What Materials are Suitable for Printing with Thermal Crosslinking Bioinks?


In recent years, the field of bioprinting has seen remarkable advancements, offering promising solutions in tissue engineering, regenerative medicine, and drug delivery. Among various techniques, thermal crosslinking bioprinting has emerged as a significant approach due to its ability to create complex structures with high precision and cell viability. However, the success of this technique heavily relies on the selection of suitable materials, known as bioinks. This article delves into the characteristics of materials compatible with thermal crosslinking bioprinting, exploring their properties, applications, and future prospects.

Overview of the main application scenarios of sacrificial biomaterials based on physical and chemical polymer crosslinking principles in 3D bioprinting.Figure 1. Overview of the main application scenarios of sacrificial biomaterials based on physical and chemical polymer crosslinking principles in 3D bioprinting.(Liu S, et al.; 2022)

Thermal crosslinking bioprinting is a process that involves the precise deposition of bioinks, which are then solidified through thermal stimulation. This technique offers several advantages, including minimal damage to encapsulated cells, high printing resolution, and the ability to create intricate structures. The crosslinking process typically occurs at mild temperatures, preserving the viability and functionality of embedded cells, making it suitable for various biomedical applications.

Suitable Materials for Thermal Crosslinking Bioinks

Gelatin-based Hydrogels:

Gelatin is a widely used biomaterial derived from collagen, offering excellent biocompatibility and biofunctionality. Gelatin-based hydrogels undergo thermal crosslinking upon exposure to temperatures above their gelation point, forming stable networks. These hydrogels provide a conducive environment for cell proliferation, making them ideal for tissue engineering applications such as skin, cartilage, and bone regeneration.


Alginate is a natural polysaccharide extracted from seaweed, renowned for its biocompatibility and ease of gelation. Thermal crosslinking of alginate occurs through the formation of junction zones between polymer chains upon heating. Alginate-based bioinks are commonly utilized in bioprinting due to their ability to support cell growth and maintain structural integrity. They find applications in creating vascularized tissue constructs, wound dressings, and organ scaffolds.


Collagen is a major structural protein in the extracellular matrix, offering a biomimetic environment for cell adhesion and proliferation. Thermal crosslinking of collagen-based bioinks involves the denaturation and reassembly of collagen molecules upon heating, leading to the formation of stable matrices. Collagen-based bioinks are extensively used in bioprinting skin substitutes, cardiac patches, and neural tissue constructs, owing to their resemblance to native tissues.


Fibrin is a fibrous protein involved in blood clotting, capable of forming biodegradable hydrogels upon crosslinking. Thermal crosslinking of fibrinogen occurs through the conversion of fibrinogen to fibrin upon heating, resulting in the formation of stable networks. Fibrin-based bioinks offer excellent cell adhesion and angiogenic properties, making them suitable for applications such as vascular grafts, wound healing, and myocardial regeneration.

Silk Fibroin:

Silk fibroin is a natural protein derived from silkworm silk, characterized by its biocompatibility, mechanical strength, and tunable degradation properties. Thermal crosslinking of silk fibroin bioinks involves the formation of physical and chemical crosslinks upon heating, leading to the stabilization of printed structures. Silk fibroin-based bioinks hold great potential in bioprinting load-bearing tissues, such as tendons, ligaments, and bone scaffolds, due to their robustness and flexibility.

Applications and Future Perspectives

The materials suitable for thermal crosslinking bioprinting hold immense potential across various biomedical applications:

Tissue Engineering:

These materials enable the fabrication of complex tissue constructs with controlled architecture and cellular organization. They offer solutions for repairing damaged tissues, regenerating organs, and developing personalized implants tailored to individual patients.

Drug Delivery:

Thermal crosslinking bioinks can be loaded with therapeutic agents, enabling localized and sustained drug delivery. These bioinks can be designed to release drugs in response to specific stimuli, offering precise control over dosage and release kinetics.

Disease Modeling:

By incorporating patient-derived cells into bioinks, researchers can create disease models for studying pathophysiology, drug responses, and personalized medicine. These models provide insights into disease mechanisms and facilitate the development of novel therapies.

Organ-on-a-Chip Systems:

Bioinks compatible with thermal crosslinking bioprinting can be utilized to fabricate organ-on-a-chip systems, mimicking the physiological microenvironment of human organs. These systems serve as platforms for drug screening, toxicity testing, and studying organ-level responses in vitro.

Despite significant progress, several challenges need to be addressed to unlock the full potential of thermal crosslinking bioprinting:

Enhanced Biocompatibility:

Further optimization of bioink formulations is required to improve cell viability, functionality, and long-term stability. Strategies for minimizing immune responses and promoting tissue integration need to be explored.

Scalability and Reproducibility:

Standardization of printing parameters, bioink formulations, and fabrication techniques is essential for achieving reproducible results across different bioprinting platforms. Scalable manufacturing processes are needed to translate laboratory findings into clinical applications.

Multimaterial Printing:

Developing methods for printing multimaterial constructs with spatial control is crucial for fabricating complex tissues with diverse cell types and functionalities. Integration of multiple bioinks within a single printing process presents technical challenges that require innovative solutions.


Thermal crosslinking bioprinting offers a versatile platform for fabricating complex tissue constructs with high precision and cell viability. The selection of suitable materials plays a critical role in determining the success of this technique across various biomedical applications. Gelatin-based hydrogels, alginate, collagen, fibrin, and silk fibroin are among the materials compatible with thermal crosslinking bioprinting, each offering unique properties and applications. Continued research efforts aimed at optimizing bioink formulations, enhancing biocompatibility, and addressing scalability challenges will drive the advancement of thermal crosslinking bioprinting towards clinical translation and widespread adoption in regenerative medicine and beyond.

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  1. Liu S, et al.; Application Status of Sacrificial Biomaterials in 3D Bioprinting. Polymers (Basel). 2022, 14(11):2182.
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