In typical little sister fashion, Torres yearned to mimic her older siblings (a fairly common trait among younger kinfolk). Hence her enrollment in training at a Culver City, Calif., swim club at age 7, without so much as an introductory lesson.
And so, Torres began swimming. Just like her brothers.
Torres quickly transcended her siblings in the sport, winning the national open championship in the 50-yard freestyle at age 14 (she defeated a college junior for the title) and training for the Olympics while still in high school.
At the 1984 games, Torres was a member of the winning U.S. women’s 4x100-meter freestyle relay team, competing in the first-round qualifying heat and earning a gold medal in the event final. She collected silver and bronze medals in relays during the 1988 Olympics and won another gold in the 4x100 relay in 1992.
A 12-time medalist, Torres is one of the most decorated female Olympians in sports history. She was also one of the oldest to compete: In both the 2000 and 2008 games, she was the senior (U.S.) team member (Michael Phelps jokingly referred to her as “Mom” during the latter Olympics). Torres almost qualified for the 2012 team at age 45, but missed by a mere .09 seconds in the 50-meter freestyle.
“Obviously, I was hoping to make the team. That was my goal and missing it by less than a tenth of a second is tough, but I don’t think there’s anything I could have changed,” Torres told reporters after falling short in her sixth Olympic bid. “Being 45, getting fourth in Olympic trials against girls almost half my age, it’s OK. I’m used to winning, but that wasn’t the goal here. The goal was to try to make it. I didn’t quite do it, but I’m really happy with how I did. I was able to hang in there.”
So did her body, which is a testament not only to Torres’ determination and physical fitness, but also her ability to recover from injury. The former world record holder underwent knee surgery after the 2008 Beijing Games to replace damaged cartilage brought on by years of grueling training regimens and mild arthritis.
A masterpiece of functional design, articular cartilage is—for all intents and purposes—the body’s proverbial Achilles heel. It is a natural shock absorber, cushioning joints and distributing weight-bearing loads, but the tissue gradually deteriorates with age, making it particularly vulnerable to injury. Such decay can be painful and life-altering.
“I love exercise, it’s just part of my DNA. [But] the chronic knee pain I had pretty much put the kabosh on all my daily routines,” Torres said in an online video. “Things I would take for granted like swimming, walking the dog, or climbing stairs, was just stuff I couldn’t do. The real clincher was that I could not bend down to pick up my daughter Tessa, and that really hurt me a lot. The [knee] pain was so unbearable and she couldn’t understand why Mommy couldn’t play with her. That was tough to bear. So I knew I had to do something.”
And she had to do it quickly: Unlike other types of tissue, articular cartilage cannot repair itself due to the lack of blood cells or nerves. Without intervention, Torres’ knee pain would surely worsen and lead to acute osteoarthritis.
Indeed, Torres’ condition worsened: In just one month, the measurable amount of arthritis in her knee advanced from stage 1 (minor) to stage 4 (severe).
“The surgeon said my cartilage was really damaged, and that’s what was causing my pain. We talked about what it would mean for me, what it would mean for my everyday life and my future, and I decided that I just didn’t want my knee to dictate what my future would be,” Torres said. “To be honest, I wasn’t really surprised by this diagnosis. I had the same problem in the other knee and when I went to the World Championships in 2009, the pain was so bad I actually had to use the ladder to get out of the pool. I talked to my doctor, I talked to other doctors around the country searching for the right treatment for my knee.”
Torres had several treatment options available to her. One was microfracture surgery, a procedure that creates small holes in the knee bone (under the damaged cartilage) to stimulate a natural healing response. This remedy, however, is generally not considered a long-term solution because the repair tissue eventually breaks down.
Torres also could have had healthy cartilage from a deceased donor implanted into her knee (allograft transplant) but there are challenges with this therapy as well—namely, storage, matching donor and patient tissue types, and the limited supply of cartilage cells.
Ultimately, Torres used her own (healthy) cartilage cells to fix the deficiency in her knee. She underwent a matrix-induced autologous chondrocyte implantation (MACI), which uses a biocompatible collagen scaffold to generate healthy cartilage tissue. The surgery is considered the “next-generation approach” to traditional ACI (autologous chondrocyte implantation), a technique first used in the late 1980s.
