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Biomimetic Approaches for the Design and Fabrication of Bone-to-Soft Tissue Interfaces

Bone-to-soft tissue interfaces are responsible for transferring loads between tissues with significantly dissimilar material properties. The examples of connective soft tissues are ligaments, tendons, and cartilages. Such natural tissue interfaces have unique microstructural properties and characteristics which avoid the abrupt transitions between two tissues and prevent formation of stress concentration at their connections. Here, they review some of the important characteristics of these natural interfaces. The native bone-to-soft tissue interfaces consist of several hierarchical levels which are formed in a highly specialized anisotropic fashion and are composed of different types of heterogeneously distributed cells. The characteristics of a natural interface can rely on two main design principles, namely by changing the local microarchitectural features (e.g., complex cell arrangements, and introducing interlocking mechanisms at the interfaces through various geometrical designs) and changing the local chemical compositions (e.g., a smooth and gradual transition in the level of mineralization). Implementing such design principles appears to be a promising approach that can be used in the design, reconstruction, and regeneration of engineered biomimetic tissue interfaces. Furthermore, prominent fabrication techniques such as additive manufacturing (AM) including 3D printing and electrospinning can be used to ease these implementation processes. Biomimetic interfaces have several biological applications, for example, to create synthetic scaffolds for osteochondral tissue repair.


Most of natural organisms consist of assemblages of hard and soft tissues. These hard–soft compartments can create interfaces that are functionally adaptive, sustainable, and less prone to failure. Therefore, they can be a source of inspiration for engineers and biologists who aim to design and build synthetic hard–soft interfaces (HSIs).

When joining two dissimilar materials, the elastic stiffness mismatches determine how effectively a contact between two materials can occur. This is due to the fact that the distinct deformation between the extreme hard–soft connection gives rise to interfacial stresses, decreasing structural integrity and making the interface susceptible to failure. In Nature, however, the union of two materials with nonidentical properties can be frequently seen. These natural interfaces provide structural and functional integration between different tissues, where the mechanical properties can gradually change through variations in mineral contents and matrix compositions.

An example of such interfaces is the connection of bone that possesses an elastic stiffness of ∼20 GPa to soft tissues such tendons and ligaments whose elastic stiffnesses are 2 to 3 orders of magnitude lower.

Bone-to-soft tissue interfaces (BSTIs) are critical for the musculoskeletal system’s complexity, which needs to ensure the efficiency of load transferring between distinct tissues. The microstructures of BSTIs are highly heterogeneous and anisotropic, consisting of gradual variations in materials composition from bone to soft tissues for the human knee joint. Although these interfaces are durable, they experience various defects over the life span of humans and can be damaged by loading, particularly when the joint interfaces are degenerated. Failure of BSTIs usually leads to long-term injuries, as the healing process fails to regenerate the complexity of the native tissue interface. Due to the inability of the body to regenerate the natural structure of the BSTIs, the scar tissues that form the interfaces and also the surgically repaired interfaces can both be susceptible to retear even under normal physiological loading conditions. These observations underline the importance of re-establishing the original properties of the native BSTIs for creating artificial biomimetic tissue interfaces.


Structure of bone-to-soft interfaces in the human knee joint. (a) Human knee (from Servier Medical Art) illustrating a blue box for the osteochondral interface (OI) and a red box for the enthesis (E). (b) Schematic of the osteochondral interface divided into the morphology and distribution of the cells (left) and the matrix organization (right) within the different zones in the OI. Panel b is reproduced with permission. (c) Diagram showing the gradients observed in the OI. (d) Histological image of the osteochondral unit showing the different zones in the OI. The subfigure corresponds to a picrosirius red stained sample, imaged with a polarized light filter that shows the collagen distribution (aligned in orange and random in green). Panel d is reproduced with permission. (e) Schematic of the ligament/tendon interface (enthesis, E) showing the predominant type of collagen and its orientation, and the type and morphology of the cells present in each zone. Panel e is reproduced with permission. (f) Diagram showing the gradients observed in the enthesis. (g) Histological image of the enthesis showing the different zones connecting the tendon and bone. The subfigure corresponds to a fluorescence microscope image showing the fibers of collagen type II in bright orange.

