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Building a 3D innervated and irrigated muscle on a chip.

Periodic Reporting for period 2 - MyoChip (Building a 3D innervated and irrigated muscle on a chip.)

Reporting period: 2019-11-01 to 2021-04-30

The aim of the MyoChip project is to build a 3D human skeletal muscle irrigated by vasculature and innervated by neurons. The reconstituted 3D muscle will mirror the architecture and function found in vivo, namely in shape, contractility and microenvironment, while irrigation by a vascular network and innervation by human motor neurons will bring additional physiologic pertinence to it. This organ-on-a-chip technology will have numerous applications including but not limited to research on muscle building and aging, drug testing and screening, as well as prosthetics and biorobotics. The feasibility of the project relies on an interdisciplinary approach which joins a team of cell biologists, material engineers, experts in microfluidics and mathematical modellers. The architecture of skeletal muscle and its regenerative capabilities make muscle a prime candidate to push the 3D tissue engineering field. As such the project will lay the technical, material and methodological foundations to tackle the next generation of complex organ-on-a-chip systems that the MyoChip consortium can exploit for the generation of highly complex 3D in vitro systems of many organs.
- Different types of instructive surfaces were fabricated: fibronectin micropatterns (in 2D) and microgrooves (2.5D). Although biochemical patterns show good ability to confine cells and induce alignment, the formation of thick fibers is more robust on topographical cue.
- Design and Production of a tri-culture 2.5D microdevice with different compartments conditioned accordingly for specific cultures of biomimetic constructs (i e muscle, vessel, neurons). This device is instrumental in performing the first co-culture experiments.
- Identified a co-culture medium for muscle and endothelial cells.
- Differentiating hiPSCs into skeletal muscle cells.
- Differentiating hiPSCs motor neurons.
- Coat channels with endothelial cells.

- Implement automatic switch in software and associated electronics to control flow.

- Motor neurons can grow axons through 5um microchannels.
- Design and production of a multi-microtube scaffold to grow in parallel myofiber and endothelial cells
- Different biomimetic hydrogel have been tested to reproduce/mimic the extracellular matrix properties, among them agarose and collagen I at different concentrations.
- Several wire types have also been tested among them: tungsten wires, peek tubing, nylon wires and acupuncture needles presenting different diameters, mechanical and chemical properties.

- Modelling of oxygen transport to muscle tissue. An enclosed MyoChip bioreactor will provide a controllable oxygen supply for muscle growth.
- Modelling of efficient tube configurations. A more efficient arrangement of microtubes can sustain a larger volume of muscle tissue.
- Segmentation of myoblasts and myotubes from experimental images.
We expect that this project will ultimately generate a muscle-on-chip that reproduces the architecture and contractility of in vivo skeletal muscle. The applications of such a chip are numerous and diverse. Nevertheless, our primary target is to provide an in vitro tool for biological and drug studies in the realm of muscle disorders, aging and neuromuscular diseases.
Skeletal muscle disorders pose a significant socioeconomic burden since patients quickly become dependent with reduced or no mobility. Costs of illness are estimated to approximately €1 billion/year in the US, whereas funds allocated to muscular dystrophy research amount to €150 million/year by NIH alone (excluding clinical trials). Although certain drugs recently approved by FDA appear to slow down the progression of dystrophies in a subset of affected individuals, these are certainly not providing a cure for the disease itself.
Natural loss of muscle mass is of particular concern as aged individuals spiral down a negative feedback loop of decreased muscle mass and physical activity. Sarcopenia is the natural atrophy of skeletal muscle during old age. Sarcopenia is linked with the development of obesity, osteoporosis and diabetes type II all of which are highly prevalent in the elderly. Together these diseases increase risk of falling, hospitalization, institutionalization and ambulatory care which has a strong psychological impact on affected individuals and an important economic burden for society. Alone, sarcopenia costs were estimated at 18.5$ billion per year in the US in 2004 and it increases hospitalization costs of other disorders by 58.5%. These numbers will all be inflated by the growing aging population. It is estimated that by 2050 the world’s population above 60 year’s old will double reaching around 2 billion world-wide. This generalized aging poses a series of challenges for society being a burden for increasingly dependent individuals and for our healthcare system.
This project will provide a human system mimicking in vivo conditions in which all properties of muscles can be monitored (contractility, force generation, hypertrophy, structure) and different drug delivery methods can be applied (direct or intravenous). More importantly, this system will arise from hIPSCs and can therefore recapitulate specific patient mutations, which are the main cause of muscle disorders. This 3D muscle system is destined to feed most sectors of the muscle healthcare industry: drug screening, genetic and regenerative therapies, muscle building and prosthetics.

The short term impact of the project will be reflected in:
- new tools for biological investigation, especially in the field of muscle and neuromuscular junction regeneration and maintenance.
- greater accuracy of drug screening and validation thereby reducing time and costs.
- reduction of animal use for drug testing.
- increased interest of the pharmaceutical industry for muscle disorders.

The long term impact of our project includes:
- reducing the 'time to market' for drugs.
- novel drugs and other treatments for (neuro)muscular diseases.
- the foundation for other bioengineered tubular organ systems.
- modelling muscle function for optimal strength performance.
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