Metallosis is defined as the accumulation and deposition of metallic particles secondary to abnormal wear from prosthetic implants that may be visualized as abnormal macroscopic staining of periprosthetic soft tissues. This phenomenon occurs secondary to the release of metal ions and particles from metal-on-metal hip implants in patients with end-stage osteoarthritis. Ions and particles shed from implants can lead to local inflammation of surrounding tissue and less commonly, very rare systemic manifestations may occur in various organ systems. With the incidence of total hip arthroplasty increasing as well as rates of revisions due to prosthesis failure from previous metal-on-metal implants, metallosis has become an important area of research. Bodily fluids are electrochemically active and react with biomedical implants. Particles, especially cobalt and chromium, are released from implants as they abrade against one another into the surrounding tissues. The body’s normal defense mechanism becomes activated, which can elicit a cascade of events, leading to inflammation of the immediate surrounding tissues and eventually implant failure. In this review, various mechanisms of metallosis are explored. Focus was placed on the atomic and molecular makeup of medical implants, the component/surgical associated factors, cellular responses, wear, tribocorrosion, joint loading, and fluid pressure associated with implantation. Current treatment guidelines for failed implants include revision surgery. An alternative treatment could be chelation therapy, which may drive future studies. Lay Summary Arthroplasty is an invasive procedure which disrupts surrounding joint tissues, and can greatly perturb the joint’s immune homeostasis. In some instances, this may pose a difficult challenge to implant integration. Particles released from implants into the surrounding joint tissues activate the body’s defense mechanism, eliciting a cascade of events, which leads to biotribocorrosion and electrochemical attacks on the implant. This process may lead to the release of even more particles. Besides, implant makeup and designs, frictions between bearing surfaces, corrosion of non-moving parts with modular junctions, surgical mistakes, patient factor, comorbidities, and loosened components can alter the expected function of implants. High accumulations of these ions and particulates result in metallosis, with accompanying adverse complications. Current recommended treatment for failed prosthesis is revision surgeries. However, chelation therapy as a prophylactic intervention may be useful in future efforts but more investigation is required.
Background: Severe brain edema appears early after cardiopulmonary resuscitation (CPR) in a subset of patients and portends a poor prognosis. We tested whether clinical features of patients or resuscitation during out-of-hospital cardiac arrest (OHCA) are associated with early, severe cerebral edema.Method/research design: We reviewed pre-hospital and hospital records for comatose patients surviving to hospital admission after OHCA who had computed tomography (CT) of brain at the time of hospital admission available for inspection. We measured the gray-white ratio (GWR) of X-ray attenuation between the caudate nucleus and posterior limb of the internal capsule, defining severe cerebral edema as GWR < 1.20. We calculated associations between severe cerebral edema and patient or resuscitation variables.Results: Between 2010 and 2019, 1340 subjects were admitted of whom 296 (22%) showed severe cerebral edema on initial CT. Subjects with severe edema had lower survival (5/296, 2% vs. 377/1044, 36%). Severe edema was independently associated with total CPR duration, total dose of epinephrine, younger age, non-shockable arrest rhythms, fewer total number of rescue shocks, rearrest after initial return of pulses, and non-cardiac arrest etiology.Prevalence of severe cerebral edema increased from 2% among subjects with 0À10 min of CPR to 31% among subjects with >40 min of CPR. Conclusion:CPR duration along with easily measurable clinical and resuscitation characteristics predict early severe cerebral edema after OHCA. Future interventional trials should consider targeting or preventing cerebral edema after prolonged hypoxic-ischemic brain injury especially in patients with high risk clinical features.
