The Orthopaedic Research Society’s on-demand educational platform, LearnORS, featured in American Academy of Orthopaedic Surgeons’ AAOS Now.
“When you look at the programs offered through these online courses, there is a real benefit for surgeons in training. The courses provide additional content, feedback, and access to the experts, above and beyond what they can get in textbooks alone.” – Martin Stoddart, PhD, FRSB, FIOR
In a first-of-its-kind clinical trial, a human has received a 3D-bioprinted ear implant grown from the patient’s own living cells – thanks to a technology platform developed by a Cornellian-founded startup company.
ORS Recognizes the 2021 Fellows of the Orthopaedic Research Society (ORS)
40 members of the ORS were honored Monday, February 15, 2021, 7:00 AM – 8:00 AM (Pacific) by the Orthopaedic Research Society as part of their ORS 2021 virtual Annual Meeting.
ORS Fellows are selected by the ORS Board of Directors and represent longstanding members of the ORS who have demonstrated exemplary service and leadership, substantial achievement, expert knowledge, and significant contributions to the ORS, its governance, and the field of musculoskeletal research. Fellows are thought leaders and experts in their respective disciplines and serve as role models in the ORS community and in the field of musculoskeletal research exemplifying the core values of the Society.
2021 Fellows of Orthopaedic Research Society include:
Mauro Alini, PhD
Benjamin Alman, MD
Bruce Beynnon, PhD, MS
Scott Boden, MD
Lawrence Bonassar, PhD
Barbara Boyan, PhD
Scott Bruder, MD, PhD
Denis Clohisy, MD
Daisuke Sakai, PhD
Henry Donahue, PhD
Stuart Goodman, MD, PhD
Warren Haggard, PhD
Clark Hung, PhD
James Iatridis, PhD
Gun-il Im, PhD
Lynne Jones, PhD
Rita Kandel, MD
James Kang, MD
Francis Lee, MD, PhD
Gayle Lester, PhD
Gang Li, MD, PhD
Richard Lieber, Ph
Gloria Matthews, DVM, PhD
Rob Mauck, PhD
George Muschler, MD
Fred Nelson, MD
Maurizio Pacifici, PhD
Cathleen Raggio, MD
Geoff Richards, PhD
Scott Rodeo, MD
Robert Sah, MD, ScD
Hamish Simpson, PhD
Lou Soslowsky, PhD
Rick Sumner, PhD
Rocky Tuan, PhD
Jennifer Wayne, PhD
Stuart Weinstein, MD
Mark Wilkinson, MD
Michael Yaszemski, MD, PhD
Clare Yellowley, PhD
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medication across the world given their ability to reduce pain and inflammation. Daily NSAID users include up to 50% of patients over age 65 and 80% of active duty military personnel, among others. Despite their widespread use, the effects of NSAIDs on the skeleton are still not fully understood.
Evidence presented at the 2019 Annual Meeting of the Orthopaedic Research Society suggests that some NSAIDs may actually have adverse effects on stress fracture risk and repair. Two popular NSAIDs, naproxen (Aleve) and aspirin were compared in a stress fracture study in mice. While both NSAIDs were able to relieve the pain associated with stress fracture, exposure to naproxen had negative effects on bone healing and increased the risk for future stress fracture by reducing bone toughness.
Dr. Ryan Tomlinson of Thomas Jefferson University, senior author of the work commented, “One of the surprising aspects of this study was the relatively limited effect of aspirin, as compared to naproxen, even though the dosage of both drugs was sufficient to relieve stress fracture-related pain. This result highlights the heterogeneity of the NSAID class of medications, and we are currently investigating whether other popular NSAIDs and pain relievers have negative, neutral, or even positive effects on load-induced bone formation and stress fracture repair.”
NSAIDs work by blocking the enzymes responsible for production of prostaglandin molecules, which are involved in the inflammatory cascade after tissue injury. Prostaglandin signaling is also necessary for load-induced bone remodeling, which leads to strengthening of bone in areas where it experiences the highest strains. Therefore, if prostaglandin production is decreased by NSAID use, areas of bone undergoing strain may become weaker over time, increasing the risk for new stress fractures. Even more importantly, stress fractures may not heal as well in the presence of certain NSAIDs like naproxen.
