A little over ten years ago, Professor Jeff Schwartz from the Chemistry department decided to redirect his studies. It all began when, in the course of a medical examination, he had been told that orthopedic implants could fail because of poor tissue integration with the implant materials and, in particular, titanium. This was a well-known problem with implants – though cells may initially interface with titanium bone implants, they will eventually reject it, necessitating replacement. The body surrounds the foreign implant material with inflammatory cells, driving the implant away from the bone and tissue it is supposed to connect to. Schwartz however, who had previously been building catalysts by attaching metallic complexes to oxide surfaces, felt that the implant problem was something he could change. He decided to address this problem by coating metals with phosphonates – a wide class of organic molecules with various chains of atoms branching off a central phosphorus atom. These groups can be changed individually, creating structures with properties that can easily be fine-tuned. If cells could be induced to adhere to these phosphonates, the implant technique could be adapted to improve orthopedic technology. If bone forming cells – osteoblasts – were encouraged to adhere to the implants, Schwartz thought, this effect could be reversed.
A COLLABORATION BORN
To test the coating, he called a colleague he had never met before, Professor Jean Schwarzbauer of the Molecular Biology department. Her research focused on how cells adhere to and interact with the natural organizing structure of the extracellular matrix, so she was ideally situated to test cells’ adhesion to Schwartz’s material. She agreed to run the tests, but not out of passion for the research; she says “I said yeah, sure, thinking, you know, I’ll never hear from this guy again … and like two weeks later, he calls me back ‘Oh, we figured it all out, we’re ready to go!’”
Small teams from each lab began collaborating – coating titanium samples in Schwartz’s lab, then testing in Schwarzbauer’s. They found that the cells adhered well to the treated metal – and that the teams were integrating as well. “We could tell pretty early that there was a good rapport and a good interest on both sides,” says Schwarzbauer, noting that poor collaboration could have ruined the project as surely as any scientific issue.
TESTING THE TECHNIQUE
Schwartz’s technique for coating the titanium with phosphonates exploits the natural titanium oxide layer which forms at the metal’s surface when it is exposed to air. When titanium is placed in phosphonate solution, dissolved phosphonates will assemble a molecule-thick layer on the oxide, creating what Schwartz calls a SAMP – Self-Assembling Monolayer of Phosphonates. The phosphonates present a surface to which cells will readily and directly adhere.
Animal trials yielded promising results. In rabbits, SAMP-coated titanium implants consistently integrated with the bone better than the industry-standard hydroxyapatite-coated implants. The monolayer’s thinness also proved advantageous: Titanium implants often have a porous surface to provide more surface area for the bone to adhere to, but hydroxyapatite coatings are so thick that they block these pores, rendering them useless. The phosphonate coating is one million times thinner than the hydroxyapatite coating, and can coat the insides of the pores without blocking them. The bone is thus encouraged to grow within the implant, further increasing the implant’s strength and lifetime.
To fully exploit the SAMP process, the team began to apply SAMPs to softer materials, moving beyond rigid titanium. They focused on organic polymers, whose huge variety allows an equally large collection of applications. But first, Schwarzbauer says, “Jeff had to develop a new type of chemistry” to attach the phosphonates to the polymers, which lack the oxide anchor found on titanium. The basic process is similar to that for titanium – SAMPs still bind to a metal oxide layer – but the oxide (often zirconium-based) must be artificially attached, adding another step to the process. Here, the diversity of polymers works against the researchers, as slightly different coating techniques must be developed for each substrate. However, each material yields exciting new possibilities.
For example, consider the difference between polyether ether ketone (PEEK, a rigid plastic), and silk, a quintessentially soft polymer. PEEK, when combined with carbon fiber, mimics the properties of bone more closely than titanium. It is seldom used in orthopedics, though, because the plastic is even less adhesive to cells than titanium is. SAMP treatment, however, opens the door to new bone-like implants from this material. Silk, on the other hand, does not mimic bones, but SAMP-treated silk can act as a temporary soft-tissue graft, degrading once cells have grown back around it. The substrates do not even have to be used structurally – fixing cells to silicon, for instance, could create extremely sensitive biosensors, as silicon microchips would interface directly with cells.
Beyond simply applying SAMPs haphazardly, the two professors are now laying down the phosphonates in specific patterns, organizing the cells in whatever pattern is expressed on the substrate. If this technique can be applied to guide cells as they regrow over damaged tissue, it could promote faster healing with far more cell organization, reducing scarring. Since the strength of tendons and ligaments is derived from parallel cell growth, this guided healing would provide improved functionality and strength to torn connective tissue, when compared to unsupported regrowth. These advantages have caught the attention of none other than the National Football League, a significant sponsor of Schwartz’s research. To Schwartz and Schwarzbauer, new regenerative techniques are just over the horizon; “And then we’re going to use that on Jean’s knee and on my back!”, Schwartz quips.
The patterned SAMPs have allowed Schwarzbauer to return to projects from before Schwartz contacted her, with a new perspective. She had long hoped to construct an artificial extracellular matrix to explore how matrix organization affects cell behavior. Schwarzbauer’s previous collaborators had failed to order the matrix on a small enough scale, as they were simply “painting” arbitrarily arranged matrix proteins. Now, with her and Schwartz’s technique, she can arrange the cells in incredibly precise patterns and have them generate a well-ordered matrix on their own. Such fine control allows Schwarzbauer to explore matrix properties in ways not previously possible, including studying how the extracellular matrix affects tumors and stem cells.
When Schwartz first called Schwarzbauer, he wanted to only test a few samples, and she never thought he’d come through with anything. Now, the collaboration between the two has pushed the limits of medical science and prodded Schwarzbauer’s work in exciting new directions. With fascinating research in the pipeline and a strong team that continues to collaborate with passion and cohesiveness, the Schwartz and Schwarzbauer labs have produced a new biochemical interface between cells and synthetics – and a new collaborative interface between chemistry and biology.