Extracellular Targets to Reduce Excessive Scarring in Response to Tissue Injury.

Excessive scar formation is a hallmark of localized and systemic fibrotic disorders. Despite extensive studies to define valid anti-fibrotic targets and develop effective therapeutics, progressive fibrosis remains a significant medical problem. Regardless of the injury type or location of wounded tissue, excessive production and accumulation of collagen-rich extracellular matrix is the common denominator of all fibrotic disorders. A long-standing dogma was that anti-fibrotic approaches should focus on overall intracellular processes that drive fibrotic scarring. Because of the poor outcomes of these approaches, scientific efforts now focus on regulating the extracellular components of fibrotic tissues. Crucial extracellular players include cellular receptors of matrix components, macromolecules that form the matrix architecture, auxiliary proteins that facilitate the formation of stiff scar tissue, matricellular proteins, and extracellular vesicles that modulate matrix homeostasis. This review summarizes studies targeting the extracellular aspects of fibrotic tissue synthesis, presents the rationale for these studies, and discusses the progress and limitations of current extracellular approaches to limit fibrotic healing.

Mechanisms of reducing joint stiffness by blocking collagen fibrillogenesis in a rabbit model of posttraumatic arthrofibrosis.

Posttraumatic fibrotic scarring is a significant medical problem that alters the proper functioning of injured tissues. Current methods to reduce posttraumatic fibrosis rely on anti-inflammatory and anti-proliferative agents with broad intracellular targets. As a result, their use is not fully effective and may cause unwanted side effects. Our group previously demonstrated that extracellular collagen fibrillogenesis is a valid and specific target to reduce collagen-rich scar buildup. Our previous studies showed that a rationally designed antibody that binds the C-terminal telopeptide of the α2(I) chain involved in the aggregation of collagen molecules limits fibril assembly in vitro and reduces scar formation in vivo. Here, we have utilized a clinically relevant arthrofibrosis model to study the broad mechanisms of the anti-scarring activity of this antibody. Moreover, we analyzed the effects of targeting collagen fibril formation on the quality of healed joint tissues, including the posterior capsule, patellar tendon, and subchondral bone. Our results show that blocking collagen fibrillogenesis not only reduces collagen content in the scar, but also accelerates the remodeling of healing tissues and changes the collagen fibrils' cross-linking. In total, this study demonstrated that targeting collagen fibrillogenesis to limit arthrofibrosis affects neither the quality of healing of the joint tissues nor disturbs vital tissues and organs.

Orthopedic Specialty Hospitals Are Associated With Lower Rates of Deep Surgical Site Infection Compared With Tertiary Medical Centers.

Orthopedic specialty hospitals may allow for more streamlined and efficient care, resulting in shorter lengths of stay, lower costs, and fewer complications. Surgical site infection can be a devastating complication of orthopedic procedures and is difficult to treat successfully, requiring substantial cost and resources. The goal of this study was to determine whether specialty hospitals had lower rates of infection than tertiary care institutions. Records were reviewed for patients undergoing primary total hip, knee, or shoulder arthroplasty and single-level lumbar fusion from 2010 to 2017 at 2 academic tertiary hospitals and 2 specialty hospitals. Patient demographic information, comorbidities, and the development of deep surgical site infection within 1 year of the index procedure were recorded and compared between the groups. Multivariate analysis identified variables that significantly correlated with infection rates. A total of 20,264 patients (73.9%) underwent surgery at a tertiary hospital, and 7169 (26.1%) underwent a procedure at a specialty hospital. Patients treated at orthopedic specialty hospitals had lower rates of infection at 1 year (0.6% vs 0.2%, P<.0001). Of the infections, 42 (32.3%) occurred in the knee, 50 (38.5%) in the hip, 24 (18.5%) in the spine, and 12 (10.8%) in the shoulder. When controlling for a healthier patient population, procedures performed at specialty hospitals were an independent predictor of infection within 1 year (odds ratio, 0.3693; P=.0012). Although tertiary hospitals care for older patients with more medical comorbidities, patients undergoing orthopedic procedures at a specialty hospital may be at lower risk for infection. Further study is needed to identify the processes associated with reduced infection rates and to determine whether they can be adopted at tertiary centers. [Orthopedics. 2021;44(4):e521-e526.].

Adjuvant antibiotic-loaded bone cement: Concerns with current use and research to make it work.

