Browsing by Subject "Collagen"
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Item Open Access Biomimetic hydroxyapatite/collagen composite drives bone niche recapitulation in a rabbit orthotopic model.(Materials today. Bio, 2019-03) Minardi, S; Taraballi, F; Cabrera, FJ; Van Eps, J; Wang, X; Gazze, SA; Fernandez-Mourev, Joseph S; Tampieri, A; Francis, L; Weiner, BK; Tasciotti, ESynthetic osteoinductive materials that mimic the human osteogenic niche have emerged as ideal candidates to address this area of unmet clinical need. In this study, we evaluated the osteoinductive potential in a rabbit orthotopic model of a magnesium-doped hydroxyapatite/type I collagen (MHA/Coll) composite. The composite was fabricated to exhibit a highly fibrous structure of carbonated MHA with 70% (±2.1) porosity and a Ca/P ratio of 1.5 (±0.03) as well as a diverse range of elasticity separated to two distinct stiffness peaks of low (2.35 ± 1.16 MPa) and higher (9.52 ± 2.10 MPa) Young's Modulus. Data suggested that these specific compositional and nanomechanical material properties induced the deposition of de novo mineral phase, while modulating the expression of early and late osteogenic marker genes, in a 3D in vitro model using human bone marrow-derived mesenchymal stem cells (hBM-MSCs). When tested in the rabbit orthotopic model, MHA/Col1 scaffold induction of new trabecular bone mass was observed by DynaCT scan, only 2 weeks after implantation. Bone histomorphometry at 6 weeks revealed a significant amount of de novo bone matrix formation. qPCR demonstrated MHA/Coll scaffold full cellularization in vivo and the expression of both osteogenesis-associated genes (Spp1, Sparc, Col1a1, Runx2, Dlx5) as well as hematopoietic (Vcam1, Cd38, Sele, Kdr) and bone marrow stromal cell marker genes (Vim, Itgb1, Alcam). Altogether, these data provide evidence of the solid osteoinductive potential of MHA/Coll and its suitability for multiple approaches of bone regeneration.Item Open Access Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254).(Arthritis Res Ther, 2010) Catterall, Jonathan B; Stabler, Thomas V; Flannery, Carl R; Kraus, Virginia BINTRODUCTION: Acute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers. METHODS: We collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA. RESULTS: We observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for (sf)C-Reactive protein (CRP) (P = 0.039), (sf)lubricin (P = 0.008) and the proteoglycan biomarkers: (sf)Glycosaminoglycan (GAG) (P = 0.019), and (sf)Alanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: (sf)C-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), (sf)C1,2C (P = 0.039), (sf)C-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and (sf)N-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1β (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038). CONCLUSIONS: These data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis. TRIAL REGISTRATION: The samples used in this study were derived from a clinical trial NCT00332254 registered with ClinicalTrial.gov.Item Open Access Decreased hernia recurrence using autologous platelet-rich plasma (PRP) with Strattice™ mesh in a rodent ventral hernia model.(Surgical endoscopy, 2016-08) Van Eps, Jeffrey; Fernandez-Moure, Joseph; Cabrera, Fernando; Wang, Xin; Karim, Azim; Corradetti, Bruna; Chan, Paige; Dunkin, Brian; Tasciotti, Ennio; Weiner, Bradley; Ellsworth, WarrenBackground
Recurrence after ventral hernia repair (VHR) remains a multifactorial problem still plaguing surgeons today. Some of the many contributing factors include mechanical strain, poor tissue-mesh integration, and degradation of matrices. The high recurrence rate witnessed with the use of acellular dermal matrices (ADM) for definitive hernia repair has reduced their use largely to bridging repair and breast reconstruction. Modalities that improve classic cellular metrics of successful VHR could theoretically result in improved rates of hernia recurrence; autologous platelet-rich plasma (PRP) may represent one such tool, but has been underinvestigated for this purpose.Methods
Lewis rats (32) had chronic ventral hernias created surgically and then repaired with Strattice™ mesh alone (control) or mesh + autologous PRP. Samples were harvested at 3 and 6 months postoperatively and compared for gross, histologic, and molecular outcomes of: neovascularization, tissue incorporation, peritoneal adhesions, hernia recurrence, and residual mesh thickness.Results
Compared to control at 3 months postoperatively, PRP-treated rats displayed significantly more neovascularization of implanted mesh and considerable upregulation of both angiogenic genes (vEGF 2.73-fold, vWF 2.21-fold) and myofibroblastic genes (αSMA 9.68-fold, FSP-1 3.61-fold, Col1a1 3.32-fold, Col31a1 3.29-fold). Histologically, they also showed enhanced tissue deposition/ingrowth and diminished chronic immune cell infiltration. Peritoneal adhesions were less severe at both 3 (1.88 vs. 2.94) and 6 months (1.63 vs. 2.75) by Modified Hopkins Adhesion Scoring. PRP-treated rats experienced decreased hernia recurrence at 6 months (0/10 vs. 7/10) and had significantly improved ADM preservation as evidenced by quantification of residual mesh thickness.Conclusions
