“The world of spinal biologics is very exciting, not only because the spine has so many different tissues to regenerate, but also because the conditions that affect the spine are very different. Cost and regulatory issues, as well as efficacy and safety, are among the considerations that must be addressed,” said Wellington K. Hsu, MD, the Clifford C. Raisbeck Distinguished Professor of Orthopaedic Surgery at Northwestern University’s Feinberg School of Medicine.
Yet during the 2014 AAOS Now-sponsored forum on “Stem Cells in Orthopaedics: Myth, Miracle, or Something In-Between,” Dr. Hsu also admitted some personal skepticism about stem cell therapy, largely based on his own research into using cell-based therapies to form bone. One of his early studies found that using adipose-derived stem cells (ADSC) alone was insufficient to induce bone formation and spinal fusion in a rat model. However, when ADSC were combined with recombinant human bone morphogenetic protein (rhBMP-2), the results were impressive.
“I realized,” said Dr. Hsu, “that these cells are powerful, but there are so many different pathways that getting them to do just one thing requires blocking all the other options. And that can be very difficult.”
Who needs data?
Despite a lack of data, public interest in stem cell technology remains high. As Dr. Hsu noted, “Professional athletes have spent up to $25,000 for a stem cell injection to help regenerate a nerve without any data whatsoever.” Additionally, orthopaedics accounts for approximately two-thirds of the world market for tissue engineering and stem cells. Revenues are expected to triple over the next 6 years.
With this probable future, the need for data is strong. Dr. Hsu pointed out that 50 current U.S. Food and Drug Administration (FDA) trials are focused on using mesenchymal stem cells (MSC) to improve bone fusion in the spine. An additional six trials are studying the use of ADSC for fusion, and three others are concentrating on reconstituting disk height and controlling pain in patients with degenerative disk disease.
Dr. Hsu discussed the concept of allogeneic stem cells, in which stem cells from one individual are stored, cultured, and introduced into another patient. Allogeneic cell technologies are being developed, and several products for spine applications are already commercially available.
“One of the reasons these products are so popular,” noted Dr. Hsu, “is that they are currently regulated as ‘minimally manipulated tissue,’ and registered with the FDA as a human cellular tissue product. So to get these products to market, companies do not need the depth of data that they would for something like demineralized bone matrix, growth factors, or other kinds of biologics.”
Dr. Hsu then focused on the potential for stem cell use in lumbar spinal fusion and degenerative disk disease (DDD).
Stem cells and spinal fusion
Published data provide evidence suggesting that combining bone marrow aspirate with allograft or a ceramic carrier is capable of forming bone, noted Dr. Hsu. “After years of using autologous cell-based techniques in spinal fusion, we can say today that clinical, peer-reviewed data prove its worth. We have good evidence that demonstrates that bone marrow aspirate with allograft in a posterolateral lumbar fusion leads to high rates of fusion.”
He cited his systematic review published earlier this year showing fusion rates ranging from 52 percent (using an allograft alone) to 85 percent (using bone marrow aspirate) to 94 percent (using rhBMP-2 and an absorbable collagen sponge). He also reviewed two ovine studies examining the use of mesenchymal progenitor cells (MPC) to increase fusion.
In discussing the results of a phase two lumbar fusion stem cell clinical trial using allogeneic MPC, Dr. Hsu cautioned that the results had not yet been published, but announced in a press release. At 12 months, more than 85 percent of patients who had received the low-dose (25 million cells) allogeneic MPC had achieved fusion, compared to 75 percent of patients who received a bone autograft. Patients in the MPC group also had significantly less pain and less blood loss than those in the autograft group.
Stem cells and DDD
“In my opinion,” said Dr. Hsu, “degenerative disk disease is at times as much of a biomechanical problem as it is a biologic problem. I think that even if stem cells could be proven to regenerate the height and contents of the disk, the biomechanical problem would still exist. Many proponents of this technology would argue that they are trying to relieve the pain, not necessarily correct the biomechanical properties of the disk.”
He cited the results of a clinical trial currently underway at 13 sites in the United States and Australia. Patients who qualified for the trial had chronic discogenic low back pain for more than 6 months and less than 30 percent loss in disk height (early DDD). Patients were randomized to receive a single direct intradiskal injection of one of the following compounds:
- saline (n=20)
- hyaluronic acid (HA, n=20)
- 6 million allogeneic MPCs in HA carrier (n=30)
- 18 million allogeneic MPCs in HA (n=30)
At 12 months, MPC treatment resulted in significant greater pain reduction, less use of opioids for pain relief, and fewer treatment interventions (surgical and nonsurgical) than the control group.
The success of using stem cells with scaffolds to encourage bone regeneration, noted Dr. Hsu, may depend on the scaffold. “Not all carriers are the same,” he said. “For example, an absorbable collagen sponge has very favorable, cell-friendly characteristics, and cells attached to them will begin to grow in 10 to 14 days. Some ceramics and tricalcium phosphate also have favorable growth characteristics. But stem cells typically do not attach to or grow with allografts and some other ceramics.
“It doesn’t matter how great your cell is, if you don’t deliver it with the right carrier with appropriate cell-friendly characteristics, cells will not likely survive after implantation,” he warned.
The regulatory climate
Finally, Dr. Hsu addressed the regulatory concepts that apply to stem cells. In general, autologous stem cells are regulated under the FDA’s Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) pathway. However, this requires that the product meet the following characteristics:
- be minimally manipulated
- be intended for homologous use only
- not be combined with a drug or device
- not have a systemic effect or be dependent on the metabolic activity of living cells for its primary function
Under the HCT/P pathway, noted Dr. Hsu, such products “essentially don’t need data to be brought to market.” However, he cautioned, the FDA may “change its tune” when it comes to regulating these products in the future. He cited several recent cases involving products that were initially classified as HCT/P but were later reclassified as drugs.
“The difference between the HCT/P pathway and the drug pathway is more than $50 million,” noted Dr. Hsu, “which is certainly a significant barrier to getting some products to market.”
Disclosure information: Dr. Hsu—Medtronic, Stryker, Pioneer/RTI, DePuy-Synthes, AONA, Lifenet, Globus, Bioventus, Spinesmith, Graftys, Zimmer, Lumbar Spine Research Society, Cervical Spine Research Society, Orthopaedic Research and Education Foundation.
Frank B. Kelly, MD, cochaired the AAOS Now Forum on “Stem Cells in Orthopaedics: Myth, Miracle, or Something In-Between” and is a member of the AAOS Now editorial board. Mary Ann Porucznik is managing editor of AAOS Now. She can be reached at email@example.com
- Although data supporting the use of stem cells in treating conditions of the spine is sparse, good evidence is available on the use of other types of biologic materials.
- The effectiveness of biologics may depend heavily on the characteristics of the carrier.
- Regulatory considerations and cost factors will have a significant impact on the use of biologic products.
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- Wheeler DL, Lane JM, Seim HB, Puttlitz CM, Itescu S, Turner AS. Allogeneic mesenchymal progenitor cells for posterolateral lumbar spine fusion in sheep. Spine J. 2014 Mar 1;14(3):435-44. doi: 10.1016/j.spinee.2013.09.048. Epub 2013 Oct 23.
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- Press release: Mesoblast’s NeoFuse Stem Cell Product Shows Positive Results in Phase 2 Lumbar Spinal Fusion Trial.
- Press release: Positive Spinal Disc Repair Trial Results Using Mesoblast Adult Stem Cells.