Stephen L. Kates

3D Printing of Calcium Phosphate Ceramics for Bone Tissue Engineering and Drug Delivery

Additive manufacturing, also known as 3D printing, has emerged over the past 3 decades as a disruptive technology for rapid prototyping and manufacturing. Vat polymerization, powder bed fusion, material extrusion, and binder jetting are distinct technologies of additive manufacturing, which have been used in a wide variety of fields, including biomedical research and tissue engineering. The ability to print biocompatible, patient-specific geometries with controlled macro- and micro-pores, and to incorporate cells, drugs and proteins has made 3D-printing ideal for orthopaedic applications, such as bone grafting. Herein, we performed a systematic review examining the fabrication of calcium phosphate (CaP) ceramics by 3D printing, their biocompatibility in vitro, and their bone regenerative potential in vivo, as well as their use in localized delivery of bioactive molecules or cells. Understanding the advantages and limitations of the different 3D printing approaches, CaP materials, and bioactive additives through critical evaluation of in vitro and in vivo evidence of efficacy is essential for developing new classes of bone graft substitutes that can perform as well as autografts and allografts or even surpass the performance of these clinical standards.

Infection after fracture fixation: Current surgical and microbiological concepts.

One of the most challenging complications in trauma surgery is infection after fracture fixation (IAFF). IAFF may result in permanent functional loss or even amputation of the affected limb in patients who may otherwise be expected to achieve complete, uneventful healing. Over the past decades, the problem of implant related bone infections has garnered increasing attention both in the clinical as well as preclinical arenas; however this has primarily been focused upon prosthetic joint infection (PJI), rather than on IAFF. Although IAFF shares many similarities with PJI, there are numerous critical differences in many facets including prevention, diagnosis and treatment. Admittedly, extrapolating data from PJI research to IAFF has been of value to the trauma surgeon, but we should also be aware of the unique challenges posed by IAFF that may not be accounted for in the PJI literature. This review summarizes the clinical approaches towards the diagnosis and treatment of IAFF with an emphasis on the unique aspects of fracture care that distinguish IAFF from PJI. Finally, recent developments in anti-infective technologies that may be particularly suitable or applicable for trauma patients in the future will be briefly discussed.

Length of hospital stay after hip fracture and risk of early mortality after discharge in New York state: retrospective cohort study.

Study question Can the length of hospital stay for hip fracture affect a patient’s risk of death 30 days after discharge? Methods In a retrospective cohort study, population based registry data from the New York Statewide Planning and Research Cooperative System (SPARCS) were used to investigate 188 208 patients admitted to hospital for hip fracture in New York state from 2000 to 2011. Patients were aged 50 years and older, and received surgical or non-surgical treatment. The main outcome measure was the mortality rate at 30 days after hospital discharge. Study answer and limitations Hospital stays of 11-14 days for hip fracture were associated with a 32% increased odds of death 30 days after discharge, compared with stays lasting one to five days (odds ratio 1.32 (95% confidence interval 1.19 to 1.47)). These odds increased to 103% for stays longer than 14 days (2.03 (1.84 to 2.24)). Other risk factors associated with early mortality included discharge to a hospice facility, older age, metastatic disease, and non-surgical management. The 30 day mortality rate after discharge was 4.5% for surgically treated patients and 10.7% for non-surgically treated patients. These findings might not be generalizable to populations in other US states or in other countries. The administrative claims data used could have been incomplete or include inaccurate coding of diagnoses and comorbid conditions. The database also did not include patient socioeconomic status, which could affect access to care to a greater extent in New York state than in European countries. Specific cause of death was not available because few autopsies are performed in this population. What this study adds By contrast with recent findings in Sweden, decreased length of hospital stay for hip fracture was associated with reduced rates of early mortality in a US cohort in New York state. This could reflect critical system differences in the treatment of hip fractures between Europe and the USA. Funding, competing interests, data sharing University of Rochester grant from the Clinical Translational Science Institute for statistical analyses used in this work (National Institutes of Health (UL1 TR000042)) and the National Institutes of Health (K-08 AR060164-01A). No competing interests declared. Data may be obtained through SPARCS at https://www.health.ny.gov/statistics/sparcs/access/.

