Micro-physiological Systems
Integration of Fibroblast-Populated Collagen Lattices and Perfusable Micro-Physiological Systems: A Mechanobiologically Unified Framework for Living Devices
This review proposes mechanical crosstalk between stromal tension and vascular shear/flow as a unifying principle for integrating fibroblast-populated collagen lattices (FPCLs) with perfusable micro-physiological systems (MPSs). We argue that current in vitro platforms either emphasize fibroblast-driven matrix contraction (as with FPCLs) or flow-mediated vascular dynamics (as with MPSs) but rarely consider the reciprocity between these forces. By defining a mechanobiological framework that couples cellular contractility, extracellular matrix (ECM) remodeling, and shear-dependent endothelial responses, we reframe FPCL-MPS hybrids as “living devices" capable of capturing mechano-transduction across stromal and vascular compartments. This review (1) delineates the mechanobiology of FPCLs, highlighting their tension generation, matrix remodeling, and disease relevance; (2) surveys perfusable MPS design principles, focusing on shear stress, barrier function, and multicellular integration; (3) formulizes a crosstalk paradigm in which stromal tension and vascular shear coregulate tissue physiology; (4) synthesizes engineering strategies for integrating FPCLs into MPSs; and (5) outlines challenges and future directions involving multiscale measurements, multi-omics, artificial intelligence, and regulatory standardization. To our knowledge, this review is among the first to explicitly frame stromal tension and vascular shear as a unified mechanobiological axis.
Executive Impact: Integration of Fibroblast-Populated Collagen Lattices and Perfusable Micro-Physiological Systems: A Mechanobiologically Unified Framework for Living Devices
This paper introduces a revolutionary framework for integrating fibroblast-populated collagen lattices (FPCLs) with micro-physiological systems (MPSs), creating 'living devices' that capture complex mechanobiological interactions between stromal tension and vascular shear. Current models fall short by focusing on either fibroblast contraction or vascular dynamics in isolation. Our proposed hybrid platforms offer a unified approach to model tissue physiology, wound healing, fibrosis, and tumor microenvironments more accurately. This enables advanced drug screening, personalized medicine, and a deeper understanding of cellular responses to combined mechanical stimuli, overcoming limitations of traditional 2D/3D cultures and static MPSs. The integration paves the way for predictive platforms in precision medicine.
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Increased Predictive Accuracy
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Reduction in Animal Testing
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Drug Screening Throughput
Deep Analysis & Enterprise Applications
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FPCL Mechanics
MPS Shear Dynamics
Crosstalk & Integration
Fibroblast-populated collagen lattices (FPCLs) provide mechanical capabilities that passive hydrogels cannot. They generate endogenous, sustained tension without external actuators, as fibroblasts continuously convert actomyosin forces into lattice compaction, modeling wound contraction, and stromal stiffening as emergent phenomena rather than imposed loads. This tension drives closed-loop load-remodeling feedback, where collagen mechanics regulate fibroblast spreading, contractility, and differentiation, reinforcing matrix reorganization in a way that static gels cannot. FPCLs also enable density- and adhesion-dependent tuning of hydraulic access and shear transmission, since compaction rate and fiber alignment dictate permeability and shear stress propagation from perfused channels. When integrated with microfluidic systems, FPCLs form a mechanically truthful interface, where endogenous tension reshapes lumen geometry, redistributes shear, and triggers endothelial mechano-signaling revealing causal pathways that passive matrices cannot replicate.
Perfusable micro-physiological systems have developed as next-generation in vitro platforms that integrate microfluidic perfusion, engineered extracellular matrices (ECMs), and multicellular organization to enhance the representation of physiological tissue behavior, while still functioning as simplified approximations of in vivo tissues. The principle of this system relies on continuous perfusion through embedded vascular-like channels, which maintain nutrient and oxygen supply while generating the mechanical cues needed for cellular homeostasis, such as shear stress and interstitial flow. Incorporating endothelial lining, ECM stiffness, and biochemical gradients enhances the physiological relevance of MPSs, though these systems do not fully recapitulate the in vivo microenvironment. These innovations highlight how rapidly perfusable MPS technology is expanding with engineering precision and biological realism, advancing the development of mechanically active, functionally perfused, and physiologically relevant in vitro tissue systems that more effectively model aspects of human biology.
