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Ostechondritis dissecans (OCD) is an orthopaedic disease characterized by formation of osteochondral defects in developing joints. Epiphyseal cartilage necrosis (osteochondrosis [OC]) caused by focal failure of vascular supply is the known precursor lesion of OCD, but it remains to be established how the severity of vascular failure drives lesion healing or progression. In the current study we have implemented a novel piglet model of induced osteochondrosis of the lateral trochlear ridge of the femur to determine the role that the extent of ischemia plays in the development and progression of OC/OCD lesions. Ten 4-week-old Yorkshire piglets underwent surgical interruption of the vascular supply to the entirety (n = 4 pigs) or the distal half (n = 6 pigs) of the lateral trochlear ridge of the femur. At 2, 6, and 12 weeks postoperatively, distal femora were evaluated by magnetic resonance imaging (MRI) to determine the fate of induced OC lesions. At 12 weeks, piglets were euthanized, and the surgical sites were examined histologically. After complete devascularization, lesion size increased between the 6- and 12-week MRI by an average of 24.8 mm 2 (95% CI: [-2.2, 51.7]; p = 0.071). During the same period, lesion size decreased by an average of 7.6 mm 2 (95% CI: [-24.5, 19.4]; p = 0.83) in piglets receiving partial devascularization. At 12 weeks, average ± SD lesion size was larger (p<0.001) in piglets undergoing complete (73.5 ± 17.6 mm 2 ) vs. partial (16.5 ± 9.8 mm 2 ) devascularization. Our study demonstrates how the degree of vascular interruption determines lesion size and likelihood of healing in a large animal model of trochlear OC.

Clinical management of children with Legg-Calvé-Perthes Disease (LCPD) is hampered by incomplete understanding of how the extent of ischemic injury and the duration and quality of subsequent repair determine patient outcome. The traditional piglet model of LCPD is limited to capturing global femoral head ischemia; thus, a new model is needed in which the extent of ischemia can be varied to replicate the spectrum of disease seen in children. In this exploratory study, we used an iterative approach to test and refine methods to bilaterally occlude vessels supplying the femoral heads in n = 8 young piglets under angiographic control. The deep and/or acetabular medial femoral circumflex arteries (DMFCA and AMFCA) were identified and embolized using either embolic particles or liquid embolic agents. The extent of ischemia was assessed immediately post-embolization (4 piglets) and/or 7 days following embolization (7 piglets) using contrast-enhanced magnetic resonance imaging (CE-MRI). After the final CE-MRI, piglets were euthanized, and their femora were harvested for histologic evaluation. Embolization of the DMFCA alone caused transient ischemia that largely resolved by 7 days with small regions of fibrovascular repair of ischemic injury remaining on histology. Embolization of both the DMFCA and AMFCA resulted in a greater degree of pathologic changes at 7 days post-operatively, but also with nearly complete restoration of femoral head perfusion. We found that combining injection of embolic particles with subsequent placement of an embolic micro-coil was the most effective approach to induce ischemic injury, which may be aided in larger piglets. While our findings should be interpreted cautiously due to the wide range in the age and size of animals investigated, they demonstrate that transarterial embolization of the vascular supply of the femoral head results in transient ischemia and histological changes consistent with partial ischemic injury. These results will inform further development of a minimally invasive piglet model of LCPD that offers a unique representation of the spectrum of pathophysiology of LCPD compared to the traditional model.

Meniscal tears are a common orthopedic injury, yet their healing is difficult to assess post-operatively. This impedes clinical decisions as the healing status of the meniscus cannot be accurately determined non-invasively. Thus, the objectives of this study were to explore the utility of a goat model and to use quantitative magnetic resonance imaging (MRI) techniques, histology, and biomechanical testing to assess the healing status of surgically induced meniscal tears. Adiabatic T1ρ, T2, and T2* relaxation times were quantified for both operated and control menisci ex vivo. Histology was used to assign healing status, assess compositional elements, and associate healing status with compositional elements. Biomechanical testing determined the failure load of healing lesions. Adiabatic T1ρ, T2, and T2* were able to quantitatively identify different healing states. Histology showed evidence of diminished proteoglycans and increased vascularity in both healed and non-healed menisci with surgically induced tears. Biomechanical results revealed that increased healing (as assessed histologically and on MRI) was associated with greater failure load. Our findings indicate increased healing is associated with greater meniscal strength and decreased signal differences (relative to contralateral controls) on MRI. This indicates that quantitative MRI may be a viable method to assess meniscal tears post-operatively.

