Ellen Zhang

All Publications

• Engineering a biomimetic multiphasic suture anchor system for enhanced rotator cuff enthesis regeneration SCIENCE ADVANCES Li, Z., Lee, S., Xu, L., Santos, M., Lu, R., Zhang, E. Y., Kim, D., Tumenbayar, B., Blanch, T. E., Jung, J., Shin, J., Bae, Y., Tran, R. T., Schaer, T., Heo, S. 2026; 12 (34): eaea3128

  Abstract

  The rotator cuff plays a vital role in shoulder movement and joint stability. Unfortunately, tears at the rotator cuff enthesis are common and frequently lead to retears after surgical intervention, particularly at the suture location and its anchor sites. These failures are typically due to the inability of current surgical treatments to mimic the native tissue complexity and provide the necessary metabolic, bioactive, and biophysical cues for effective enthesis regeneration. In this study, we engineered a biomimetic multiphasic scaffold system (BMS) to integrate with conventional suture anchor systems and deliver spatially organized structural and biological cues to enhance enthesis regeneration. The BMS consists of three distinct phases: Phase 1 features an aligned, nanofibrous decellularized tendon extracellular matrix (dECM) combined with "stiff" methacrylated hyaluronic acid (MeHA); phase 2 incorporates nonaligned, nanofibrous dECM with "soft" MeHA; and phase 3 uses a porous, bioenergetic, citrate-based composite scaffold for bone integration. In vitro, the BMS notably enhanced tenogenic, fibrochondrogenic, and chondrogenic differentiation, facilitating zone-specific rotator cuff enthesis regeneration. Further, in vivo, the BMS promoted successful integrative healing, forming distinct tendon, fibrocartilage, and bone regions at the repair site. This advanced multiphasic scaffold closely replicates native tissue properties, offering a promising strategy to improve rotator cuff repair. Its integration with conventional suture anchors provides an innovative design that enhances mechanical fixation and guides enthesis healing to reduce retear rates. Broadly, this platform offers a versatile solution for biointegrative repair strategies across complex soft-to-hard tissue interfaces.

  View details for DOI 10.1126/sciadv.aea3128

  View details for Web of Science ID 001854893900029

  View details for PubMedID 42627896

  View details for PubMedCentralID PMC13496182

• Hyperactive BMP and mechanosignaling remodel chromatin to drive aberrant osteogenesis in Fibrodysplasia Ossificans Progressiva JOURNAL OF BONE AND MINERAL RESEARCH Zhang, E. Y., Roberts, D., Lee, S., Tumenbayar, B., Jung, J., Rivera, L., Jung, I., Mauck, R. L., Shore, E., Heo, S. 2026

  Abstract

  Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a recurrent ACVR1 (R206H) mutation drives progressive heterotopic ossification (HO). Although hypersensitive BMP signaling is well established, the mechanisms by which this mutation stabilizes a pro-osteogenic cell state remain unclear. Here, we integrated super-resolution stochastic optical reconstruction microscopy (STORM), transposase-accessible chromatin with sequencing (ATAC-Seq), and RNA sequencing (RNA-Seq) to determine how Acvr1R206H remodels chromatin to influence lineage commitment. Mutant mouse embryonic fibroblasts exhibited globally decondensed chromatin and enhanced accessibility at developmental and osteogenic loci, accompanied by transcriptional programs enriched for ossification, extracellular matrix organization, and cell adhesion. Upon BMP stimulation, Acvr1R206H/+ cells exhibited exaggerated chromatin remodeling, revealing markedly heightened ligand sensitivity. Notably, pharmacological inhibition of Rho/ROCK or BMP-SMAD signaling restored chromatin condensation, demonstrating that these chromatin alterations are dynamic and reversible. Together, these findings show that Acvr1R206H establishes a pro-osteogenic chromatin landscape through convergent Rho/ROCK-dependent mechanotransduction and BMP-dependent pathways, revealing potential therapeutic opportunities to prevent pathological bone formation in FOP.