The MACI treatment consists of two procedures: One to harvest healthy cartilage cells (chondrocytes), and the second to implant those cells directly into the knee defect. After processing, the chondrocytes are extracted from the patient biopsy, expanded, and embedded on a porcine-derived collagen membrane; that scaffold reportedly delivers a controlled, uniform dose of chondrocytes with a density of 500,000 to 1 million per square centimeter.
Developed by Cambridge, Mass.-based Vericel Corporation, MACI received U.S. Food and Drug Administration (FDA) approval in December 2016. Clinical data from the company show the MACI implant is more effective than microfracture treatment, and equally as safe. The biological solution also is better than microfracture at treating lesions larger than three centimeters, five-year study data indicate.
“MACI seemed like a natural way to repair my damaged cartilage. I love how it uses my own cells,” Torres noted. “When it came to training, I always used the latest and best technologies, and that’s how I approached my treatment. I wanted the latest proven method to repair my cartilage injury—a treatment that would go the distance. My surgeon said MACI’s been shown to be better at reducing knee pain than microfracture. It’s also better at getting you back to playing your favorite sports again. And that’s what I wanted to hear. As an athlete, I’ve always relied on my body to help me perform my best. And that’s how I look at MACI—it uses my own body, my own cells, to help me be my best.”
Cellular-based solutions like MACI are becoming more prevalent as patients seek less invasive, more clinically efficient treatments for various musculoskeletal conditions. Harnessing the human body’s regenerative prowess to mend these conditions has spawned a relatively new class of orthobiological products and therapies in the last 30 years.
Orthobiologics function by mimicking the body’s natural growth factors (there are more than 1,000 types in blood) and diverting them to the damaged tissue for healing. The use of biologics has grown steadily over the last few decades, ballooning into a $4.87 billion industry that encompasses bone grafts, growth factors, stem cells, platelet-rich plasma, autologous blood, and autologous conditioned serum. The global market for these products is forecast to reach $6.87 billion in the next five years, expanding annually by 4.3 percent, industry data indicate.
“According to market reports, the major factors attributing to the growth of the orthobiologics [market] include incidences of sports injury, road accidents, and osteoarthritis,” noted Alla Danilkovitch, vice president of R&D for Smith+Nephew. “By definition, orthobiologics are substances that orthopedic surgeons use to support the healing of injured bones and soft tissues. With aging and diseases such as diabetes, the regenerative potential of the body is significantly decreased. Surgical procedures alone are not sufficient, and orthobiologics as an adjunct to surgical procedures can lead to a significant improvement of surgical outcomes.”
Orthobiologics procedures have risen steadily over the last decade to nearly 4.5 million annually in the United States, iData Research statistics show. That total is expected to exceed 7 million by 2025, driven largely by market developments and demand for stem cell treatments.
Fact or Fiction?
As the basic building blocks of all human tissue, stem cells hold enormous potential for treating numerous orthopedic conditions. Their promise, in large part, lies mainly in their regenerative prowess: Stem cells can divide and morph into more specialized cells (i.e., brain, liver, muscle, etc.), and they also can relay valuable information about tissue growth and healing to the body’s other cells. Mesenchymal stem cells (MSCs) work the same way, only they produce the cell types found in musculoskeletal tissues like bone, cartilage, and ligaments.
Many orthopedic stem cell therapies currently being sold or developed use multipotent MSCs, such as NuVasive Inc.’s Osteocel, Orthofix Holdings’ Trinity Evolution and ELITE, and Mesoblast Ltd.’s MPC-06-ID. The latter product—not yet approved for clinical use—aims to relieve chronic low back pain caused by degenerative disc disease (DDD).
MPC-06-ID is presently under evaluation in a five-year, Phase III U.S. study scheduled to end in March. A previous Phase II trial in the United States linked the allogenic cell candidate to decreased back pain and better functionality over a three-year period.