Background Client‐owned dogs presenting clinically with intervertebral disc disease (IVDD) are a potential comparative animal model to help advance the understanding of disc degeneration and its treatment. To utilize dog patients as a model, noninvasive imaging techniques are needed that can characterize subtle and progressive changes in disc health in longitudinal and treatment efficacy studies. The purpose of this study was to assess the sensitivity of quantitative MRI techniques in detecting disc degeneration in client‐owned, nonchondrodystrophic‐breed dogs. Methods Thoracolumbar vertebral columns from the donated bodies of 15 dogs without a history of IVDD were imaged at 3T MRI. Quantitative MRI maps (T2, T2*, T1ρ, adiabatic T1ρ, adiabatic T2ρ, and ADC) were acquired axially for 10 discs (T11‐T12 to L7‐S1), and median values were measured in the nucleus pulposus and annulus fibrosus. Four disc health measures (Pfirrmann grade, histology score, water content, and glycosaminoglycan content) were evaluated for each disc. The quantitative MRI and disc health measures were compared using linear models, and partial correlations (Rpartial) were calculated. Results Most dogs had both relatively healthy and degenerated discs as assessed by Pfirrmann grade and histology score. Quantitative MRI values in relatively healthy discs varied greatly between dogs but were similar across disc levels. In the nucleus pulposus, T2 relaxation times were moderately correlated with Pfirrmann grade (Rpartial = −0.62; p < 0.0001), histology score (Rpartial = −0.63; p < 0.0001), and water content (Rpartial = +0.45; p < 0.0001), and weakly correlated with glycosaminoglycan content (Rpartial = +0.31; p = 0.0047). T2, T2*, T1ρ, adiabatic T1ρ, and adiabatic T2ρ had similar relationships to the disc health measures in the nucleus pulposus. No notable relationships were observed with ADC or in the annulus fibrosus. Conclusions Quantitative T2, T2*, T1ρ, adiabatic T1ρ, and adiabatic T2ρ relaxation time mapping techniques are similarly related to radiological and histological measures of disc health and water and glycosaminoglycan content in nonchondrodystrophic‐breed dogs. The purpose of this study was to assess the sensitivity of quantitative MRI techniques in detecting disc degeneration in client‐owned, nonchondrodystrophic‐breed dogs. Thoracolumbar vertebral columns from the donated bodies of 15 dogs without a history of IVDD were imaged ex vivo at 3T MRI, and quantitative MRI values of the discs were compared to radiological Pfirrmann grade, histology score, water content, and glycosaminoglycan content. We found that quantitative T2, T2*, T1ρ, adiabatic T1ρ, and adiabatic T2ρ relaxation time mapping techniques are similarly related to radiological and histological measures of disc health and water and glycosaminoglycan content.