Antibiotic Resistance of Commensal Staphylococcus aureus and Coagulase-Negative Staphylococci in an International Cohort of Surgeons: A Prospective Point-Prevalence Study

Nasal colonization with antibiotic resistant bacteria represents both a risk factor for the colonized individual and their immediate contacts. Despite the fact that healthcare workers such as orthopedic surgeons are at a critical interface between the healthcare environment and an at-risk patient population, the prevalence of antibiotic resistant bacteria within the surgical profession remains unclear. This study offers a snapshot of the rate of nasal colonization of orthopedic surgeons with multi-resistant staphylococci including methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS). We performed a prospective, observational study obtained at a single time point in late 2013. The participants were active orthopedic, spine and head & neck surgeons from 75 countries. The prevalence of nasal carriage of the different bacteria and the corresponding 95% confidence interval were calculated. From a cohort of 1,166 surgeons, we found an average S. aureus nasal colonization rate of 28.0% (CI 25.4;30.6) and MRSA rate of 2.0% (CI 1.3;2.9), although significant regional variations were observed. The highest rates of MRSA colonization were found in Asia (6.1%), Africa (5.1%) and Central America (4.8%). There was no MRSA carriage detected within our population of 79 surgeons working in North America, and a low (0.6%) MRSA rate in 657 surgeons working in Europe. High rates of MRCoNS nasal carriage were also observed (21.4% overall), with a similar geographic distribution. Recent use of systemic antibiotics was associated with higher rates of carriage of resistant staphylococci. In conclusion, orthopedic surgeons are colonized by S. aureus and MRSA at broadly equivalent rates to the general population. Crucially, geographic differences were observed, which may be partially accounted for by varying antimicrobial stewardship practices between the regions. The elevated rates of resistance within the coagulase-negative staphylococci are of concern, due to the increasing awareness of their importance in hospital acquired and device-associated infection.

Hip fracture programs: are they effective?

This manuscript will evaluate the published evidence on efficacy of organized hip fracture programs to determine if they improve patient outcomes. A detailed literature search was conducted to find manuscripts published in the past 20 years about organized hip fracture care programs. Seventeen programs with published results were identified from this detailed search and these were evaluated and synthesized in the following manuscript. Organized hip fracture programs offer significant benefits to patients, care providers and health systems. The more complex program designs have a more profound effect on improvement in outcomes for hip fracture patients. Most programs have reported reduced length of stay, reduced in-hospital mortality rates, and reduced complications. Some programs have reported reduced costs and reduced readmission rates after implementing an organized hip fracture program.

Orthopaedic device-related infection: current and future interventions for improved prevention and treatment

Orthopaedic and trauma device-related infection (ODRI) remains one of the major complications in modern trauma and orthopaedic surgery. Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, leading to infections that negatively impact clinical outcome and significantly increase healthcare expenditure. The following review summarises the microbiological profile of modern ODRI, the impact antibiotic resistance has on treatment outcomes, and some of the principles and weaknesses of the current systemic and local antibiotic delivery strategies. The emerging novel strategies aimed at preventing or treating ODRI will be reviewed. Particular attention will be paid to the potential for clinical impact in the coming decades, when such interventions are likely to be critically important. The review focuses on this problem from an interdisciplinary perspective, including basic science innovations and best practice in infectious disease. Cite this article: Moriarty TF, Kuehl R, Coenye T, et al. Orthopaedic device related infection: current and future interventions for improved prevention and treatment. EFORT Open Rev 2016;1:89-99. DOI: 10.1302/2058-5241.1.000037.

Fracture-related infection: A consensus on definition from an international expert group

Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare. In order to address this issue, an expert group comprised of a number of scientific and medical organizations has been convened, with the support of the AO Foundation, in order to develop a consensus definition. The process that led to this proposed definition started with a systematic literature review, which revealed that the majority of randomized controlled trials in fracture care do not use a standardized definition of FRI. In response to this conclusion, an international survey on the need for and key components of a definition of FRI was distributed amongst all registered AOTrauma users. Approximately 90% of the more than 2000 surgeons who responded suggested that a definition of FRI is required. As a final step, a consensus meeting was held with an expert panel. The outcome of this process led to a consensus definition of FRI. Two levels of certainty around diagnostic features were defined. Criteria could be confirmatory (infection definitely present) or suggestive. Four confirmatory criteria were defined: Fistula, sinus or wound breakdown; Purulent drainage from the wound or presence of pus during surgery; Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens; Presence of microorganisms in deep tissue taken during an operative intervention, as confirmed by histopathological examination. Furthermore, a list of suggestive criteria was defined. These require further investigations in order to look for confirmatory criteria. In the current paper, an overview is provided of the proposed definition and a rationale for each component and decision. The intention of establishing this definition of FRI was to offer clinicians the opportunity to standardize clinical reports and improve the quality of published literature. It is important to note that the proposed definition was not designed to guide treatment of FRI and should be validated by prospective data collection in the future.