“Key to the mechanisms of action of Mesoblast’s mesenchymal lineage cells is their ability to be activated by and then counter severe inflammation at various disease states,” the Australian firm noted in a September 2019 newsletter detailing DDD demographics and MPC-06-ID’s modus operandi. “It is now well-recognized that inflammation plays a key role in the development of chronic low back pain accompanying degenerative disc disease. The multi-modal mechanisms of action of Mesoblast’s mesenchymal lineage cell platform could represent a fundamental advantage over other therapies in disease modification, resulting in symptomatic relief as well as tissue repair and regeneration.”
In addition to touting the healing potential of MPC-06-ID, Mesoblast’s September newsletter outlined the benefits of its commercialization and development partnership with German pain management specialist Grunenthal. The agreement—announced last fall—entitles Mesoblast to roughly $150 million in upfront and milestone payments before product launch, as well as further commercialization milestone awards, and tiered double-digit royalties on product sales. Cumulative milestone payments could exceed $1 billion, depending on Phase III study outcomes and patient adoption.
Another potential windfall for Mesoblast could arise from Ryoncil (clinical name: remestemcel-L), an investigational therapy for treating children with steroid refractory disease, a potentially life-threatening condition induced by an allogenic bone marrow transplant. The company is currently completing its rolling Biologics License Application (BLA) to the FDA and will likely soon request an accelerated review of the document in order to gain approval and commercialize the product later this year.
remestemcel-L is an investigational therapy comprised of donor bone marrow MSCs. The product reportedly counteracts steroid refractory disease-associated inflammation by increasing production of anti-inflammatory cytokines (small proteins) and recruiting naturally-occurring anti-inflammatory cells.
“Graft versus host disease is the most serious complication of an allogeneic transplant and it occurs when the donor cells that have engrafted in the patient attack the patient’s organs,” Joanne Kurtzberg, M.D., senior investigator in Mesoblast’s completed Phase III steroid refractory disease trial, explained in the company’s July 2019 newsletter. “As a pediatric transplanter who cares for children with graft host disease, [remestemcel-L] is one of the most promising agents that I’ve seen in my entire career...I’m really happy that Mesoblast submitted the first module of their BLA. I hope this results in approval.”
Mesoblast has the same hope, as FDA approval would give the company a competitive edge in the increasingly crowded stem cell therapy sector, a field projected to be worth $11.5 billion by 2025. Stem cells and related therapies, including platelet-rich plasma, are expected to be main drivers of that growth due to their potential applications in various practice areas, including neurodegeneration, brain and spinal cord injury, osteoarthritis, and sports medicine.
Indeed, there is a tremendous amount of potential in stem cell therapies; yet just as much uncertainty exists, given that relatively few of these treatments are backed by science. Nevertheless, thousands of clinics, hospitals, and health systems now offer stem cell therapies in an effort to capitalize on the public’s perpetual thirst for a cure-all. Typical treatments involve injecting joints with a patient’s own fat or bone marrow cells, or with extracts of platelets—cell fragments known for their blood clotting ability.
These injections, however, seldom live up to their promise. Medical experts note that adult MSCs are in short supply within the body, and can be difficult to properly identify without complex diagnostic techniques. Moreover, only a small percentage of fat tissue or bone marrow cells are actually MSCs; and even when located, these cells don’t always convert into their intended tissue structures.
“Getting MSCs to multiply and to differentiate correctly into the right specialised cell lines is extremely difficult. Getting MSCs to then grow or regenerate the correct specialised tissue structures and to repair or regenerate actual damaged anatomical structures is an enormous leap on from this,” Ian McDermott, specialist knee surgeon and managing partner of the London Sports Orthopaedics practice, wrote in a January web article for Orthopaedic Product News. “When cells are taken either from fat tissue or from bone marrow, only a very tiny percentage of these cells are actually genuine MSCs. The reality is that the cells are a disparate mix of all kinds of different cell types, and the ‘stem cell’ injections that are currently being touted to patients for clinical use privately, are really nothing of the sort. Even if these injections did contain large numbers of MSCs, there is no scientific evidence at all that just injecting cells into a badly damaged arthritic joint will actually in any way reverse the arthritic damage at all.”
