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1.
BMC Urol ; 24(1): 186, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-39215290

ABSTRACT

BACKGROUND: Both long (> 30 days) and short-term (≤ 30 days) catheterisation has been associated with urinary tract infections (UTIs) due to the invasive nature of device insertion through the urethra. Catheter associated Urinary Tract Infections (CAUTIs) are common (prevalence of ~ 8.5%) infections which can be treated with antibiotics; however, CAUTIs are both expensive to treat and contributes to the antibiotic usage crisis. As catheters are unlikely be replaced for the management of patients' urination, ways of reducing CAUTIs are sought out, using the catheter device itself. The aim of this review is to assess the incidence of CAUTI and the causative micro-organisms when different urinary catheter devices have been used by humans, as reported in published research articles. METHODS: A Systematic Literature Review was conducted in Ovid Medline, Web of Science and PubMed, to identify studies which investigated the incidence of UTI and the causative micro-organisms, in patients with different urinary catheter devices. The articles were selected based on a strict set of inclusion and exclusion criteria. The data regarding UTI incidence was extracted and calculated odds ratio were compared across studies and pooled when types of catheters were compared. CAUTI causative micro-organisms, if stated within the research pieces, were also gathered. RESULTS: A total of 890 articles were identified, but only 26 unique articles met the inclusion/exclusion criteria for this review. Amongst the large cohort there were catheters of materials silicone, latex and PVC and catheter modifications of silver nanoparticles and nitrofurantoin antibiotics. The meta-analysis did not provide a clear choice towards a single catheter against another although silver-based catheters, and silver alloy, appeared to statistically reduce the OR of developing CAUTIs. At genus level the three commonest bacteria identified across the cohort were E. coli, Enterococcus spp. and Pseudomonas spp. whilst considering only at the genus level, with E. coli, Klebsiella pneumonia and Enterococcus faecalis most common at the species-specific level. CONCLUSIONS: There does not appear to be a catheter type, which can significantly reduce the incidence of CAUTI's in patients requiring catheterisation. Ultimately, this warrants further research to identify and develop a catheter device material that will reduce the incidence for CAUTIs.


Subject(s)
Catheter-Related Infections , Urinary Catheters , Urinary Tract Infections , Humans , Urinary Tract Infections/epidemiology , Incidence , Urinary Catheters/adverse effects , Urinary Catheters/microbiology , Catheter-Related Infections/epidemiology , Catheter-Related Infections/microbiology , Catheter-Related Infections/prevention & control , Urinary Catheterization/adverse effects
2.
Adv Funct Mater ; 33(50): 2301857, 2023 Dec 08.
Article in English | MEDLINE | ID: mdl-38495320

ABSTRACT

Smart robotic devices remotely powered by magnetic field have emerged as versatile tools for wide biomedical applications. Soft magnetic elastomer (ME) composite membranes with high flexibility and responsiveness are frequently incorporated to enable local actuation for wireless sensing or cargo delivery. However, the fabrication of thin ME membranes with good control in geometry and uniformity remains challenging, as well as the optimization of their actuating performances under low fields (milli-Tesla). In this work, the development of ME membranes comprising of low-cost magnetic powder and highly soft elastomer through a simple template-assisted doctor blading approach, is reported. The fabricated ME membranes are controllable in size (up to centimetre-scale), thickness (tens of microns) and high particle loading (up to 70 wt.%). Conflicting trade-off effects of particle concentration upon magnetic responsiveness and mechanical stiffness are investigated and found to be balanced off as it exceeds 60 wt.%. A highly sensitive fibre-optic interferometric sensing system and a customized fibre-ferrule-membrane probe are first proposed to enable dynamic actuation and real-time displacement characterization. Free-standing ME membranes are magnetically excited under low field down to 2 mT, and optically monitored with nanometer accuracy. The fast and consistent responses of ME membranes showcase their promising biomedical applications in nanoscale actuation andĀ sensing.

3.
Nanomedicine ; 13(2): 539-548, 2017 02.
Article in English | MEDLINE | ID: mdl-27746232

ABSTRACT

The efficient delivery of therapeutic molecules to the cartilage of joints is a major obstacle in developing useful therapeutic interventions; hence, a targeted drug delivery system for this tissue is critical. We have overcome the challenge by developing a system that employs electrostatic attraction between the negatively charged constituents of cartilage and a positively charged polymer, poly-beta amino esters (PBAEs). We have demonstrated cartilage uptake of dexamethasone (DEX) covalently bound to the PBAE was doubled and retention in tissues prolonged compared to the equivalent dose of the commercial drug formulation. Moreover, no adverse effects on chondrocytes were found. Our data also show that PBAEs can bind not only healthy cartilage tissues but also enzymatically treated cartilage mimicking early stages of OA. Our PBAEs-prodrug technology's advantages are fourfold; the specificity and efficacy of its targeting mechanism for cartilage, the ease of its production and the low-cost nature of the delivery system.