PRP is an autologous source of pro-regenerative growth factors and chemokines uniquely suited to soft tissue wound healing. When applied to a model of chronic VHR, it incites enhanced angiogenesis, myofibroblast recruitment and tissue ingrowth, ADM preservation, less severe peritoneal adhesions, and diminished hernia recurrence. We advocate further investigation regarding PRP augmentation of human VHR.Item Open Access Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway.(Biochemistry, 2018-01) Cox, Nathan J; Unlu, Gokhan; Bisnett, Brittany J; Meister, Thomas R; Condon, Brett M; Luo, Peter M; Smith, Timothy J; Hanna, Michael; Chhetri, Abhishek; Soderblom, Erik J; Audhya, Anjon; Knapik, Ela W; Boyce, MichaelThe COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities, and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic, or pathological cues. Several COPII proteins are modified by O-linked β-N-acetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular, and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein-protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of SEC23A, an essential COPII component, are required for its function in human cells and vertebrate development, because mutation of these sites impairs SEC23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway.Item Open Access Effect of surface topography on in vitro osteoblast function and mechanical performance of 3D printed titanium.(Journal of biomedical materials research. Part A, 2021-10) Abar, Bijan; Kelly, Cambre; Pham, Anh; Allen, Nicholas; Barber, Helena; Kelly, Alexander; Mirando, Anthony J; Hilton, Matthew J; Gall, Ken; Adams, Samuel BCritical-sized defects remain a significant challenge in orthopaedics. 3D printed scaffolds are a promising treatment but are still limited due to inconsistent osseous integration. The goal of the study is to understand how changing the surface roughness of 3D printed titanium either by surface treatment or artificially printing rough topography impacts the mechanical and biological properties of 3D printed titanium. Titanium tensile samples and discs were printed via laser powder bed fusion. Roughness was manipulated by post-processing printed samples or by directly printing rough features. Experimental groups in order of increasing surface roughness were Polished, Blasted, As Built, Sprouts, and Rough Sprouts. Tensile behavior of samples showed reduced strength with increasing surface roughness. MC3T3 pre-osteoblasts were seeded on discs and analyzed for cellular proliferation, differentiation, and matrix deposition at 0, 2, and 4 weeks. Printing roughness diminished mechanical properties such as tensile strength and ductility without clear benefit to cell growth. Roughness features were printed on mesoscale, unlike samples in literature in which roughness on microscale demonstrated an increase in cell activity. The data suggest that printing artificial roughness on titanium scaffold is not an effective strategy to promote osseous integration.Item Open Access Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.(Kidney Int, 2016-05) Madan, Babita; Patel, Mehul B; Zhang, Jiandong; Bunte, Ralph M; Rudemiller, Nathan P; Griffiths, Robert; Virshup, David M; Crowley, Steven DActivated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.Item Open Access Functional outcome measures in a surgical model of hip osteoarthritis in dogs.(J Exp Orthop, 2016-12) Little, Dianne; Johnson, Stephen; Hash, Jonathan; Olson, Steven A; Estes, Bradley T; Moutos, Franklin T; Lascelles, B Duncan X; Guilak, FarshidBACKGROUND: The hip is one of the most common sites of osteoarthritis in the body, second only to the knee in prevalence. However, current animal models of hip osteoarthritis have not been assessed using many of the functional outcome measures used in orthopaedics, a characteristic that could increase their utility in the evaluation of therapeutic interventions. The canine hip shares similarities with the human hip, and functional outcome measures are well documented in veterinary medicine, providing a baseline for pre-clinical evaluation of therapeutic strategies for the treatment of hip osteoarthritis. The purpose of this study was to evaluate a surgical model of hip osteoarthritis in a large laboratory animal model and to evaluate functional and end-point outcome measures. METHODS: Seven dogs were subjected to partial surgical debridement of cartilage from one femoral head. Pre- and postoperative pain and functional scores, gait analysis, radiographs, accelerometry, goniometry and limb circumference were evaluated through a 20-week recovery period, followed by histological evaluation of cartilage and synovium. RESULTS: Animals developed histological and radiographic evidence of osteoarthritis, which was correlated with measurable functional impairment. For example, Mankin scores in operated limbs were positively correlated to radiographic scores but negatively correlated to range of motion, limb circumference and 20-week peak vertical force. CONCLUSIONS: This study demonstrates that multiple relevant functional outcome measures can be used successfully in a large laboratory animal model of hip osteoarthritis. These measures could be used to evaluate relative efficacy of therapeutic interventions relevant to human clinical care.Item Open Access Functional properties of cell-seeded three-dimensionally woven poly(epsilon-caprolactone) scaffolds for cartilage tissue engineering.