To evaluate multiple MRI parameters in a surgical model of osteochondrosis (OC) in goats. Focal ischemic lesions of two different sizes were induced in the epiphyseal cartilage of the medial femoral condyles of goats at 4 days of age by surgical transection of cartilage canal blood vessels. Goats were euthanized and specimens harvested 3, 4, 5, 6, 9 and 10 weeks post-op. Ex vivo MRI scans were conducted at 9.4 Tesla for mapping the T1, T2, T1ρ, adiabatic T1ρ and TRAFF relaxation times of articular cartilage, unaffected epiphyseal cartilage, and epiphyseal cartilage within the area of the induced lesion. After MRI scans, safranin O staining was conducted to validate areas of ischemic necrosis induced in the medial femoral condyles of six goats, and to allow comparison of MRI findings with the semi-quantitative proteoglycan assessment in corresponding safranin O-stained histological sections. All relaxation time constants differentiated normal epiphyseal cartilage from lesions of ischemic cartilage necrosis, and the histological staining results confirmed the proteoglycan (PG) loss in the areas of ischemia. In the scanned specimens, all of the measured relaxation time constants were higher in the articular than in the normal epiphyseal cartilage, consistently allowing differentiation between these two tissues. Multiparametric MRI provided a sensitive approach to discriminate between necrotic and viable epiphyseal cartilage and between articular and epiphyseal cartilage, which may be useful for diagnosing and monitoring OC lesions and, potentially, for assessing effectiveness of treatment interventions.

Background Intervertebral disc (IVD) degeneration contributes significantly to chronic low back pain and represents a major clinical challenge. Quantitative MRI (qMRI) techniques offer the potential to assess biochemical and structural disc changes noninvasively, but its use has been slow to be incorporated into studies utilizing spontaneous large animal models. This study characterizes qMRI‐derived biomarkers of IVD degeneration across the lifespan in a clinically relevant ovine model. Methods Ex vivo thoracolumbar spine segments from 10 sheep (13–130 months old) were assessed using 3T MRI, including T2, T2*, T1ρ, adiabatic T1ρ, adiabatic T2ρ, and ADC mapping. Relaxation times were compared with Pfirrmann grade, disc height index, biomechanical testing, GAG/water content, and histological scores. Results T2 and T2* values in the nucleus pulposus (NP) were negatively correlated with age, Pfirrmann grade, and histological degeneration, and positively correlated with GAG and water content. T2 relaxation times in the annulus fibrosus (AF) were inversely related to biomechanical stiffness, whereas T2* relaxation times in the NP were positively associated. Strong inter‐metric correlations were observed between most qMRI measures, but aT1ρ and ADC showed more distinct profiles. Conclusion These findings support the sensitivity of qMRI in detecting regional and age‐related IVD changes and reinforce its utility for noninvasive disc assessment in translational models of degeneration. Quantitative MRI reveals age‐related degeneration of lumbar intervertebral discs. Axial T2 and T2* relaxation time maps from representative young (15‐month) and old (130‐month) sheep demonstrate substantially higher relaxation times in young discs, particularly within the nucleus pulposus, indicating a well‐hydrated and proteoglycan‐rich matrix. In contrast, older discs exhibit markedly reduced relaxation times consistent with dehydration and matrix degeneration. These imaging biomarkers highlight the sensitivity of T2 and T2* mapping for detecting age‐related changes in disc composition.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

The pig is an important animal model increasingly used for biomedical research, particularly in transplantation strategies involving xenotransplantation or the development of human organs in pig for exotransplantation. Pigs, however, are less characterized than other animal models. In this study, we produced wildtype (WT) pig embryos via somatic cell nuclear transfer (SCNT) technology and compared them to skeletal muscle null embryos (lacking MYF5 / MYOD / MYF6 ) at embryonic day 41, 62, and 90, critical stages of porcine myogenesis. Magnetic resonance imaging (MRI) and histological analyses revealed progressive development of skeletal muscle in WT embryos but not in null embryos whereas development of viscera progressed equally in both groups. Molecular analyses highlighted dynamic changes in myogenic gene expression and myofiber formation, demonstrating an organized progression of myogenesis in WT embryos. Morphologically, the null embryos exhibited abnormalities, including marked edema and underdeveloped limbs. MRI revealed severe skeletal abnormalities, including the absence of ribs, sternum, and associated vertebral malformations. In addition, histological analysis confirmed the complete lack of myofiber formation. Immunohistochemical analysis revealed the absence of myogenic stem cells and muscle differentiation, and RNA sequencing demonstrated that the skeletal muscle development process was entirely disrupted in null embryos. Additionally, analysis of neuromuscular junctions (NMJs) in the null embryos revealed that functional NMJ formation was absent, consistent with the lack of skeletal muscle formation. Importantly, these defects culminated in embryonic lethality after day 62 in the null embryos. We determined that the myogenic regulatory gene cascade is crucial for porcine embryo development and viability. The deletion of skeletal muscle is essential for the creating a vacant niche to allow for complementation of null porcine embryos with human induced pluripotent stem cells. Characterization of this skeletal muscle null pig model provide an important platform for engineering humanized muscle in gene-edited pigs. Triple knockout of myogenic regulatory genes (MYF5/MYOD/MYF6) completely disrupts skeletal muscle formation, causing embryonic lethality in pigs and highlighting the critical role of myogenesis, providing a platform for humanized muscle engineering in pigs.

