Can mimicking marine biology cure osteoporosis?
What if you were able to inject a magic material into your body that repaired a broken part without the need for invasive surgery? What if that material allowed your body to grow its way to repair? And what if that material was made from one of the most common elements on earth?
Amazing? Yes. Unheard of? No, not really. This very material has been employed in the medical industry since the mid-1990s, and indeed has become one of the most successful biomedical procedures of the last decade. It is synthetic bone cement and its development is a classic tale of bio-inspired design that holds lessons for inventors and product developers.
The name Norian presents a clue to its development. Its inventor was not a medical doctor, but a marine biologist and geologist. Norian is the name of a division of the upper Triassic geologic period distinguished by the presence of ammonites, ancient invertebrates with beautiful spiral shells. Stony coral reefs are believed to have started in the mid-Triassic.
Brent Constantz was not really thinking about medical inventions the day he plopped down in his dad's study to watch a football game. He started to peruse some of his father's medical journals and came across an article on osteoporosis. He was surprised by the statistics showing its costs to patients and hospitals. Days later, he was in the south Pacific studying corals when he put two ideas together.
Why not mimic the way corals quickly produce minerals and apply it to bone fractures? The basic materials were the same. Time was of the essence in bone healing and current practices were less than adequate because most implant coatings and defect fillers were relatively brittle ceramics.
Corals offer a clue
Constantz already was an expert on biomineralization, having studied Caribbean coral reefs under a National Science Foundation grant while at University of California-Santa Cruz. He'd later become a Fulbright scholar at the Weismann Institute under Heinz Lowenstam, considered the father of biomineralization studies. His dissertation addressed three aspects of scelerotinian, or stony, corals: their structure and mechanical performance; their behavior during biogenesis; and how they produced their skeletons.
The animals that make up corals are anthozoans, a class of invertebrate within the phylum Cnidaria, which includes a diverse assortment of creatures such as jellies, hydroids and sea anemones. The stony corals make up one of four major taxa that form coral reefs. In this mostly marine and entirely carnivorous club, you can either float or anchor yourself to a surface, and many do both within their lifespan. The corals have a mutualistic relationship with algae that produce sugars in exchange for protection and the nutritious waste from the polyps.
When corals anchor themselves, they do so as attached polyps in large colonies, and they do it by using calcium carbonate, or lime, as a cement. The Great Barrier Reef along Australia's northeastern coast, for example, is a huge collection of these colonies, built on the 10,000-year-old ruins of their ancestors' exoskeletons.
Each polyp within the colony will secrete an external skeleton of calcium carbonate or aragonite from the epidermis of its lower body and this will form a cup around the living creature. The cup is made of upwardly radiating plates joined by soft tissue. Both the hard mineral skeleton and the soft gastrovascular tissue of these corals will be joined, so that when the colony feeds at night by waving its tentacles in the water, everyone eats.
During his investigation of corals, Constantz made a key discovery: The Golgi bodies within the polyps' cells were forming seed crystals that could be used to reproduce specific coral species in a test tube. It was then that he had a vision of seeding these crystals to make roads and other artificial structures.
The early days of Norian
He launched Norian in 1987 when he was a postdoc at the U.S. Geological Survey. The company's initial goal was to make analogs of seed crystals in order to grow bone in situ. By 1995 the Norian team had performed animal and human trials of the procedure, and published "Skeletal Repair by in Situ Formation of the Mineral Phase of Bone" in Science, the American Academy of Sciences journal. It was the most cited journal article of the year and showed how injecting a paste of monocalcium phosphate, tricalcium phosphate, calcium carbonate and a sodium phosphate solution into a damaged bone created an effective cement.
The injected paste hardened quickly and gained strength from the crystallization of the carbonated apatite contained. As this dahllite crystallized more and more, the compressive strength of the material increased, eventually achieving a final strength of around 55 MegaPaascals (MPa), with a tensile strength of more than 2 MPa. This was better than cancellous bone in compressive strength and comparable in tensile strength.
The new method was successful for initial bone repair, but it was as a scaffold for new bone growth where it was most valuable. The dahllite mimicked the lattice disorder and impurities found in the mineral phase of natural bone, and most important, the solubility of the natural material. This allowed the body, using carbonic acid, to tunnel through the material to spread its capillaries and reform, thus making the material alive with the nutrients and cells necessary. In effect, the injected calcium phosphate formed a composite with new natural bone.
Spreading the use of this method had its challenges because, as Constantz put it, "the product is being manufactured by the client." He recalls one panicked call from Sweden in which an 88-year-old woman had been on the operating table for four hours and the cement had not set when they applied it.
"I explained to them how critical body temperature was to the setting," he says. "And, of course, this had been compromised after such a long time in a tourniquet."
The company set up an entire system of trainings to introduce the method.
Constantz and the Norian team continued to make refinements to the initial product, and his cross-disciplinary capabilities again proved useful. They wanted to make the cement more injectable without compromising its setting time by dilution or other side effects. From his study of a marine geological feature called the coastal anoxic ooze that was famously slippery, he knew that calcium and phosphate minerals had combined with silica for the effect. The team was able to integrate this chemistry into the cement formula, and this formed the basis for a new company, Skelekinetics.
Life after Norian
Constantz typically starts with a problem and labors to make a natural solution that will work, rather than seeking applications for an observed phenomenon. He credits his training under Jim Valentine, an evolutionist at the University of California-Santa Barbara, for his approach.
"More evolutionary training is needed for designers and inventors," he says. "It's here where you see what has worked and why."
Synthes of Davos, Switzerland, acquired Norian in 1998. Johnson and Johnson later bought Synthes; its product is now called the Norian Skeletal Repair System (SRS).
Constantz returned to Stanford to teach and since has formed several new companies, including Calera, a carbon capture and cement manufacturing operation, and Blue Planet, a deepwater desalination business. The SRS procedure is now used "round the world," and he estimates a million patients are served each year by the process, many in China.
"They must be doing pretty well still," he deadpans. "I'm still receiving royalty checks."
X-ray image by Jesper Jensen via Shutterstock.