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International Journal of Bioprinting Redefined collagen inks in cartilage printing

1. Introduction higher temperature, while a basic pH slows it down.
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However, the numerous studies on collagen fibrillogenesis
Additive manufacturing, encompassing 3D printing and have had limited impact on its bioink formulations, which
bioprinting, has become a mainstay in biomedical research, is apparent in the most recent reviews. For instance, no
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with technologies like custom implant, prosthesis, and bioprinting study has utilized, as we have done in this study,
surgical guide fabrication already integrated into clinical the acceleration of the gelation kinetics by decreasing the
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practice, enhancing personalized care. However, areas ionic strength below the physiological range. Furthermore,
like bioprinting for tissue and organ regeneration remain most of the accumulated data on fibrillogenesis may be
largely in research and development. This field is advancing, applicable in suspended bioprinting, but its utility in
yet it faces ongoing challenges related to replicating the direct bioprinting is limited due to the narrow window of
intricacies of biological structures, ensuring cell viability, gelation kinetics, enabling sufficiently good printability. In
and fine-tuning material properties to meet the stringent particular, many studies were not conducted at 37°C, 8,11,13-
demands of biological compatibility and functionality. 15,23,24 at which the fastest gelation occurs, or at high ionic
Before bioprinting can be applied clinically, it is crucial strength, further slowing down the fibrillation process. This
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to develop materials that comply with local laws and is important because lower polymerization temperatures
regulations. For example, in the European Union (EU), per produce stiffer, less flexible fibers, slowing down cell
Regulation (EU) 2017/745, medical devices are defined as spreading, while higher temperatures yield more compact
products or equipment intended for medical purposes. In structures with thinner fibers. 25,26 Additionally, the gelation
bioprinting, the bioink can be considered a medical device temperature determines the fibrillar and network structure
when it serves a function similar to that of established independent of subsequent increases in temperature.
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clinical scaffolds used in tissue engineering. Thus, the Another shortcoming is that most studies utilize turbidity
development and availability of compliant materials and measurements that can mislead the estimation of the
standardized procedures are foundational to the clinical gelation kinetics, as the induction and gelation times, as
adoption of bioprinting-based therapeutic solutions. determined by rheology, are systematically shorter than

Collagen is the most abundant extracellular matrix the induction and fibrillation times seen in turbidity
(ECM) protein in the human body. Its structural and measurements. Worse still, fibrillation, deduced by fast
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functional importance for cell function and homeostasis and large turbidity change, might not correspond to any
has made it a popular biomaterial for biomedical change in storage modulus during rheology or result in
applications, including in vitro tissue engineering and a weak gel even at very high concentrations. Similarly,
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regenerative medicine. For instance, collagen promotes cell calcium ions may inhibit gelation1 even if fibrillation
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adhesion, differentiation, and many functions governing takes place. 11
regeneration and embryonic development. However, Growth factors (GFs) are vital for cellular processes,
collagen is also involved in various cell pathologies. For such as proliferation, maturation, and differentiation,
instance, overproduction of collagen and subsequent making them essential in tissue regeneration. However,
ECM stiffening accelerate cancer progression by activating their application in tissue engineering is challenging due
signaling pathways for tumor invasion and metastasis to difficulties in maintaining GF activity and ensuring
and impede T-cell anti-tumor activity. In the context of consistent, controlled exposure over time. Collagen-
biomedical applications, this intricate balance highlights based hydrogels can serve as reservoirs for GFs, but their
collagen’s pivotal role in both advancing regenerative effectiveness varies, with GF retention ranging from 5 to
therapies and necessitating careful consideration of its 50% after seven days, depending on the specific chemical
potential in pathological tissue remodeling.
affinities of the GFs. Although GFs have been incorporated
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Type I collagen bioinks are central to extrusion into various bioinks, reports on TGF-β1, a key regulator
bioprinting. However, their use is challenging due to low of cartilage homeostasis and repair, in collagen bioinks
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viscosity and slow gelation, which can hinder high-fidelity are lacking. TGF-β1 plays a crucial role in chondrocyte
3D printing. Strategies like blending collagen with other proliferation, differentiation, and ECM production,
biomaterials or printing in support materials, i.e. suspended making it a therapeutic target for osteoarthritis. A single
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bioprinting, help enhance printability. Fine-tuning day of TGF-β exposure can trigger chondrogenic induction
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parameters like pH, concentration,10 ionic strength, 11,12 in bone marrow-derived mesenchymal stromal cells (BM-
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ion type,11 and temperature is essential for optimizing MSCs). Previous reports on TGF-β bioinks include a
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the fibrillation, morphology, porosity, and mechanical polycaprolactone (PCL)-alginate scaffold, which promoted
properties. 13-19 Moreover, its self-assembly is accelerated nasal chondrocyte proliferation and glycosaminoglycan
at lower ionic strength, increased concentration, and deposition, Gelatin methacryloyl-Polyethylene glycol
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Volume 10 Issue 6 (2024) 497 doi: 10.36922/ijb.4566