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Disrupting “Quorum Sensing” Could Help Fight Biofilms

Biofilm for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

A biofilm is a complex combination of extracellular carbohydrates, proteins, lipids, and one or more species of bacteria that may adhere to an orthopaedic implant and surrounding tissue (see related OrthoBuzz post). Staphylococci bacteria are believed to account for more than 50% of all biofilm infections of medical devices.

Researchers recently summarized what we know about the biofilm formation process.1 In the attachment phase, free-floating bacteria attach to a prosthetic surface via proteins. Extracellular DNA from autolysis add to the mix. Then begins the irreversible attachment phase, during which the initial bacteria are incarcerated while more free-floating bacteria are added. During this phase, autoinducers are expressed, which serve as inter- and intrabacterial signals.

In the presence of an adequate quorum of bacteria, the maturation phase begins, during which the bacterial population cohesively shifts from replication to expression of virulence factors such as secretion systems, toxins, or biofilm formation. A mature biofilm is immune-resistant, although bacterial replication decreases. In the dispersal phase bacteria become planktonic again, potentially available to repeat the process.

Once a biofilm has formed, antibiotic administration becomes problematic because of the toxicity of the high doses needed to treat biofilm colonies. An underlying challenge with pharmacologic intervention is the variety of quorum-sensing communication pathways between bacterial species. The authors suggest that a future biofilm-fighting strategy may be to force bacteria into biofilm-forming behavior before they reach the necessary critical density to become virulent, although this notion remains unexplored. Researchers are investigating other possible strategies to disrupt the quorum-sensing communication among bacteria that enable them to behave as a “social” group.

Reference

  1. Mooney JA, Pridgen EM, Manasherob R, Suh G, Blackwell HE, Barron AE, Bollyky PL, Goodman SB, Amanatullah DF. Periprosthetic bacterial biofilm and quorum sensing. J Orthop Res. 2018 Sep;36(9):2331-2339. doi: 10.1002/jor.24019. Epub 2018 May 24.

Surgical Infection Prevention: Local Antibiotic Powders Beat IV Agents in Rats

Culture for OBuzzWhen it comes to preventing infections associated with orthopaedic procedures, the question of which antibiotic to use is only one of several concerns. How and where to administer antibiotics is another relevant question, not only in terms of infection-fighting effectiveness but also in terms of combatting the proliferation of antibiotic-resistant microbes.

In the September 19, 2018 issue of The Journal of Bone & Joint Surgery, Sweet et al. report on findings from a study in rats that compared the infection-prevention efficacy of intravenous (IV) cefazolin (n = 20) and IV vancomycin (n = 20) with local application of 4 antimicrobials—vancomycin powder (n = 20), cefazolin powder (n = 20), tobramycin powder (n = 20), and dilute Betadine lavage (n = 20).

The researchers induced infection by surgically implanting a polytetrafluoroethylene vascular graft near each rat’s thoracic spine and inoculating it with methicillin-sensitive Staphylococcus aureus (MSSA). After 7 days, all of the rats in each of the IV cefazolin, IV vancomycin, and Betadine lavage groups had grossly positive cultures for MSSA, “with bacterial colonies too numerous to count.” Ninety percent of the rats in the local cefazolin-powder group also had positive cultures, but the infection rates with vancomycin and tobramycin powder were much lower than those with the other four approaches (p <0.000001).

In addition to the main “disclaimer” about this study (namely, that its findings cannot be extrapolated to clinical practice in humans), the authors caution that “the effect of locally applied antibiotics on the emergence of resistant organisms is unknown,” while citing evidence that systemic administration of antibiotics is “associated with the emergence of resistant organisms at an alarming rate.”

Sweet et al. say they plan to follow up this study with a similar model to investigate the efficacy of local antimicrobials against the more problematic methicillin-resistant Staphylococcus aureus (MRSA)—and they suggest further that “clinical studies should be considered to determine the relative clinical efficacy of local versus systemic antibiotics for surgical infection prophylaxis in humans.”