“Naproxen is often the recommendation of choice by physicians in orthopaedic clinics. Due to its longer half-life, naproxen has a recommended dosing frequency of 8-12 hours, compared to 4-6 hours for those of aspirin and ibuprofen (Advil),” said Jino Park, lead-author of the study and a medical student at Geisinger Commonwealth School of Medicine. The popularity of naproxen for treatment of orthopaedic pain and inflammation underscores the urgency for continued research on the effects of NSAIDs on skeletal health. In the meantime, those at increased risk for stress fracture may want to reconsider use of naproxen to treat musculoskeletal pain.
Journal of Orthopaedic Research Establishes a New Category of Publication
Musculoskeletal infections (MSKI) remain the bane of orthopaedic surgery, resulting in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis and treatment remain largely unchanged over the last fifty years, a 2nd International Consensus Meeting on MSKI (ICM 2018) was completed on July 25-27, 2018 in Philadelphia, PA, USA. This 2-year long process derived the final set of 652 consensus questions, which were discussed and voted on by 658 scientists, internists and orthopaedic surgeons representing 92 countries. As critical outcomes of ICM 2018 include determining the current incidence and costs of MSKI, establishing what is currently known about the basic science of MSKI and effective standards of care, and deriving the greatest research priorities, two ICM 2018 research workgroups (RW) were assembled to accomplish these tasks. The findings appear in the May, 2019 issue of the Journal of Orthopaedic Research. The Consensus Article by Saeed et al reports the findings of the 28-member Biofilm RW, which highlights 13 cutting-edge areas of MSKI and fundamental knowledge gaps in this field. The RW’s consensus spans conclusions on the molecular nature and function of biofilm, mechanism by which biofilms resist antibiotics and host immunity, microbial synergizes in polymicrobial infections, diagnostics for biofilm on implants, definitions for minimum biofilm eradication concentration (MBEC) of anti-infective agents, and the potential of bacteriophage therapy. The Consensus Article by Schwarz et al presents the results of the 29-member General RW, and has two salient features: up-to-date data on the current and projected incidences of infection, and costs per patient for all orthopaedic subspecialties, which range from 0.1%-30%, and $17,000-$150,000. The RW also reviewed all of the questions from ICM 2018 and determined that 23 of them are high priorities for research funding. These questions fall within six thematic categories: Acute vs. Chronic Infection, Host Immunity, Antibiotics, Diagnosis, Research Caveats, and Modifiable Factors.
To disseminate this information, the Journal of Orthopaedic Research established a new category of publication: Consensus Articles. These invited peer-reviewed manuscripts are submitted by a large group of recognized thought leaders who utilize an established methodology (e.g. the Delphi method) to derive a consensus on important issues based on established literature, non-peer reviewed information, and expert opinion. The resulting summary is intended to provide a broad audience guidance on the controversies and major unmet needs in the field, and to define the clinical and economic significance of the problems by providing consensus data on the incidences of the clinical problem, and costs. The Orthopaedic Research Society is supporting this effort by hosting free down-loadable PDFs of the consensus questions, response and rationale: Biofilm RW’s PDFs and General Assembly RW’s PDFs. These high-impact Consensus Articles can positively influence multidisciplinary investigative teams with the will to solve these problems and private foundations, governmental agencies and commercial funding mechanisms who need to provide the medical community the resources necessary to establish best practices with scientific evidence.
Brittany M. Wilson
ORS Media Relations & Communications Committee
Many factors influence a woman’s risk of developing post-menopausal osteoporosis, including physical activity, medication use, nutrition, and peak bone mass attained in young adulthood. Reproduction, which utilizes the maternal skeleton as a reservoir of mineral to provide for the developing fetus and nursing newborn, may also impact the development of post-menopausal osteoporosis. During pregnancy and lactation the mother loses bone mass which appears to be recovered within one year of weaning, based on bone mineral density determinations. However, the long-term effects of reproduction on bone structure and how it may impact post-menopausal osteoporosis and fracture risk remain unclear.
