Periodic Reporting for period 1 - BioCHIPs (BioCHIPS - Biofabricated microfluidcs CHIPS based on self assembling of CNCs to recreate the hierarchical fibrillar structure of human tissues ECM)
Berichtszeitraum: 2022-11-01 bis 2024-04-30
Drug and pharmaceutical companies lose billions of dollars due to high drug failure rates in clinical trials or post‐market safety events, largely due to the prediction limitations of current animal models and static/2D cell culture systems. This creates a direct need for in vitro models that better simulate the physiology of human organs and tissues, yielding human analogous drug responses while also contributing to reduce inconsequent animal experimentation. Organ/tissue-on-chip (OoC) technology has seen increasing interest for the development of microphysiological systems with improved predictive power for their in vitro–in vivo extrapolations. However, although addressing reasonably well the question of sample replicate throughput, the OoC platforms developed so far tend to sacrifice the ability to recreate the biophysical cues of 3D extracellular environment, which are fundamental for function in living organisms.
BioCHIPS proposes an innovative bottom-up strategy to directly fabricate cell-laden devices that recreate the unique biophysical cues from the native fibrillar ECMs and allow the design of bioengineered microtissues with arbitrary geometries for anatomical and physiological function. The proposed platform combines the concepts of matrix-assisted 3D free-form bioprinting with the controlled self-assembly of colloidal cellulose nanocrystals (CNCs) to fabricate cell-laden constructs embedded within its own fibrillar CNC hydrogel device. Our platform can array multiple independent single organ models in a high-throughput manner (number will depend on the desired model complexity and well plate used) or link multiple tissue/organ models together with microfluidic circuits that can be user-defined on their CAD designs.
BioCHIPS proposes an innovative bottom-up strategy to directly fabricate cell-laden devices that recreate the unique biophysical cues from the native fibrillar ECMs and allow the design of bioengineered microtissues with arbitrary geometries for anatomical and physiological function. The proposed platform combines the concepts of matrix-assisted 3D free-form bioprinting with the controlled self-assembly of colloidal cellulose nanocrystals (CNCs) to fabricate cell-laden constructs embedded within its own fibrillar CNC hydrogel device. Our platform can array multiple independent single organ models in a high-throughput manner (number will depend on the desired model complexity and well plate used) or link multiple tissue/organ models together with microfluidic circuits that can be user-defined on their CAD designs.
BioCHIPS builds on the 3D matrix assisted bioprinting technology developed under the scope of the ERC CoG MagTendon, combining it with a Celulose Nanocrystals (CNC) fluid gel support media, providing an innovative concept/solution for the production of free-form cellular constructs embedded within its own ECM-mimetic bioreactor. While being specifically explored by MagTendon to support the long-term in vitro maturation of tendon constructs, we observed that the developed platform shows great versatility and can be broadly applied as a general technology for the fabrication of OoC models. The main goal of Biochips was to provide proof-of-concept and explore its commercial/industrial potential using cancer modeling as the biotechnological application challenge.
As proposed, we have used the controlled self-assembly of plant-derived cellulose nanocrystals (CNC) combined with the concept of 3D bioprinting in suspension baths for the direct biofabrication of microphysiological systems embedded within an ECM mimetic fibrillar support material. The proposed CNC-based platform supports high-resolution printing of perfusable microuidic channels and embedded constructs with arbitrary freeform 3D shapes using different low viscosity hydrogel bioinks and cell types. The controlled self-assembly of CNC after printing induces their fibrillation into networks that recreate the characteristic topography of native ECMs and allows the easy interstitial diffusion of macromolecules. It enables the direct writing of living constructs/tissue models in the 3D space of a perfusable bioinspired housing material that allows diffusion of signaling biomolecules for cell–cell communications, using a simple extrusion 3D bioprinter without the need for specific microfabrication processes, equipment, or skills. The automated nature of this biofabrication platform further provides significant advantages of throughput, reproducibility, and scalability for the manufacturing of miniaturized multicellular systems with complex bioinspired 3D architectures. Additionally, the CNC matrix is transparent for real-time monitoring and embedded tissue models can be easily harvested under mild biocompatible conditions by enzymatic digestion with cellulase for further processing/characterization. This unique set of properties in a single system has not been reported to date by previous support materials used in embedded 3D bioprinting demonstrates that it provides a very promising platform for the manufacturing of OoC.
Altogether, the studies performed so far allowed to establish the the optimal characteristics and components of a marketable prototype product of BioCHIPS for future presentation to industry contacts and commercialization. As a starting point, the prototype BioCHIPS kit will be composed of multiwell plate with fibrillar matrix (tissue plate), hardener, CAD design and optionally the construct releaser (see Figure attached BioCHIPSPrototype).
Concurrently, an extensive benchmarking analysis was performed that enabled to understanding the competitive landscape and strategically position of our product to address unmet needs and emerging trends in the biofabrication and microfluidics market.