BOG Fracture-Risk Score Combines DNA Info with Physiological Factors

Fracture Risk Image for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

During childhood and adulthood, we often put ourselves at risk for future fractures based on our activity, diet, and social habits. Many factors affect the risk of both stress fractures in younger people and fragility fractures later in life. Everyone—but especially athletes and active-duty military personnel—could benefit from an early heads-up regarding their genetic and phenotypic predisposition to stress fractures. Later in life, the FRAX index is a very useful multifactor risk score, but it is usually calculated only after a sentinel event, such as a fragility fracture.

Ultrasound is a readily available and inexpensive way to obtain an estimated heel bone mineral density (eBMD). Many common genetic variants contribute to the genetic basis for the eBMD phenotype. These variants are most commonly characterized by single nucleotide polymorphisms (SNPs, pronounced “snips”). Stanford researcher Stuart Kim developed the BMD Osteoporosis Genetic (BOG) risk score by combining 22,886 SNPs with data on height, weight, sex, and age.1 The correlation between actual eBMD and the BOG algorithm was 0.496, which was higher than the correlations achieved using the 22,886 genetic predictors or the four covariates alone.

Individuals with low BOG scores had a 17.4-fold increased risk for osteoporosis compared to those with the median BOG score. Low BOG scores were also associated with a 1.9-fold higher risk for bone fractures compared to median BOG values. However, the algorithm’s ability to discriminate cases from controls in the overall population was modest. The receiver operator area under the curve for predicting osteoporosis or fracture by the BOG algorithm was 0.78 and 0.57, respectively.

Although the effect of an individual SNP may be inconsequential, the cumulative effect from many SNPs can be large. The author stated that “an algorithm such as the BOG risk score might be useful to screen the general population…to identify individuals that warrant closer examination, such as BMD measurement via DXA [dual-energy X-ray absorptiometry].”

Reference

  1. Kim SK. Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS One. 2018 Jul 26;13(7):e0200785. doi: 10.1371/journal.pone.0200785. eCollection 2018. PMID: 30048462

Getting to the Core of Bone Marrow Lesions

Bone Marrow Lesion for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

The terms “bone marrow edema,” “bone marrow lesion” (BML), and “bone bruise” are often used interchangeably to refer to areas in cancellous bone that have hyperintense marrow signal in fluid-sensitive, fat-suppressed MRI sequences. Although most commonly observed in knee MRIs, BMLs can be seen in a variety of joints. In the hip, they are seen in transient osteoporosis and rapid-onset osteoarthritis. The term “bone bruise” is often specifically applied in the setting of an injury, such as lateral tibial plateau hyperintense changes that are seen after an anterior cruciate ligament rupture.

In the setting of knee osteoarthritis, BMLs are a response to degeneration of menisci, articular cartilage, synovium, or bone itself. One of the mechanisms associated with BMLs seems to be secondary to circulatory response and bone turnover. In one study covered in a 2017 review article1, patients with OA and associated BMLs were randomized to receive the bone antiresorptive agent zoledronic acid (ZA) or placebo. At 6 months, VAS pain scores in the ZA group were reduced by ZA, the reduction in BML area was greater in the ZA group than in the placebo group, and a greater proportion in the ZA group achieved a clinically significant reduction in BML size (39% vs. 18%, p <0.044). A larger study is planned to further define the relationship between reduction in BML size and pain scores.

Regarding “crosstalk” between subchondral bone and articular cartilage in joint disease, recent data suggest that numerous canals and porosities connect the bone to cartilage at the interface. Treatment of the bone compartment with antiresorptives and anti-TGF-β at specific early time points has been shown to have chondroprotective effects in animal models. Additionally, one study identified s14-3-3ε, a short extracellular protein, as a mediator critical in the communication between subchondral bone and cartilage in OA. This may prove to be a potential target for therapeutic or prognostic use.

Numerous articles have outlined the abundance of trabecular microfractures seen in areas where BMLs are present. A commonly held hypothesis is that resorption cavities caused by bone remodeling can act as stress concentrations, promoting further microdamage and leading to a cycle of damage-remodeling-damage. Some individuals may be more prone to rapid bone turnover and thus more prone to developing bone edema.

