Have scientists engineered the perfect regenerative bone therapy?
Have scientists engineered the perfect regenerative bone therapy?
New "HyTEC" implants were 4.5 times more effective than the clinical gold standard
A team of researchers at Stanford University recently engineered a new, better way to regenerate bone—using a completely acellular, 3D-printed, biodegradable, off-the-shelf implant. The skeptical scientist in me wanted to add “may” in front of that statement: “Scientists at Stanford University may have engineered a new, better way to regenerate bone,” but the proof is in the pilot—or should I say pudding? Chunky, boney, collagenous pudding. With hydroxyapatite sprinkles. Don’t forget the sprinkles.
In their recently-completed pilot large animal study, the research team, led by Dr. Yunzhi Peter Yang, Professor of Orthopaedic Surgery, of Materials Science, and of Bioengineering at Stanford, showed that their 3D-printed implants, known as Hybrid Tissue Engineering Constructs (or HyTEC for short) encouraged 4.5 times more bone deposition at the injury site than did the clinical gold standard—a collagen sponge soaked in Bone Morphogenetic Protein-2 (BMP-2).
Before we dive into the specifics though of what makes these HyTEC scaffolds so successful, I want to answer a question that’s been gnawing at the front of my mind. Why are so many scientists interested in devising a better method for delivering BMP-2 if we’ve been successfully treating spinal fusions with BMP-2 for decades?
The answer to that question is complicated, more complicated than I imagined it would be, and I first needed a history lesson to fully understand how BMP-2 became our fields most controversial growth factor.
BMP-2 was first approved as a bone therapy by the FDA in 2002 as part of Medtronic’s INFUSE™ Bone Graft/LT-Cage™ for the treatment of intervertebral disc degeneration. The system consists of a proprietary interbody fusion cage which surgeons fill with a collagen sponge soaked in BMP-2. The cage provides mechanical stability for the spine while the growth factor and collagen scaffold promote new bone formation. At the time, the implant revolutionized spinal fusion surgery, providing an alternative to the use of autografts in fusion cages and eliminating the need for donor bone to be invasively harvested from other parts of a patient’s body.
By 2007, it was estimated that INFUSE™ Bone Grafts were being used in 30% to 50% of all spinal fusions performed in the United States, and after more than two decades on the market, Medtronic says the implant “has been used in more than 1 million patients worldwide,” specifically for anterior and lumbar fusions.
But not all those patients experienced benefits. As surgeons experimented with using INFUSE™ Bone Grafts in an “off-label” capacity (mostly for cervical fusions and for patients who required alternative surgical approaches to those definitively approved), the incidence of complications grew. A much publicized 2011 review suggested that 10% to 50% of patients experienced “adverse events” as a result of the use of BMP-2 in conjunction with spinal fusion. Adverse events included displacement of the implant cage as well as subsidence (collapse) of the neighboring bone. Some patients experienced heterotopic ossifications and ectopic bone formation—meaning bone formed where it wasn’t supposed to. Often these complications presented asymptomatically, but a small fraction of patients experienced neurological deficits after bone formed in the spinal canal.
An inquisition led by the Senate Finance Committee spurred by these retrospective analyses led Medtronic to commission a team of Yale Scientists to conduct a $2.5 million independent third-party review of “data from more than 17 spinal studies involving more than 2,0000 INFUSE™ recipients.” The verdict? The use of BMP-2 provided no substantial benefit over the use of autografts in spinal fusions. In most cases, it didn’t perform worse than an autograft, but, according to the review, it certainly didn’t perform as well as Medtronic claimed it did.
At the same time, Stryker Biotech was manufacturing an implant to deliver BMP-7, otherwise known as Osteogenic Protein-1 (OP-1), for the repair of long bone fractures. As defined in the product’s package insert, The OP-1 Implant is “supplied as a powder comprised of recombinant human Osteogenic Protein-1 and bovine bone collagen that is mixed with sterile saline solution to form a paste which is then placed between the broken ends of the bone during surgery.”