The benchmarking analysis also provided further basis for the development of our business models (both are presented in detail in the attached report).
As proposed, we have used the controlled self-assembly of plant-derived cellulose nanocrystals (CNC) combined with the concept of 3D bioprinting in suspension baths for the direct biofabrication of microphysiological systems embedded within an ECM mimetic fibrillar support material. The proposed CNC-based platform supports high-resolution printing of perfusable microuidic channels and embedded constructs with arbitrary freeform 3D shapes using different low viscosity hydrogel bioinks and cell types. The controlled self-assembly of CNC after printing induces their fibrillation into networks that recreate the characteristic topography of native ECMs and allows the easy interstitial diffusion of macromolecules. It enables the direct writing of living constructs/tissue models in the 3D space of a perfusable bioinspired housing material that allows diffusion of signaling biomolecules for cell–cell communications, using a simple extrusion 3D bioprinter without the need for specific microfabrication processes, equipment, or skills. The automated nature of this biofabrication platform further provides significant advantages of throughput, reproducibility, and scalability for the manufacturing of miniaturized multicellular systems with complex bioinspired 3D architectures. Additionally, the CNC matrix is transparent for real-time monitoring and embedded tissue models can be easily harvested under mild biocompatible conditions by enzymatic digestion with cellulase for further processing/characterization. This unique set of properties in a single system has not been reported to date by previous support materials used in embedded 3D bioprinting demonstrates that it provides a very promising platform for the manufacturing of OoC.
Altogether, the studies performed so far allowed to establish the the optimal characteristics and components of a marketable prototype product of BioCHIPS for future presentation to industry contacts and commercialization. As a starting point, the prototype BioCHIPS kit will be composed of multiwell plate with fibrillar matrix (tissue plate), hardener, CAD design and optionally the construct releaser (see Figure attached BioCHIPSPrototype).
Concurrently, an extensive benchmarking analysis was performed that enabled to understanding the competitive landscape and strategically position of our product to address unmet needs and emerging trends in the biofabrication and microfluidics market.
The benchmarking analysis also provided further basis for the development of our business models (both are presented in detail in the attached report).
As proposed, we have used the controlled self-assembly of plant-derived cellulose nanocrystals (CNC) combined with the concept of 3D bioprinting in suspension baths for the direct biofabrication of microphysiological systems embedded within an ECM mimetic fibrillar support material. The developed support CNC fluid gel allowed exceptionally high-resolution bioprinting of 3D constructs with arbitrary geometries and low restrictions of bioink choice. The further induction of CNC self-assembly with biocompatible calcium ions results in a transparent biomimetic nanoscaled fibrillar matrix that allows hosting different compartmentalized cell types and perfusable channels, has tailored permeability for biomacromolecules diffusion and cellular crosstalk, and holds structural stability to support long-term in vitro cell maturation. In summary, this xeno-free nanoscale CNC fibrillar matrix allows the biofabrication of hierarchical living constructs, opening new opportunities not only for developing physiologically relevant 3D in vitro models but also for a wide range of applications in regenerative medicine.
Although general BioCHIPS features are advantageous for building the proposed cancer models, they can be leveraged to virtually develop any tissue and OoC by simply adapting the design of the embedded constructs and microfluidic channels. Thus, BioCHIPS has a clear ptential impact in biotechnological and pharmaceutical industries. It may contribute for a faster identification of effective drugs or drug repurposing, and to bridge the gap between preclinical testing and human trials through better predictive models and safety profiles, thus reducing the research and development costs and animal experimentation. In addition to the healthcare sectors, a number of additional industries might benefit from BioCHIPS. These include, among others, the food (for testing allergenic potential of food ingredients), cosmetics (for testing cosmetic products in particular because of the ban on animal use for skin and eye tests in Europe), chemical (for testing hazardous effects of chemicals) and veterinary industries (for testing household pet medications and medical treatments), thus extending the impact beyond the scope of the human healthcare sector.
Although general BioCHIPS features are advantageous for building the proposed cancer models, they can be leveraged to virtually develop any tissue and OoC by simply adapting the design of the embedded constructs and microfluidic channels. Thus, BioCHIPS has a clear ptential impact in biotechnological and pharmaceutical industries. It may contribute for a faster identification of effective drugs or drug repurposing, and to bridge the gap between preclinical testing and human trials through better predictive models and safety profiles, thus reducing the research and development costs and animal experimentation. In addition to the healthcare sectors, a number of additional industries might benefit from BioCHIPS. These include, among others, the food (for testing allergenic potential of food ingredients), cosmetics (for testing cosmetic products in particular because of the ban on animal use for skin and eye tests in Europe), chemical (for testing hazardous effects of chemicals) and veterinary industries (for testing household pet medications and medical treatments), thus extending the impact beyond the scope of the human healthcare sector.