When your clinical attention is directed to BMLs, their shape and extent may influence nonsurgical treatment decisions. Conservative management may be directed by a better understanding of how BMLs contribute to pain and OA progression.

Reference

  1. Alliston T, Hernandez CJ, Findlay DM, Felson DT, Kennedy OD. Bone marrow lesions in osteoarthritis: What lies beneath. J Orthop Res. 2017 Dec 21. doi: 10.1002/jor.23844. [Epub ahead of print] PMID: 29266428

Structural Allografts Can Work for Acetabular Defects in THA

Structural Allograft for OBuzzAllograft bone is used often in orthopaedic surgery. However, the use of structural allografts to address large acetabular defects in total hip arthroplasty (THA) is not common. But it may become more so in light of the study by Butscheidt et al. in the August 15, 2018 issue of JBJS. The authors add to our knowledge about these relatively rare procedures by evaluating the incorporation of structural acetabular allografts into host bone among 13 complete pelvic explants containing allograft that had been in place for a mean of 13 years.

Using sophisticated imaging and histological techniques, the authors found that in 10 out of the 13 specimens retrieved, 100% of the interface was characterized by direct contact and additional overlap of the allograft bone and the host bone. The remaining 3 allografts showed direct contact along 25% to 80% of the interface.  The authors found no correlation between ingrowth of the host bone into the allograft and the amount of time the allograft had spent in situ, leading them to surmise that “a large proportion of the incorporation process may be completed within the first weeks.”

Large, structural allografts are not commonly used for acetabular reconstructions, as most surgeons seem to favor other options.  (See the JBJS Clinical Summary on “Managing Acetabular Defects in Hip Arthroplasty.”) While a postmortem study of 13 cases may not be “practice-changing,“ the Butscheidt et al. analysis does provide some detailed clarity as to what surgeons can expect from these large allograft reconstructions in terms of incorporation with host bone. Obviously, one limitation of this study is that structural allografts that never incorporated with the host bone probably failed early and would not be available for analysis in a long-follow-up retrieval study.

Chad A. Krueger, MD
JBJS Deputy Editor for Social Media

New Findings in Muscle Injury—An Under-Researched Subject

Periostin for OBuzzThe goal of orthopaedic surgery is to help the entire musculoskeletal system function in harmony, but the preponderance of orthopaedic research focuses on the skeletal system instead of muscles and tendons. Bone is the only organ that can heal by regenerating tissue that is usually just as effective as the original structure. Consequently, we have focused on developing systems to hold bone intact as it heals so that postinjury function is maximized. Decades have been spent understanding the critical biologic pathways of bone healing and developing implantable, pharmacologic, and cell-based therapies to optimize it.

However, we sometimes overlook the fact that the skeleton can’t move without muscles. Only a few researchers have devoted their careers to understanding skeletal muscle’s response to injury and approaches to enhance muscle recovery after disuse and injury. In the August 15, 2018 issue of The Journal, Hara et al. report on experiments with the protein periostin in mice. Periostin is involved with the process of muscle fibrosis, during which fibroblasts proliferate in the injured area of the muscle and create “scar tissue” that eventually inhibits muscle function.

In one experiment, the authors found that “knockout” mice without the gene that encodes for periostin had improved recovery in a lacerated gastrocnemius muscle, less fibrosis in the muscle, and a significantly reduced number of infiltrating fibroblasts than “wild” mice with the same induced injury. In a similar experiment, they found reduced muscle fibrosis in injured muscles of mice whose production of periostin was neutralized by an antibody injected into the injured muscle. Although a sharp injury to muscle (the laceration model used in these mouse experiments) is not a common clinical scenario in patients seen by orthopaedists, the Hara et al. study represents a step forward in understanding muscle response to injury.

While these findings need to be replicated and then translated into clinical applications for humans, they shed new light on the importance of preventing periostin-induced fibroblast migration after skeletal muscle injury. This research hints at a potential therapeutic strategy to enhance muscle’s functional recovery, which is the most sought-after outcome for patients.

