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Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and, optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the hip, including osteonecrosis (aseptic necrosis) involving bone marrow, bone, and cartilage, and chondral injuries involving articular cartilage, synovium, and bone marrow. Promising and established treatment modalities for osteonecrosis include nonweightbearing; pharmacological treatments including low molecular-weight heparin, prostacyclin, statins, bisphosphonates, and denosumab, a receptor activator of nuclear factor-kB ligand inhibitor; extracorporeal shock wave therapy; pulsed electromagnetic fields; core decompression surgery; cellular therapies including bone marrow aspirate comprising mesenchymal stromal cells (MSCs aka mesenchymal stem cells) and bone marrow autologous concentrate, with or without expanded or cultured cells, and possible addition of bone morphogenetic protein-2, vascular endothelial growth factor, and basic fibroblast growth factor; and arterial perfusion of MSCs that may be combined with addition of carriers or scaffolds including autologous MSCs cultured with beta-tricalcium phosphate ceramics associated with a free vascularized fibula. Promising and established treatment modalities for chondral lesions include autologous platelet-rich plasma; hyaluronic acid; MSCs (in expanded or nonexpanded form) derived from bone marrow or other sources such as fat, placenta, umbilical cord blood, synovial membrane, and cartilage; microfracture or microfracture augmented with membrane containing MSCs, collagen, HA, or synthetic polymer; mosaicplasty; 1-stage autologous cartilage translation (ACT) or 2-stage ACT using 3-dimensional spheroids; and autologous cartilage grafting; chondral flap repair, or flap fixation with fibrin glue. Hip pain is catastrophic in young patients, and promising therapies offer an alternative to premature arthroplasty. This may address both physical and psychological components of pain; the goal is to avoid or postpone an artificial joint. Level of Evidence Level V, expert opinion.

A 75-year-old woman who had previously undergone a left revision total hip arthroplasty with the use of a constrained acetabular liner presented with recurrent dislocation of the hip. Intraoperatively, there was metallic staining of the hip capsule and significant notching of the femoral neck, consistent with impingement of the intact locking ring, necessitating stem revision. Constrained acetabular liners have high failure rates due to intraprosthetic impingement, but to our knowledge, failure due to notching of the femoral component and metallosis from repeated impingement has not been described. Surgeons should be aware of this potential mode of failure.

The longitudinal assessment of physical function with high temporal resolution at a scalable and objective level in patients recovering from surgery is highly desirable to understand the biological and clinical factors that drive the clinical outcome. However, physical recovery from surgery itself remains poorly defined and the utility of wearable technologies to study recovery after surgery has not been established.Prolonged postoperative recovery is often associated with long-lasting impairment of physical, mental, and social functions. While phenotypical and clinical patient characteristics account for some variation of individual recovery trajectories, biological differences likely play a major role. Specifically, patient-specific immune states have been linked to prolonged physical impairment after surgery. However, current methods of quantifying physical recovery lack patient specificity and objectivity.Here, a combined high-fidelity accelerometry and state-of-the-art deep immune profiling approach was studied in patients undergoing major joint replacement surgery. The aim was to determine whether objective physical parameters derived from accelerometry data can accurately track patient-specific physical recovery profiles (suggestive of a 'clock of postoperative recovery'), compare the performance of derived parameters with benchmark metrics including step count, and link individual recovery profiles with patients' preoperative immune state.The results of our models indicate that patient-specific temporal patterns of physical function can be derived with a precision superior to benchmark metrics. Notably, six distinct domains of physical function and sleep are identified to represent the objective temporal patterns: "activity capacity" and "moderate and overall activity" (declined immediately after surgery); "sleep disruption and sedentary activity" (increased after surgery); "overall sleep", "sleep onset", and "light activity" (no clear changes were observed after surgery). These patterns can be linked to individual patients' preoperative immune state using cross-validated canonical-correlation analysis. Importantly, the pSTAT3 signal activity in M-MDSCs predicted a slower recovery.Accelerometry-based recovery trajectories are scalable and objective outcomes to study patient-specific factors that drive physical recovery.

Background Postoperative arrhythmias are associated with increased morbidity and mortality in total joint arthroplasty (TJA) patients. HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) decrease atrial fibrillation rates after cardiac surgery, but it is unknown if this cardioprotective effect is maintained after joint reconstruction surgery. We aim to determine if perioperative statin use decreases the incidence of 90-day postoperative arrhythmias in patients undergoing primary TJA. Methods We performed a single-center retrospective cohort study in which 231 primary TJA patients (109 hips, 122 knees) received simvastatin 80 mg daily during their hospitalization as part of a single surgeon’s standard postoperative protocol. This cohort was matched to 966 primary TJA patients (387 hips and 579 knees) that did not receive simvastatin. New-onset arrhythmias (bradycardia, atrial fibrillation/tachycardia/flutter, paroxysmal supraventricular tachycardia, and ventricular tachycardia) and complications (readmissions, thromboembolism, infection, and dislocation) within 90 days of the procedure were documented. Categorical variables were analyzed using Fisher’s exact tests. Our study was powered to detect a 3% difference in arrhythmia rates. Results Within 90 days postoperatively, arrhythmias occurred in 1 patient (0.4%) who received a perioperative statin, 39 patients (4.0%) who did not receive statins (P = .003), and 24 patients (4.2%) who were on outpatient statins (P = .005). This is 10-fold reduction in the relative risk of developing a postoperative arrhythmia within 90 days of arthroplasty and an absolute risk reduction of 3.6%. Conclusion Treating as few as 28 patients with perioperative simvastatin prevents one new cardiac arrhythmia within 90 days in statin-naive patients undergoing TJA.

Core decompression is the most common procedure for early-stage osteonecrosis of the femoral head (ONFH). This study investigated outcomes of core decompression with/without bone marrow aspirate concentrate (BMAC), based on the Kerboul combined necrotic angles using magnetic resonance imaging.We reviewed 66 patients (83 hips) with early ONFH, Association Research Circulation Osseous stages I-IIIa, who underwent core decompression alone (26 patients, 33 hips) or in combination with BMAC (40 patients, 50 hips). Survival rate and progressive collapse were analyzed using the Kaplan-Meier method, and conversion to total hip arthroplasty (THA) was evaluated. Subgroup analyses based on the modified Kerboul angle were performed: grade I (200°), grade II (200°-249°), grade III (250°-299°), and grade IV (≥300°).Mean follow-up was 36 ± 23 months. Femoral head collapse with BMAC (16 hips, 32%) was significantly lower than without BMAC (19 hips, 58%, P = .019). Conversion THA was significantly lower with BMAC (28%) than without (58%, P = .007). Survival rates among groups showed significant differences (P = .017). In grade I, 0/12 hips with BMAC collapsed while 3/9 (33%) without BMAC collapsed (P = .063); in grade II, 2/16 hips (12%) with BMAC collapsed while 7/13 (54%) without BMAC collapsed (P = .023). There was no significant difference in collapse with (64%) or without (82%) BMAC in grade III-IV hips (P = .256).Core decompression with/without BMAC had a high failure rate, by increasing disease progression and the necessity for THA, for combined necrotic angles250°. In our study, addition of BMAC had more reliable outcomes than isolated core decompression for precollapse ONFH if the combined necrotic angles were250°.