A new study presented earlier this year at the annual meeting of the Orthopaedic Research Society addresses the aforementioned gap in knowledge. The work was led by Chantal de Bakker in the laboratory of Dr. X. Sherry Liu at the University of Pennsylvania. Using a rat model, the group demonstrated that a history of reproduction and lactation prior to the induction of menopause (by removing the ovaries) resulted in structural adaptations in the maternal skeleton that led to a slower rate of bone loss compared to virgin rats.
The structural adaptations induced by pregnancy and lactation included reduced mass of the trabecular (i.e., inner or “spongy”) bone but increased cortical (“outer”) bone mass compared to virgin rats. These alterations resulted in a similar mechanical competency of the tibia between the two groups. Using an innovative labeling technique to analyze individual trabeculae over time, the group reported that reproduction resulted in a reduced number of trabeculae in reproductive compared to virgin rats, with thicker trabeculae observed in the reproductive rats. Furthermore, the rate of bone loss from thicker trabeculae was reduced compared to that of thinner trabeculae and reproductive rats underwent a lower rate of postmenopausal bone loss as compared to virgin controls over the same time period. Hence, while virgin rats started menopause with a greater trabecular bone volume, there was no longer a difference between groups in tibial trabecular bone volume 12 weeks after the induction of menopause.
These results provide important insights into the long-term effects of pregnancy and lactation on the maternal skeleton and may indicate that thicker trabecular bone around the start of menopause may provide protection by reducing the rate of bone loss when estrogen becomes deficient. The lead author of the study, Chantal de Bakker, noted, “[these results] provide new insight into osteoporosis prevention and treatment for post-menopausal women by considering their reproductive histories.” The group plans to further investigate the long-term effects of reproduction on the bone’s response to mechanical loading to elucidate how exercise can be utilized to maintain bone health after menopause in women with and without a history of reproduction.
Old bones can heal with proper signals: Targeting macrophages to stimulate osteoblasts
Repair and regeneration capacity of skeletal tissues diminishes with age, often leading to delayed or impaired fracture healing. While the cause of diminished healing capacity is probably driven by a concert of many factors, evidence suggests that aged cells retain the capacity for repair when provided the proper signals. Work led by Orthopaedic Research Society Members, Gurpreet Baht and Benjamin Alman at Duke University has shown that exposure of old mice to circulation of young mice leads to improvements in bone healing, attributed in part to increased osteoblast differentiation in response to signals provided by young circulation.
Baht and colleagues have determined that M2 macrophages, a macrophage phenotype associated with repair and reduction of inflammation, are important in fracture healing. Through mass spectrometry studies, a list of ‘youth factors’ and ‘aging factors’ associated with M2 macrophages were identified. One of the factors, low-density lipoprotein receptor-related protein 1 (LRP1), stood out as a potential candidate to improve fracture repair. LRP1 is a Wnt antagonist that decreases with age and has been implicated in Alzheimer’s disease (AD), cardiovascular disease, and cancer. Interestingly, in all three of those diseases, age-related reduction in LRP1 leads to reduced clearance of particular molecules associated with the disease states (e.g. reduced clearance of amyloid-beta proteins in AD).
Working under the hypothesis that loss of LRP1 in macrophages would be associated with reduced osteoblast differentiation and subsequently impaired fracture healing, the team set out to investigate the role of macrophage-derived LRP1 in fracture repair. Initial in vitro work showed that LRP1 was 60% more abundant in media from young bone marrow cells compared with cells from older mice. Osteoblastic potential of bone marrow cells was also increased by incubation with LRP1 during differentiation.
