Microfluidics and Tissue Engineering: A Novel Approach to Regenerative Medicine

Each year, thousands of people across the globe are added to an organ transplant waiting list, hoping for a miracle that will save their lives. As of 2022, there were over 106,000 people on the U.S. organ transplant list¹, while approximately 40,000 transplants were performed in 2021. Clearly, the demand for organs far exceeds the supply, and for many the wait is heartbreaking and painful—many people die every day while waiting.
 
Imagine a world where organ transplant is no longer needed, or organs can be created without the need for a donor. Currently, researchers are utilizing tissue engineering to design and bio-manufacture functional tissues and organs in-vitro. Tissue engineering is a rapidly growing multidisciplinary field involving cells, biomaterials, and growth factors to create tissues and organs that may be used to replace damaged body tissues.
 
Advancements in the microfluidics field have helped to develop complex 3D scaffolds for regenerative medicine that can support long-term viable cell incorporation and function. Scaffolds are three-dimensional structures that mimic natural tissues' architecture and support cell growth and differentiation in tissue engineering applications.

Materials for Microfluidic Scaffolds

Material selection is a crucial part of scaffold development. Materials are often selected for a specific application based on their properties because of the unique structural components of different organs/tissues. Ideally, a scaffold in tissue engineering should possess a combination of properties that promote optimal cell behavior, such as proliferation, differentiation, and tissue regeneration. These properties include the following:

• Surface properties promote cell adhesion, proliferation, and differentiation or phenotype maintenance, allowing for successful tissue growth, development, and function.
• Biocompatibility ensures the scaffold does not cause cell toxicity, inflammation, or foreign body response; in other words, the scaffold's ability to retain high cell viability and promote cell growth and proliferation.
• Biodegradability allows the scaffold to degrade in a safe (releasing non-toxic degradation products) and timely manner to allow for eventual replacement by newly formed tissue.
• Mechanical properties, such as strength, flexibility, and elasticity provide structural support for the growing tissue and maintain appropriate cell phenotype.
• High porosity and a high surface-to-volume ratio, with an interconnected pore network, provide a suitable environment for cell growth and the flow of oxygen, nutrients, and metabolic waste.

Various materials have been used to construct scaffolds for tissue engineering via microfluidic systems. Some examples include the following:

Natural materials: Scaffolds are often developed from natural materials sourced from plants and animals. These materials include alginate from seaweed, gelatin from animal skin, silk from worm cocoons, Matrigel from the basement membrane of cultured mouse cells, and fibrin from blood. Natural materials generally possess good biocompatibility and may contain cell adhesion and growth factors that mediate cell integration and proliferation, making them a popular choice in scaffold manufacturing. However, these materials have limited mechanical properties, highly variable biodegradability and may also suffer from significant batch-to-batch variability due to feedstock variation.
 
Synthetic materials: These materials are artificially developed to tackle the issues associated with their naturally sourced counterparts. They can encompass a greater range of mechanical properties with improved stiffness and elasticity. These materials commonly include homo and co-polymers of polylactic acid (PLA), polyglycolic acid (PGA) and polyethylene glycol (PEG) due to their accepted biocompatibility and/or biodegradability.

Scaffold Development Techniques

Different techniques have been applied to engineer organ-specific scaffolds that mimic the complex microenvironment of the tissue and are used to study tissue microphysiology as a non-animal model for drug toxicity screening. Microfabrication techniques, including photolithography, soft lithography, etching, and micro molding, are used to develop microfluidic tissue scaffold devices for small-scale tissue engineering applications, such as organ-on-a-chip devices. The microfluidic channels in these scaffolds can be used to deliver nutrients and other bioactive molecules to the cells and remove waste products.

For even more complex 3D scaffolds, microfluidics combined with additive manufacturing has given birth to the field of 3D bioprinting that enables the creation of a controllable environment for reconstructing tissues and organs with great accuracy. Briefly, 3D bioprinting involves building a scaffold layer by layer using natural or synthetic polymers embedded with living cells and nutrients, often called bioinks. Bioinks are hydrogel-based materials that have been engineered to recapitulate the in-vivo properties of the same tissue. Once printed, these bioinks often depend on crosslinking to transform into a gel-like structure with embedded cells. Then, the constructed biomaterial is cultured in a medium with nutrients to promote cell growth and improve viability.
 
Some bioinks use targeted drug delivery techniques to manipulate the activity of embedded cells. These bioinks are often called "smart" bioinks, which have the ability to respond to changes in the scaffold's physical or chemical structure by releasing drugs. The drugs are usually encapsulated within micro/nanostructures such as nanoparticles/fibers and microspheres. Microfluidics is crucial to develop systems for the high-throughput production of drug-releasing microspheres. Advances in the development of smart bioinks for tissue engineering will revolutionize the field of regenerative medicine and tissue engineering.

Concluding Remarks

Tissue engineering is an exciting field that aims to engineer human tissue to replace damaged tissues and organs. In tissue engineering, scientists use a combination of biomaterials, cells, and bioactive molecules to construct different functional tissues and help them integrate seamlessly into the body. One crucial aspect of tissue engineering is developing scaffolds that can promote tissue growth while transporting therapeutic agents and providing the necessary mechanical structure for the new tissue to thrive.
 
The use of microfluidics in tissue engineering enables development of scaffolds with precise control over the flow of fluids and introduction of bioactive molecules. Microfluidics combined with additive manufacturing allows creation of a 3D bioprinter for printing complex, multi-layered structures that can mimic the in-vivo characteristics of native tissue, further advancing the regenerative medicine field toward the ultimate goal of on-demand tissue-engineered replacement organs.

Reference

¹ HRSA (2022) Organ Donation Statistics. Available at: https://www.organdonor.gov/learn/organ-donation-statistics (Accessed: February 2, 2023).

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Khaled Youssef is a microfluidics engineer at StarFish Medical, where he specializes in designing and developing microfluidic-based systems for life sciences applications. Khaled holds a Ph.D. in Mechanical Engineering and a diploma in Neuroscience from York University. During his Ph.D. studies, Khaled's research focused on the intersection of engineering and life sciences, specifically utilizing microfluidics for drug and microplastic toxicity screening and further understanding the neuronal network of biological model organisms. His contributions to the field earned him over 10 prestigious scholarships. After completing his Ph.D., Khaled continued his research in microfluidics and life sciences as a Postdoctoral Fellow. During this time, he worked on developing smart bandages and microfluidic-based fluorometric sensors for bacteria/virus detection.