Antibiotic-loaded bone cement (ALBC) is broadly used to treat orthopaedic infections based on the rationale that high-dose local delivery is essential to eradicate biofilm-associated bacteria. However, ALBC formulations are empirically based on drug susceptibility from routine laboratory testing, which is known to have limited clinical relevance for biofilms. There are also dosing concerns with nonstandardized, surgeon-directed, hand-mixed formulations, which have unknown release kinetics. On the basis of our knowledge of in vivo biofilms, pathogen virulence, safety issues with nonstandardized ALBC formulations, and questions about the cost-effectiveness of ALBC, there is a need to evaluate the evidence for this clinical practice. To this end, thought leaders in the field of musculoskeletal infection (MSKI) met on 1 August 2019 to review and debate published and anecdotal information, which highlighted four major concerns about current ALBC use: (a) substantial lack of level 1 evidence to demonstrate efficacy; (b) ALBC formulations become subtherapeutic following early release, which risks induction of antibiotic resistance, and exacerbated infection from microbial colonization of the carrier; (c) the absence of standardized formulation protocols, and Food and Drug Administration-approved high-dose ALBC products to use following resection in MSKI treatment; and (d) absence of a validated assay to determine the minimum biofilm eradication concentration to predict ALBC efficacy against patient specific micro-organisms. Here, we describe these concerns in detail, and propose areas in need of research.

Bacterial toxins in musculoskeletal infections.

Musculoskeletal infections (MSKIs) remain a major health burden in orthopaedics. Bacterial toxins are foundational to pathogenesis in MSKI, but poorly understood by the community of providers that care for patients with MSKI, inducing an international group of microbiologists, infectious diseases specialists, orthopaedic surgeons and biofilm scientists to review the literature in this field to identify key topics and compile the current knowledge on the role of toxins in MSKI, with the goal of illuminating potential impact on biofilm formation and dispersal as well as therapeutic strategies. The group concluded that further research is needed to maximize our understanding of the effect of toxins on MSKIs, including: (i) further research to identify the roles of bacterial toxins in MSKIs, (ii) establish the understanding of the importance of environmental and host factors and in vivo expression of toxins throughout the course of an infection, (iii) establish the principles of drug-ability of antitoxins as antimicrobial agents in MSKIs, (iv) have well-defined metrics of success for antitoxins as antiinfective drugs, (v) design a cocktail of antitoxins against specific pathogens to (a) inhibit biofilm formation and (b) inhibit toxin release. The applicability of antitoxins as potential antimicrobials in the era of rising antibiotic resistance could meet the needs of day-to-day clinicians.

N-acetylcysteine use as an adjuvant to bone cement to fight periprosthetic joint infections: A preliminary in vitro efficacy and biocompatibility study.

When antibiotic laden bone cement is used to manage periprosthetic joint infection (PJI), failure still occurs with its use in up to 30% of cases. Therefore, we designed an in vitro study to assess the bactericidal effect of N-acetylcysteine (NAC), an antibacterial adjuvant, in cement against planktonic and biofilm forms of common PJI pathogens. NAC (10%, 20%, 30%, 40%, and 50% w/v) added to polymethyl methacrylate (PMMA) and incubated in broth at 36°C. PMMA-alone and/or culture bacteria alone were used as a negative control. Aliquots of cement elution from each group were taken at 1 day and 1 week and then were investigated for antimicrobial efficacy against the planktonic-form and the biofilm-form of Staphylococcus aureus and Escherichia coli. The primary outcome was the residual colony-forming unit count. The cytotoxicity and mechanical properties of the NAC-PMMA cement-blocks were also assessed. NAC-PMMA efficacy against the planktonic bacteria was demonstrated at a minimum of 30% at Day 1 and a minimum of 20% at 1 week after (p < .001). NAC-PMMA cement was effective against biofilm at a minimum of 30% of NAC at 1 day and 1 week of cement immersion (p < .001). The PMMA alone group was identified as having the highest cytotoxicity (p < .001). NAC decreased the stiffness (p = .004) and maximum load breaking point of the cement (p = .029). NAC is an effective and biocompatible adjuvant to PMMA in terms of antibacterial activity against Staphylococcus aureus and Escherichia coli. The broad antibacterial spectrum of NAC, its low expense, and minimal cytotoxicity makes it an ideal agent for addition to PMMA cement.

Preoperative Sedative Use and Other Risk Factors for Continued Narcotic Use After Total Knee Arthroplasty: A Comprehensive Analysis of a Mandatory Database.