Not long after the OP-1 Implant’s FDA approval in 2001, it began making headlines for all the wrong reasons. NPR reported that Stryker allegedly encouraged medical technicians to blend the putty with a bone filler called Calstrux, a combination the FDA never approved. These bone forming “sausages,” as NPR referred to them, often migrated in a patient’s body, forming bone in areas it wasn’t supposed to and forcing some patients to undergo secondary surgeries for removal of the new bone fragments.
In 2009, the federal government indicted Stryker and its executives for unlawfully promoting the OP-1/Calstrux implant and for misrepresenting its sales data to the FDA. In the end, federal charges against the executives were dropped in 2012 after an investigation for which Stryker pled guilty to one federal misdemeanor and agreed to pay a $15 million fine. In 2014, the OP-1 product was ultimately discontinued after being sold to Olympus.
So, after all this, why are we still trying to work with BMP-2? Although, BMP-2 is blanketed in controversy, it is still an extremely powerful endogenous signaling molecule. Our bodies naturally produce it to maintain bone health and mediate bone remodeling. Without it, in one form or another, “bone healing does not occur,” Dr. Yang told me, and it has a long history of actually improving bone formation when used appropriately. Not taking advantage of its potential would be a mistake.
Dr. Yang and his team knew there was still vital work to be done using BMP-2, so they set out to better control its release, developing an implant that maximizes BMP-2’s positive outcomes while minimizing its off-target effects.
Before Dr. Yang and his team of scientists and surgeons completed their successful pilot study in sheep, they originally studied their HyTEC implants in rats. Both large and small animal studies involved Distraction Osteogenesis, a procedure typically employed to elongate bones and repair skeletal deformities.
This brilliant animation of a Distraction Osteogenesis procedure explains it better than I ever could, but I’m going to give it a shot anyway, because you’re already here. During Distraction Osteogenesis treatment, surgeons remove a large segment of the deformed or injured bone, creating a void in the process that won’t be able to heal on its own. A series of metal rods and external fixtures (think braces and their associated headgear) are then attached to the bone on either side of the hole. Sometimes implants are placed in this void space to accelerate the deposition of new bone. These implants are often metal rods but can also be biodegradable polymers, such as the HyTEC scaffolds.
During the “distraction” phase of treatment, the external fixtures are moved, dragging bone on one side of the gap towards its fixed counterpart on the other side. This movement applies mechanical tension to the bone, stimulating new bone growth, and continues half a millimeter a day until the gap is closed. After the gap is closed, the bone is given time to fuse and finish healing in a period known as the “consolidation” phase of treatment. Ultimately, the entire process spans a few months.
Although 99% of patients eventually heal successfully, they commonly suffer from complications. Two recent retrospective analyses revealed that 21.4% of patients experienced delayed union, prolonging their treatment and its associated risk factors, and up to 32% of patients required additional surgical interventions to fully regenerate the missing bone.
For a new regenerative therapy, it’s a pretty intense test to prove whether the device is effective or not.
In fact, it’s such a rigorous test that even Dr. Elaine Lui, recent PhD graduate of the Yang Lab and current Postodoctoral Scholar who was deeply involved in the testing of the lab’s HyTEC implants, was surprised the HyTEC implants performed so well.
“We did our small animal studies with the rat, and we had really good results,” she explained. “But, to be honest, from the very beginning, we weren't 100% confident that it would scale. So when we did our pilot study [in a large animal], we were very ecstatic. These results aren’t just significant, they’re very significant!”
So what makes these implants so special? It all comes back to minimizing the burst release of BMP-2.
“Our main purpose,” Dr. Lui said, “was to be able to deliver a desired dosage of BMP-2 in a very sustained and controlled way.” With that purpose in mind, the HyTEC implants combine a 3D-printed polycaprolactone-beta tricalcium phosphate (PCL-beta TCP) lattice for implant stability with a multifaceted interpenetrating, dual crosslinked hydrogel coating for sustained drug release. You can check out the particulars in their 2023 Nature Communications paper if you really want to get down and nerdy about biomaterials design; it truly is a beautiful feat of chemical engineering.
