A team of UConn Health researchers have designed a new hybrid hydrogel system to help address some of the challenges of bone repair in the event of an injury. The UConn Health team, led by Associate Professor of Orthopedic Surgery Syam Nukavarapu, described their findings in a recent issue of Journal of Biomedical Materials Research-Part B, where the work is featured on the cover of the newspaper.
There are over 200 bones in an adult human skeleton, ranging in size from a few millimeters to over a foot. How these bones are formed and how they are repaired when injured varies, and has posed a challenge for many researchers in the field of regenerative medicine.
Two processes involved in the development of the human skeleton help all of the bones in our body to form and grow. These processes are called intramembranous and endochondral ossification, IO and EO respectively. Although they are both essential, IO is the process responsible for forming flat bones, and EO is the process that forms long bones like the femora and humerus.
For both processes, generic mesenchymal stem cells (MSCs) are needed to trigger the growth of new bone. Despite this similarity, OI is much easier to recreate in the lab, as MSCs can directly differentiate, or specialize, into bone-forming cells without taking any additional action.
However, this relative simplicity has its limits. To work around the problems associated with OI, the UConn Health team set out to develop a modified extracellular matrix that uses hydrogels to guide and support bone formation by EO.
“So far, very few studies have focused on designing matrices for endochondral ossification to regenerate and repair long bones,” says Nukavarapu, who holds joint positions in the departments of biomedical engineering and of materials science and engineering. “By developing a hybrid hydrogel combination, we were able to form a modified extracellular matrix that could support the formation of model cartilage.”
Nukavarapu notes that vascularity is the key to the repair and regeneration of segmental bone defects. The main problem with bone formed by IO is caused by a lack of blood vessels, also called vascularity. This means that IO is not able to regenerate enough bone tissue to be applied to large bone defects resulting from trauma or degenerative diseases like osteoporosis. Although many researchers have tried various strategies, the successful vascularization of bone regenerated by IO remains a significant challenge.
On the other hand, vascularization is a natural result of EO due to the development of a cartilage pattern, chondrocyte hypertrophy and possible formation of bone tissue.
While the simplicity of IO has caused limitations, the benefits of EO translate into a complex balancing act. EO requires precise spatial and temporal coordination of different elements, such as cells, growth factors, and an extracellular matrix, or scaffold, on which MSCs attach, proliferate, and differentiate.
To achieve this delicate balance in the lab, Nukavarapu and his colleagues combined two materials known to promote tissue regeneration – fibrin and hyaluronan – to create an effective extracellular matrix for long bone formation. The fibrin gel mimics human bone mesenchymal stem cells and facilitates their condensation, which is necessary for the differentiation of MSCs into chondrogenic cells. Hyaluronan, a naturally occurring biopolymer, mimics the later stages of the process by which differentiated chondrogenic cells develop and proliferate, also known as hypertrophic-chondrogenic differentiation.
The researchers predict that cartilage models with hypertrophic chondrocytes will release bone and vessel-forming factors and also initiate the formation of vascularized bone. Nukavarapu says that “the use of cartilage-model matrices would lead to the development of new bone repair strategies that do not involve harmful growth factors.”
Although they are still in the early stages of the research phase, these developments hold promise for future innovations.
“Dr Nukavarapu’s work speaks not only of the preeminence of UConn’s faculty, but also of the potential applications of their research in the real world,” said Radenka Maric, vice president of research at UConn and UConn Health. . “UConn Laboratories are teeming with these types of innovations that contribute to scientific breakthroughs in health, engineering, materials science, and many other fields.”
The researchers then plan to integrate the hybrid extracellular matrix into a load-bearing scaffold to develop models of cartilage suitable for repairing defects in long bones. According to Nukavarapu, the UConn research team hopes this is the first step towards forming a model of hypertrophic cartilage with all the right ingredients to initiate the formation of bone tissue, vascularity, remodeling and ultimately the establishment of a functioning bone marrow to repair defects in long bones. via EO.
The work was supported by grants from the AO Foundation (S-13-122N), NSF Emerging Frontiers in Research and Innovation (EFRI) (1332329), and NSF Emerging Frontiers and Multidisciplinary Activities (EFMA) (1640008).
Research in Syam Nukavarapu’s laboratory focuses on biomaterials and tissue engineering, with an emphasis on tissue engineering of bone, cartilage and the bone-cartilage interface. UConn’s other authors include graduate students Paiyz E. Mikael and Hyun S. Kim.