Using 3D printing, scientists have, for the first time, simultaneously controlled the shape, type and organization of musculoskeletal tissue engineered in a laboratory to more closely mimic native developmental processes.

“This opens the door to combining large-scale cell production with advanced 3D printing methods to produce different grafts for regenerative medicine,” explains Daniel Kelly, Professor and Chair of Tissue Engineering at Trinity College Dublin and author of the study. 

“As people live longer, diseases that affect musculoskeletal tissues like cartilage are becoming more common […] Using 3D bioprinted grafts that mimic the structure and composition of target tissues should lead to better healing outcomes and hopefully delay or prevent the need for more invasive surgical procedures such as total joint replacement.”

No bones about it: The challenges of tissue engineering  

Our musculoskeletal system provides mechanical stability and support to our joints, facilitating movement. Degeneration of this system can lead to osteoarthritis (wear and tear of the protective tissues between joints) and sarcopenia (the loss of muscle strength). Musculoskeletal conditions affect mobility and are the greatest contributor to disability worldwide.

Tissue engineering aims to generate tissues and organs to help these musculoskeletal conditions and replace tissue damaged by injury or disease. To do this successfully, conditions where tissues develop naturally need to be closely replicated. During natural development, tissues form in the presence of others which provide mechanical structure and tension. These physical influences impact tissue development including the type of tissue that develops.

However, in a laboratory, only individual tissues are engineered so these cells are not supported by an extracellular environment representative of the physical and mechanical conditions during human development. Therefore, current techniques battle to replicate the tissue structure, patterning, composition, and cell-cell interactions that develops naturally in the body.

Furthermore, current methods are based on stimulating cells seeded into a scaffold material and trying to grow the tissue. These methods do not produce the different types of tissue needed and what is produced does not contain the complex collagen network essential for function. The result is tissues that do not mimic those produced by our bodies and have limited clinical utility. 

Another challenge is generating tissues at the scale needed for clinical application as Kelly explains: “When many of these cell aggregates or ’microtissues‘ are placed together, the ones in the middle often struggle to get enough nutrients and oxygen, so they can become unhealthy or die.”

Addressing these challenges are scientists at Trinity College Dublin whose goal is to engineer tissues for regenerative medicine by employing technologies such as 3D printing and devising novel strategies that more closely mimic natural processes.   

Tuneable support baths to control tissue organization

They started by printing clumps of cells that join to form filaments consisting of multiple microtissues. These are the ‘biological building blocks’ needed to produce larger tissues. Gelatin helped hold the clumps of cells in place during printing before dissolving and allowing the microtissues to fuse together. They then printed these cells into a support bath made of methacrylated xanthan gum which provided mechanical structure for the microtissues. 

“Imagine piping melted chocolate into a bowl. If the bowl is empty, the chocolate collapses into a puddle […] But if the bowl is filled with whipped cream, the piping tip can move through it. So, the cream softens where you move, then firms up again when you stop. That’s how a support bath works,” explains Kelly.

Through a series of experiments, the researchers adjusted the stiffness of the bath to the right level to optimise cell printing. Interestingly, they discovered that the shape, organization and musculoskeletal phenotype (cartilage, ligament or tendon) could be controlled by adjusting the stiffness of the support baths.

“In simple terms, we can shape living building blocks and help them become what we want,” remarks Kelly. “This is important because control of tissue organization is integral to engineering functional tissues.”

This novel bioprinting platform and ‘support baths’ provide the mechanical cues needed for cells to mature and organize in the correct way. The baths enable fusion of the microtissues and their  differentiation and structural organization can be finely tuned and directed.

This study marks a vital step forward in bioprinting and novel tissue engineering technology, but challenges remain before such tissues can be used in clinical practice. For example, one limitation of the study was incomplete microtissue filament fusion, which the team say will be addressed in future optimisation work. Other future aims include ensuring the support bath material degrades in a controlled manner as the tissues expands and aiding transport of nutrients into the centre of tissues. 

“Our work, along with others in the field, moves us closer to treatments that use a patient’s own cells to repair tissue damage. That could mean more personalised and effective therapies in the future,” remarks Daniel Kelly.

Reference: F. D. Spagnuolo, Bioprinting of Microtissues Within Mechanically Tunable Support Baths to Engineer Anisotropic Musculoskeletal Tissues, Advanced Science (2026), DOI: 10.1002/advs.202509313

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