(Tissue Eng Part A, 2010-04) Moutos, Franklin T; Guilak, FarshidArticular cartilage possesses complex mechanical properties that provide healthy joints the ability to bear repeated loads and maintain smooth articulating surfaces over an entire lifetime. In this study, we utilized a fiber-reinforced composite scaffold designed to mimic the anisotropic, nonlinear, and viscoelastic biomechanical characteristics of native cartilage as the basis for developing functional tissue-engineered constructs. Three-dimensionally woven poly(epsilon-caprolactone) (PCL) scaffolds were encapsulated with a fibrin hydrogel, seeded with human adipose-derived stem cells, and cultured for 28 days in chondrogenic culture conditions. Biomechanical testing showed that PCL-based constructs exhibited baseline compressive and shear properties similar to those of native cartilage and maintained these properties throughout the culture period, while supporting the synthesis of a collagen-rich extracellular matrix. Further, constructs displayed an equilibrium coefficient of friction similar to that of native articular cartilage (mu(eq) approximately 0.1-0.3) over the prescribed culture period. Our findings show that three-dimensionally woven PCL-fibrin composite scaffolds can be produced with cartilage-like mechanical properties, and that these engineered properties can be maintained in culture while seeded stem cells regenerate a new, functional tissue construct.Item Open Access Histoarchitecture of the fibrillary matrix of human fetal posterior tibial tendons.(Scientific reports, 2022-10) Macedo, Rodrigo Sousa; Teodoro, Walcy Rosolia; Capellozzi, Vera Luiza; Rosemberg, Dov Lagus; Sposeto, Rafael Barban; de Cesar Netto, Cesar; Deland, Jonathan T; Maffulli, Nicola; Ellis, Scott J; Godoy-Santos, Alexandre LemeAdult tendons are highly differentiated. In mature individuals, tendon healing after an injury occurs through fibrotic tissue formation. Understanding the intrinsic reparative properties of fetal tendons would help to understand the maturation tissue process and tendon tissue repair. The present study evaluated the evolution of histoarchitecture, cellularity and the distribution of collagens I, III and V in the posterior tibial tendon in human fetuses at different gestational ages. Morphological profiles were assessed in nine fresh spontaneously aborted fetuses (Group I: five fetuses aged between 22 and 28 weeks of gestation; Group II: four fetuses aged between 32 and 38 weeks of gestation), characterized by a combination of histology, fluorescence and immunohistochemistry. In Group I, the posterior tibial tendon showed statistically significant greater cellularity and presence of collagen III and V than in Group II tendon, which showed a predominance of collagenous I and a better organization of the extracellular matrix compared with Group I tendons. In addition, a statistically significant higher rate of CD90, a marker of mesenchymal cells, was found in Group I tendons. In fetuses with gestational age between 22 and 28 weeks, the posterior tibialis tendons showed a thin and disorganized fibrillar structure, with an increase in collagen III and V fibers and mesenchymal cells. In the posterior tibialis tendons of fetuses with gestational age between 32 and 38 weeks, the fibrillar structure was thicker with a statistically significant increase in type I collagen and decreased cellularity.Item Open Access Ligament-derived matrix stimulates a ligamentous phenotype in human adipose-derived stem cells.(Tissue Eng Part A, 2010-07) Little, Dianne; Guilak, Farshid; Ruch, David SHuman adipose stem cells (hASCs) can differentiate into a variety of phenotypes. Native extracellular matrix (e.g., demineralized bone matrix or small intestinal submucosa) can influence the growth and differentiation of stem cells. The hypothesis of this study was that a novel ligament-derived matrix (LDM) would enhance expression of a ligamentous phenotype in hASCs compared to collagen gel alone. LDM prepared using phosphate-buffered saline or 0.1% peracetic acid was mixed with collagen gel (COL) and was evaluated for its ability to induce proliferation, differentiation, and extracellular matrix synthesis in hASCs over 28 days in culture at different seeding densities (0, 0.25 x 10(6), 1 x 10(6), or 2 x 10(6) hASC/mL). Biochemical and gene expression data were analyzed using analysis of variance. Fisher's least significant difference test was used to determine differences between treatments following analysis of variance. hASCs in either LDM or COL demonstrated changes in gene expression consistent with ligament development. hASCs cultured with LDM demonstrated more dsDNA content, sulfated-glycosaminoglycan accumulation, and type I and III collagen synthesis, and released more sulfated-glycosaminoglycan and collagen into the medium compared to hASCs in COL (pItem Open Access Mechanobiology of the meniscus.