The bone matrix as it developed over time. (Scale bar: 5 mm.) Click here to enlarge image.
PNAS et al.

Bones often come in complex, delicate shapes, making it hard to find matching natural replacements for them in patients suffering from injuries, diseases or birth defects. Now researchers have grown bone grafts in the exact shape of a desired bone, an advance that could help provide doctors with just what they need for face, skull and other skeletal reconstructions.

Although missing bone can be replaced by titanium, "there is no better substitute for lost tissue than living tissue," bioengineer Gordana Vunjak-Novakovic at Columbia University explains. "Although titanium is better than nothing—you need something to help bear loads—real bones also have bone marrow inside that has many important metabolic functions."

Patients also could rely on donated bones, but these run the risk of contamination and tissue rejection. Or surgeons can harvest bone from elsewhere in a patient's body and carve it to fit where they need to, "but this is very hard on patients," Vunjak-Novakovic says. "The damage at the site of harvest is major, and it takes long to regenerate this tissue, and patients often report doing so hurts much more and longer than the implant itself."

Instead, bioengineer Warren Grayson, along with Vunjak-Novakovic and their colleagues, grew their own grafts. They started with the temporomandibular joint, found at the point where the jaw meets the skull in front of the ear. "It was the greatest challenge we could think of, the most complex piece in the skull in terms of shape, based on surgeons we asked," she says. "If we can grow this piece, we think we can grow anything."

The temporomandibular joint, or TMJ, is also of growing clinical relevance, Vunjak-Novakovic adds. As many as roughly one out of four people experience symptoms of disorders involving the TMJ, such as pain in the chewing muscles and jaw stiffness as well as painful clicking, popping or grating in the joint.

The researchers first used real bone as a scaffold—"we know actual bones are ideal because they work in real life," Vunjak-Novakovic says. They stripped the knee joints of calves of all their cells with detergents and enzymes and then, based on digitized x-ray images from an anonymous patient, had machines carve them into cubic-centimeter-size human jaw joints.

They next seeded each scaffold with three million commercially available human mesenchymal stem cells, which can give rise to bone, cartilage, fat and other tissues. The cells, which lined the pores of the scaffold, were regularly fed with streams of nutrients, growth factors and oxygen in a bioreactor. The pattern and rate of this perfusion guides how the bone structure grows, just as blood does in vivo, and the physical stimulation of the cells provided by this flow is critical for proper growth.