McDermott is right, to an extent. A few years ago, Mayo Clinic researchers found that bone marrow stem cells were on par with saline placebos in relieving arthritic knee pain. Other studies failed to find evidence of cartilage regrowth (though most have linked stem cells to some symptom relief), and regulatory agencies like the FDA and Health Canada have yet to warm to MSC knee therapies.
Still, some research shows promise: Regenexx’s patient registry data show positive results for the company’s bone marrow and platelet-rich plasma treatments. Australian researchers are jazzed about clinical trial outcomes indicating cartilage regrowth as well as significant pain and quality of life improvements (290 percent!) for osteoarthritis patients, and schools like UC and Johns Hopkins are experimenting with scaffolds and sheaths to bolster stem cells’ potency.
Nevertheless, overall evidence supporting stem cell efficacy remains mixed at best. “Stem cells seem to be declining in popularity as price pressures from hospitals as well as a lack of solid clinical data has called into question stem cells’ value proposition,” stated James J. Cassidy, Ph.D., president and chief operating officer of St. Cloud, Minn.-headquartered Artoss Inc. “Surgeons have begun moving back to using Infuse as alternative treatments have come up short. NanoBone Bone Graft is one of a handful of truly novel technologies that have entered the market in the last 10 years. As surgeons continue to look for new and better technologies, NanoBone continues to gain market share.”
Used in Europe and the United States for more than a decade, NanoBone Bone Grafts are comprised of nano-crystalline hydroxyapatite (HA) particles that are similar in size, chemistry, and morphology to human bone HA. Artoss claims the grafts have been used in more than 100,000 clinical cases (nearly 400,000 in Europe) across all indications, and perform equally as well as the “competing gold standards” for bone grafting, with lower risks than autograft and at a lower cost than BMP (bone morphogenetic protein) or stem cell products.
Last spring, Artoss received FDA clearance to use its NanoBone SBX Putty in posterolateral spinal fusion. The highly porous putty is designed to fill bony voids or skeletal gaps in the extremities, pelvis, or posterolateral spine due to surgery or traumatic injury. Over time, the SBX putty resorbs and is replaced with bone during the healing process.
The material can be implanted in the body in two different ways—through a sterile applicator with attached plunger, or a sterile cartridge with a separate sterile plunger.
“Artoss is committed to developing a number of surgical tool kits that facilitate implantation of NanoBone. Most orthobiologics companies are content in providing only an orthobiologic to their surgeon customers,” Cassidy noted. “Artoss has five products under development that will help surgeons address difficult cases in new and unique ways using NanoBone.”
Artoss, however, is not unique in its bone graft delivery system options. Swedish biotech firm BONESUPPORT AB offers a biologic and delivery tool for its CERAMENT product line; the bioceramic bone graft substitute is created by mixing a powder (40 percent HA and 60 percent calcium sulfate) with a liquid (iohexol) to form an injectable paste. Like NanoBone, CERAMENT is used to fill bone gaps or voids to promote healing; it is radiopaque, osteoconductive, and drug-eluting, and has been proven to repair defects in host bone within six to 12 months.
Once applied, a layer of native HA forms on the surface of CERAMENT, restricting calcium sulfate resorption. Contact with bone is enhanced since the bone’s cells recognize the apatite layer as natural bone mineral.
Similar skulduggery occurs within the shoulder during implantation of Smith+Nephew’s REGENETEN Bioinductive Implant, a collagen-based solution for repairing large rotator cuff tears. The product stimulates the body’s natural healing response by inducing the growth of new tendon-like tissue to thicken the damaged joint and fill in defects. A study of 23 patients published last year in the American Journal of Sports Medicine showed a 96 percent tendon healing rate at two years, and no significant difference in treatment success between primary repairs and revision surgery.
“Our understanding of the structural and functional properties of native tissue, and mechanisms of healing of injured tissue is driving development of new innovative biomaterials and cellular therapies,” Smith+Nephew’s Danilkovitch said. “The main goal is to address conditions and diseases with unmet medical needs and significantly improve the outcome of surgical procedures and patients’ quality of life.”