness and significant decreases in cross-sectional area, % relaxation, and QLV constant "C" between 12 and 19 days, whereas Defect showed no change. Conclusions: This study demonstrates acute differences in mechanical properties of the rat supraspinatus tendon in the presence and absence of surgical repair. Understanding the longitudinal recovery of mechanical properties can facilitate more accurate characterization of RC pathology or future treatments.

Publications 1 - 10 of 75

Tristan März

Last Name

First Name

ORCID

Organisational unit

Filters

Search Results