Periodic Reporting for period 1 - MagnetoPrint (MagnetoPrint: Sizing and Magnetically-assisted 3D Printing of Smart Metamaterial Hydrogels for Tissue Engineering)
Reporting period: 2021-08-01 to 2023-07-31
Tissue engineering is a rapidly growing field with significant potential for repairing damaged organs and improving drug testing methods. One of the primary challenges in tissue engineering is achieving biomimicry, where engineered tissues closely emulate their natural counterparts in terms of structure, function, and mechanical properties. This requires replicating the extracellular matrix (ECM) found in native tissues, which offers mechanical support, biochemical cues, and a scaffold for cell adhesion, playing a pivotal role in tissue development and maturation. Traditional static tissue culture methods have limitations in mimicking the dynamic and mechanically active environments that tissues encounter in the body. Especially for musculoskeletal tissues, maturation under dynamic loading conditions promotes cell proliferation and anisotropic matrix deposition which is important for biomimicry.
In the realm of tissue engineering, traditional mechanical contact-based approaches have played a significant role in providing the dynamic loading cues to engineered tissues. However, these methods are not without their limitations. One of the primary drawbacks is the challenge of maintaining sterility during direct mechanical contact with the cultured tissues, which can introduce contamination risks and complicate long-term cultivation. Furthermore, mechanical contact-based methods often offer limited control over the directionality and magnitude of the forces applied to the tissues, which can hinder the precise manipulation necessary for achieving biomimicry and promoting optimal tissue maturation.
To address this challenge, this project aimed at developing a new MagnetoPrint system which allows integration of the electromagnetic straining apparatus within the biofabricated tissues to facilitate remote loading and enhancing maturation of engineered tissues. In the system engineered during the course of this project, the electromagnetic forces can be controlled around the tissues, which can induce mechanical strain and deformation in cultured tissues. This closely mimics the dynamic conditions experienced by natural tissues during development and daily activities. In the scope of the project, systems for cartilage have been developed, where both compressive and shear forces can be generated by changing the magnetic domain orientations within the electromagnetic straining system placed over the biofabricated cell-laden constructs. In short-term maturation over 3 weeks (long-term culture experiments are ongoing), the constructs demonstrated enhanced cartilage tissue maturation under dynamic loading compared to the constructs grown in static conditions. This research is currently still ongoing, where long-term maturation of cartilage is being explored and also the system is being adapted to other musculoskeletal tissues such as muscle and tendons.
In the realm of tissue engineering, traditional mechanical contact-based approaches have played a significant role in providing the dynamic loading cues to engineered tissues. However, these methods are not without their limitations. One of the primary drawbacks is the challenge of maintaining sterility during direct mechanical contact with the cultured tissues, which can introduce contamination risks and complicate long-term cultivation. Furthermore, mechanical contact-based methods often offer limited control over the directionality and magnitude of the forces applied to the tissues, which can hinder the precise manipulation necessary for achieving biomimicry and promoting optimal tissue maturation.
To address this challenge, this project aimed at developing a new MagnetoPrint system which allows integration of the electromagnetic straining apparatus within the biofabricated tissues to facilitate remote loading and enhancing maturation of engineered tissues. In the system engineered during the course of this project, the electromagnetic forces can be controlled around the tissues, which can induce mechanical strain and deformation in cultured tissues. This closely mimics the dynamic conditions experienced by natural tissues during development and daily activities. In the scope of the project, systems for cartilage have been developed, where both compressive and shear forces can be generated by changing the magnetic domain orientations within the electromagnetic straining system placed over the biofabricated cell-laden constructs. In short-term maturation over 3 weeks (long-term culture experiments are ongoing), the constructs demonstrated enhanced cartilage tissue maturation under dynamic loading compared to the constructs grown in static conditions. This research is currently still ongoing, where long-term maturation of cartilage is being explored and also the system is being adapted to other musculoskeletal tissues such as muscle and tendons.
The following objectives were identified to establish the MagnetoPrint process and to demonstrate its effectiveness: 1) Successful synthesis of electromagnetically-deformable ferrogels and the MagnetoPrint process for controlled deformation. 2) Controlled straining of the fabricated structures under external magnetic fields due to the presence of preferential magnetic domain orientation. 3) Demonstration of enhanced tissue maturation under electromagnetic straining. The specific outcomes of each objective have been detailed below:
Research Objective 1 Synthesizing the electromagnetically-deformable ferrogels and the MagnetoPrint process for controlled deformation (WP1).
1. Ferrogels were fabricated by addition of impulse magnetized NdFeB microparticles within PDMS and curing the gels in the presence of external magnets.
2. MagnetoPrint setup consisted of an array of electromagnets which could be assembled underneath a 6 well plate arrangement contained bio-printed/fabricated tissue. The ferrogel was placed above the tissues to allow for controlled force generation for maturation.
Research Objective 2: Controlled straining of the fabricated structures under external magnetic fields due to the presence of preferential magnetic domain orientation (WP2).
1. Deformation of the Ferrogel discs placed over sham tissue samples was analysed using computational image analysis.
2. Changing the domain orientation of the NdFeB microparticles within the Ferrogels demonstrated that both compression and shear forces could be generated over the tissue samples, thereby enabling a broad range of mechanical stimulation of the tissues and introducing the possible to mimicking the joint mechanics.