Gadolinium chelates have been used as standard contrast agents for clinical MRI for several decades. However, several investigators recently reported that rare Earth metals such as gadolinium are deposited in the brain for months or years. This is particularly concerning for children, whose developing brain is more vulnerable to exogenous toxins compared to adults. Therefore, a search is under way for alternative MR imaging biomarkers. The United States Food and Drug Administration (FDA)-approved iron supplement ferumoxytol can solve this unmet clinical need: ferumoxytol consists of iron oxide nanoparticles that can be detected with MRI and provide significant T1- and T2-signal enhancement of vessels and soft tissues. Several investigators including our research group have started to use ferumoxytol off-label as a new contrast agent for MRI. This article reviews the existing literature on the biodistribution of ferumoxytol in children and compares the diagnostic accuracy of ferumoxytol- and gadolinium-chelate-enhanced MRI. Iron oxide nanoparticles represent a promising new class of contrast agents for pediatric MRI that can be metabolized and are not deposited in the brain.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a condition documented in humans and animals exposed to chronic steroid administration. The rabbit has become a preferred animal model for investigating the pathogenesis and treatment of SONFH due to its shared femoral vascular anatomy with human patients, relative size of the femoral head, and general fecundity. However, morbidity and mortality are frequent during the steroid induction period, prior to surgical manipulation. These problems are poorly reported and inadequately described in the literature. In this study, we report the clinical, gross, and histopathologic findings of New Zealand white (NZW) rabbits undergoing the steroid induction phase of the SONFH model. Severe weight loss (>30%), lipemia, hypercholesterolemia, hyperglycemia, and elevations in ALT and AST were consistent findings across all rabbits, although these changes did not differentiate asymptomatic rabbits from those that became clinically symptomatic or died. Euthanized and spontaneously deceased rabbits exhibited hepatomegaly, hepatic lipidosis/glycogenosis, and hepatocellular necrosis, in addition to a lipid-rich and proteinaceous thoracic effusion. A subset of rabbits developed opportunistic pulmonary infections with Bordetella bronchiseptica and Escherichia coli and small intestine infections with Lawsonia intracellularis superimposed on hepatic and thoracic disease. Together, these findings allowed us to establish a clinical decision-making flowchart that reduced morbidities and mortalities in a subsequent cohort of SONFH rabbits. Recognition of these model-associated morbidities is critical for providing optimal clinical care during the disease induction phase of SONFH.

Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II–IV clinical trials. Next, current in vitro, ex vivo, and in vivo OA models are summarized and the respective advantages and disadvantages of each are highlighted. Of note, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine. IMPACT STATEMENT: At present, no disease-modifying osteoarthritis (OA) drugs (DMOADs) have been approved for widespread clinical use by regulatory bodies. The failure of developing effective DMOADs is likely owing to multiple factors, not the least of which are the intrinsic differences between the intact human knee joint and the preclinical models. This work summarizes the current OA models for the development of DMOADs, discusses the advantages/disadvantages of each, and then proposes future model development to aid in the discovery of effective and personalized DMOADs. The review also highlights the microphysiological systems, which are emerging as a new platform for drug development.

Background Secondary osteonecrosis of the knee (SOK) generally occurs in relatively young patients; at advanced stages of SOK, the only viable surgical option is total knee arthroplasty (TKA). We conducted a retrospective study to investigate implant survivorship, clinical and radiographic outcomes, and complications of contemporary cemented bicompartmental TKA with/without patellar resurfacing for SOK. Methods Thirty-eight cemented TKAs in 27 patients with atraumatic SOK, mean age 43 years (17 to 65), were retrospectively reviewed. Seventy-four percent had a history of corticosteroid use, and 18% had a history of alcohol abuse. Patellar osteonecrosis was coincidentally found in six knees (16%), and all were asymptomatic without joint collapse. The mean followup was 7 years (2 to 12). Knee Society Score (KSS) and radiographic outcomes were evaluated at 6 weeks, 1 year, then every 2 to 3 years. Results Ninety-two percent had implant survivorship free from revision with significant improvement in KSS. Causes of revision included aseptic tibial loosening (one), deep infection (one), and instability with patellofemoral issues (one). Four of six cases also with patellar osteonecrosis received resurfacing, including one with periprosthetic patellar fracture after minor trauma, with satisfactory clinical results after conservative treatment. None of the unrevised knees had progressive radiolucent lines or evidence of loosening. An unresurfaced patella, use of a stem extension or a varus-valgus constrained prosthesis constituted 18%, 8% and 3%, respectively. Conclusion Cemented TKAs with selective stem extension in patients with SOK had satisfactory implant survivorship and reliable outcomes. Secondary osteonecrosis of the patella should be carefully evaluated prior to operation.

Jennifer M Hah,1 Heather Hilmoe,2 Peter Schmidt,2 Rebecca McCue,2 Jodie Trafton,3,4 Debra Clay,2 Yasamin Sharifzadeh,2 Gabriela Ruchelli,2 Tina Hernandez Boussard,5 Stuart Goodman,6 James Huddleston,7 William J Maloney,7 Frederick M Dirbas,8 Joseph Shrager,9 John G Costouros,7 Catherine Curtin,10 Sean C Mackey,1 Ian Carroll1 1Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA; 2Stanford Systems Neuroscience and Pain Lab, Stanford University, Stanford, CA, USA; 3Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA; 4VA Program Evaluation and Resource Center, VHA Office of Mental Health Operations, Palo Alto, CA, USA; 5Department of Medicine, Department of Biomedical Data Science, Stanford University, Stanford, CA, USA; 6Department of Orthopaedic Surgery and (by Courtesy) Bioengineering, Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; 7Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; 8Department of General Surgery, Stanford University, Stanford, CA, USA; 9Division of Thoracic Surgery, Stanford University, Stanford, CA, USA; 10Division of Hand and Plastic Surgery, Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USACorrespondence: Jennifer M HahDivision of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, 1070 Arastradero Road, Suite 200, Palo Alto, CA 94304, USATel +1 650-736-9415Fax +1 650-725-9642Email jhah@stanford.eduBackground: Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.Methods: In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18– 75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Results: Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87– 1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68– 0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40– 0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39– 0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80– 0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89– 1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06– 1.77; P=0.016).Conclusion: Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.Keywords: persistent postsurgical pain, persistent postoperative opioid use, chronic opioid use after surgery, chronic pain after surgery

