This is cartilage template formation via engineered extracellular matrix. Credit: Syam Nukavarapu/UConn Photo

Researchers from the University of Connecticut have created a hybrid hydrogel system that could help doctors repair injured bones.

When bones are injured, the body goes through a pair of processed called intramembranous ossification (IO) and endochondral ossification (EO) to repair the injured bone. In both processes, generic mesenchymal stem cells (MSC) are required to trigger the growth of new bone.

Intramembranous ossification is significantly easier to recreate in the lab because MSCs can directly differentiate, or become specialized, into bone-forming cells without taking any additional steps.

While there are limitations of what scientists can do in the lab, the UConn team was able to develop an engineered extracellular matrix that uses hydrogels to guide and support the formation of bone through EO.

“Thus far, very few studies have been focused on matrix designs for endochondral ossification to regenerate and repair long bone,” Syam Nukavarapu, who holds joint appointments in the departments of biomedical engineering and materials science and engineering, said in a statement. "By developing a hybrid hydrogel combination, we were able to form an engineered extracellular matrix that could support cartilage-template formation."

According to Nukavarapu, IO-formed bone can cause a lack of blood vessels called vascularization, which means that IO is not capable of regenerating enough bone tissue to be applied to large bone defects that result from trauma or degenerative diseases like osteoporosis.

Vascularization is also a natural outcome of EO because of the development of a cartilage template, chondrocyte hypertrophy and eventual bone tissue formation. EO requires precise spatial and temporal coordination of different elements, including cells, growth factors and an extracellular matrix onto which the MSCs attach, proliferate and differentiate.

To achieve this, the researchers combined fibrin and hyaluronan, both know to encourage tissue regeneration, to create an effective extracellular matrix for long bone formation.

Fibrin gel mimics human bone mesenchymal stem cells and facilitates their condensation, which is required for MSC differentiation into chondrogenic cells. Hyaluronan is a naturally occurring biopolymer and mimics the later stages of the process by which differentiated chondrogenic cells grow and proliferate, also known as hypertrophic-chondrogenic differentiation.

The team expects cartilage templates with hypertrophic chondrocytes will release bone and vessel forming factors, as well as initiating vascularized bone formation.

Nukavarapu said the use of cartilage-template matrices could lead to new repair strategies that do not involve harmful growth factors.

The team will now try to integrate the hybrid extracellular matrix with a load-bearing scaffold to develop cartilage templates suitable for long-bone defect repair.