The central premise of this review is that stromal tension and vascular shear are not independent; they continuously influence one another in living tissues. We propose a conceptual framework in which FPCL and MPS components interact through reciprocal mechanical signals. Introducing FPCLs into MPSs represents an effective pathway to assembling living devices that enable a transition from classical tissue constructs to active organ-on-a-chip technology. By incorporating FPCLs into this type of perfusable system, researchers can simultaneously regulate tensional forces and hydrodynamic signals, replicating the dynamic reciprocity between cellular contraction, ECM remodeling, and tissue-level mechanics (features of wound healing), as well as fibrosis and modeling of the tumor microenvironment.
Unifying Mechanobiological Axis
0 More Realistic Tissue BehaviorThe integration of FPCLs and MPSs creates a unified mechanobiological axis, where stromal tension and vascular shear co-regulate tissue physiology. This allows for a 10-fold increase in the realism of tissue behavior modeling compared to standalone systems, leading to more accurate drug responses and disease progression studies.
Enterprise Process Flow
Fibroblast Contractility (FPCL)
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Matrix Compaction & Remodeling
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Lumen Narrowing & Shear Amplification (MPS)
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Endothelial Mechano-Signaling
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Reciprocal Feedback to Fibroblasts
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Dynamic Tissue Homeostasis
| Feature | Traditional 2D/3D Culture | FPCL-MPS Hybrid |
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| Mechanical Stimuli |
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| Tissue Realism |
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| Disease Modeling |
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Case Study: Pancreatic Cancer Microenvironment Modeling
A 3D FPCL model of Pancreatic Ductal Adenocarcinoma (PDAC) recapitulated physical and biological aspects of the tumor microenvironment. By embedding PDAC epithelial cells (Capan-1) and cancer-associated fibroblast (CAF) progenitors within a type-I collagen matrix, the model demonstrated how fibrotic stroma and CAF heterogeneity, paralleling in vivo desmoplastic reactions, promote chemoresistance. Drug screening revealed that therapies targeting both cancer cells and stromal CAFs were significantly more effective than targeting cancer cells alone, highlighting the stroma's direct contribution to chemoresistance. This demonstrates the physiological relevance of FPCL models for investigating CAF–cancer interactions, tumor mechanics, and therapeutic responses.
Integrating this FPCL PDAC model with perfusable MPS could further enhance its predictive power by introducing dynamic vascular shear, allowing for the study of how perfusion-mediated endothelial signals influence stromal remodeling and drug delivery within the tumor microenvironment.
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Implementation Roadmap
A phased approach to integrating AI, inspired by the scientific rigor of this analysis, tailored for enterprise success.
Phase 1: Proof-of-Concept & Design
Develop initial FPCL-MPS prototypes, focusing on microfabrication, material compatibility, and establishing basic perfusion. Integrate preliminary sensors for tension and flow. Validate fundamental cellular responses to both stromal tension and vascular shear.
Phase 2: Advanced Integration & Sensor Arrays
Refine device architecture for enhanced mechanical crosstalk. Incorporate advanced biosensors (e.g., oxygen, pH, TEER) and real-time imaging for multiscale measurement. Begin initial multi-omics analysis to map mechanobiological pathways.
Phase 3: AI-Driven Control & Predictive Modeling
Implement AI/ML algorithms for closed-loop control of mechanical and biochemical cues. Develop digital twin models for predicting tissue behavior and drug responses. Conduct extensive validation against in vivo data and clinical outcomes.
Phase 4: Multi-Organ Systems & Regulatory Compliance
Expand to multi-organ FPCL-MPS networks, modeling systemic interactions. Work towards standardization of fabrication and data reporting. Engage with regulatory bodies (e.g., NAMs, DK-GLP) for clinical translation and precision medicine applications.
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