Osteonecrosis of the epiphyseal and metaphyseal regions of major weight-bearing bones of the extremities is a condition that is associated with local death of bone cells and marrow in the afflicted compartment. Chronic inflammation is a prominent feature of osteonecrosis. If the persistent inflammation is not resolved, this process will result in progressive collapse and subsequent degenerative arthritis. In the pre-collapse stage of osteonecrosis, attempt at joint preservation rather than joint replacement in this younger population with osteonecrosis is a major clinical objective. In this regard, core decompression, with/without local injection of bone marrow aspirate concentrate (BMAC), is an accepted and evidence-based method to help arrest the progression and improve the outcome of early-stage osteonecrosis. However, some patients do not respond favorably to this treatment. Thus, it is prudent to consider strategies to mitigate chronic inflammation concurrent with addressing the deficiencies in osteogenesis and vasculogenesis in order to save the affected joint. Interestingly, the processes of inflammation, osteonecrosis, and bone healing are highly inter-related. Therefore, modulating the biological processes and crosstalk among cells of the innate immune system, the mesenchymal stem cell-osteoblast lineage and others are important to providing the local microenvironment for resolution of inflammation and subsequent repair. This review summarizes the clinical and biologic principles associated with osteonecrosis and provides potential cutting-end strategies for modulating chronic inflammation and facilitating osteogenesis and vasculogenesis using local interventions. Although these studies are still in the preclinical stages, it is hoped that safe, efficacious, and cost-effective interventions will be developed to save the host's natural joint.

BACKGROUND Joint preservation is more effective in early-stage osteonecrosis of the femoral head (ONFH); thus, prompt diagnosis when the femoral head is still salvageable is important. We report a 20-year retrospective study that summarizes age at presentation, etiology, and Association Research Circulation Osseous stage at diagnosis. METHODS Our database was reviewed to identify patients younger than 65 years of age who were diagnosed with atraumatic ONFH between 1998 and 2018. Demographic characteristics of patients were evaluated and categorized into different subgroups. RESULTS Four hundred thirteen patients were identified. At initial presentation, 23% were diagnosed with early-stage ONFH, while 77% were diagnosed with late-stage ONFH. Forty-nine percent had a history of corticosteroid use, of which 13% were diagnosed with hematologic malignancy and 8% were diagnosed with lupus. Ethanol abuse, idiopathic, sickle cell disease, and human immunodeficiency virus were present in 11%, 30%, 3%, and 3%, respectively. The mean age of patients with corticosteroid use (40 ± 14 years) was significantly younger than ethanol use (46 ± 11 years, P = .014) and idiopathic causes (48 ± 11 years, P < .001), but significantly older than sickle cell disease (32 ± 11 years, P = .031). There was no difference in the age of presentation for early-stage and late-stage ONFH by etiology. CONCLUSION Nearly 80% of the patients presented with late-stage ONFH. Hence, we have a narrow window of opportunity for hip preservation surgery before femoral head collapse. A multidisciplinary approach to improve screening awareness for early detection by focusing on the etiologic identification and patient education might reduce the incidence of hip arthroplasty in young patients.

The hip joint is commonly affected in Juvenile Idiopathic Arthritis (JIA), especially in cases of systemic polyarticular disease. Chronic synovitis of the hip leads to joint destruction, therefore, systemic and local control of the disease is of paramount importance. Non-steroidal anti-inflammatory drugs, Disease Modifying Anti-Rheumatic Drugs (DMARDs), biologics, intra-articular corticosteroid injections, and physical therapy are the mainstay for controlling ongoing inflammation and hip joint contractures. Synovectomy with soft tissue releases is useful in the early stages of the disease, when the joint cartilage is largely preserved. Total joint arthroplasty (THA) is successful in relieving pain, and improving function, ambulation and range of motion in end-stage degenerative arthritis. With improved designs of smaller prostheses and modern bearing couples, it is hoped that the longevity of THA will facilitate a more normal and enduring lifestyle.

Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2–4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5–7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA. Endogenous skeletal stem cells are recruited to form cartilage in mice when stimulated by microfracture surgery together with localized delivery of growth factors, pointing to a new approach for treating cartilage defects.

Background Total knee arthroplasty (TKA) and lumbar spine surgery have been reported to affect the outcomes of each other. There is insufficient evidence to guide the choice of treatment order for patients with both disorders that are equally symptomatic. Methods Five clinical scenarios of concurrent, advanced, degenerative knee and lumbar spinal disorders were designed to survey surgeons’ choices of treatment order and rationale. The spinal disorder was consistently degenerative lumbar spinal stenosis, but the knee conditions varied to include (1) osteoarthritis (OA) with varus deformity, (2) OA with valgus deformity, (3) rheumatoid arthritis with a severe flexion contracture, (4) OA without deformity, and (5) bilateral OA with windswept deformities. The survey was distributed to selected clinical members of the Knee Society and Scoliosis Research Society in North America. The surgeons’ choices were compared among the 5 scenarios, and their comments were analyzed using text-mining. Results Responses were received from 42 of 74 (57%) knee arthroplasty surgeons and 55 of 100 (55%) spine surgeons. The percentages of knee arthroplasty surgeons recommending “TKA first” differed significantly among scenarios: 29%, 79%, 55%, 7%, and 81% for scenarios 1 through 5, respectively (P Conclusion For patients with concurrent degenerative knee and lumbar spinal disorders, the severity and type of knee deformity influenced the preference of treatment order in both specialties. Severe valgus deformity and windswept deformities of the knee would drive the decision toward “TKA first.”

Increasing utilization of unicompartmental knee arthroplasty (UKA) has driven a greater push for outpatient treatment and cost containment in the setting of bundled payments. The purpose of this study is to evaluate utilization trends of inpatient vs outpatient UKA, index episode and 90-day reimbursement, and any differences in medical or surgical complications.The PearlDiver database was employed to identify all inpatient and outpatient UKAs performed between 2007 and 2016 with 2-year follow-up. Patients were matched by age, gender, and Elixhauser Comorbidity Index. We tracked index procedure and global period reimbursement, 90-day medical and surgical complications, and 2-year surgical complications.The reimbursement and utilization cohort included 3181 outpatient and 5490 inpatient UKAs. Outpatient UKA and overall utilization of UKA increased over the study period. Mean index reimbursement of inpatient UKA was $2486.16 higher per procedure (P.001) while mean global period reimbursement was $2782.13 higher per inpatient procedure (P.001). Ninety-day medical complications including postoperative anemia (P.001), transfusion (P = .024), and arrhythmia (P = .004) were more common with inpatient UKAs, whereas surgical wound complications (P = .001) and operative debridement (P = .028) were more common among outpatient UKAs. Outpatient UKA was not associated with an increased risk of periprosthetic joint infection (P.05), aseptic loosening (P.05), or revision surgery (P.05) when compared to inpatient UKA.Outpatient UKA utilization is increasing and is associated with decreased reimbursement compared to inpatient UKA without increased risk of major medical complications, although it is associated with increased risk of wound complication and need for operative debridement at 90 days.