To investigate the role of LRP1 in fracture repair in vivo, a conditional LRP1 knockout mouse driven by the macrophage/granulocyte-specific promoter, LysM-cre was generated. Bone marrow cells from young control and LRP1 knockout mice were transplanted into old mice that had previously been irradiated. Two months after transplant, old mice were subjected to a tibial fracture. A substantial reduction in healing, based on reduced calcified callus volume and increased callus fibrosis, was observed in mice that had received the LRP1 deficient bone marrow.
While further investigation is still required to elucidate the specific role of LRP1 in bone healing, the evidence that LRP1 appears to attenuate tissue repair in aged individuals is noteworthy. When asked about the work Baht noted, “This finding presents exciting possibilities in future discovery of pharmacologic agents able to enhance fracture healing. Currently, we are identifying the biological changes which occur in response to treatment of aged animals with LRP1 protein. We hope to better understand the effects of such a treatment so that we can move such a system closer to a treatment strategy.”
Study suggests link between gut microbiome and joint health in obese mice By Brittany Wilson
The gastrointestinal microbiome is currently a hot topic of research concerning serious diseases affecting large portions of the world’s population. It has been implicated in a variety of conditions such as asthma, obesity, and now osteoarthritis (OA). Recent work presented at the Orthopaedic Research Society 2017 Annual Meeting by Eric Schott, Robert Mooney, Steve Gill, Michael Zuscik and colleagues at the Center for Musculoskeletal Research at the University of Rochester Medical Center have shown that prebiotic manipulation of the gut microbiome may lead to decelerated progression of OA. The work utilized a mouse model of high fat diet-induced obesity along with an injury to the medial meniscus to initiate degeneration in the knee. Specifically, mice that were fed a high fat diet along with the prebiotic supplement, oligofructose, demonstrated reduced systemic inflammation and decelerated cartilage degeneration after meniscal injury.
Prebiotic supplements are intended to nourish and support particular bacterial strains present in the gut. This is in contrast to probiotic supplements, often found and discussed in yogurt, which attempt to confer specific bacterial cultures directly to the gut. In the experiment reported by Schott et al, it is believed that an increased abundance of microbes from the genus Bifidobacterium, resulting from prebiotic supplementation, may be responsible for the reduction in systemic inflammation and deceleration of OA symptoms.
A link between altered gut microbiome and systemic inflammation in obesity has previously been established; however, the mechanisms by which the gut microbiome affect joint health are still largely unknown. Schott speculates that either the increased numbers of Bifidobacteria are crowding out other inflammation-inducing strains, or that these Bifidobacteria are producing a metabolic byproduct(s) that has positive effects on the host, including supporting healthy joints. Answers to these questions may provide the first evidence connecting the gut microbiome to joint health.
Future work in the Zuscik lab will further investigate the gut microbiome in OA, without obesity as a comorbid factor. They hope to determine if OA patients have an altered gut microbiome compared to healthy individuals. If the microbiome is altered in OA, perhaps correction of the abnormalities will protect against or even reverse OA symptoms. Additional clarification of the gut-joint connection may lead to novel therapeutic strategies involving the manipulation of the intestinal microbial community to treat or prevent OA. Results from this work may help to address a clinical problem of enormous scope for which no effective disease-modifying therapy has been established.
The Sport Professional Orthopaedic Research Tool (SPORT) group assesses long-term effects in recent study By Brittany Wilson
Professional athletes are highly susceptible to orthopaedic injuries due to the inherent physical nature of their work. While types of orthopaedic procedures and their associated recovery times are well-documented, empirical evidence assessing athlete performance after returning to play is quite limited.
Wellington K. Hsu, the Clifford C. Raisbeck Distinguished Professor of Orthopaedic Surgery at Northwestern University in Chicago is working to change that. His research team, the Sport Professional Orthopaedic Research Tool (SPORT) group, has been compiling a database to elucidate how orthopaedic procedures affect professional athletes of four major athletic associations: National Basketball Association (NBA), National Football League (NFL), Major League Baseball, and National Hockey League (NHL).