Opioids are used for pain control after total knee arthroplasty (TKA) and carry risk for abuse. Mandatory statewide databases have been created to monitor their use. The goal of this study was to identify patient risk factors for prolonged opioid use after TKA. The authors retrospectively reviewed a consecutive series of 676 primary TKA procedures performed between January 2017 and July 2017. Information on fulfillment of narcotic, sedative, benzodiazepine, and stimulant prescriptions was obtained from the Pennsylvania State Controlled Substance Monitoring website 6 months before and 1 year after the procedure. Bivariate and multivariate analyses were used to identify risk factors for the need for a second prescription and opioid use for longer than 6 months. Of this cohort, 30.3% used preoperative opioids, 60.5% filled a second opioid prescription, and 11.8% continued opioid use for longer than 6 months. Patients who had opioid use before the index procedure had more than 3-fold (odds ratio [OR], 3.29; P<.001) increased odds of filling a second opioid prescription and 8-fold (OR, 8.05; P<.001) increased odds of postoperative opioid use for longer than 6 months. Multivariate analysis was used to identify independent risk factors for requiring a second prescription, including discharge to a rehabilitation facility (OR, 2.77), bilateral procedures (OR, 1.88), preoperative narcotic use (OR, 1.70), and younger age (OR, 0.95). Independent risk factors for narcotic use for longer than 6 months included preoperative sedative (OR, 3.30) or narcotic use (OR, 1.49). This study identified several risk factors associated with prolonged narcotic use after TKA, including preoperative sedative use, and determined their relative weight. [Orthopedics. 2021;44(1):e50-e54.].

Infection in Arthroplasty: The Basic Science of Bacterial Biofilms in Its Pathogenesis, Diagnosis, Treatment, and Prevention.

In the past, the diagnosis and treatment of periprosthetic joint infection (PJI) in joint arthroplasty has often been frustrating for orthopaedic surgeons. The application of certain diagnostic criteria and different treatment strategies can be better directed if these infections are placed in the context of microbial biofilms. An understanding of this biofilm mode of microbial infection can help to explain the phenomenon of culture-negative infection as well as provide an understanding of why certain treatment modalities often fail. Continued basic research into the role of biofilms in infection will likely provide improved strategies for the clinical diagnosis and treatment of PJI. This is a review of the current preclinical knowledge of biofilm in relation to PJI with an overview of current practices applied in the diagnosis, treatment, and prevention of biofilm formation in this setting.

Understanding Opioid Use After Total Hip Arthroplasty: A Comprehensive Analysis of a Mandatory Prescription Drug Monitoring Program.

INTRODUCTION: Opioids remain the most prescribed medication after total hip arthroplasty (THA) despite the potential for abuse and adverse effects. Given the high rates of opioid abuse and potential adverse effects, the reporting of controlled substances is now mandatory in many statewide databases. This study aimed to use a mandatory statewide database to analyze opioid prescription patterns in postoperative THA patients and identify independent risk factors for those patients who need a second prescription and/or require prolonged use (>6 months). METHODS: We retrospectively reviewed a consecutive series of 619 primary THAs. Demographic and comorbidity information were collected for all patients. Narcotic prescription data (converted to morphine milligram equivalents) as well as prescription data for sedatives, benzodiazepines, and stimulants were collected from the State's Controlled Substance Monitoring websites 6 months before and 9 months after the index procedure. Bivariate and multivariate analyses were done for second prescription and continued use. RESULTS: Of the 619 patients who underwent THA, 34.9% (216/619) used preoperative opioids, 36.2% (224/619) filled a second opioid prescription, and 10.5% (65/619) had continued use past 6 months. Patients with preoperative opioids were at an approximately 4-fold increased odds of requiring a second script and 12 times odds of continued opioid use. In the multivariate analysis, independent risk factors for requiring a second prescription, in descending order of magnitude, included the use of any sedative or sleep aid prescription and preoperative narcotic use. Independent risk factors for continued narcotic use longer than 6 months after THA included preoperative narcotic use and increased length of stay. DISCUSSION: Several risk factors and their relative weight have been identified for continued narcotic consumption after THA. It is important for surgeons to consider these predisposing factors preoperatively during the informed consent process and for managing postoperative pain expectations.

Treatment Outcomes and Attrition in Gram-Negative Periprosthetic Joint Infection.