Aims To establish the utility of adding the laboratory-based synovial alpha-defensin immunoassay to the traditional diagnostic work-up of a prosthetic joint infection (PJI). Methods A group of four physicians evaluated 158 consecutive patients who were worked up for PJI, of which 94 underwent revision arthroplasty. Each physician reviewed the diagnostic data and decided on the presence of PJI according to the 2014 Musculoskeletal Infection Society (MSIS) criteria (yes, no, or undetermined). Their initial randomized review of the available data before or after surgery was blinded to each alpha-defensin result and a subsequent randomized review was conducted with each result. Multilevel logistic regression analysis assessed the effect of having the alpha-defensin result on the ability to diagnose PJI. Alpha-defensin was correlated to the number of synovial white blood cells (WBCs) and percentage of polymorphonuclear cells (%PMN). Results Intraobserver reliability and interobserver agreement did not change when the alpha-defensin result was available. Positive alpha-defensin results had greater synovial WBCs (mean 31,854 cells/μL, SD 32,594) and %PMN (mean 93.0%, SD 5.5%) than negative alpha-defensin results (mean 974 cells/μL, SD 3,988; p < 0.001 and mean 39.4% SD 28.6%; p < 0.001). Adding the alpha-defensin result did not alter the diagnosis of a PJI using preoperative (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.14 to 1.88; p = 0.315) or operative (OR 0.52, CI 0.18 to 1.55; p = 0.242) data when clinicians already decided that PJI was present or absent with traditionally available testing. However, when undetermined with traditional preoperative testing, alpha-defensin helped diagnose (OR 0.44, CI 0.30 to 0.64; p < 0.001) or rule out (OR 0.41, CI 0.17 to 0.98; p = 0.044) PJI. Of the 27 undecided cases with traditional testing, 24 (89%) benefited from the addition of alpha-defensin testing. Conclusion The laboratory-based synovial alpha-defensin immunoassay did not help diagnose or rule out a PJI when added to routine serologies and synovial fluid analyses except in cases where the diagnosis of PJI was unclear. We recommend against the routine use of alpha-defensin and suggest using it only when traditional testing is indeterminate. Cite this article: Bone Joint J 2020;102-B(5):593–599.

Background The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. Methods In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. Results Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I—X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II—X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III—fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV—X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. Conclusion A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

Selective supplementation of acetabular component fixation with a screw during primary total hip arthroplasty (THA) assumes that the surgeon can detect when an acetabular component needs additional stability. In contrast, nonselective screw users do not alter their practice based on their interpretation of stability and either use screws all or none of the time. We aimed to determine the effect of selective screw use on aseptic acetabular component loosening. We retrospectively reviewed aseptic failures of acetabular components after primaty THA. We compared the survivorship of selective and nonselective supplementation of acetabular fixation with respect to time to revision, obesity, and screw use. Selective screw use (n = 16) was associated with earlier acetabular component aseptic loosening (median: 1.9 years; interquartile range [IQR]: 1.1-5.0) compared to nonselective screw use (n = 22; median: 5.6 years; IQR: 2.0-15.3; P = .010). Selective screw use was independently associated with earlier revision after adjusting for patient obesity. Obesity was associated with selective screw use in 50% of the cases vs 14% of nonselective cases (odds ratio: 6.3; confidence interval: 1.2-25.2; P = .028), possibly reflecting the increased difficulty in achieving acetabular component stability in this and other settings with compromised bone. Surgeons should carefully assess component stability at time of primary THA. If the acetabulum is not stable, the addition of screws alone may not be sufficient for acetabular component stability.

Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in orthopaedic clinics. The number of patients with ONFH is increasing worldwide every year. There are an estimated 8.12 million patients with nontraumatic osteonecrosis in China alone. Treatment of nontraumatic osteonecrosis has always been a clinical challenge for orthopaedic surgeons. To further standardize diagnosis and treatment of ONFH, these guidelines provide not only basic diagnosis, treatment, and evaluation systems for ONFH but also expert advice and standards in many aspects, including epidemiology, aetiology, diagnostic criteria, pathological staging, prevention and treatment options, and postoperative rehabilitation. The aetiological factors of ONFH can currently be divided into two major categories: traumatic and nontraumatic; however, the specific pathological mechanism of ONFH is not completely clear. Currently, the staging system of ONFH formulated by the Association Research Circulation Osseous is widely used in clinical practice. Based on the changes in the intraosseous blood supply at different stages, the corresponding nonsurgical and surgical treatments are recommended, and when there are risk factors for possible ONFH, certain preventive measures to avoid the occurrence of osteonecrosis are recommended. These guidelines provide brief classification criteria and treatment regimen for osteonecrosis. Specification of the aetiology, treatment plan based on comprehensive consideration of the different stages of osteonecrosis, hip function, age, and occupation of the patients are important steps in diagnosis and developing treatment strategies. Translational potential of this article: New advances in the epidemiology, etiology, pathophysiology, imaging, diagnosis and treatment of ONFH have been renewed in this revision. This guideline can be used for reference by orthopedic professionals and researchers, and for standardized diagnosis and treatment management under the clinical guidance, which is conducive to the prevention, treatment and further research of ONFH, improving the diagnosis and treatment level, making patients' symptoms under good control, and improving their quality of life. Keywords: Diagnosis, Guideline, Osteonecrosis of the femoral head (ONFH), Treatment

Background The purpose of this study is to determine the impact of total knee arthroplasty (TKA) on mental health. Methods A total of 205 patients who underwent primary TKA with baseline and 1-year postoperative Short Form-12 Mental Component Score (MCS) were included in this retrospective analysis. Eighty-five (41%) patients had a preoperative MCS less than 50 points, while 120 (59%) patients had a preoperative MCS over 50 points. Two groups were assigned to the patients based on their preoperative MCS: low MCS 50. Results A preoperative MCS less than 50 points was predictive of greater improvement in MCS at 1 year after TKA (P Conclusion Patients with lower baseline mental health had greater improvement in postoperative mental health following TKA than patients with higher baseline mental health. Low preoperative MCS was associated with less improvement in patient-reported outcome measures. Patients with lower baseline mental health scores before TKA benefit mentally and physically from the procedure.

Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (μCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

BackgroundApproximately one third of patients undergoing core decompression (CD) for early-stage osteonecrosis of the femoral head (ONFH) experience progression of the disease, and subsequently require total hip arthroplasty (THA). Thus, identifying adjunctive treatments to optimize bone regeneration during CD is an unmet clinical need. Platelet-derived growth factor (PDGF)-BB plays a central role in cell growth and differentiation. The aim of this study was to characterize mesenchymal stromal cells (MSCs) that were genetically modified to overexpress PDGF-BB (PDGF-BB-MSCs) in vitro and evaluate their therapeutic effect when injected into the bone tunnel at the time of CD in an in vivo rabbit model of steroid-associated ONFH.MethodsIn vitro studies:Rabbit MSCs were transduced with a lentivirus vector carrying the human PDGF-BB gene under the control of either the cytomegalovirus (CMV) or phosphoglycerate (PGK) promoter. The proliferative rate, PDGF-BB expression level, and osteogenic differentiation capacity of unmodified MSCs, CMV-PDGF-BB-MSCs, and PGK-PDGF-BB-MSCs were assessed. In vivo studies: Twenty-four male New Zealand white rabbits received an intramuscular (IM) injection of methylprednisolone 20 mg/kg. Four weeks later, the rabbits were divided into four groups: the CD group, the hydrogel [HG, (a collagen-alginate mixture)] group, the MSC group, and the PGK-PDGF-BB-MSC group. Eight weeks later, the rabbits were sacrificed, their femurs were harvested, and microCT, mechanical testing, and histological analyses were performed.ResultsIn vitro studies:PGK-PDGF-BB-MSCs proliferated more rapidly than unmodified MSCs (P P P P P = 0.07) than CMV-PDGF-BB-MSCs. In vivo:The PGK-PDGF-BB-MSC group had a trend towards greater bone mineral density (BMD) than the CD group (P = 0.074). The PGK-PDGF-BB-MSC group demonstrated significantly lower numbers of empty lacunae (P P P ConclusionThe use of PGK-PDGF-BB-MSCs as an adjunctive treatment with CD may reduce progression of osteonecrosis and enhance bone regeneration and angiogenesis in the treatment of early-stage ONFH.

Osteonecrosis of the femoral head (ONFH) is a disease in which inadequate blood supply to the subchondral bone causes the death of cells in the bone marrow. Decalcified histology and assessment of the percentage of empty lacunae are used to quantify the severity of ONFH. However, the current clinical practice of manually counting cells is a tedious and inefficient process. We utilized the power of artificial intelligence by training an established deep convolutional neural network framework, Faster-RCNN, to automatically classify and quantify osteocytes (healthy and pyknotic) and empty lacunae in 135 histology images. The adjusted correlation coefficient between the trained cell classifier and the ground truth was R = 0.98. The methods detailed in this study significantly reduced the manual effort of cell counting in ONFH histological samples and can be translated to other fields of image quantification.

Background: Total hip and knee arthroplasties are generally very successful surgical procedures; however, if there is a complication or if the patient is dissatisfied with the outcome, the patient may initiate a legal suit against the surgeon. Methods and Results: We evaluated the reasons for instigating a legal suit after hip or knee arthroplasty surgery in the State of California between 1981 and 2018. Using a verified database and the keywords hip, knee, replacement, arthroplasty, we identified 12 legal suits filed and adjudicated on during this time period. Of the 12 cases, the major complaints were pain (seven cases), foot drop (three cases) numbness (two cases), foreign item left in the body of the patient (one case), general physical problems (one case), and wrongful death (one case). In some cases, more than one reason was listed (note: the total is greater than 12 because some cases had more than one reason listed). Conclusion: In reviewing these cases and the literature on this subject, we conclude that in order to avoid legal suits, doctors should be communicative, honest, and compassionate with patients, be highly competent in their specialty, and maintain meticulous medical record documentation.

INTRODUCTION: Total joint replacement is one of the most common, safe, and efficacious operations in all of surgery. However, one major long-standing and unresolved issue is the adverse biological reaction to byproducts of wear from the bearing surfaces and modular articulations. These inflammatory reactions are mediated by the innate and adaptive immune systems. AREAS COVERED: We review the etiology and pathophysiology of implant debris-associated inflammation, the clinical presentation and detailed work-up of these cases, and the principles and outcomes of non-operative and operative management. Furthermore, we suggest future strategies for prevention and novel treatments of implant-related adverse biological reactions. EXPERT OPINION: The generation of byproducts from joint replacements is inevitable, due to repetitive loading of the implants. A clear understanding of the relevant biological principles, clinical presentations, investigative measures and treatments for implant-associated inflammatory reactions and periprosthetic osteolysis will help identify and treat patients with this issue earlier and more effectively. Although progressive implant-associated osteolysis is currently a condition that is treated surgically, with further research, it is hoped that non-operative biological interventions could prolong the lifetime of joint replacements that are otherwise functional and still salvageable.

Suboptimal implant rotation has consequences with respect to knee kinematics and clinical outcomes. We evaluated the functional outcomes of revision total knee arthroplasty (TKA) for poor axial implant rotation.We retrospectively reviewed 42 TKAs undergoing aseptic revision for poor axial implant rotation. We assessed improvements in Knee Society Score (KSS) and final range of motion (ROM). Subgroup analyses were performed for preoperative instability and stiffness, as well as the number of components revised and level of implant constraint used.Revision for poor axial rotation in isolation improved KSS from 52 ± 22 to 84 ± 25 (P.001), and flexion increased from 105 ± 21° to 115 ± 13° (P = .001). Revision in the setting of instability significantly improved the KSS (P.001) but did not affect ROM (P = .172). Revision in the setting of stiffness significantly improved both KSS (P.001) and ROM (P = .002). There was no statistically significant difference between the postoperative KSS (P = .889) and final knee flexion (P = .629) with single- or both-component revision TKA for isolated poor axial rotation or between the postoperative KSS (P = .956) and final knee flexion (P = .541) with or without the use of higher constraint during revision TKA for isolated poor axial rotation.Revision TKA for poor axial alignment improves clinical outcomes scores and functional ROM.

Introduction: Debate over the ideal agent for venous thromboembolism (VTE) prophylaxis after total hip arthroplasty (THA) has led to changes in prescribing trends of commonly used agents. We investigate variation in utilisation and the differences in VTE incidence and bleeding risk in primary THA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors. Methods: 8829 patients were age/sex matched from a large database of primary THAs performed between 2007 and 2016. Utilisation was calculated using compound annual growth rate. Incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications, postoperative anaemia, and transfusion were identified at 2 weeks, 30 days, 6 weeks, and 90 days. Results: Aspirin use increased by 33%, enoxaparin by 7%, and factor Xa inhibitors by 31%. Warfarin use decreased by 1%. Factor Xa inhibitors (1.7%) and aspirin (1.7%) had the lowest incidence of DVT followed by enoxaparin (2.6%), and warfarin (3.7%) at 90 days. Factor Xa inhibitors (12%) and aspirin (12%) had the lowest incidence of blood transfusion followed by warfarin (15%) and enoxaparin (17%) at 90 days. There was no difference in incidence of blood transfusion or bleeding-related complications nor any detectable difference in symptomatic PE incidence. Conclusions: The utilisation of aspirin and factor Xa inhibitors increased over time. Aspirin and factor Xa inhibitors provided improved DVT prophylaxis with lower rates of postoperative anaemia compared to enoxaparin and warfarin.

Adult stem cells are a promising tool to positively influence bone regeneration. Concentrated bone marrow therapy entails isolating osteoprogenitor cells during surgery with, however, only low cells yield. Two step stem cell therapy requires an additional harvesting procedure but generates high numbers of progenitor cells that facilitate osteogenic pre-differentiation. To further improve bone regeneration, stem cell therapy can be combined with growth factors from platelet rich plasma (PRP) or its lysate (PL) to potentially fostering vascularization. The aim of this study was to investigate the effects of bone marrow concentrate (BMC), osteogenic pre-differentiation of mesenchymal stromal cells (MSCs), and PL on bone regeneration and vascularization. Bone marrow from four different healthy human donors was used for either generation of BMC or for isolation of MSCs. Seventy-two mice were randomized to six groups (Control, PL, BMC, BMC + PL, pre-differentiated MSCs, pre-differentiated MSCs + PL). The influence of PL, BMC, and pre-differentiated MSCs was investigated systematically in a 2 mm femoral bone defect model. After a 6-week follow-up, the pre-differentiated MSCs + PL group showed the highest bone volume, highest grade of histological defect healing and highest number of bridged defects with measurable biomechanical stiffness. Using expanded and osteogenically pre-differentiated MSCs for treatment of a critical-size bone defect was favorable with regards to bone regeneration compared to treatment with cells from BMC. The addition of PL alone had no significant influence; therefore the role of PL for bone regeneration remains unclear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1318-1328, 2019.

Autogenous bone grafting is the gold standard for replacing large bone defects. Due to limitations in the quantity and quality of harvested bone from the iliac crest, and the potential associated morbidity, the technique of cell grafting has been developed. Autogenous bone marrow aspirate is concentrated (so called BMAC) and delivered locally to the intended site with minimally invasive techniques. However, there are only about 1 in 30,000 Colony Forming Unit-Fibroblast (CFU-F) progenitor cells in unconcentrated iliac crest aspirate. Current techniques for cell concentration only increase these numbers by about 5-fold. Thus, BMAC is not equivalent to “stem cell therapy”.

Chronic inflammation is a common feature in many diseases of different organ systems, including bone. However, there are few interventions to mitigate chronic inflammation and preserve host tissue. Previous in vitro studies demonstrated that preconditioning of mesenchymal stem cells (pMSCs) using lipopolysaccharide and tumor necrosis factor-α polarized macrophages from a pro-inflammatory to an anti-inflammatory phenotype and increased osteogenesis compared to unaltered MSCs. In the current study, we investigated the local injection of MSCs or pMSCs during the acute versus chronic inflammatory phase in a murine model of inflammation of bone: the continuous femoral intramedullary polyethylene particle infusion model. Chronic inflammation due to contaminated polyethylene particles decreased bone mineral density and increased osteoclast-like cells positively stained with leukocyte tartrate resistant acid phosphatase (TRAP) staining, and resulted in a sustained M1 pro-inflammatory macrophage phenotype and a decreased M2 anti-inflammatory phenotype. Local injection of MSCs or pMSCs during the chronic inflammatory phase reversed these findings. Conversely, immediate local injection of pMSCs during the acute inflammatory phase impaired bone healing, probably by mitigating the mandatory acute inflammatory reaction. These results suggest that the timing of interventions to facilitate bone healing by modulating inflammation is critical to the outcome. Interventions to facilitate bone healing by modulating acute inflammation should be prudently applied, as this phase of bone healing is temporally sensitive. Alternatively, local injection of MSCs or pMSCs during the chronic inflammatory phase may be a potential intervention to mitigate the adverse effects of contaminated particles on bone.

Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH., Graphical Abstract

Acetabular revision surgery accompanied by severe bone defects can be challenging. Innovative research in orthopedics and bioengineering has helped formulate successful techniques, instrumentation, and surgical implants to re-establish the normal anatomy of the hip. Careful preoperative planning should be the first step for reconstruction. Infection must be ruled out initially, and if there is any doubt, a hip aspiration should be performed. Imaging starts with standard radiographs of the pelvis and the affected hip; specialized radiographs (such as Judet oblique views) and more advanced imaging such as MARS CT can help better assess the extent of the bone loss. The Paprosky classification is the most commonly used system to describe and categorize the location and magnitude of bone loss. The surgical approach chosen for reconstruction should provide a wide view of the acetabulum and therefore be as extensile as necessary. Current options for reconstruction include impaction grafting and cementless implants for minor defects. For major defects, new implants such as trabecular metal augments, cup-cage constructs, or custom-made devices are available. The principal idea is to restore the anatomic position of the hip as closely as possible, and have a stable reconstruction able to withstand daily physiologic loading.

Osteonecrosis of the femoral head (ONFH) is a devastating disease frequently leading to femoral head collapse and hip arthritis. Specifically, non-traumatic ONFH primarily affects young and middle-aged adults. Although compromised local circulation of the femoral head seems to be pathognomonic for the disease, the pathogenesis is perplexing and continues to be an area of scrutiny and research. Comprehension of the pathogenesis is of crucial importance for developing and guiding treatments for the disease. Therefore, we provide an up-to-date consensus on the pathogenesis of non-traumatic ONFH., Graphical Abstract

Introduction Patient satisfaction has increasingly been used to assess physician performance and quality of care. Although there is evidence that patient satisfaction is associated with patient-reported health outcomes and communication-related measures, there is debate over the use of patient satisfaction in reimbursement policy. Patient characteristics that influence satisfaction have been studied, but the effects of personal and demographic characteristics of physicians on patient satisfaction have yet to be explored. Methods Outpatient satisfaction scores from 11,059 patients who rated 25 orthopaedic surgeons from a single institution were studied. In this study, we sought to explore the relationship between nonmodifiable physician characteristics, such as sex and race, and patient satisfaction with outpatient orthopaedic surgery care, as expressed in the Press Ganey Satisfaction Scores. Univariate logistic regression models were used to test the associations between each provider characteristic and patient satisfaction on the Press Ganey patient satisfaction questionnaire. Results Three nonmodifiable physician personal and demographic characteristics were markedly associated with lower patient satisfaction scores across overall satisfaction, communication, and empathy domains: (1) female gender, (2) Asian ethnicity, and (3) being unmarried. Asian ethnicity reduced the odds of receiving a 5-star rating for likelihood to recommend the provider by nearly 40%, but none of these nonmodifiable physician personal and demographic characteristics affected the likelihood to recommend the practice. Discussion Sex, ethnicity, and marital status are nonmodifiable provider characteristics, each associated with markedly lower odds of receiving a 5-star rating on Press Ganey patient satisfaction survey. These data reveal inherent patient biases that negatively affect physician-patient interactions and may exacerbate the lack of diversity in orthopaedic surgery. More research is necessary before using patient satisfaction ratings to evaluate surgeons or as quality measures that affect reimbursement policies.

