SCRM 580: Coulombe

Introduction

• Greetings from Brown University.
• Mention of speaker's background and affiliation.
• Personal background: Raised in Massachusetts; involvement in playing and coaching sports.

Corrine's Academic Journey

• PhD: University of Washington in Seattle in bioengineering.
• Research lab: Worked under Mike and Mary focusing on cardiac biomechanics.
• Postdoctoral experience: Five-year collaboration in the lab of Chuck.
• Achievements: Recipient of NIH K99/R00 award.
• Faculty Position: Associate professor at Brown University for over a decade.

Research Focus

• Main areas of research:
  • Cardiovascular regenerative biology.
  • Muscular compartment of myocardium: Importance of integrating vasculature, connective tissue, and immune regulation for tissue building.
  • Design-build approach using biomaterials and manufacturing techniques for biocompatibility and tissue integration.

Presentation Overview

• Discussion on electrical elements in cardiac tissue engineering and new lab developments.
• Introduction to the first project: Engineered cardiac tissue from human-induced pluripotent stem cells (iPSCs).
• Observation of tissue beating behavior in a mold leading to curly edges due to architecture.
• Plan to discuss both current and upcoming research projects.

Heart Disease Context

• Overview of cardiovascular disease as a global epidemic (World Health Organization - WHO, 2011).
  • Leading cause of death since the 1950s:
    • One in three people affected.
    • Major causes include ischemic heart disease and stroke, leading to heart attack and eventual heart failure.
  • Statistical data:
    • Over 50% of heart attack patients may develop heart failure.
    • Each year, over 50,000 heart failure patients in the US become refractory to medication.

Stages of Heart Failure

• Classification of heart failure stages A to D:
  • Stage A: At risk without symptoms.
  • Stage B: Structural heart disease without symptoms.
  • Stage C: Structural heart disease with symptoms.
  • Stage D: Advanced heart failure requiring specialized treatment (e.g., ventricular assist devices, heart transplants, hospice care).
• Emphasis on limited therapeutic options as disease progresses.

Novel Therapeutic Approaches

• Objective: Develop new regenerative therapies for heart function at all stages of heart failure progression.
• Utilization of human engineered cardiac tissues as in vitro disease models.
• Projects underway in:
  • Bioelectric threads for cardiac resynchronization.
  • Angiogenic biomaterials addressing vascular components of heart disease.
  • Engineered human myocardial tissues aiming for contractile support without invasive device reliance.

Approaches to Heart Regeneration

• Categorization into three strategies:
  1. Inducing native cardiomyocyte proliferation.
  2. Inducing cardiomyocyte types from fibroblasts.
  3. Remuscularizing the heart by delivering new cardiomyocytes.
• Insights from developmental biology (e.g., zebrafish, neonatal mice) on cardiomyocyte regeneration.
• Challenges in cardiac cell transplantation pioneered by Chuck:
  • Image reference from a 2018 paper depicting human graft in the heart.
  • Considerations for delivery methods: injections, patches, engineered tissue.

Clinical Trials and Challenges

• The remuscularization approach is currently in clinical trials with a focus on:
  • Safety and efficacy in heart function metrics (ejection fraction).
  • Specific studies ongoing in Germany and Japan.
• Discussion of challenges encountered during implantation:
  • Variabilities in electrical coupling and geometry, vascularization issues, nutrient diffusion in larger engineered tissues.

Mechanical Function Analysis

• Finite element modeling of left ventricle:
  • Effects of simulated injuries on contractility measured via ejection fraction.
  • Studies on contraction and stiffness interactions of implanted materials.
  • Positive correlation between mechanical properties and ejection fraction metrics.

Scale-up Challenges

• Transitioning from clinical studies with limited cell numbers to larger doses.
• Wolfram Zimmerman's study example:
  • Quantity of patches required to deliver a billion cardiomyocytes.
• Calculations lead to challenges in delivering sufficient cells effectively.
• Strategies for increasing cardiomyocyte density in engineered tissues.

Engineered Tissue Development

• Use of biphasic link modulation to derive cardiomyocytes from iPSCs:
  • Stages leading to high-density tissue formation.
  • Ensuring metabolic sustainability and healthy tissue organization through hydrogel scaffolding.
• Studies on the tissue mechanics and stress-strain relationships and their interactions with external loading conditions.

In Vivo Implantation and Assessment

• Examination of in vivo heart conditions:
  • Routine assessment of electrical coupling post-implantation using electrocardiograms.
  • Preventing arrhythmias and assessing rhythm stability postoperative.

Bioelectric Threads Development

• Introduction of bioelectric threads to establish electrical connections between engineered and host tissues.
• Phases of replacement of damaged myocardial tissues with bioengineered constructs built for optimal electrical activity.
• Studies focused on optimizing cardiomyocyte cell density for maximum conduction.
  • Electrophysiology experiments revealing electrical conduction properties of engineered threads.

Future Directions

• Investigating potential enhancements in electrical syncytium formation through direct interventions in culture.
• Continuation of vascularization discussions in engineered tissue contexts for long-term viability.
• Reassessment of parameters prioritizing tissue handling, addressing mechanical stiffness, and electrical performance of bioengineered tissues.

Conclusion

• Summary of multiple avenues of research in heart regeneration, combining mechanical, electrical, vascular approaches, supported by innovative biomanufacturing techniques.
• Acknowledgment of collaborators, lab members, and funding sources supporting ongoing research.
• Invitation for questions and engagement from the audience.

Discussion on Ethical and Practical Implications

• Discussions about the cost and utilization of engineered tissues.
• Thoughts on addressing patient-specific needs and scalability of solution implementation.
• Focus on developing engineered tissues for specific disorders and exploring bioelectric pathways to foster clinical applications.