Staphylococcal orthopaedic device-related infections in older patients

INTRODUCTION Staphylococci are the most common pathogens causing orthopaedic device-related infections (ODRI). The treatment of these infections often involves multiple surgical procedures combined with systemic antibiotic therapy to treat the infection and restore functionality. Older patients frequently present with a compromised health-status and/or low bone quality, and despite growing importance their outcomes are not well described to date. The primary aim of the current study is to describe outcomes in older patients with ODRIs and to determine if they demonstrate lower cure rates and greater risk for complications in contrast to younger patients. PATIENTS AND METHODS Patients treated with an ODRI of the lower extremity at our institution were included in this study. Demographic data, comorbidities and infecting organisms were recorded. Older adult patients were defined as those aged 60 and older. At two-year follow-up post-discharge, we recorded the clinical course, the Lower-Extremity-Functional-Score, the patient reported general health status (SF-12-questionnaire) and the status of infection. The antibiotic resistance pattern of the disease causing pathogens was analysed and compared between the two age groups. RESULTS In total, 163 patients (age: 19-94 years) with a staphylococcal ODRI were included. Sixty-four of these infections occurred in older patients, which showed a significantly higher mortality rate (9%). Within follow-up period recurrence of infection occurred significantly more frequently in younger patients (41%) than in older patients (17%). At two-years follow-up cure, which was defined as eradication of infection and terminated therapy, was achieved in 78% of younger and 75% of older patients. However, an ODRI resulted in older patients in a significantly worse functional outcome and impaired physical quality of live, as well as more frequently in an on-going infection, such as a persisting fistula (14% versus 3% in younger patients). Disease causing staphylococci, isolated from older patients showed more frequently a methicillin or multi-drug resistance than those associated with infections in younger patients. CONCLUSIONS ODRIs in older patients demonstrated higher morality rates rate, poor functional outcome and higher rates of persistent infections. A compromised health status and a poor bone quality may play a crucial role in this specific patient cohort.

Definition of infection after fracture fixation: A systematic review of randomized controlled trials to evaluate current practice.

INTRODUCTION One of the most challenging musculoskeletal complications in modern trauma surgery is infection after fracture fixation (IAFF). Although infections are clinically obvious in many cases, a clear definition of the term IAFF is crucial, not only for the evaluation of published research data but also for the establishment of uniform treatment concepts. The aim of this systematic review was to identify the definitions used in the scientific literature to describe infectious complications after internal fixation of fractures. The hypothesis of this study was that the majority of fracture-related literature do not define IAFF. MATERIAL AND METHODS A comprehensive search was performed in Embase, Cochrane, Google Scholar, Medline (OvidSP), PubMed publisher and Web-of-Science for randomized controlled trials (RCTs) on fracture fixation. Data were collected on the definition of infectious complications after fracture fixation used in each study. Study selection was accomplished through two phases. During the first phase, titles and abstracts were reviewed for relevance, and the full texts of relevant articles were obtained. During the second phase, full-text articles were reviewed. All definitions were literally extracted and collected in a database. Then, a classification was designed to rate the quality of the description of IAFF. RESULTS A total of 100 RCTs were identified in the search. Of 100 studies, only two (2%) cited a validated definition to describe IAFF. In 28 (28%) RCTs, the authors used a self-designed definition. In the other 70 RCTs, (70%) there was no description of a definition in the Methods section, although all of the articles described infections as an outcome parameter in the Results section. CONCLUSION This systematic review shows that IAFF is not defined in a large majority of the fracture-related literature. To our knowledge, this is the first study conducted with the objective to explore this important issue. The lack of a consensus definition remains a problem in current orthopedic trauma research and treatment and this void should be addressed in the near future.

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

ABSTRACT Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery. Staphylococcus aureus, the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation of S. aureus to the unique environment of the obese/T2D host accounts for its increased virulence and persistence in this population is unknown. Thus, we assessed implant-associated osteomyelitis in normal versus high-fat-diet obese/T2D mice and found that S. aureus infection was more severe, including increases in bone abscesses relative to nondiabetic controls. S. aureus isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (clfA, clfB, bbp, and sdrC), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice. In vitro coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients. S. aureus with an inactivating mutation in clumping factor A (clfA) showed a reduction in bone infection severity that eliminated the effect of obesity/T2D, while infections in control mice were unchanged. In infected mice that overexpress plasminogen activator inhibitor-1 (PAI-1), S. aureusclfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to S. aureus expression of clfA and infection severity. Together, these results demonstrate an adaptation by S. aureus to obesity/T2D with increased expression of clfA that is associated with the hypercoagulable state of the host and increased virulence of S. aureus.