Although core decompression (CD) is often performed in the early stage of osteonecrosis of the femoral head (ONFH), the procedure does not always prevent subsequent deterioration and the effects of CD are not fully clarified. The aim of this study is to evaluate the efficacy of CD for steroid-associated ONFH in rabbits. Twelve male and 12 female New Zealand rabbits were injected intramuscularly 20 mg/kg of methylprednisolone once and were divided into the disease control and CD groups. In the disease control group, rabbits had no treatment and were euthanized at 12 weeks postinjection. In the CD group, rabbits underwent left femoral CD at 4 weeks postinjection and were euthanized 8 weeks postoperatively. The left femurs were collected to perform morphological, biomechanical, and histological analysis. Bone mineral density and bone volume fraction in the femoral head in the CD group were significantly higher than in the disease control group. However, no difference in the mechanical strength was observed between the two groups. Histological analysis showed that alkaline phosphatase and CD31 positive cells significantly increased in the males after CD treatment. The number of empty lacunae in the surrounding trabecular bone was significantly higher in the CD group. The current study indicated that CD improved the morphological properties, but did not improve the mechanical strength in the femoral head at early-stage ONFH. These data suggest the need for additional biological, mechanical strategies, and therapeutic windows to improve the outcome of early-stage steroid-associated ONFH.

Healing of fractures and bone defects normally follows an orderly series of events including formation of a hematoma and an initial stage of inflammation, development of soft callus, formation of hard callus, and finally the stage of bone remodeling. In cases of severe musculoskeletal injury due to trauma, infection, irradiation and other adverse stimuli, deficient healing may lead to delayed or non-union; this results in a residual bone defect with instability, pain and loss of function. Modern methods of mechanical stabilization and autologous bone grafting are often successful in achieving fracture union and healing of bone defects; however, in some cases, this treatment is unsuccessful because of inadequate biological factors. Specifically, the systemic and local microenvironment may not be conducive to bone healing because of a loss of the progenitor cell population for bone and vascular lineage cells. Autologous bone grafting can provide the necessary scaffold, progenitor and differentiated lineage cells, and biological cues for bone reconstruction, however, autologous bone graft may be limited in quantity or quality. These unfavorable circumstances are magnified in systemic conditions with chronic inflammation, including obesity, diabetes, chronic renal disease, aging and others. Recently, strategies have been devised to both mitigate the necessity for, and complications from, open procedures for harvesting of autologous bone by using minimally invasive aspiration techniques and concentration of iliac crest bone cells, followed by local injection into the defect site. More elaborate strategies (not yet approved by the U.S. Food and Drug Administration-FDA) include isolation and expansion of subpopulations of the harvested cells, preconditioning of these cells or inserting specific genes to modulate or facilitate bone healing. We review the literature pertinent to the subject of modifying autologous harvested cells including MSCs to facilitate bone healing. Although many of these techniques and technologies are still in the preclinical stage and not yet approved for use in humans by the FDA, novel approaches to accelerate bone healing by modifying cells has great potential to mitigate the physical, economic and social burden of non-healing fractures and bone defects.

The optimal treatment for complex fractures and large bone defects is an important unsolved issue in orthopedics and related specialties. Approximately 5-10% of fractures fail to heal and develop non-unions. Bone healing can be characterized by three partially overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase. Eventual healing is highly dependent on the initial inflammatory phase, which is affected by both the local and systemic responses to the injurious stimulus. Furthermore, immune cells and mesenchymal stromal cells (MSCs) participate in critical inter-cellular communication or crosstalk to modulate bone healing. Deficiencies in this inter-cellular exchange, inhibition of the natural processes of acute inflammation, and its resolution, or chronic inflammation due to a persistent adverse stimulus can lead to impaired fracture healing. Thus, an initial and optimal transient stage of acute inflammation is one of the key factors for successful, robust bone healing. Recent studies demonstrated the therapeutic potential of immunomodulation for bone healing by the preconditioning of MSCs to empower their immunosuppressive properties. Preconditioned MSCs (also known as "primed/ licensed/ activated" MSCs) are cultured first with pro-inflammatory cytokines (e.g., TNFα and IL17A) or exposed to hypoxic conditions to mimic the inflammatory environment prior to their intended application. Another approach of immunomodulation for bone healing is the resolution of inflammation with anti-inflammatory cytokines such as IL4, IL10, and IL13. In this review, we summarize the principles of inflammation and bone healing and provide an update on cellular interactions and immunomodulation for optimal bone healing.

Background Patients with advanced knee arthritis who develop a septic joint are not adequately treated with irrigation and debridement and intravenous antibiotics because of antecedent cartilage damage. The gold standard treatment has been a 2-stage approach. The periprosthetic joint infection literature has demonstrated the superiority of articulating spacers, and metal-on-poly (MOP) spacers are being used with increasing frequency. The purpose of this study was to compare the postoperative outcomes of patients with infected, arthritic knees treated by a 2-stage approach to those of patients who received single-stage treatment with a MOP spacer. Methods Sixteen patients with native knee septic arthritis treated with an antibiotic spacer between 1998 and 2019 were reviewed. Demographic data, clinical data, knee motion, Knee Society score, Timed-Up-and-Go, and pain scores were collected. Survivorship of final implants was compared. Results Six of 16 knees (38%) received single-stage treatment, and 10 received 2-stage treatment (62%). Five of 6 MOP spacers (83%) were retained at a mean follow-up of 3 ± 1.2 years. Nine of 10 (90%) receiving static spacers had subsequent reconstruction, with 9 (100%) surviving at mean follow-up of 7 ± 3.2 years. The patients who received MOP spacers trended toward greater terminal flexion, higher Knee Society score, and faster Timed-Up-and-Go at final follow-up. Conclusion Infection in a native, arthritic knee may be effectively treated using single-stage MOP spacer. Postoperative outcomes of single-stage MOP spacers compare favorably to staged static spacers and with those undergoing revision surgery for other indications. Longer follow-up is needed to evaluate durability of MOP spacers.