BACKGROUND: While the prevailing belief is that periprosthetic joint infection (PJI) caused by Gram-negative (GN) organisms confers a poorer prognosis than Gram-positive (GP) cases, the current literature is sparse and inconsistent. The purpose of this study is to compare the treatment outcomes for GN PJI vs GP PJI and Gram-mixed (GM) PJI. METHODS: A retrospective review of 1189 PJI cases between 2007 and 2017 was performed using our institutional PJI database. Treatment failure defined by international consensus criteria was compared between PJI caused by GN organisms (n = 45), GP organisms (n = 663), and GM (n = 28) cases. Multivariate regression was used to predict time to failure. RESULTS: GM status, but not GN, had significantly higher rates of treatment failure compared to GP PJI (67.9% vs 33.2% failure; hazards ratio [HR] = 2.243, P = .004) in the multivariate analysis. In a subanalysis of only the 2-stage exchange procedures, both GN and GM cases were significantly less likely to reach reimplantation than GP cases (HR = .344, P < .0001; HR = .404, P = .013). CONCLUSION: Although there was no observed difference in the overall international consensus failure rates between GN (31.1% failure) and GP (33.2%) PJI cases, there was significant attrition in the 2-stage exchange GN cohort, and these patients were significantly less likely to reach reimplantation. Our findings corroborate the prevailing notion that GN PJI is associated with poorer overall outcomes vs GP PJI. These data add to the current body of literature, which may currently underestimate the overall failure rates of GN PJI treated via 2-stage exchange and fail to identify pre-reimplantation morbidity.

2018 international consensus meeting on musculoskeletal infection: Summary from the biofilm workgroup and consensus on biofilm related musculoskeletal infections.

Biofilm-associated implant-related bone and joint infections are clinically important due to the extensive morbidity, cost of care and socioeconomic burden that they cause. Research in the field of biofilms has expanded in the past two decades, however, there is still an immense knowledge gap related to many clinical challenges of these biofilm-associated infections. This subject was assigned to the Biofilm Workgroup during the second International Consensus Meeting on Musculoskeletal Infection held in Philadelphia USA (ICM 2018) (https://icmphilly.com). The main objective of the Biofilm Workgroup was to prepare a consensus document based on a review of the literature, prepared responses, discussion, and vote on thirteen biofilm related questions. The Workgroup commenced discussing and refining responses prepared before the meeting on day one using Delphi methodology, followed by a tally of responses using an anonymized voting system on the second day of ICM 2018. The Working group derived consensus on information about biofilms deemed relevant to clinical practice, pertaining to: (1) surface modifications to prevent/inhibit biofilm formation; (2) therapies to prevent and treat biofilm infections; (3) polymicrobial biofilms; (4) diagnostics to detect active and dormant biofilm in patients; (5) methods to establish minimal biofilm eradication concentration for biofilm bacteria; and (6) novel anti-infectives that are effective against biofilm bacteria. It was also noted that biomedical research funding agencies and the pharmaceutical industry should recognize these areas as priorities. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Epiphyseal growth plate architecture is unaffected by early postnatal activation of the expression of R992C collagen II mutant.

Spondyloepiphyseal dysplasia (SED) exemplifies a group of heritable diseases caused by mutations in collagenous proteins of the skeletal system. Its main feature is altered skeletal growth. Pathomechanisms of SED include: changes in the stability of collagen II molecules, inability to form proper collagen fibrils, excessive intracellular retention of mutant molecules, and endoplasmic reticulum stress. The complexity of this pathomechanism presents a challenge for designing therapies for SED. Our earlier research tested whether such therapies only succeed when applied during a limited window of development. Here, employing an inducible mouse model of SED caused by the R992C mutation in collagen II, we corroborate our earlier observations that a therapy must be applied at the prenatal or early postnatal stages of skeletal growth in order to be successful. Moreover, we demonstrate that blocking the expression of the R992C collagen II mutant at the early prenatal stages leads to long-term positive effects. Although, we could not precisely mark the start of the expression of the mutant, these effects are not significantly changed by switching on the mutant production at the early postnatal stages. By demonstrating the need for early therapeutic interventions, our study provides, for the first time, empirically-based directions for designing effective therapies for SED and, quite likely, for other skeletal dysplasias caused by mutations in key macromolecules of the skeletal system.

Blocking collagen fibril formation in injured knees reduces flexion contracture in a rabbit model.

Post-traumatic joint contracture is a frequent orthopaedic complication that limits the movement of injured joints, thereby severely impairing affected patients. Non-surgical and surgical treatments for joint contracture often fail to improve the range of motion. In this study, we tested a hypothesis that limiting the formation of collagen-rich tissue in the capsules of injured joints would reduce the consequences of the fibrotic response and improve joint mobility. We targeted the formation of collagen fibrils, the main component of fibrotic deposits formed within the tissues of injured joints, by employing a relevant rabbit model to test the utility of a custom-engineered antibody. The antibody was delivered directly to the cavities of injured knees in order to block the formation of collagen fibrils produced in response to injury. In comparison to the non-treated control, mechanical tests of the antibody-treated knees demonstrated a significant reduction of flexion contracture. Detailed microscopic and biochemical studies verified that this reduction resulted from the antibody-mediated blocking of the assembly of collagen fibrils. These findings indicate that extracellular processes associated with excessive formation of fibrotic tissue represent a valid target for limiting post-traumatic joint stiffness. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1038-1046, 2017.

