The architect Antoni Gaudí is famous for designing most of the Basílica de la Sagrada Família in Barcelona. If you’ve seen a photo of Barcelona, you’ve seen this church. It’s legendary for several reasons, one of which is because it remains unfinished, despite construction having started in the late 1800s.
Construction was painfully slow at the beginning partially because Gaudi was fanatical in his approach to detail. He wanted to portray pivotal scenes from the Bible along the church’s walls by creating stone sculptures. As such, on the façade there is a sculpture of the namesake family, Joseph, Mary and Jesus, all leaving Bethlehem for Egypt with Mary holding her new baby while astride a donkey.
To make the sculptures as life-like as possible, Gaudi had a worker search Barcelona for a pitiful-looking donkey. Once found, he had the donkey anesthetized and took a plaster mold of it to make his sculpture.
The rationale for the approach likely can be found in a quote attributed to Gaudi: “Man does not create, he discovers…originality consists in returning to origin.”
While the quote ostensibly applies to art and design, one Penn Medicine researcher has taken it to heart in his research. Joel Boerckel, PhD, an assistant professor of Orthopaedic Surgery and Bioengineering at the University of Pennsylvania, is working back from his discoveries about the origins of bone development in the womb to fix devastating bone defects that can be caused by tumor removal or traumatic injury.
With Eben Alsberg, PhD, a professor of Bioengineering and Orthopaedics at the University of Illinois at Chicago, Boerckel and a team of researchers are trying to find new methods to heal large (more than two centimeters) defects in bones, especially the long bones in people’s arms and legs. Currently, if a gap that wide exists due to the removal of a bone tumor or significant trauma like shattering, healing is impossible without treatment. And even then, with current state-of-the-art treatments, there’s only about a 50 percent chance of a full, proper repair. Failure often results in amputations.
“As a field, tissue engineering has generally operated by the argument that if we want to fix these large defects, to replace the missing tissue, we need to use an engineered construct that has similar qualities to the mature tissue itself.” Boerckel said. “But in our work, we’ve gone back to the origin, and reasoned that if you want to build a tissue, you should look to how the embryo builds that tissue.”
In a pair of papers published this summer, Boerckel and Alsberg describe a bone tissue engineering method that seeks to mimic the process of embryonic bone development for bone defect repair. The team, which included first-authors and former members of Alsberg and Boerckel’s labs, Anna McDermott and Samuel Herberg delivered “mesenchymal condensations” — specially engineered stem cell collections — that featured protein growth factors that could mimic the conditions that lead to prenatal bone development.
In addition to mimicking the organization and behavior of cells in the embryo, they added another important variable: the mechanical environment.
“We know through the work of pioneering development biologist Viktor Hamburger that mechanical forces such as muscle contraction in the embryo or the forces exerted by the baby kicking in the womb, are important for embryonic bone development,” Boerckel said.
In a similar way, bone fractures only heal when their mechanical environment is right — not too much movement early on, and not too little later.
Boerckel and Alsberg therefore reasoned that since these mechanical forces are important for both bone development and natural bone fracture repair, these cues would also be important for healing of large bone defects. So they created new orthopaedic plates that can be locked and unlocked. The method they found works best starts with the plates around the defect being locked for several weeks before they’re unlocked and progressively loosened to add more movement.
“While some degree of stabilization is necessary, our findings indicate the rigidity of current stabilization strategies may be less than optimal,” Alsberg said.
They also saw that if there’s too much movement early on, it disrupts blood vessel development and doesn’t allow tissues to mature properly.
However, locking up a significant fracture for the entire healing process — the current widely used method — may not yield the best results, either.
With that established, the team then took a further step to improve the developmental mimicry.
“During embryonic development, there isn’t just one growth factor,” Boerckel explained. “In our next experiments, we increased the biological complexity to more closely recreate the developmental environment.”
They did this by adding in a new protein, BMP-2, to the TGF-ß1 they used in the first paper.
“We found that regardless of whether BMP-2 was present, TGF-ß1 was critical to support repair that mirrored development,” Boerckel said. That discovery inches them closer to discovering exactly how to mimic fetal bone growth outside the womb.
Their next steps could mirror what happened with Gaudi’s church. Although the Basílica de la Sagrada Família was never finished, it likely won’t stay that way. In recent years, work has restarted in the hopes of completing the church based on Gaudi’s original concepts and vision.
Similarly, Boerckel and Alsberg are hoping that their concepts can be advanced to create new therapies and orthopaedic plates that are better suited to facilitating controlled, healing movement.
Alsberg takes the long view: “It’s our hope that this approach will one day lead to advancements that greatly enhance both the rate and quality of bone healing for patients.”