Z26 - Spatially Heterogeneous Bioprinted Model of the Myocardial Infarction Border Zone for Assessing Patient-Specific Disease Trajectories and Therapeutic Outcomes

Friday, October 10, 2025

10:00 AM - 11:00 AM PDT

Location: Exhibit Hall F, G & H

Presenting Author(s)

Natalie Celt

PhD Student, Biomedical Engineering
University of California, Irvine, United States

Co-Author(s)

YK

Yuyao Kuang

Ph.D. student
University of California, Irvine, United States

Last Author(s)

Herdeline Ann Ardona

Assistant Professor
University of California, Irvine
Irvine, California, United States

Primary Investigator(s)

Herdeline Ann Ardona

Assistant Professor
University of California, Irvine
Irvine, California, United States

Introduction: : Acute myocardial infarction (MI) often results in irreversible structural and functional damage to cardiac tissue. While pharmaceutical interventions can mitigate some of the pathological remodeling that follows MI, they fall short in regenerating healthy myocardium. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a promising therapeutic alternative by potentially halting or reversing post-MI remodeling. However, their clinical application remains limited due to patient-specific safety concerns and variability in therapeutic outcomes. Notably, the post-MI heart develops spatial heterogeneity across three distinct zones, each with differing mechanical properties, which can significantly affect iPSC-CM engraftment and function.
This work presents the fabrication of a biomimetic model of post-MI cardiac tissue that replicates the variability of tissue anisotropy and stiffness across patients. This model aims to serve as a pre-screening platform for evaluating iPSC-CM therapeutic efficacy under conditions that reflect the mechanical complexity of infarcted myocardium. In parallel, we introduce a polymeric force sensor capable of detecting spatial heterogeneity in cardiomyocyte force generation in situ. Unlike current methods—such as traction force microscopy, which requires extensive processing, or bulk-assessing techniques like muscular thin films and micropillars—this sensor enables real-time, localized measurement of contractile performance.
Together, this work establishes a novel platform for modeling myocardial infarction and offers a more precise method to assess the functional integration of stem cell therapies in mechanically heterogeneous cardiac tissue.

Materials and

Methods: : Hydrogel-based models of post-myocardial infarction (MI) cardiac tissue were fabricated using digital light processing (DLP) bioprinting (BIONOVAX, CELLINK), a high-resolution bioprinting platform capable of generating constructs with stiffness gradients and micropatterned topographies down to 10 μm, utilizing 405 nm light for photopolymerization. Construct designs were created in Fusion 360, incorporating groove patterns (20 μm width, 50 μm spacing) to replicate the native anisotropy of healthy myocardium.
Hydrogels were composed of methacrylated gelatin (GelMA), methacrylated collagen (ColMA), and polyethylene glycol diacrylate (PEGDA) (all from Advanced Biomatrix), blended in varying ratios to mimic the mechanical heterogeneity of post-MI tissue. Constructs were engineered to achieve region-specific stiffnesses: ~100kPa for the infarct zone, ~5-10 kPa for the remote (healthy) zone, and an intermediate stiffness gradient between these zones, replicating the infarct border region.
Cardiomyocyte alignment and intercellular connectivity were assessed via immunostaining for cardiac markers α-actinin and connexin-43, respectively. Cell spreading and mechanosensing behavior were evaluated through staining of cytoskeletal and focal adhesion proteins, including actin and vinculin. To quantify extracellular matrix remodeling and contractile force output, chromogenic polymer films embedded within the constructs were analyzed for spectral shifts between day 0 and day 7 post-cell seeding, serving as an in-situ readout of stiffness-dependent cardiomyocyte actuation.

Results, Conclusions, and Discussions:: Preliminary results validate the successful replication of region-specific stiffness representative of the three characteristic zones observed during myocardial infarction (MI) remodeling, namely, the remote, border, and infarct zones. iPSC-derived cardiomyocytes (iPSC-CMs) seeded onto these regions exhibit distinct morphological and behavioral responses consistent with their mechanical environments. Immunostaining for vinculin and α-actinin revealed stiffness-mediated differences in focal adhesion formation and sarcomere organization, respectively. Additionally, recognition of the micropatterned topographies promoted cardiomyocyte alignment, particularly in the anisotropic, lower-stiffness regions.
Early experiments, using iPSC-CMs prior to electrical conditioning, revealed asynchronous contractility and arrhythmic behavior, particularly in stiffer, fibrotic regions. These findings highlight the potential need for electrical preconditioning and point toward future strategies to overcome mechanical barriers in infarcted tissue—promoting functional integration, synchronous contraction, and regeneration of healthy myocardium.
Implementation of the chromogenic polymer system as a force sensor provided an initial in situ readout of force actuation over a 7-day culture period. Enhancing conjugation between the sensor and hydrogel substrate is expected to improve force transmission and detection fidelity in future iterations.
In conclusion, this work demonstrates the feasibility of a physiologically relevant, mechanically heterogeneous in vitro model of post-MI cardiac tissue. It establishes a foundation for patient-specific screening of stem cell therapies and introduces a novel chromogenic force-sensing platform for real-time monitoring of cardiomyocyte function. Continued optimization of sensor sensitivity and incorporation of electrically conditioned iPSC-CMs will advance the model’s utility for therapeutic assessment and myocardial regeneration research.

Acknowledgements and/or References (Optional): : Equipment: UC Irvine Materials Research Institute (IMRI), NIH S10 (1S10OD025064)

Funding: California Institute for Regenerative Medicine under Award Number EDUC4-12822
CIRM SRL INFR6.2-15368