In 2011, the SPORT group assessed the outcomes of professional athletes from these four professional athletic associations who underwent surgery to repair a herniated lumbar disc. While the return to play rate was over 80% for athletes diagnosed with lumbar disc herniation, surgical repair of a herniated lumbar disc led to different outcomes in athletes based upon sport and experience level at the time of diagnosis. The findings from the Professional Athlete Spine Initiative highlight the need for additional studies assessing orthopaedic procedures for other injuries in professional athletes. Hsu adds, “It is likely that different types of injuries will lead to different outcomes in an athlete depending on the relative demands of each sport.”
The SPORT group has published studies assessing post-injury outcomes in professional basketball and football players. It was found that NBA players who had treatment for a hand or wrist fracture had the greatest return to play rate (98.1%), while those who underwent Achilles tendon repair had the lowest rate (70.8%). Achilles tendon repair and arthroscopic knee surgery led to a greater decline in post-operative performance outcomes and shorter career lengths in NBA players than other orthopaedic procedures. Assessment of performance outcomes in NFL players undergoing various orthopaedic procedures revealed that anterior cruciate ligament repair, Achilles tendon repair, and patellar tendon repair have the greatest effect on an NFL career.
Continued research by the SPORT group will include the assessment of hockey and baseball players.
In the United States, there are hundreds of thousands of amputees caused by trauma alone, and this number is expected to steadily rise as the population continues to grow.
Although socket-type prostheses are the most common, an optimal fit is difficult to achieve, often resulting in painful sores and other complications. Socket prosthetic devices also lack stability due to their inefficient integration with the body. This has led to an increased interest in improving the methods of attaching prosthetic devices to amputees.
One approach gaining popularity is the integration of a prosthetic implant directly with the amputees’ residual bone. This implant penetrates the skin to connect to a prosthetic limb. This direct prosthesis-bone interface allows for a more stable connection to the skeleton enabling greater control of the prosthesis and heightened sensory feedback of the environment while eliminating pain and sores experienced with socket prosthetics.
Although this type of prostheses offers promise, it is not without issues. “Unfortunately, these implants face several challenges which prevent their approval by the FDA outside of clinical trials,” explains David Ruppert, a researcher at the University of North Carolina at Chapel Hill and North Carolina State University. “The implants need to conform to patients’ specific anatomy; the skin penetration of the implant is susceptible to infection; and a 12 month rehabilitation period is required to produce a stable bone-implant interface.” Ruppert, along with his collaborators, are currently conducting research focused on addressing the patients’ specific anatomy as well as reducing the lengthy rehabilitation period.
“Our findings showed that rough textured implants created though 3D printing exhibit stronger bone integration than machine threaded counterparts,” says Ruppert. “This highlights the superiority of using 3D printing to not only produce custom designs, but also custom surfaces that interface with amputees’ residual bones.”
In addition, the team of scientists found that vibrating the whole body at low-magnitude and high-frequency at a specific amplitude range can increase bone density around the implant. These results demonstrate that whole-body vibration can be used to minimize bone loss during rehabilitation.
Previous work investigating fracture healing has indicated that low intensity pulsed ultrasound (LIPUS) can be beneficial to bone healing through as yet undetermined mechanisms. It is also unclear if sufficient levels of the stimulus can reach the inner surfaces of the bone to stimulate bone healing. “In our future work we’ll investigate the effects of LIPUS on bone integration into an implant to see if further improvement on the rehabilitation period can be made,” Ruppert explains. “We will also investigate whether there is a cumulative effect of using LIPUS in conjunction with vibration. Finally, we aim to validate additional methods of 3D printing to the one used in our study to improve the level of detail in implant design. Ultimately, we hope to improve the quality of life for amputees.”
Ruppert’s work was presented at the 2016 Annual Meeting of the Orthopaedic Research Society.
As we get older, our ability to heal after breaking a bone declines. This leads to a prolonged healing time and, in some instances, the bone does not heal at all, resulting in significant mobility impairments. While it is not fully understood how aging alters our capacity for fracture repair, Linda Vi, along with a team of researchers at the University of Toronto has been studying mice in the hopes of gaining a better understanding of how bone ages. The team of scientists has recently shown that old mice retain the capacity for bone repair when they are exposed to a circulation of youthful blood.