A traditional INFUSE™ Bone Graft delivers anywhere between 1.05 milligrams and 12 milligrams of BMP-2 to the injury site, depending on the size of the spinal fusion cage needed, and an OP-1 Implant delivered 3.5 milligrams - 7.0 milligrams of BMP-7 to each patient’s bone fracture, depending on the size of the fracture and how much putty was required to fill it. Both typically release their payload over the course of a few days. While HyTEC implants deliver a similar dose (2.0 milligrams) of BMP-2, they continue to release growth factor from their gel network for more than 50 days of implantation.
While the dose of growth factor impacted the quality of bone healing in Dr. Yang’s rat study, the rate of release had a much more potent influence. In rats, HyTEC scaffolds delivering 2.0 micrograms of BMP-2 successfully healed 100% of bone injuries after 55 days. In comparison, only 62.5% of bone injuries were completed healed when the same dose of BMP-2 was loaded onto the “clinical gold standard”—those collagen sponges popularized by INFUSE™. Only 37.5% of bone injuries were completely healed using BMP-2-free HyTEC scaffolds, strengthening the idea that prolonged delivery of BMP-2 is critical for mediating successful bone healing.
Dr. Lui explains why this may be the case: “During distraction you’re applying tensile stress to the interface between the transport bone segment and the other fixed end. You’re stretching the bone. That stress and the exposure from the osteotomy of periosteal stem cells is stimulating that local region to produce its own BMP-2. So there is localized BMP production. There’s usually very good bone formation at that distraction end. But during consolidation [after the bone has successfully been transported across the gap], there’s no more of those stresses. Endogenous BMP-2 levels go way down during consolidation. Distraction is only a very small part of that procedure, whereas consolidation can last for many months. [During that time] there’s no intervention causing the body to produce more BMP-2. Our implant is having this steady release over time, so even during consolidation—when our native bodies aren’t producing BMP-2—we’re providing it.”
Although the HyTEC implants were originally designed for the controlled delivery of BMP-2, Dr. Lui emphasized that the system could also be used to deliver other drugs.
So HyTEC scaffolds mediate successful bone healing by retaining BMP-2 and releasing it slowly over the course of many weeks. But that’s not the only thing they’ve been designed to do. They’re also easier for surgeons to work with. An INFUSE™ Bone Graft requires surgeons to prep implants on the operating table. They must first resuspend the BMP-2 in a solution of saline, load it onto the collagen sponges using a syringe, and allow at least 15 minutes for the growth factor to adequately soak through the biomaterial. The Stanford research team was able to make their implants ready to use straight out of the package, preloading them with BMP-2 that maintained its bioactivity after electron beam sterilization and two-months of cold storage.
And because they’re 3D-printed, the scaffolds can be custom tailored to the geometries and needs of individual patients without compromising their off-the-shelf viability.
Still there are improvements to be made. Increasing vascularization of implants remains a critical challenge for almost every tissue engineering application, since invading cells won’t survive if there isn’t an adequate supply of blood to the new tissue. Dr. Yang believes blood vessels can be designed into their system, and his lab’s latest efforts focus on hybrid 3D-printing technology to prepattern vascular channels into scaffolds. Perhaps we may one day see this printing technique combined with the lab’s innovative gel coating to enable some truly extraordinary clinical outcomes.
As the team pushes towards clinical translation, Dr. Yang reflected on the challenges of acquiring FDA-approval for a tissue-engineered therapy. “In order for us to really push towards translation, we need to simplify the system. Right now we combine growth factors with a scaffold, which provides us with good results. This makes translation much less challenging.”
I’m excited to see where these HyTEC implants go now that the first large animal pilot study is complete, but until then, I’m looking forward to seeing what other methods scientists concoct for the delivery of BMP-2 and other exceptional growth factors.