(J Biomech, 2015-06-01) McNulty, Amy L; Guilak, FarshidThe meniscus plays a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Importantly, growing evidence indicates that the mechanobiologic response of meniscal cells plays a critical role in the physiologic, pathologic, and repair responses of the meniscus. Here we review experimental and theoretical studies that have begun to directly measure the biomechanical effects of joint loading on the meniscus under physiologic and pathologic conditions, showing that the menisci are exposed to high contact stresses, resulting in a complex and nonuniform stress-strain environment within the tissue. By combining microscale measurements of the mechanical properties of meniscal cells and their pericellular and extracellular matrix regions, theoretical and experimental models indicate that the cells in the meniscus are exposed to a complex and inhomogeneous environment of stress, strain, fluid pressure, fluid flow, and a variety of physicochemical factors. Studies across a range of culture systems from isolated cells to tissues have revealed that the biological response of meniscal cells is directly influenced by physical factors, such as tension, compression, and hydrostatic pressure. In addition, these studies have provided new insights into the mechanotransduction mechanisms by which physical signals are converted into metabolic or pro/anti-inflammatory responses. Taken together, these in vivo and in vitro studies show that mechanical factors play an important role in the health, degeneration, and regeneration of the meniscus. A more thorough understanding of the mechanobiologic responses of the meniscus will hopefully lead to therapeutic approaches to prevent degeneration and enhance repair of the meniscus.Item Open Access Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair.(ACS nano, 2018-12) Li, Zhenhua; Shen, Deliang; Hu, Shiqi; Su, Teng; Huang, Ke; Liu, Feiran; Hou, Lei; Cheng, KeStem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clinical application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chemistry, we engineered a pretargeting and bioorthogonal chemistry (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administrated with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochemistry assessment all confirmed effective heart repair by the PTBC system.Item Open Access The effect of nitric oxide surface flux on the foreign body response to subcutaneous implants.(Biomaterials, 2012-09) Nichols, Scott P; Koh, Ahyeon; Brown, Nga L; Rose, Michael B; Sun, Bin; Slomberg, Danielle L; Riccio, Daniel A; Klitzman, Bruce; Schoenfisch, Mark HAlthough the release of nitric oxide (NO) from biomaterials has been shown to reduce the foreign body response (FBR), the optimal NO release kinetics and doses remain unknown. Herein, polyurethane-coated wire substrates with varying NO release properties were implanted into porcine subcutaneous tissue for 3, 7, 21 and 42 d. Histological analysis revealed that materials with short NO release durations (i.e., 24 h) were insufficient to reduce the collagen capsule thickness at 3 and 6 weeks, whereas implants with longer release durations (i.e., 3 and 14 d) and greater NO payloads significantly reduced the collagen encapsulation at both 3 and 6 weeks. The acute inflammatory response was mitigated most notably by systems with the longest duration and greatest dose of NO release, supporting the notion that these properties are most critical in circumventing the FBR for subcutaneous biomedical applications (e.g., glucose sensors).Item Open Access Utility of telomerase-pot1 fusion protein in vascular tissue engineering.(Cell Transplant, 2010) Petersen, Thomas H; Hitchcock, Thomas; Muto, Akihito; Calle, Elizabeth A; Zhao, Liping; Gong, Zhaodi; Gui, Liqiong; Dardik, Alan; Bowles, Dawn E; Counter, Christopher M; Niklason, Laura EWhile advances in regenerative medicine and vascular tissue engineering have been substantial in recent years, important stumbling blocks remain. In particular, the limited life span of differentiated cells that are harvested from elderly human donors is an important limitation in many areas of regenerative medicine. Recently, a mutant of the human telomerase reverse transcriptase enzyme (TERT) was described, which is highly processive and elongates telomeres more rapidly than conventional telomerase. This mutant, called pot1-TERT, is a chimeric fusion between the DNA binding protein pot1 and TERT. Because pot1-TERT is highly processive, it is possible that transient delivery of this transgene to cells that are utilized in regenerative medicine applications may elongate telomeres and extend cellular life span while avoiding risks that are associated with retroviral or lentiviral vectors. In the present study, adenoviral delivery of pot1-TERT resulted in transient reconstitution of telomerase activity in human smooth muscle cells, as demonstrated by telomeric repeat amplification protocol (TRAP). In addition, human engineered vessels that were cultured using pot1-TERT-expressing cells had greater collagen content and somewhat better performance in vivo than control grafts. Hence, transient delivery of pot1-TERT to elderly human cells may be useful for increasing cellular life span and improving the functional characteristics of resultant tissue-engineered constructs.Item Open Access Vesicoureteral reflux and the extracellular matrix connection.(Pediatr Nephrol, 2016-05-02) Tokhmafshan, Fatima; Brophy, Patrick D; Gbadegesin, Rasheed A; Gupta, Indra RPrimary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes.