Antimicrobial drug LbL-assembled delivery system for orthopaedic nanocomposite bone cements

Total joint replacement (TJR) is commonly used for the treatment of end stage arthritis. The use of Poly-methylmethacrylate (PMMA) bone cement is a gold standard TJR, where it is frequently used for local delivery of antibiotics to provide prophylaxis from prosthetic joint infections (PJI). Currently used antibiotic loaded bone cements have many limitations, including burst release which fall below inhibitory levels leading to the selection of antibiotic resistant strains. This study aims to provide a controlled release for antimicrobial agents from bone cement to provide prophylaxis from postsurgical infections. For this purpose, gentamicin and chlorhexidine were loaded alone or in combination on silica nanoparticles surface using layer-by-layer coating technique (LbL). A novel LbL construct was built using hydrolysable and non-hydrolysable polymers. The nanoparticles were characterised by transmission electron microscopy, thermogravimetric analysis, zeta measurement, and drug release in different media. Then, antimicrobial agents LbL coated nanoparticles were incorporated into PMMA cement and the nanocomposite is characterized for drug release, antimicrobial, mechanical, rheological properties and cytocompatibility. The build-up of LbL coating was confirmed by thermogravimetric analysis and zeta measurements. The release of antimicrobial agents was controlled for > 30 days for different drugs used. The nanocomposite drug release profile also continued > 30 days at concentration higher than the commercial formula t ion containing the same amount of antibiotics, where burst release for few days were observed. Moreover, the nanocomposite showed superior antimicrobial inhibit ion for bacterial growth, without adversely affecting the mechanical properties. Different nanocomposites showed cytocompatibility when tested against Saos-2 cells. Techniques from a variety of disciplines were employed in this study and this interdisciplinary approach has allowed many features of PMMA bone cement to be investigated. The developed nanocomposites can have the potential to reduce PJIs, and the newly developed LbL nano-delivery system may have wider application in a variety of biomaterials

Role of poly-beta-amino-esters hydrolysis and electrostatic attraction in Gentamicin release from Layer-by-Layer coatings

Layer-by-layer (LbL) deposition is a versatile techniques that has been employed in numerous industrial applications i.e. biomaterials, drug delivery and electronics to confer peculiar properties to the system. When employed in drug delivery, the active molecule is sandwiched between layers of polyelectrolytes and the release is controlled by the diffusion of the drug through the layers and the possible hydrolysis of the coating (delamination). Poly-beta-amino-esters (PBAEs) are a class of hydrolysable polyelectrolytes that have been widely used in DNA delivery and in LbL on medical devices. Their use allowed controlled release of antibiotics and other bioactive compounds from the surface of medical devices without cytotoxic effects. The general accepted consensus is that drug released from LbL coating assembled using PBAE is the results of the polymer hydrolysis; however no attention has been paid to the role of the electrostatic attraction between PBAE and the other polyelectrolyte utilised in the LbL assembly. In this work, we prepared LbL coating on the surface of silica nanoparticles entrapping gentamicin as model drug and demonstrated that the drug release from PBAE containing LbL coating is predominantly controlled by the electrostatic attractions between opposite charged electrolytes. The positive charge of PBAE decreases from pH5 to pH7.4 while alginate negative charges remained unchanged in this pH range while PBAE hydrolysis kinetics was faster, as determined with Gel Permeation Chromatography (GPC), in acidic conditions. When PBAE were employed in the LbL construct higher levels of drug were released at pH=7.4 than at pH5; additionally, replacing PBAE with chitosan (the charge of chitosan is not influenced in this pH range) resulted in comparable gentamicin release kinetics at pH=5

Role of processing parameters on surface and wetting properties controlling the behaviour of layer-by-layer coated nanoparticles

Wetting phenomena at surfaces and interfaces is an important field of research with numerous commercial applications. As example, superhydrophobic surfaces are used as self-cleaning, antibiofilm forming and antimicrobial materials nowadays. Given the potential impact, creating surfaces with tailored wetting characteristics employing various fabrication techniques is of great interest. One very promising fabrication technique, for creating such materials is the layer-by-layer (LbL) self-assembly. LbL is a versatile technique allowing incorporation of different types of drugs and materials and the ability to coat substrates of complex geometries. This review summarises recent progress in preparation of Layer-by-layer constructs and a role of surface and wetting parameters in this technique. Effect of various physicochemical properties on LbL construct characteristics also were discussed

