What is Host-Guest Interaction Crosslinking Bioinks?


In the realm of tissue engineering, the quest for innovative and efficient bioinks has led to the emergence of host-guest interaction crosslinking bioinks. These bioinks represent a promising approach to construct complex and functional three-dimensional (3D) structures that mimic the intricate architecture of native tissues. To understand the significance of host-guest interaction crosslinking bioinks, it is essential to delve into the basics of bioinks, tissue engineering, and the crosslinking mechanisms involved.

Guest-host cross-linking. Figure 1. Guest-host cross-linking.(Asim S, et al.; 2023)

Bioinks and Tissue Engineering

Bioinks serve as the building blocks in 3D bioprinting, a revolutionary technique in tissue engineering. Tissue engineering aims to create functional tissues and organs by combining cells, biomaterials, and signaling factors. Bioinks act as the supportive matrix that encapsulates cells and provides a structural framework for their growth and differentiation. The choice of bioink is crucial, as it directly influences the success of 3D bioprinting by determining the mechanical properties, biocompatibility, and printability of the final construct.

Traditional bioinks rely on physical or chemical crosslinking methods to solidify the printed structure. Physical crosslinking involves processes like cooling or gelation, while chemical crosslinking utilizes chemical reactions to create a stable network. However, these methods often come with challenges such as toxicity, limited control over the crosslinking process, and potential damage to encapsulated cells.

Host-Guest Interaction Crosslinking:

Host-guest interaction crosslinking represents a novel and versatile approach to address the limitations of traditional crosslinking methods. This technique is inspired by supramolecular chemistry, a field that explores non-covalent interactions between molecules. In the context of bioinks, host-guest interaction crosslinking involves the use of host and guest molecules that can form reversible bonds, allowing for dynamic and controllable crosslinking.

The host molecules typically have cavities or pockets that can accommodate the guest molecules. Common host-guest pairs include cyclodextrin and adamantane, cucurbituril and guest molecules, or pillar[n]arenes and guest molecules. The reversible nature of these interactions enables the bioink to maintain its structural integrity while providing the flexibility needed for cellular activities, such as migration, proliferation, and differentiation.

Advantages of Host-Guest Interaction Crosslinking Bioinks


Host-guest interaction crosslinking relies on non-covalent bonds, reducing the risk of toxicity associated with some chemical crosslinkers. This enhances the biocompatibility of the bioink, ensuring a supportive environment for encapsulated cells.

Controllable Crosslinking:

The reversible nature of host-guest interactions allows for precise control over the crosslinking process. Researchers can modulate the strength of the bonds, enabling dynamic adjustments to the mechanical properties of the bioink and the printed structure.

Cell Viability and Functionality:

Compared to traditional crosslinking methods, host-guest interaction crosslinking minimizes the impact on cell viability and functionality. The gentle crosslinking process preserves the cellular microenvironment, promoting better cell survival and physiological behavior.


Host-guest interaction crosslinking bioinks often exhibit improved printability, enabling the creation of intricate 3D structures with high resolution. This is crucial for replicating the complex architecture of native tissues and organs.

Applications in Tissue Engineering

Cartilage Regeneration:

Host-guest interaction crosslinking bioinks have shown promise in cartilage regeneration. The dynamic crosslinking allows the bioink to mimic the mechanical properties of native cartilage, and the biocompatible nature supports the growth and differentiation of chondrocytes.

Vascular Tissue Engineering:

Creating functional vascular networks is a key challenge in tissue engineering. Host-guest interaction crosslinking bioinks offer a solution by facilitating the construction of intricate vascular structures that support nutrient and oxygen transport, crucial for the viability of thicker tissue constructs.

Skin Tissue Engineering:

In skin tissue engineering, host-guest interaction crosslinking bioinks can be employed to produce skin substitutes with enhanced mechanical properties and improved integration with the host tissue. The reversible bonds contribute to the flexibility required for natural skin movement.

Neural Tissue Engineering:

Mimicking the complexity of neural tissues is a demanding task. Host-guest interaction crosslinking bioinks provide a platform for creating 3D neural constructs that support the growth and connectivity of neurons, paving the way for advancements in brain tissue engineering.

Challenges and Future Directions

While host-guest interaction crosslinking bioinks hold tremendous potential, there are challenges that researchers must address to fully harness their benefits. Achieving optimal mechanical properties, scalability, and long-term stability without compromising biocompatibility remains a focus of ongoing research.

Future directions in this field involve exploring new host-guest pairs, refining crosslinking kinetics, and developing bioinks that respond to external stimuli, such as light or temperature. Additionally, efforts are underway to combine host-guest interaction crosslinking with other innovative approaches, such as incorporating bioactive molecules or utilizing multiple materials in a single bioink.


Host-guest interaction crosslinking bioinks represent a significant advancement in the field of tissue engineering and 3D bioprinting. Their biocompatibility, controllable crosslinking, and applicability across various tissues make them a promising tool for creating functional and intricate constructs. As researchers continue to refine and expand the capabilities of these bioinks, the prospect of generating complex, personalized, and therapeutically relevant tissues and organs comes closer to realization. The intersection of supramolecular chemistry and tissue engineering opens new avenues for overcoming challenges and pushing the boundaries of regenerative medicine.


  1. Asim S, et al.; Advances in Gelatin Bioinks to Optimize Bioprinted Cell Functions. Adv Healthc Mater. 2023, 12(17):e2203148.
For research use only, not intended for any clinical use.