“Bone is a remarkable organ in that it has the capacity to regenerate itself,” Vi explains. “It is a highly dynamic structure, laying down new bone and removing old bone, in response to changes on the forces applied to them.” However, when people age, there is a dysregulation of this process. Our bones become easier to injure and are more difficult to heal. While we do not fully understand how aging alters this bone healing process, aging is associated with a decline in the abundance and activity of osteoblasts, or our bone-forming cells, during fracture healing.
The group of researchers is interested in understanding how aging alters the recruitment and activation of these osteoblasts during repair. They wondered whether old cells can be stimulated to make bone. “In our study,” explains Vi, “we have identified that these improvements in fracture repair are derived from a type of immune cell, called macrophage. We show that different subtypes of macrophages are present within the healing bones of young and old mice, and that these young macrophages produce ‘youthful factors’, which are greatly diminished in the old macrophage population. When old mice were given just these young macrophages, the older animals showed remarkable improvements in both the pace and quality of fracture repair.”
What’s next for this group? Vi and her team are currently testing some of the ‘youthful factors’ identified in their study to learn more about their ability to promote fracture healing in old mice. “The long term goal of our work,” she explains, “is to be able to develop these ‘youthful factors’ into a potential therapy in the treatment of fracture healing for older individuals.”
Vi’s work was presented at the 2016 Annual Meeting of the Orthopaedic Research Society.
Osteoarthritis is a disease that affects millions of people. Osteoarthritis affects the entire joint, progressively destroying the articular cartilage, including damage to the bone. Patients suffering from osteoarthritis have decreased mobility as the disease progresses, eventually requiring a joint replacement since cartilage does not heal or regenerate. According to a 2010 Cleveland Clinic study, Osteoarthritis is the most prevalent form of arthritis in the United States, affecting more than 70% of adults between 55 and 78 years of age.
“My father was in major pain from his osteoarthritis,” explains Riccardo Gottardi, a scientist at the University of Pittsburgh supported by a Ri.MED Foundation fellowship. “He was in so much pain that he had to undergo a double hip replacement followed by a knee replacement soon afterwards. I could see the debilitating and disabling effects the disease had on him, as he was restricted in his mobility and never fully recovered even after surgery. This was very different from the person that I knew, who had always been active and never shied away from long hours of work in his life – he just could not do it anymore.”
For scientists like Gottardi, a key obstacle in understanding the mechanisms of osteoarthritis and finding drugs that could heal cartilage, is that cartilage does not exist separately from the rest of the body. Cartilage interacts with other tissues of the joint, especially with bone. Bone and cartilage strongly influence each other and this needs to be taken into account when developing new drugs and therapies.
Gottardi and a team of researchers at the Center for Cellular and Molecular Engineering, led by Dr. Rocky Tuan, have developed a new generation system to produce engineered cartilage, bone and vasculature, organized in the same manner as they are found in the human joint. This system is able to produce a high number of identical composite tissues starting from human cells. The team will use this system to study the interactions of cartilage with vascularized bone to identify potential treatments for osteoarthritis.
The team’s research has two main objectives: to help understand how cartilage interacts with the other joint tissues, especially bone; and to help develop new effective treatments that could stop or even reverse the disease. Their patent pending system is the first of its kind, and offers a number of advantages including the use of human cells that replicate native tissues. This system more closely matches the effects on humans than standard animal testing could achieve.
The team of scientists is further developing their system to produce tissues composed of more and different cell types that could better replicate the human joint. They have also started a number of collaborations with other research groups and companies that are interested in using the system to investigate other joint diseases and to test their product.
“After seeing what my father went through,” says Gottardi, “I decided that I did not want to just watch by working on diagnostics, but rather, I wanted to be able to do something about osteoarthritis and contribute to the improvement of current treatment options.”
Gottardi’s work was presented at the 2016 Annual Meeting of the Orthopaedic Research Society.
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