PMMA bone cement containing long releasing silica-based chlorhexidine nanocarriers

Prosthetic joint infections (PJI) are still an extremely concerning eventuality after joint replacement surgery; growing antibiotic resistance is also limiting the prophylactic and treatment options. Chlorhexidine (a widely used topical non-antibiotic antimicrobial compound) coatings on silica nanoparticles capable of prolonged drug release have been successfully developed and characterised. Such nanocarriers were incorporated into commercial formulation PMMA bone cement (Cemex), without adversely affecting the mechanical performance. Moreover, the bone cement containing the developed nanocarriers showed superior antimicrobial activity against different bacterial species encountered in PJI, including clinical isolates already resistant to gentamicin. Cytocompatibility tests also showed non inferior performance of the bone cements containing chlorhexidine releasing silica nanocarriers to the equivalent commercial formulation

LbL-assembled gentamicin delivery system for PMMA bone cements to prolong antimicrobial activity

Introduction Antibiotic-loaded poly(methyl methacrylate) bone cements (ALBCs) are widely used in total joint replacement (TJR), for local delivery of antibiotics to provide prophylaxis against prosthetic joint infections (PJI). One of the shortcomings of the current generation of ALBCs is that the antibiotic release profile is characterized by a burst over the first few hours followed by a sharp decrease in rate for the following several days (often below minimum inhibitory concentration (MIC)), and, finally, exhaustion (after, typically, ~ 20 d). This profile means that the ALBCs provide only short-term antimicrobial action against bacterial strains involved PJI. Rationale The purpose of the present study was to develop an improved antibiotic delivery system for an ALBC. This system involved using a layer-by-layer technique to load the antibiotic (gentamicin sulphate) (GEN) on silica nanoparticles, which are then blended with the powder of the cement. Then, the powder was mixed with the liquid of the cement (NP-GEN cement). For controls, two GEN-loaded brands were used (Cemex Genta and Palacos R+G). Gentamicin release and a host of other relevant properties were determined for all the cements studied. Results Compared to control cement specimens, improved GEN release, longer antimicrobial activity (against clinically-relevant bacterial strains), and comparable setting time, cytocompatibility, compressive strength (both prior to and after aging in PBS at 37 oC for 30 d), 4-point bend strength and modulus, fracture toughness, and PBS uptake. Conclusions NP-GEN cement may have a role in preventing or treating PJI

Nanocomposite orthopaedic bone cement combining long-acting dual antimicrobial drugs

Antibiotic loaded bone cements are widely used in total joint replacement (TJR); despite many limitations such as a burst release which leads to antibiotic concentration below inhibitory levels and possibly contributing to the selection of antibiotic resistant strains. In order to address such limitations and to simultaneously address antibiotic resistance and short-term antimicrobial activity, we developed a nanocomposite bone cement capable of providing a controlled release of antimicrobial agents from bone cement to act as prophylaxis or treatment against prosthetic joint infections (PJIs). Gentamicin and chlorhexidine were loaded in combination on silica nanoparticles surface using layer-by-layer coating technique (LbL) combining hydrolysable and non-hydrolysable polymers. The drug release from the nanocomposite continued for >50 days at concentrations higher than the commercial formulation containing the same amount of antimicrobial drugs, where burst release for few days were observed. Moreover, the nanocomposite bone cement showed superior antimicrobial inhibition without adversely affecting the mechanical properties or the ability of osteoblasts to grow. In vivo experiments with an infected bone lesion model along with mass-spectrometric analysis also provided further evidence of efficacy and safety of the implanted nanocomposite material as well as its prolonged drug eluting profile. The developed nanocomposite bone cement has the potential to reduce PJIs and enable treatment of resistant established infections; moreover, the newly developed LbL based nano-delivery system may also have wider applications in reducing the threat posed by antimicrobial resistance

Global, regional, and national burden of other musculoskeletal disorders, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Background Musculoskeletal disorders include more than 150 different conditions affecting joints, muscles, bones, ligaments, tendons, and the spine. To capture all health loss from death and disability due to musculoskeletal disorders, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) includes a residual musculoskeletal category for conditions other than osteoarthritis, rheumatoid arthritis, gout, low back pain, and neck pain. This category is called other musculoskeletal disorders and includes, for example, systemic lupus erythematosus and spondylopathies. We provide updated estimates of the prevalence, mortality, and disability attributable to other musculoskeletal disorders and forecasted prevalence to 2050. Methods Prevalence of other musculoskeletal disorders was estimated in 204 countries and territories from 1990 to 2020 using data from 68 sources across 23 countries from which subtraction of cases of rheumatoid arthritis, osteoarthritis, low back pain, neck pain, and gout from the total number of cases of musculoskeletal disorders was possible. Data were analysed with Bayesian meta-regression models to estimate prevalence by year, age, sex, and location. Years lived with disability (YLDs) were estimated from prevalence and disability weights. Mortality attributed to other musculoskeletal disorders was estimated using vital registration data. Prevalence was forecast to 2050 by regressing prevalence estimates from 1990 to 2020 with Socio-demographic Index as a predictor, then multiplying by population forecasts. Findings Globally, 494 million (95% uncertainty interval 431–564) people had other musculoskeletal disorders in 2020, an increase of 123·4% (116·9–129·3) in total cases from 221 million (192–253) in 1990. Cases of other musculoskeletal disorders are projected to increase by 115% (107–124) from 2020 to 2050, to an estimated 1060 million (95% UI 964–1170) prevalent cases in 2050; most regions were projected to have at least a 50% increase in cases between 2020 and 2050. The global age-standardised prevalence of other musculoskeletal disorders was 47·4% (44·9–49·4) higher in females than in males and increased with age to a peak at 65–69 years in male and female sexes. In 2020, other musculoskeletal disorders was the sixth ranked cause of YLDs globally (42·7 million [29·4–60·0]) and was associated with 83 100 deaths (73 600–91 600). Interpretation Other musculoskeletal disorders were responsible for a large number of global YLDs in 2020. Until individual conditions and risk factors are more explicitly quantified, policy responses to this burden remain a challenge. Temporal trends and geographical differences in estimates of non-fatal disease burden should not be overinterpreted as they are based on sparse, low-quality data.publishedVersio

Nano-carrier based drug delivery systems for sustained antimicrobial agent release from orthopaedic cementous material

Total joint replacement (TJR), such as hip and knee replacement, is a popular procedure worldwide. Prosthetic joint infections (PJI) after this procedure have been widely reported, where treatment of such infections is complex with high cost and prolonged hospital stay. In cemented arthroplasties, the use of antibiotic loaded bone cement (ALBC) is a standard practice for the prophylaxis and treatment of PJI. Recently, the development of bacterial resistance by pathogenic microorganisms against most commonly used antibiotics increased the interest in alternative approaches for antimicrobial delivery systems such as nanotechnology. This review summarizes the efforts made to improve the antimicrobial properties of PMMA bone cements using nanotechnology based antibiotic and non-antibiotic delivery systems to overcome drawbacks of ALBC in the prophylaxis and treatment of PJIs after hip and knee replacement

Antimicrobial PMMA Bone Cement Containing Long Releasing Multi-Walled Carbon Nanotubes

Prosthetic joint infections (PJIs) ensued from total joint replacement (TJR) pose a severe threat to patients that involve poor health outcomes, severe pain, death (in severe cases), and negative influence patients’ quality of life. Antibiotic-loaded bone cement (ALBC) is frequently used for the prevention and treatment of PJI. This work aims to study gentamicin release from carbon nanotubes (CNTs) incorporated in polymethyl methacrylate (PMMA) bone cement to prolong release over several weeks to provide prophylaxis from PJIs after surgery. Different CNT concentrations were tested with the presence of gentamicin as a powder or preloaded onto carboxyl functionalized CNTs. The different types of bone cement were tested for drug release, mechanical properties, water uptake, antimicrobial properties, and cytocompatibility with human osteoblast cells (MTT, LDH, alizarin red, and morphology). Results showed prolonged release of gentamicin from CNT-loaded bone cements over several weeks compared to gentamicin-containing bone cement. Additionally, the presence of CNT enhanced the percentage of gentamicin released without adversely affecting the nanocomposite mechanical and antimicrobial properties needed for performance. Cytotoxicity testing showed non-inferior performance of the CNT-containing bone cement to the equivalent powder containing cement. Therefore, the developed nanocomposites may serve as a novel PMMA bone cement to prevent PJIs