Stem cells are of great interest in tissue regeneration due to their ability to modulate the local microenvironment by secreting bioactive factors (collectively, secretome). However, secretome delivery through conditioned media still requires time-consuming cell isolation and maintenance and also may contain factors antagonistic to targeted tissue regeneration. We have therefore engineered a synthetic artificial stem cell (SASC) system which mimics the paracrine effect of the stem cell secretome and provides tailorability of the composition for targeted tissue regeneration. We report the first of many applications of the SASC system we have formulated to treat osteoarthritis (OA). Choosing growth factors important to chondrogenesis and encapsulating respective recombinant proteins in poly (lactic-coglycolic acid) 85:15 (PLGA) we fabricated the SASC system. We compared the antiinflammatory and chondroprotective effects of SASC to that of adipose-derived stem cells (ADSCs) using in vitro interleukin 1B-induced and in vivo collagenase-induced osteoarthritis rodent models. We have designed SASC as an injectable therapy with controlled release of the formulated secretome. In vitro, SASC showed significant antiinflammatory and chondroprotective effects as seen by the up-regulation of SOX9 and reduction of nitric oxide, ADAMTS5, and PRG4 genes compared to ADSCs. In vivo, treatment with SASC and ADSCs significantly attenuated cartilage degeneration and improved the biomechanical properties of the articular cartilage in comparison to OA control. This SASC system demonstrates the feasibility of developing a completely synthetic, tailorable stem cell secretome which reinforces the possibility of developing a new therapeutic strategy that provides better control over targeted tissue engineering applications.
Osteoarthritis (OA) of the knee is the most common synovial joint disorder worldwide, with a growing incidence due to increasing rates of obesity and an aging population. A significant amount of research is currently being conducted to further our understanding of the pathophysiology of knee osteoarthritis to design less invasive and more effective treatment options once conservative management has failed. Regenerative engineering techniques have shown promising preclinical results in treating OA due to their innovative approaches and have emerged as a popular area of study. To investigate these therapeutics, animal models of OA have been used in preclinical trials. There are various mechanisms by which OA can be induced in the knee/stifle of animals that are classified by the etiology of the OA that they are designed to recapitulate. Thus, it is essential to utilize the correct animal model in studies that are investigating regenerative engineering techniques for proper translation of efficacy into clinical trials. This review discusses the various animal models of OA that may be used in preclinical regenerative engineering trials and the corresponding classification system. Lay Summary Osteoarthritis (OA) of the knee is the most common synovial joint disease worldwide, with high rates of occurrence due to an increase in obesity and an aging population. A great deal of research is currently underway to further our understanding of the causes of osteoarthritis, to design more effective treatments. The emergence of regenerative engineering has provided physicians and investigators with unique opportunities to join ideas in tackling human diseases such as OA. Once the concept is proven to work, the initial procedure for the evaluation of a treatment solution begins with an animal model. Thus, it is essential to utilize a suitable animal model that reflects the particular ailment in regenerative engineering studies for proper translation to human patients as each model has associated advantages and disadvantages. There are various ways by which OA can occur in the knee joint, which are classified according to the particular cause of the OA. This review discusses the various animal models of OA that may be used in preclinical regenerative engineering investigations and the corresponding classification system.
Tears in the rotator cuff are challenging to repair because of the complex, hypocellular, hypovascular, and movement‐active nature of the tendon and its enthesis. Insulin‐like Growth Factor‐1 (IGF‐1) is a promising therapeutic for this repair. However, its unstable nature, short half‐life, and ability to disrupt homeostasis has limited its clinical translation. Pegylation has been shown to improve the stability and sustain IGF‐1 levels in the systemic circulation without disrupting homeostasis. To provide localized delivery of IGF‐1 in the repaired tendons, we encapsulated pegylated IGF‐1 mimic and its controls (unpegylated IGF‐1 mimic and recombinant human IGF‐1) in polycaprolactone‐based matrices and evaluated them in a pre‐clinical rodent model of rotator cuff repair. Pegylated‐IGF‐1 mimic delivery reestablished the characteristic tendon‐to‐bone enthesis structure and improved tendon tensile properties within 8 weeks of repair compared to controls, signifying the importance of pegylation in this complex tissue regeneration. These results demonstrate a simple and scalable biologic delivery technology alternative to tissue‐derived grafts for soft tissue repair.
Regenerative engineering is defined as the convergence of the disciplines of advanced material science, stem cell science, physics, developmental biology and clinical translation for the regeneration of complex tissues and organ systems. It is an expansion of tissue engineering, which was first developed as a method of repair and restoration of human tissue. In the past three decades, advances in regenerative engineering have made it possible to treat a variety of clinical challenges by utilizing cutting-edge technology currently available to harness the body’s healing and regenerative abilities. The emergence of new information in developmental biology, stem cell science, advanced material science and nanotechnology have provided promising concepts and approaches to regenerate complex tissues and structures.
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