The clinical sports and orthopaedic communities are in need of approaches to limit scarring and atrophy in the setting of muscle disuse and injury. Any of us who unavoidably injure muscle during surgical approaches to bones and joints or for graft harvests and other procedures should be heartened by these findings. It is my hope that more early-career researchers will focus on the first half of the term “musculoskeletal” to advance therapeutic approaches to problems that impact function to a much more permanent degree than do most bone injuries.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

Sept. 11 Webinar – Assessment of Bone Health for the Orthopaedic Surgeon

Sept Webinar Speakers

Orthopaedic care teams can play an active role in evaluating and optimizing their patients’ bone health to help prevent primary and secondary fragility fractures and to improve postsurgical outcomes. In just about any orthopaedic scenario, helping patients optimize their bone health is an imperative for the delivery of quality care.

On Tuesday, September 11, 2018 at 8 pm EDTthe American Orthopaedic Association (AOA) and The Journal of Bone & Joint Surgery (JBJS) will host a complimentary one-hour webinar that will cover the basics of a bone-health assessment by orthopaedists.

  • Christopher Shuhart, MD will discuss the fundamentals of bone-related laboratory workups and bone densitometry studies.
  • Joe Lane, MD, FAOA will identify bone-health “red flags” in orthopaedic patients, including common nutritional deficiencies.
  • Paul Anderson, MD, FAOA will cover recent advances in bone-density measurements.

Moderated by Douglas Lundy, MD, MBA, FAOA, orthopaedic trauma surgeon at Resurgens Orthopaedics, this webinar will include a 15-minute live Q&A session during which attendees can ask questions of the panelists.

Seats are limited so REGISTER NOW.

JBJS 100: Proximal Humeral Fractures, Stem Cells

JBJS 100Under one name or another, The Journal of Bone & Joint Surgery has published quality orthopaedic content spanning three centuries. In 1919, our publication was called the Journal of Orthopaedic Surgery, and the first volume of that journal was Volume 1 of what we know today as JBJS.

Thus, the 24 issues we turn out in 2018 will constitute our 100th volume. To help celebrate this milestone, throughout the year we will be spotlighting 100 of the most influential JBJS articles on OrthoBuzz, making the original content openly accessible for a limited time.

Unlike the scientific rigor of Journal content, the selection of this list was not entirely scientific. About half we picked from “JBJS Classics,” which were chosen previously by current and past JBJS Editors-in-Chief and Deputy Editors. We also selected JBJS articles that have been cited more than 1,000 times in other publications, according to Google Scholar search results. Finally, we considered “activity” on the Web of Science and The Journal’s websites.

We hope you enjoy and benefit from reading these groundbreaking articles from JBJS, as we mark our 100th volume. Here are two more:

Displaced Proximal Humeral Fractures: Classification and Evaluation
C Neer: JBJS, 1970 September; 52 (6): 1077
Complex distal humeral fractures have long challenged orthopaedic surgeons and their patients. Often the first step in fracture-management decision-making is classification, and in this 1970 study, Dr. Neer proposed a 6-group classification based on the presence or absence of displacement of one or more of the four major proximal segments. Since then, this classification has been variably adapted by multiple authors, but its usefulness remains intact.

The Effect of Implants Loaded with Autologous Mesenchymal Stem Cells on the Healing of Canine Segmental Bone Defects
S F Bruder, K H Kraus, V M Goldberg, S Kadiyala: JBJS, 1998 July; 80 (7): 985
Research into mesenchymal stem cells (MSCs) to augment healing of tendons, chondral and bone defects, and other connective tissues has taken off since these authors used autologous MSCs to help heal 21-mm segmental femoral defects. Radiographic union occurred rapidly at the interface between host bone and porous ceramic cylinders loaded with MSCs, and a large collar of bone had formed around the cell-loaded implants after 16 weeks.

JBJS 100: Gait Initiation, ACL Replacement

JBJS 100Under one name or another, The Journal of Bone & Joint Surgery has published quality orthopaedic content spanning three centuries. In 1919, our publication was called the Journal of Orthopaedic Surgery, and the first volume of that journal was Volume 1 of what we know today as JBJS.