Are Preoperative Serologic Type and Screen Tests Necessary for Primary Total Joint Arthroplasty Patients in Specialty Surgical Hospitals?

BACKGROUND: Blood loss during total joint arthroplasty (TJA) has been a major concern requiring routine preoperative patient type and screen (T&S); however, with the implementation of blood conserving therapy, a marked decrease for perioperative transfusions has been observed. Many TJAs are now being performed in T&S mandated specialty surgical hospitals (SSHs) that lack on-site blood banks; therefore, the purpose of our study was to determine whether T&S (1) is necessary in SSH for TJA patients and (2) identifies patient risk factors associated with perioperative blood transfusion in SSH. METHODS: A retrospective study was conducted on 1034 consecutive primary TJAs performed between 2013 and 2014 at a 12-bed SSH who all received T&S. Patients were matched (1:1) to 964 inpatient TJA patients performed at a university hospital without routine T&S. Data on surgery type, patient demographics, hemoglobin and hematocrit results, and transfusion rates were collected. Multivariate logistic regression identified perioperative transfusion risk factors. RESULTS: Overall transfusion rates for the matched SSH (1.8% [17/964]) and university hospital populations (2.9% [28/964]) were similar (P = .13), with no emergent transfusions. SSH transfusion rates for simultaneous bilateral THA, simultaneous bilateral TKA, unilateral THA, and unilateral TKA were 21.1% (4/19), 3.1% (4/128), 2.7% (12/439), and 0.0% (0/448), respectively. Multivariate logistic regression identified unilateral THA (P ≤ .001), simultaneous bilateral TJA (P = .001), age (P = .05), and abnormal preoperative hemoglobin (P = .02) as significant transfusion risk factors at SSH. CONCLUSION: Due to low transfusion rates and lack of emergency transfusions, we recommend routinely ordering T&S for bilateral THA but not for unilateral TJA patients, at SSHs.

Auxiliary proteins that facilitate formation of collagen-rich deposits in the posterior knee capsule in a rabbit-based joint contracture model.

Post-traumatic joint contracture is a debilitating consequence of trauma or surgical procedures. It is associated with fibrosis that develops regardless of the nature of initial trauma and results from complex biological processes associated with inflammation and cell activation. These processes accelerate production of structural elements of the extracellular matrix, particularly collagen fibrils. Although the increased production of collagenous proteins has been demonstrated in tissues of contracted joints, researchers have not yet determined the complex protein machinery needed for the biosynthesis of collagen molecules and for their assembly into fibrils. Consequently, the purpose of our study was to investigate key enzymes and protein chaperones needed to produce collagen-rich deposits. Using a rabbit model of joint contracture, our biochemical and histological assays indicated changes in the expression patterns of heat shock protein 47 and the α-subunit of prolyl 4-hydroxylase, key proteins in processing nascent collagen chains. Moreover, our study shows that the abnormal organization of collagen fibrils in the posterior capsules of injured knees, rather than excessive formation of fibril-stabilizing cross-links, may be a key reason for observed changes in the mechanical characteristics of injured joints. This result sheds new light on pathomechanisms of joint contraction, and identifies potentially attractive anti-fibrotic targets.

Timing of Symptomatic Pulmonary Embolism with Warfarin Following Arthroplasty.

The purpose is to determine the incidence and timing of pulmonary embolism for patients receiving warfarin for thrombo-prophylaxis following total joint arthroplasty (TJA). Current guidelines for duration of prophylaxis are nonspecific. Chemical prophylaxis carries the risk of bleeding and associated periprosthetic joint infection. We retrospectively studied 26,415 primary and revision TJA cases performed at our institution between 2000 and 2010. The overall 90-day rate of symptomatic PE was 1.07%. Fatal PE rate was 0.02%. Out of 283 documented symptomatic PE cases, 81% occurred within three postoperative days, 89% within one postoperative week, and 94% within two postoperative weeks. The risk of symptomatic PE appears to be highest during the first week after TJA. Efforts must be made to minimize risk during this period.