Osteoarthritis (OA) is a degenerative disease of the joint, which results in pain, loss of mobility, and, eventually, joint replacement. Currently, no disease-modifying drugs exist, partly because of the multiple levels at which cartilage homeostasis is disrupted. Recent studies have highlighted the importance of epigenetic dysregulation in OA, sparking interest in the epigenetic modulation for this disease. In our previous work, we characterized a fivefold increase in cytosine hydroxymethylation (5hmC), an oxidized derivative of cytosine methylation (5mC) associated with gene activation, accumulating at OA-associated genes. To test the role of 5hmC in OA, here, we used a mouse model of surgically induced OA and found that OA onset was accompanied by a gain of ~40,000 differentially hydroxymethylated sites before the notable histological appearance of disease. We demonstrated that ten-eleven-translocation enzyme 1 (TET1) mediates the 5hmC deposition because 98% of sites enriched for 5hmC in OA were lost in Tet1-/- mice. Loss of TET1-mediated 5hmC protected the Tet1-/- mice from OA development, including degeneration of the cartilage surface and osteophyte formation, by directly preventing the activation of multiple OA pathways. Loss of TET1 in human OA chondrocytes reduced the expression of the matrix metalloproteinases MMP3 and MMP13 and multiple inflammatory cytokines. Intra-articular injections of a dioxygenases inhibitor, 2-hydroxyglutarate, on mice after surgical induction of OA stalled disease progression. Treatment of human OA chondrocytes with the same inhibitor also phenocopied TET1 loss. Collectively, these data demonstrate that TET1-mediated 5hmC deposition regulates multiple OA pathways and can be modulated for therapeutic intervention.

Background Early detection and intervention are critical to maintaining the native articular cartilage before collapse in secondary osteonecrosis of the knee (SOK). We conducted a retrospective study documenting the initial stage of presentation and the progression of SOK. Methods Our database was reviewed for patients younger than 65 years of age diagnosed with atraumatic SOK between 2002 and 2018. Demographic data, plain radiographs as well as MRI at initial evaluation, and initial treatment were classified and analyzed. Results One hundred four patients with 164 knees were identified. Mean age was 39 ± 16 years. Females (64%) with bilateral disease (58%) predominated. Seventy-five percent of patients had a history of corticosteroid use, of which 41% were diagnosed with hematologic malignancy and lupus. Fifteen percent of patients had a history of ethanol abuse. At initial presentation, 55% of patients were diagnosed with Ficat-Arlet stage I/II, while 45% were diagnosed with Ficat-Arlet stage III/IV. We found a significant difference in the mean age of patients at early stage of SOK with corticosteroid use (31 ± 12 years of age) when compared to ethanol use (43 ± 13 years of age, P = .02). Treatments included observation (57%), joint preservation surgery (20%), and total knee arthroplasty (23%). Conclusion Nearly half of patients presented at late stage compromising the potential for joint preservation. The difference in age of referral by over a decade, based on etiology of SOK, suggests a strong provider-based referral or screening bias may be present. Hence, a multidisciplinary approach to earlier detection and referral may be a more effective strategy for preventing the progression of SOK.

Background and Objective: Persistent periprosthetic joint infection (PJI) is a devastating complication after Total Knee Arthroplasty (TKA). We hypothesize that our novel treatment algorithm utilizing a customized knee spanning recon nail combined with an antibiotic eluting cement spacer improves ambulation status and prevents recurrent PJI in patients with failed TKA and severe bone loss. Methods: In a retrospective case series, 15 consecutive patients who underwent knee arthrodesis after failed ipsilateral TKA secondary to infection from 2004-2017 with at least 1 year of follow-up were enrolled. The average age of patients at the time surgery was 68 (range 50-81) years with an average follow-up of 3.2 (range 1-6) years. Post-surgical ambulation status and eradication of index infection were analyzed as primary outcomes using McNemar’s test for before-and-after study design with p Results: Cement arthrodesis significantly improved ambulation with 67% (10/15) of patients unable to ambulate before arthrodesis and 93% (14/15) of patients able to ambulate at final follow-up (p=0.004). The complication rate was 20% (3/15). There were no periprosthetic fractures. Amongst patients who presented with active PJI, 91% (10/11) had eradication of their index infection final follow-up (p=0.002). Overall prevention of recurrent index infection was 93% (14/15) (p=0.0001). Conclusion: Cement arthrodesis utilizing a custom knee spanning recon nail combined with an antibiotic eluting spacer improves ambulation status and prevents or treats recurrent infection in the majority of patients who have failed total knee arthroplasty.

Purpose: Osteonecrosis is a devastating complication of high-dose corticosteroid therapy in patients with cancer. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in osteonecrosis lesions. Experimental Design: In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MRI studies of nine hip joints of 7 patients with osteonecrosis before and after core decompression. Twenty-four to 48 hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron-labeled bone marrow cells were aspirated from the iliac crest, concentrated, and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation. Results: Iron-labeled cells could be detected in the access canal by a dark (negative) signal on T2-weighted MR images. T2* relaxation times of iron-labeled cell transplants were significantly lower compared with unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair. Conclusions: This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.

Introduction:While statins have been found to reduce postoperative atrial fibrillation after cardiac surgery, little is known about their use in total hip arthroplasty (THA). This study investigated if statins would similarly reduce postoperative arrhythmias in patients undergoing THA.Methods:We queried a large Medicare and private-payer database from 2005 to 2012 and identified 12,075 patients who were on a statin prior to THA. We then age and sex matched 34,446 non-statin users who underwent THA. Baseline comorbidities and postoperative complications were obtained and assessed via standard descriptive statistics.Results:The statin users had more preoperative comorbidities including congestive heart failure, valvular heart disease, pulmonary and renal disease, diabetes, hypertension, obesity, and anaemia (all p values < 0.001). Postoperatively, the statin users had a statistically higher 90-day incidence of transfusion, acute renal failure, heart failure, pneumonia, and sepsis/shock. All new-onset cardiac arrhythmia was significantly less frequent in the statin group at 2 weeks (3.88% vs. 4.72%, p < 0.001), 30 days (4.47% vs. 5.29%, p < 0.001), and 90 days (5.44% vs. 6.31%, p = 0.001) postoperative. There was no difference in the frequency of venous thromboembolism, myocardial infarction, postoperative anaemia, or bleeding at 90 days postoperative.Discussion:Despite being medically sicker at baseline with multiple risk factors for atrial fibrillation compared to the non-statin users, the statin users displayed a consistently lower occurrence of postoperative cardiac arrhythmia in this retrospective cohort study. Statins may therefore be beneficial in the preoperative optimisation of medically complex patients undergoing THA.

Osteonecrosis of the femoral head (ONFH) is a debilitating disease that may progress to femoral head collapse and subsequently, degenerative arthritis. Although injection of bone marrow-derived mononuclear cells (BMMCs) is often performed with core decompression (CD) in the early stage of ONFH, these treatments are not always effective in prevention of disease progression and femoral head collapse. We previously described a novel 3D printed, customized functionally-graded scaffold (FGS) that improved bone growth in the femoral head after CD in a normal healthy rabbit, by providing structural and mechanical guidance. The present study demonstrates similar results of the FGS in a rabbit steroid-induced osteonecrosis model. Furthermore, the injection of BMMCs into the CD decreased the osteonecrotic area in the femoral head. Thus, the combination of FGS and BMMC provides a new therapy modality that may improve the outcome of CD for early stage of ONFH by providing both enhanced biological and biomechanical cues to promote bone regeneration in the osteonecrotic area.