In 2009, more than 1.5 million patients received a human biologic product or implant as part of their surgery (dental included). Depending on your definition of “sales, ” biologic products generated well in excess of $2 billion in annual revenues. And, if you asked most CEO and surgeons what they think about “biologic” products they will say something along the lines of: “it is the product category of the future.”
Yet, the “future” of biologic products, from the perspective of most suppliers, continues to stretch into a barely discernible future. With the exception of a Pickard/Lukianov run at Sofamor Danek 20 years ago, no major orthopedic supplier has rushed to embrace biologics as a product category.
Do we REALLY understand the purpose, power and functionality of biologics as a product category?
The following are five commonly held myths about biologic grafts:
Myth #1: Efficacy is the key to allograft biologic products
Dr. Marshall UristAllograft products taught two generations of surgeons about bone morphogenic proteins and laid the foundation for Medtronic’s InFuse. At UCLA in the 1960s, Dr. Marshall Urist was working at the U.S. Atomic Energy Commission to research strontium 90, tetracycline, and the treatment of osteogenic sarcoma (bone cancers). Answering the question of, “Why Does Bone Grow?” Dr. Urist was able to unravel the biochemical and cellular mechanics of osteoinduction. To prove his theories, Dr. Urist used demineralized human allograft bone matrix (which had small amounts of bone morphogenic protein [BMP]) and proved in his seminal 1965 article in Science—“Bone: Formation by Autoinduction”—that BMP induced bone to grow under the skin of a rat. Dr. Urist’s work led to his nomination for the Nobel Prize in Medicine in 1991. Demineralized bone matrix (DBM) became the delivery mechanism for BMP.
Demineralized BoneBut, and this is the key point, the amount of BMP in DBM is low. Surgeons weren’t going to hurt their patients with this new biologic graft. The real question was donor safety. Efficacy in the form of BMP was mild. Ironically, this created the conditions for widespread use. Since efficacy existed at low levels, the learning curve for surgeons entailed figuring out how to maximize its mild effects. Surgeons learned to use DBM as an extender for harvested bone and the small amounts of BMP worked very well with the progenitor cells and BMP in the patient’s own bone marrow.
After a decade and a half of using BMP with various versions of demineralized bone matrix, surgeons were prepared and comfortable with the pure form of BMP—InFuse.
The same effect is currently occurring with allograft stem cells. Products like Osteocel (NuVasive) or Trinity (Orthofix) or NuCel (NuTech) are allograft products that preserve the progenitor cells of the donor. All three deliver safety, consistency and reliability to the surgeon. They also deliver small numbers of progenitor cells. So the key issue for surgeons is to learn how best to use the materials in order to maximize the mild effect of those cells in their patients. These materials, in turn, will train a generation of surgeons in the use of donated, living progenitor cells before the purer, more powerful forms of stem cells come to market.
A diagram of bone stem cells
Myth #2: Biologic products are supported by an intense R&D investment
RTI spends 5.5% of sales on R&D. Osteotech spends 6.7%. These are biotech firms? Amgen, one of the largest biotech companies in the world spends 20% of sales on research. Mid-cap biotech firms like Gilead spend about 13% to 15% of sales on R&D. Actually; suppliers of orthopedic biologic products spend about the same as their metal/plastic cousins—or roughly 5% to 8% of sales on R&D. Like Stryker, Zimmer, et al., biologic suppliers to the orthopedic industry aim for the least onerous regulatory path to market.
Myth #3: Biologic products are not cost effective
Good old polypropylene was developed in 1962 and is a strong, chemically inert, sterilizable, hypoallergenic material that resists the body’s fluids and is easily accepted in the body. As a mesh to repair soft tissue damage, it found markets in hernia repair and to a limited extent, shoulder repair. Then came AlloDerm/GraftJacket, a human skin allograft. AlloDerm is a biologic graft and is classified by the FDA as banked human tissue and when it came to market it did so under the 361 rules which do not require clinical study—even though many, many studies have been conducted on these materials.
Biologic products run the gamut in pricing—from very cheap cancellous chips to premium priced allograft soft tissue mesh/support or progenitor cells. But the vast majority of routine biologic products like DBM, bone void fills and allograft skin coverings are comparable to synthetic prices in terms of $$ per cc or $$ per square centimeter. Then there are actual savings available because biologic products interact with surrounding tissues.
Human Bone
These are the BMPs in demineralized bone matrix which create an osteogenic environment. Using BMPs in whatever form help minimize or even avoid altogether an additional harvest surgery. Allograft progenitor cells have been shown to be immune privileged and are capable of delivering anti-inflammatory effects. Biologic grafts are resistant to infection and will remodel with surrounding tissues. Biologic products have the ability to communicate with the body, signal surrounding tissues to grow in their scaffold or recruit other proteins or cells.
Myth #4: Biologic implants help grow bone and that’s about it
We know about the existence of bone morphogenic proteins in DBM, but the remodeling ability of GraftJacket is remarkable and the anti-inflammatory and immune privileged affects of allograft progenitor cells raise the possibility of a multi-functional biologic product.
In several peer review journal articles (for example the Journal of Cell Biochemistry, August 2006 issue, pages 1076-1084), Dr. Arnold Caplan of the Department of Biology, Skeletal Research Center, Case Western Reserve University, has shown that bone marrow progenitor cells (aka: mesenchymal stem cells [MSCs]) are capable of dividing and differentiating into osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon-ligament fibroblasts, and adipocytes. They have regenerative capabilities and can grow bone, cartilage, muscles and tendons.
However, these same cells, as they are dividing, secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities. To put it bluntly, Caplan and others have shown that the bioactive factors coming from the MSCs can suppress the local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis (capillary growth), stimulate mitosis and differentiation of tissue-intrinsic reparative or stem cells. Bottom line, the surgeon may use allograft MSCs to help regenerate bone but may also experience these highly beneficial trophic effects.
Myth #5: To get a permanent repair, you need a synthetic material
We’ve heard that most surgeons feel more comfortable with permanent implants and, in the case of soft tissue repair, mesh. But even permanent synthetic polymer or metal implants are not as permanent as one might expect. These materials react and change in the body and are not entirely inert. Living bone, ironically, gets stronger with stress. Metal fatigues with stress. Polymers can erode with stress. Because biologic products incorporate into the surrounding tissue (for example allograft mesh like GraftJacket/AlloDerm or DBM in a spine fusion model), the average strength of the repaired segment should come very close to that of native tissue. For most surgeons, what they want to see is a biologic graft that is eventually indistinguishable from the patient’s own healthy, living tissue.
The dilemma, however, is that biologic grafts cannot be used in patients the same way as synthetic grafts. They require different clinical considerations and surgical techniques. It is, for example, important that biologic grafts come in close contact with vascularized native tissues and that there is an ingrowth of blood vessels and that living cells can proliferate and cell signaling is robust. Securing a biologic graft can take more time and attention. It’s not like slapping in a poly patch or screwing down a plate.
Biologics’ Special Appeal
There is an old saying: “God doesn’t make mistakes.”
So when a surgeon needs a replacement part—go to the source. Yes, synthetic materials are excellent and will be required in modern surgery for as long as we can forecast. But biologics have a special appeal to both patients and their physician. Human biologic products signal the body, are resistant to infection, remodel completely, have long-term strength and do not cost appreciably more than the synthetic alternative—particularly when considering the effects of infection risk, an additional harvest surgery or the trophic effects of many biologic grafts.