  View details for DOI 10.1093/jbmr/zjag089

  View details for Web of Science ID 001800955700001

  View details for PubMedID 42261676

• O-SNAP uncovers nanoscale chromatin remodeling in dedifferentiation and stress responses NATURE COMMUNICATIONS Kim, H. H., Zhang, E. Y., Palma, F. R., Kant, A., Martinez-Sarmiento, J., Guo, Z., Mauck, R. L., Shenoy, V., Bonini, M. G., Heo, S., Lakadamyali, M. 2026; 17 (1)

  Abstract

  The multi-scale organization of chromatin underlies gene regulation and cell identity, yet how nuclear architecture remodels during cell state transitions remains poorly understood. Here, we use single-molecule localization microscopy and a comprehensive analytical framework we call O-SNAP to reveal distinct chromatin remodeling trajectories in two biological contexts: dedifferentiation in chondrocytes and nuclear oxidative stress-induced remodeling in mammary epithelial cells. Conventional analyses of single-molecule localization microscopy chromatin images based on qualitative inspection or simple metrics, such as chromatin domain size, fail to capture the subtle chromatin transitions in both contexts. In contrast, O-SNAP quantitatively integrates and compares 144 spatial features extracted from single-molecule localization microscopy data, allowing machine-learning based classification of nuclear states and systematic downstream analyses such as feature selection, volcano plots, and feature set enrichment analysis to determine which spatial features most strongly drive classification results. Our analysis shows that in chondrocytes, in vitro passaging drives heterochromatin formation at late passages, whereas intermediate passages exhibit heterogeneous chromatin remodeling. In contrast, in mammary epithelial cells, nuclear oxidative stress leads to chromatin decompaction specifically in cells overexpressing the oxidation-sensitive histone H3.1 variant. Together, these findings demonstrate that integrated, multiscale spatial features of chromatin are sufficient to robustly discriminate distinct cellular states.

  View details for DOI 10.1038/s41467-026-73784-9

  View details for Web of Science ID 001830506800005

  View details for PubMedID 42236704

  View details for PubMedCentralID PMC13396410

• Therapeutic Implants: Mechanobiologic Enhancement of Osteogenic, Angiogenic, and Myogenic Responses in Human Mesenchymal Stem Cells on 3D-Printed Titanium Truss ADVANCED HEALTHCARE MATERIALS Lee, S., Kiapour, A., Stoeckl, B. D., Zhang, E. Y., Begley, M. R., Oldham, J., Harrison, L., Hunt, J., Mauck, R. L., Heo, S. 2025; 14 (27): e2501856

  Abstract

  This study investigates the effect of mechanotransduction on human mesenchymal stem cells (hMSCs) attached to structural elements of an implant, specifically a titanium truss element. It is found that surface features generated by 3D printing technology promote osteogenic activity, comparable to conventional treatments such as acid etching. Cell morphology and differentiation are evaluated using test coupons with either smooth or rough surface features. hMSCs on smooth titanium surfaces exhibit a flat, spread morphology consistent with fibrous tissue formation. In contrast, cells on 3D printed hierarchical surfaces cluster within surface asperities, resembling a trabecular bone-like orientation, and exhibited enhanced osteogenic gene expression. Building on this static surface-induced osteogenesis, we further investigated the effect of load-induced strain on hMSCs attached to the rough surface. Upon applying dynamic mechanical loading, RNA-sequencing analysis reveals that strain not only amplified osteogenic gene expression but also significantly upregulated angiogenic and myogenic pathways compared with static conditions. These findings demonstrate a synergistic effect between surface topography and mechanical strain in promoting osteogenesis. This study highlights the potential of utilizing mechanical strain through an implant's structural design to enhance osteogenic responses, offering valuable insights for the development of next-generation therapeutic implants.

  View details for DOI 10.1002/adhm.202501856

  View details for Web of Science ID 001527926400001

  View details for PubMedID 40658892

  View details for PubMedCentralID PMC12538524

• Epigenetic regulation and mechanobiological adaptation in tenocytes during maturation APL BIOENGINEERING Zhang, E. Y., Blanch, T. E., Ahmed, S. B., Jiang, X., Dyment, N. A., Heo, S. 2025; 9 (2)

  View details for DOI 10.1063/5.0271050

  View details for Web of Science ID 001519049500002

• Precision repair of zone-specific meniscal injuries using a tunable extracellular matrix-based hydrogel system BIOACTIVE MATERIALS Lee, S., Li, Z., Zhang, E. Y., Kim, D., Huang, Z., Heo, Y., Lee, S., Kang, H., Burdick, J. A., Mauck, R. L., Heo, S. 2025; 48: 400-413

  View details for DOI 10.1016/j.bioactmat.2025.02.013

  View details for Web of Science ID 001447692900001

• Epigenetic dynamics in meniscus cell migration and its zonal dependency in response to inflammatory conditions APL BIOENGINEERING Zhang, Y., Zhang, E. Y., Cheung, C., Heo, Y., Tumenbayar, B., Lee, S., Bae, Y., Heo, S. 2025; 9 (1)

  View details for DOI 10.1063/5.0239035

  View details for Web of Science ID 001432053600001