Mahima Singh

Abstract

Engineered tissues hold immense potential for modeling human pathophysiology and testing novel pharmaceuticals before clinical trials. However, replicating interdependent organ functions remains a challenge. This study introduces a multi-organ tissue chip linked by vascular flow, allowing communication between engineered tissues such as heart, skin, bone, and liver. By integrating selectively permeable endothelial barriers, this system simulates physiological conditions while maintaining phenotypic stability. The tissue chip demonstrates practical applications in drug testing, including the pharmacokinetics and pharmacodynamics of doxorubicin. This advancement represents a significant step toward scalable and clinically relevant tissue modeling systems.

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Introduction

Animal models have traditionally been used to assess drug safety and efficacy, yet they often fail to accurately mimic human physiology. To address this, bio-engineered tissues have emerged as a superior alternative, providing better insights into human biology and drug responses.

Despite advancements in tissue engineering, existing methods fail to integrate tissues into a cohesive system that simulates organ-to-organ communication. Diseases affecting multiple organs—such as cancer or cardiotoxicity—necessitate models that replicate their interconnected effects. For example, doxorubicin-induced cardiotoxicity can only be accurately studied in systems maintaining tissue-specific phenotypes and signaling pathways.

This study focuses on designing a multi-organ tissue chip linked by vascular flow to replicate these interactions, providing a platform for drug testing and modeling complex human pathophysiology.

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Methodology

Tissue Engineering
Heart and Liver Tissues: Engineered by maturing human iPSC-derived hepatocytes and supporting fibroblasts in a fibrin matrix over 4 weeks.
Bone Tissues: Derived from mesenchymal stem cells (MSCs) seeded onto scaffolds and matured over 3 weeks.
Skin Tissues: Produced by introducing human keratinocytes into collagen matrices.
Vascular Integration
The vascular barrier consists of endothelial cells layered onto elastic meshes to ensure nutrient and

cytokine transport between tissues.
Tissues communicate through exosomes, cytokines, and immune cells in the circulating flow.

System Design

The chip includes separate chambers for each tissue type, linked by vascular flow.
Real-time computational models assess tissue-specific responses, including the pharmacokinetics and pharmacodynamics (PK/PD) of doxorubicin.

Figures and Results

Figure 1: Endothelial Barrier Design

Depicts the structural design of the vascular flow system, linking tissues through selectively permeable barriers.
Figure 2: Tissue Engineering and Chamber Design

Shows independent chambers with fluidic connections to replicate tissue interactions.
Figure 3: Nutrient and Cytokine Flow

Highlights the exchange of signals through vascular pathways.
Figure 4: Computational Model

Simulates PK/PD profiles of drugs like doxorubicin across multi-organ systems.
Figure 5: Experimental Outcomes

Demonstrates how the chip maintained stable phenotypes, enabling reliable drug testing and physiological studies.

Conclusion

The multi-organ tissue chip showcases significant advancements in tissue engineering by integrating vascular flow and endothelial barriers. Key outcomes include:

Enhanced Drug Testing: The chip demonstrated stable phenotypes and consistent PK/PD profiles for doxorubicin.
Scalability: Its modular design supports future integration of additional tissues, such as kidneys, for broader applications.
Clinical Relevance: The chip provides a physiologically accurate platform for studying organ-to-organ communication and disease progression.
By addressing challenges in current systems, the multi-organ tissue chip serves as a promising tool for modeling human pathophysiology, developing therapies, and advancing personalized medicine.

 

Acknowledgments

Special thanks to Kacey Radoslav-Rouchard and colleagues for their insights and support throughout this project, as well as Delegates Beyond Borders and my advisor Mohit Nadkarni for their guidance.

 

References

Radoslav-Rouchard, K., & Singh, M. (2023). PK/PD modeling in tissue engineering systems. Journal of Biomedical Communications.
S.Y. Lee, T. Park, & J. Kim. (2021). iPSC-derived tissue applications for modeling multi-organ diseases. Science Advances.