Graphical Abstract

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Three-dimensional (3D) bioprinting of photo-cross-linkable hydrogel precursors has attracted great interest in various tissue engineering and drug screening applications, as the biochemical and biophysical properties of the resultant hydrogel structures can be tuned spatiotemporally to provide cells with physiologically relevant microenvironments. In particular, these bioinks benefit from great biofunctional versatility that can be designed to direct cells toward a desired behavior. Despite significant progress in the field, the 3D printing of cell-laden photo-cross-linkable bioinks with low polymer concentrations has remained a challenge, as rapidly stabilizing these bioinks and transforming them to hydrogel filaments is hindered by their low viscosity. Additionally, reaching an optimized print condition has often been challenging due to the large number of print parameters involved in 3D bioprinting setups. Therefore, computational modeling has occasionally been employed to understand the impact of various print parameters and reduce the time and resources required to determine these effects in experimental settings. Here, we report a novel 3D bioprinting strategy for fabricating hydrogel fibrous structures of gelatin methacryloyl (GelMA) with superior control over polymer concentration, particularly in a relatively low range from ∼1% (w/v) to 6% (w/v), using a microfluidic printhead. The printhead features a coaxial core–sheath flow, coupled with a photo-cross-linking system, allowing for the in situ cross-linking of GelMA and the generation of hydrogel filaments. A computational model was developed to determine the optimal ranges of process parameters and inform about the diffusive and fluid dynamic behavior of the coaxial flow. The cytocompatibility of the biofabrication system was determined via bioprinting cell-laden bioinks containing U87-MG cells. Notably, the established pipeline from computational modeling to bioprinting has great potential to be applied to a wide range of photo-cross-linkable bioinks to generate living tissues with various material and cellular characteristics.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignant tumor. Treatment of RMS usually includes primary tumor resection along with systemic chemotherapy. Two-dimensional (2D) cell culture systems and animal models have been extensively used for investigating the potential efficacy of new RMS treatments. However, RMS cells behave differently in 2D culture than in vivo, which has recently inspired the adoption of three-dimensional (3D) culture environments. In the current paper, we will describe the detailed methodology we have developed for fabricating a 3D engineered model to study alveolar RMS (ARMS) in vitro. This model consists of a thermally cross-linked collagen disk laden with RMS cells that mimics the structural and bio-chemical aspects of the tumor extracellular matrix (ECM). This process is highly reproducible and produces a 3D engineered model that can be used to analyze the cytotoxicity and autophagy induction of drugs on ARMS cells. The most improtant bullet points are as following: We fabricated 3D model of ARMS. The current ARMS 3D model can be used for screening of chemotherapy drugs. We developed methods to detect apoptosis and autophagy in ARMS 3D model to detect the mechansims of chemotherapy agents.

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In situ bioprinting, also known as the process of depositing bioinks at the defect site, has emerged as a promising strategy for the repair and restoration of large tissues. This technology accomplishes these goals through the site-specific delivery of pro-healing structures. However, realising the full potential of this technology requires the ability to print multiple materials for simultaneous or sequential dispensing of a variety of drugs and cells for better tissue biomimicry. In this article, we describe a portable and modular bioprinter that is capable of depositing a variety of bioinks while allowing for precise control over their physicochemical properties. Using stereolithography (SLA) 3D printing, we construct microfluidic printheads with complex fluid circuitries that allow for the deposition of multi-component fibers with sophisticated cross-sectional geometries and material compositions. In addition, the modular design of this platform makes it possible to print a wide variety of bioinks, such as those that can be chemically or photo-crosslinked, as well as nano-composite inks with shear-thinning and self-healing properties. The versatility of this technology for biomedical applications is demonstrated by printing constructs for co-delivery of various drugs or cells at the same time, as well as generating implanted biosensors. Overall, this method not only has a significant potential for site-specific and in situ tissue printing, but it also has the potential to have applications in traditional ex vivo bioprinting for automated and high throughput tissue engineering.

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