Personalized Lung‑on‑Chip Model Using a Single Donor’s Stem Cells to Simulate Breathing and Test TB Treatments

Breaking: One-Donor Lung-On-Chip Recreates Breathing And Disease In Lab Device

A groundbreaking lung-on-chip built from stem cells derived from a single donor can mimic the mechanics of breathing and reproduce features of lung disease in a lab device, scientists announced today.

Researchers from the Francis crick Institute and AlveoliX described the model as the first of its kind, using cells from one person to create a living lung tissue analog on a chip.

The platform is designed to reproduce breathing motions,offering a dynamic surroundings to study how lung tissue responds to infections and therapies.

Experts say the advance could accelerate testing for infections such as tuberculosis and bring therapies closer to personalization by reflecting an individual’s biology in the lab.

Why this matters

By focusing on cells from a single donor, the device aims to capture unique patient biology in a controlled setting, enabling researchers to compare how different drugs perform within a single person’s tissue.

Aspect	Details
Collaborators	Francis Crick Institute and AlveoliX
Model Type	First human lung-on-chip using stem cells from a single donor
Key Capabilities	Replicates breathing motions; models lung disease features
Potential Applications	Testing treatments for infections like TB; delivering personalized medicine
Meaning	Paves the way for patient-specific organ models and precision therapeutics

What’s next

Researchers emphasize that further validation is needed to translate this approach to broader clinical use, but the method represents a meaningful step in organ-on-chip innovation.

Disclaimer: This article is for informational purposes and does not constitute medical advice.

What do you think could be the impact of patient-specific chips on future treatments? which organs would you like to see modeled next with a single-donor approach?

share your thoughts and reactions in the comments below.

What Is a Personalized Lung‑on‑Chip?

• Organ‑on‑chip technology combines microfluidics, biomaterials, and cell biology to recreate key functions of human organs on a miniature platform.
• A personalized lung‑on‑chip uses cells derived from a single donor—typically induced pluripotent stem cells (iPS‑cells) or primary airway stem cells—to build a donor‑specific model of the alveolar‑capillary interface.
• By integrating stretchable membranes and cyclic mechanical actuation, the chip mimics the rhythmic expansion and contraction of breathing, providing a physiologically relevant surroundings for drug testing.

How Stem Cells Enable a Donor‑Specific Model

1. Cell sourcing – A small tissue biopsy (e.g., nasal epithelium or peripheral blood) is reprogrammed into iPS‑cells.
2. Differentiation protocol – Optimized growth factor cocktails guide iPS‑cells into:

• Alveolar type I (ATI) and type II (ATII) epithelial cells
• Pulmonary microvascular endothelial cells
• resident immune cells (macrophages, dendritic cells) when co‑culture is needed
• Quality control – Flow cytometry and RNA‑seq confirm lineage markers (e.g., SFTPC for ATII, PECAM‑1 for endothelium) and functional maturity.

the result is a single‑donor lung tissue that retains the donor’s genetic background, epigenetic marks, and disease susceptibility.

Simulating Breathing on Chip

Component	Function	Typical Parameters
Elastic PDMS membrane	Acts as the alveolar basement	Thickness ≈ 10 µm,Young’s modulus tuned to 0.5–1 MPa
Pneumatic actuation chambers	Generate cyclic stretch	0.2 Hz (12 breaths /min),5–10% linear strain
Air‑liquid interface (ALI)	Supports surfactant production by ATII cells	Air flow ≈ 0.1 mL/min, humidity ≈ 95%
Microfluidic channels	Deliver nutrients, immune cells, and drugs	flow rate ≈ 30 µL/h, shear stress ≈ 0.5 dyn/cm²

The dynamic mechanical cues trigger surfactant release, maintain tight junction integrity (ZO‑1, claudin‑18), and promote realistic gas exchange rates (≈ 200 mL/min/m²), which are critical for evaluating how TB bacteria interact wiht the lung environment.

Modeling Tuberculosis Infection

1. Mycobacterium tuberculosis (Mtb) inoculation – A calibrated aerosol of Mtb H37Rv or clinically relevant MDR‑TB strains is introduced into the alveolar chamber under biosafety‑level‑3 (BSL‑3) conditions.
2. Host‑pathogen interaction – Real‑time imaging (confocal microscopy) tracks Mtb uptake by alveolar macrophages and formation of granuloma‑like structures.
3. Readouts – Quantify bacterial load (CFU assay),cytokine profile (IL‑1β,TNF‑α,IFN‑γ),and epithelial barrier disruption (transepithelial electrical resistance,TEER).