Intervertebral disc (IVD) degeneration is a common pathological condition associated with low back pain. Recent evidence suggests that mesenchymal signaling cells (MSCs) promote IVD regeneration, but underlying mechanisms remain poorly defined. One postulated mechanism is via modulation of macrophage phenotypes. In this manuscript, we tested the hypothesis that MSCs produce trophic factors that alter macrophage subsets. To this end, we collected conditioned medium from human, bone marrow-derived STRO3 + MSCs. We then cultured human bone marrow-derived macrophages in MSC conditioned medium (CM) and performed single cell RNA-sequencing. Comparative analyses between macrophages cultured in hypoxic and normoxic MSC CM showed large overlap between macrophage subsets; however, we identified a unique hypoxic MSC CM-induced macrophage cluster. To determine if factors from MSC CM simulated effects of the anti-inflammatory cytokine IL-4, we integrated the data from macrophages cultured in hypoxic MSC CM with and without IL-4 addition. Integration of these data sets showed considerable overlap, demonstrating that hypoxic MSC CM simulates the effects of IL-4. Interestingly, macrophages cultured in normoxic MSC CM in the absence of IL-4 did not significantly contribute to the unique cluster within our comparison analyses and showed differential TGF-β signaling; thus, normoxic conditions did not approximate IL-4. In addition, TGF-β neutralization partially limited the effects of MSC CM. In conclusion, our study identified a unique macrophage subset induced by MSCs within hypoxic conditions and supports that MSCs alter macrophage phenotypes through TGF-β-dependent mechanisms.

Bone perfusion is an essential physiological measure reflecting vasculature status and tissue viability of the skeletal system. Arterial spin labeling (ASL), as a non-invasive and non-contrast enhanced perfusion imaging method, is an attractive approach for human research studies. To evaluate the feasibility of ASL perfusion imaging of knee bone marrow in the distal femoral condyle at a 3 T MRI scanner, a study was performed with eight healthy volunteers (three males and five females, 26 ± 2 years old) and two patients (male, 15 and 11 years old) with diagnosed stage II juvenile osteochondritis dissecans (JOCD). ASL imaging utilized a flow-sensitive alternating inversion recovery method for labeling and a single-shot fast spin echo sequence for image readout. In addition to quantitative knee bone marrow ASL imaging, studies were also performed to evaluate the effects of prolonged post-bolus delay and varied labeling size. ASL imaging was successfully performed with all volunteers. Despite the benefits of hyper-intensive signal suppression within bone marrow, the use of a prolonged post-bolus delay caused excessive perfusion signal decay, resulting in low perfusion signal-to-noise ratio (SNR) and poor image quality. Bone marrow perfusion signal changed with the labeling size, suggesting that the measured bone marrow perfusion signal is flow-associated. The means and standard deviations of bone marrow blood flow, spatial SNR, and temporal SNR from the quantitative perfusion study were 38.3 ± 5.2 mL/100 g/min, 3.31 ± 0.48, and 1.33 ± 0.31, respectively. The imaging results from JOCD patients demonstrated the potential of ASL imaging to detect disease-associated bone marrow perfusion changes. This study demonstrates that it is feasible to perform ASL imaging of knee bone marrow in the distal femoral condyle at 3 T.