Research Objective 3: Demonstration of enhanced tissue maturation under electromagnetic straining (WP3).
1. Demonstrated excellent biocompatibility over cells cultured in the presence of the Ferrogels.
2. Tissue constructs (chondrocytes encapsulated within Norbornene-functionalized hyaluronic acid) demonstrated enhanced compressive modulus, Glycosaminoglycan (GAG) production and Collagen II production in the presence of compressive loading as opposed to non-loaded constructs.
3. Longer-term maturation (i.e. upto 8 weeks) of the constructs is ongoing, where groups receiving pure compression or simply static magnetic fields is also being compared to compression+shear.
4. New setups capable to providing stretching and twisting functionalities relevant to muscle and tendon tissue engineering are being developed for future work on muscle-tendon interfaces.
Research Objective 1 Synthesizing the electromagnetically-deformable ferrogels and the MagnetoPrint process for controlled deformation (WP1).
1. Ferrogels were fabricated by addition of impulse magnetized NdFeB microparticles within PDMS and curing the gels in the presence of external magnets.
2. MagnetoPrint setup consisted of an array of electromagnets which could be assembled underneath a 6 well plate arrangement contained bio-printed/fabricated tissue. The ferrogel was placed above the tissues to allow for controlled force generation for maturation.
Research Objective 2: Controlled straining of the fabricated structures under external magnetic fields due to the presence of preferential magnetic domain orientation (WP2).
1. Deformation of the Ferrogel discs placed over sham tissue samples was analysed using computational image analysis.
2. Changing the domain orientation of the NdFeB microparticles within the Ferrogels demonstrated that both compression and shear forces could be generated over the tissue samples, thereby enabling a broad range of mechanical stimulation of the tissues and introducing the possible to mimicking the joint mechanics.
Research Objective 3: Demonstration of enhanced tissue maturation under electromagnetic straining (WP3).
1. Demonstrated excellent biocompatibility over cells cultured in the presence of the Ferrogels.
2. Tissue constructs (chondrocytes encapsulated within Norbornene-functionalized hyaluronic acid) demonstrated enhanced compressive modulus, Glycosaminoglycan (GAG) production and Collagen II production in the presence of compressive loading as opposed to non-loaded constructs.
3. Longer-term maturation (i.e. upto 8 weeks) of the constructs is ongoing, where groups receiving pure compression or simply static magnetic fields is also being compared to compression+shear.
4. New setups capable to providing stretching and twisting functionalities relevant to muscle and tendon tissue engineering are being developed for future work on muscle-tendon interfaces.
The MagnetoPrint project offers several contributions to the field of tissue engineering which represent an important scientific impact. These are summarized as follows:
Accelerated Tissue Maturation: One of the most significant impacts of this innovative system lies in its potential to expedite tissue maturation processes. Unlike conventional mechanical assemblies used for tissue maturation, the use of remote magnetic fields reduces the complexity of the system, minimizing the risk of mechanical failures and contamination of the tissue culture environment. Moreover, remote magnetic actuation enables a non-contact approach, ensuring that the tissues under study remain undisturbed and sterile throughout the maturation process.
Customizable Force Directionality: The ability to modify the direction of forces applied to tissues can closely mimic the natural mechanics of joints and other anatomical structures. Researchers and clinicians could harness this capability to precisely emulate the loading conditions experienced by specific tissues within the body. Such customization holds the promise of more accurate tissue maturation and, in turn, better outcomes for patients undergoing regenerative therapies.
Musculoskeletal Research: Musculoskeletal biomechanics researchers stand to gain valuable insights from this system. It can allow them to study the effects of different loading patterns on tissue maturation and degeneration. Such research could contribute to our understanding of conditions like osteoarthritis and pave the way for the development of preventive interventions.
Education and Training: This magnetic system could serve as a valuable educational and training tool. Medical students, healthcare professionals, surgeons, and therapists could use it to deepen their understanding of tissue mechanics and the effects of loading on tissues. Moreover, it offers a platform for refining surgical and therapeutic skills in a controlled environment.
Accelerated Tissue Maturation: One of the most significant impacts of this innovative system lies in its potential to expedite tissue maturation processes. Unlike conventional mechanical assemblies used for tissue maturation, the use of remote magnetic fields reduces the complexity of the system, minimizing the risk of mechanical failures and contamination of the tissue culture environment. Moreover, remote magnetic actuation enables a non-contact approach, ensuring that the tissues under study remain undisturbed and sterile throughout the maturation process.
Customizable Force Directionality: The ability to modify the direction of forces applied to tissues can closely mimic the natural mechanics of joints and other anatomical structures. Researchers and clinicians could harness this capability to precisely emulate the loading conditions experienced by specific tissues within the body. Such customization holds the promise of more accurate tissue maturation and, in turn, better outcomes for patients undergoing regenerative therapies.
Musculoskeletal Research: Musculoskeletal biomechanics researchers stand to gain valuable insights from this system. It can allow them to study the effects of different loading patterns on tissue maturation and degeneration. Such research could contribute to our understanding of conditions like osteoarthritis and pave the way for the development of preventive interventions.
Education and Training: This magnetic system could serve as a valuable educational and training tool. Medical students, healthcare professionals, surgeons, and therapists could use it to deepen their understanding of tissue mechanics and the effects of loading on tissues. Moreover, it offers a platform for refining surgical and therapeutic skills in a controlled environment.