Thus, the 24 issues we turn out in 2018 will constitute our 100th volume. To help celebrate this milestone, throughout the year we will be spotlighting 100 of the most influential JBJS articles on OrthoBuzz, making the original content openly accessible for a limited time.

Unlike the scientific rigor of Journal content, the selection of this list was not entirely scientific. About half we picked from “JBJS Classics,” which were chosen previously by current and past JBJS Editors-in-Chief and Deputy Editors. We also selected JBJS articles that have been cited more than 1,000 times in other publications, according to Google Scholar search results. Finally, we considered “activity” on the Web of Science and The Journal’s websites.

We hope you enjoy and benefit from reading these groundbreaking articles from JBJS, as we mark our 100th volume. Here are two more:

The Initiation of Gait
R A Mann, J L Hagy, V White, D Liddell: JBJS, 1979 March; 61 (2): 232
Using electromyography and force-plate data, this study of 10 healthy men and women revealed that the deceptively simple motion of taking the first step from a standing position is initiated by the unbalanced body harnessing complex neural mechanisms, muscular activity, and biomechanical forces. The findings can inform today’s efforts to prevent falls among the elderly.

Replacement of the Anterior Cruciate Ligament using a Patellar Tendon Allograft
S P Arnoczky, R F Warren, M A Ashlock: JBJS, 1986 January; 68 (3): 376
Fresh or deep-frozen? That was the question researchers asked in this study of 25 dogs whose patellar tendons were replaced with one of these two types of allografts. The fresh allografts incited a marked inflammatory and rejection response, while the deep-frozen allografts appeared to be benign and behaved comparably to autogenous patellar tendon grafts. In the 30-plus years since this 1986 study, we have learned a lot about the immunogenicity and biologic character of transplanted allografts, and this important research continues.

PRP for Tennis Elbow: What’s the “Secret Sauce”?

Tennis Elbow Image for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

There are many suggested applications for platelet-rich plasma (PRP), including tendon repair, osteoarthritis, and other musculoskeletal conditions. However there is considerable controversy in the absence of convincing evidence about the optimal mix and concentration of white blood cells and platelets in PRP, and the most clinically effective nature and quantity of constituent cytokines or other biochemical agents in PRP.

Despite these lingering questions, PRP is commonly used to treat lateral epicondylitis (LE), commonly called “tennis elbow.” As with its other applications, the clinical use of PRP for painful tendons has received much attention, but its efficacy remains controversial.

To continue investigating the clinical effects of PRP and its individual components, researchers recruited 156 patients with LE and randomly divided them into those treated with a single injection of 2-mL autologous PRP and those who received only physical therapy without injection.1 Both groups used a tennis elbow strap and performed stretching and strengthening exercises for 24 weeks, at which point pain and functional improvements were assessed using the visual analog scale (VAS), Modified Mayo Clinic Performance Index for the elbow, and MRI. Levels of platelet-derived growth factor-AB (PDGF-AB), PDGF-BB, transforming growth factor-β (TGF-β), vascular endothelial growth factor, epithelial growth factor, and interleukin-1 β in the PRP were measured for statistical correlation with clinical scores.

At 24 weeks, all pain and functional variables—including VAS score, Mayo Clinic performance scores, and MRI grade—improved significantly in the PRP group, relative to the noninjection group (p < 0.05). The TGF-β level in the PRP significantly correlated with Mayo Clinic performance score and MRI grade improvement.

The PRP level of TGF-β appears to be important in tendon healing, but future studies will be required to determine the best relative concentrations of white blood cells and platelets that deliver specific cytokines such as TGF-β. However, these results help identify a viable protocol for measuring PRP efficacy in tendinopathies.

Reference

  1. Lim W, Park SH, Kim B, Kang SW, Lee JW, Moon YL. Relationship of cytokine levels and clinical effect on platelet-rich plasma-treated lateral epicondylitis. J Orthop Res. 2018 Mar;36(3):913-920. doi: 10.1002/jor.23714. Epub 2017 Sep 20. PMID: 28851099