Advances in tissue engineering offer promising solutions for repairing ruptured tissue interfaces through scaffold engineering and tissue grafting. Engineered tissue scaffolds have mostly been manufactured through conventional technologies such as electrospinning, freeze-drying, salt leaching, solvent-casting particulate leaching, thermally induced phase separation, gas foaming, and emulsification. Even though these fabrication techniques have shown remarkable progress, they are inadequate for accurately mimicking the hierarchical organization of native tissue interfaces. The fabrication of monolithic biomaterials using conventional techniques challenges the inclusion of heterogeneous mechanical, chemical, and biological properties required for generating scaffolds to repair the degenerated interface.Due to the intricacy of fabricating such scaffolds, recent approaches have shifted toward additive manufacturing (AM) technologies that focus on building 3D structures, also known as 3D printing. 3D printing includes very different approaches, such as vat photopolymerization, material extrusion, material jetting, binder jetting, powder bed fusion, direct energy deposition, and sheet lamination. For language simplicity, the terms AM and 3D printing are used interchangeably in this review. AM technologies, and particularly multimaterial 3D printing, enable the fabrication of complex geometrical scaffolds with a high spatial resolution, as well as multiple gradients in 3-dimensions, thereby potentially incorporating more than one material and other chemical and biological factors within a structure. AM also offers an improved strategy to fabricate intricate multilayered and graded scaffolds with interconnected networks and porosities.


(a) Histological illustration of the enthesis of a mouse supraspinatus, consisting of four zones: bone, calcified fibrocartilage, uncalcified fibrocartilage, tendon. (b) Biomimetic strategies for hard–soft interface tissue engineering, including the use of monolithic, layered, and gradient scaffolds with different cell types and materials properties resembling the native tissue. (c) Brick-and-mortar structure of nacre. (d) Illustration of a complex bone screw biomimetic design comprised of 3D-printed porous bone and fibrous scaffolds aiming at regenerating the bone–soft tissue interface. (e) Cryo-cut cross section of the porcine bone–tendon interface, displaying dense morphology to fibrous-like structure (from left to right). Panel e is reproduced with permission. (f) Biomimetic approaches for the hard–soft interface using functionally graded design by varying the composition (left), microstructure (middle), and porosity (right). Panel f is reproduced with permission.


Although recently several complex multilayered and graded scaffolds have been developed to satisfy specific mechanical and biochemical cues for tissue interface engineering, the challenge remains to reconstruct the interconnectivity of the bone-to-soft tissue to form the optimum interface that can maintain the structural integrity under different physiological loading scenarios. Previously published review articles have already described different techniques (i.e., AM or non-AM) used for the fabrication of BSTIs. Here, they discuss the limitations and challenges of those manufacturing techniques for fabricating various types of artificial interfaces. They also highlighted the current progress in extracting and implementing design motifs of natural interfaces (e.g., interlocking mechanisms, functional gradient) into the design and fabrication of biomimetic interfaces which is essential for successful interface engineering. In this review, therefore, they aim to explore the current advances in the state-of-the-art design and fabrication of BSTIs. Toward this aim, they collected some of the essential design principles and characteristics of the structure of BSTIs. They further identified the most important mechanisms mediating the load transfer in BSTIs, allowing deduction of biomimetic guidelines for tissue interface engineering.


  1. Biomimetic Approaches for the Design and Fabrication of Bone-to-Soft Tissue Interfaces Carlos Pitta Kruize, Sara Panahkhahi, Niko Eka Putra, Pedro Diaz-Payno, Gerjo van Osch, Amir A. Zadpoor, and Mohammad J. Mirzaali ACS Biomaterials Science & Engineering Article ASAP DOI: 10.1021/acsbiomaterials.1c00620