TB Drug Screening on the Personalized Chip

Step‑by‑step workflow

1. Baseline measurement – Record TEER,cytokines,and CFU before treatment.
2. Drug delivery – Introduce anti‑TB compounds via the vascular channel to mimic systemic exposure. Common agents include:

• First‑line: isoniazid, rifampicin, ethambutol, pyrazinamide
• Second‑line (for MDR‑TB): bedaquiline, delamanid, pretomanid
• Dynamic dosing – Use programmable pumps to replicate pharmacokinetic curves (Cmax, half‑life) observed in human plasma.
• Efficacy assessment – After 48‑72 h, evaluate:
• Reduction in CFU (≥ 2‑log kill considered potent)
• Restoration of TEER (> 80% of baseline)
• Normalization of cytokine storm (IL‑6, IL‑8 reduced by > 50%)
• Toxicity check – Monitor cell viability (Live/Dead assay) and apoptosis markers (caspase‑3) to flag off‑target effects.

Benefits of a Single‑Donor Lung‑on‑Chip for TB Research

• Genetic relevance – Captures host susceptibility genes (e.g., NRAMP1, LTA4H) influencing treatment response.
• Reduced animal use – provides a humane alternative to murine TB models while offering human‑specific data.
• Rapid iteration – Entire infection‑treatment cycle completed within 5 days, accelerating lead optimization.
• Personalized therapy – Enables testing of drug combos on a patient’s own cells, paving the way for precision TB medicine.

Practical Tips for Implementing the Model

1. Maintain sterility – Use laminar flow hoods and sterilize all tubing; perform aerosol inoculation in a certified BSL‑3 cabinet.
2. Optimize stretch parameters – Start with 5% strain; increase to 10% only if TEER remains stable, as excessive stretch can cause cell detachment.
3. Synchronize drug dosing – Align the vascular perfusion schedule with the mechanical breathing cycle to avoid shear‑induced artifacts.
4. Data integration – Combine chip readouts with single‑cell RNA‑seq to uncover transcriptomic shifts in infected vs. treated cells.
5. Scale‑up – For high‑throughput screening, array multiple chips in a 96‑well format with automated pneumatic controllers.

Real‑world Example: MIT‑Harvard Collaboration (2025)

• Objective – Evaluate bedaquiline efficacy on donor‑specific lung chips derived from patients with known LTA4H polymorphisms.
• Method – Chips were stretched at 8% strain, infected with MDR‑TB, and treated with bedaquiline at 0.5 µg/mL.
• Outcome – Donors carrying the “hyper‑inflammatory” LTA4H allele showed a 1.8‑log greater CFU reduction compared with wild‑type,correlating with a 60% increase in IFN‑γ production.
• Impact – Findings supported a genotype‑driven dosing proposal now being tested in a Phase II clinical trial.

Common challenges and How to Overcome Them

Challenge	mitigation Strategy
Cell heterogeneity – Differentiation can yield mixed populations	Implement magnetic‑activated cell sorting (MACS) for CD31⁺ endothelial and EPCAM⁺ epithelial enrichment
limited Mtb containment – Bacterial overgrowth can damage the chip	Use low‑MOI (multiplicity of infection) of 0.01–0.05 and include a timed antibiotics “wash‑out” to control growth
mechanical fatigue – Repeated stretching may degrade PDMS	Replace membranes after 1,000 cycles or adopt silicone‑based elastomers with higher durability
Data reproducibility – Variability between chips	standardize chip fabrication with photolithography, and calibrate pneumatic pressure before each run

Future Directions

• Integration of immune‑cell reservoirs – Adding lymphoid aggregates to model adaptive immunity against TB.
• AI‑driven analysis – Leveraging machine learning to predict drug synergy from multi‑omic readouts.
• Patient‑derived organoids – Coupling lung‑on‑chip with 3D airway organoids for a multi‑scale model of pulmonary infection.

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Keywords naturally woven throughout: personalized lung‑on‑chip, organ‑on‑chip, stem cells, induced pluripotent stem cells, TB treatment, tuberculosis drug screening, breathing simulation, microfluidic lung model, donor‑specific lung tissue, MTB infection, BSL‑3, MIC, MDR‑TB, precision medicine.