Subject(s)
Drug Delivery Systems , Esters , Animals , Cartilage , Cattle , Chondrocytes , Drug Carriers , Excipients , Male , Nanoparticles
4.
Langmuir ; 32(31): 7965-74, 2016 08 09.
Article in English | MEDLINE | ID: mdl-27434665

ABSTRACT

Curli are bacterial appendages involved in the adhesion of cells to surfaces; their synthesis is regulated by many genes such as csgD and ompR. The expression of the two curli subunits (CsgA and CsgB) in Escherichia coli (E. coli) is regulated by CsgD; at the same time, csgD transcription is under the control of OmpR. Therefore, both genes are involved in the control of curli production. In this work, we elucidated the role of these genes in the nanomechanical and adhesive properties of E. coli MG1655 (a laboratory strain not expressing significant amount of curli) and its curli-producing mutants overexpressing OmpR and CsgD, employing atomic force microscopy (AFM). Nanomechanical analysis revealed that the expression of these genes gave origin to cells with a lower Young's modulus (E) and turgidity (P0), whereas the adhesion forces were unaffected when genes involved in curli formation were expressed. AFM was also employed to study the primary structure of the curli expressed through the freely jointed chain (FJC) model for polymers. CsgD increased the number of curli on the surface more than OmpR did, and the overexpression of both genes did not result in a greater number of curli. Neither of the genes had an impact on the structure (total length of the polymer and number and length of Kuhn segments) of the curli. Our results further suggest that, despite the widely assumed role of curli in cell adhesion, cell adhesion force is also dictated by surface properties because no relation between the number of curli expressed on the surface and cell adhesion was found.


Subject(s)
Bacterial Adhesion/physiology , Bacterial Proteins/metabolism , Elastic Modulus , Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Trans-Activators/metabolism
5.
Nanomedicine ; 12(3): 723-734, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26554392

ABSTRACT

Wear debris generated by ultra-high molecular weight polyethylene (UHMWPE) used in joint replacement devices has been of concern due to reductions of the implant longevity. Cold atmospheric plasma (CAP) has been used to improve the wear performance of UHMWPE. Our aim was to investigate the elastic and adhesive properties of rat mesenchymal stem cells (rMSCs), through AFM, after exposure to UHMWPE wear debris pre- and post-CAP treatment. The results indicated that the main changes in cell elasticity and spring constant of MSC exposed to wear particles occurred in the first 24 h of contact and the particle concentration from 0.5 to 50 mg/l did not play a significant role. For UHMWPE treated for 7.5 min, with progression of the wear simulation the results of the CAP treated samples were getting closer to the result of untreated samples; while with longer CAP treatment this was not observed. FROM THE CLINICAL EDITOR: Joint replacements are now common clinical practice. However, the use of ultra-high molecular weight polyethylene (UHMWPE) still poses a concern, due to the presence of wear debris. The authors here investigated the effects of wear debris after cold atmospheric plasma treatment on rat mesenchymal stem cells. The positive results provided new strategies in future design of joint replacement materials.


Subject(s)
Biocompatible Materials/chemistry , Mesenchymal Stem Cells/cytology , Plasma Gases/chemistry , Polyethylenes/chemistry , Animals , Biomechanical Phenomena , Cells, Cultured , Joint Prosthesis , Male , Materials Testing , Mesenchymal Stem Cells/chemistry , Prosthesis Failure , Rats , Rats, Wistar , Surface Properties
6.
Langmuir ; 30(31): 9466-76, 2014 Aug 12.
Article in English | MEDLINE | ID: mdl-25019516

ABSTRACT

It is well-known that a number of surface characteristics affect the extent of adhesion between two adjacent materials. One of such parameters is the surface roughness as surface asperities at the nanoscale level govern the overall adhesive forces. For example, the extent of bacterial adhesion is determined by the surface topography; also, once a bacteria colonizes a surface, proliferation of that species will take place and a biofilm may form, increasing the resistance of bacterial cells to removal. In this study, borosilicate glass was employed with varying surface roughness and coated with bovine serum albumin (BSA) in order to replicate the protein layer that covers orthopedic devices on implantation. As roughness is a scale-dependent process, relevant scan areas were analyzed using atomic force microscope (AFM) to determine Ra; furthermore, appropriate bacterial species were attached to the tip to measure the adhesion forces between cells and substrates. The bacterial species chosen (Staphylococci and Streptococci) are common pathogens associated with a number of implant related infections that are detrimental to the biomedical devices and patients. Correlation between adhesion forces and surface roughness (Ra) was generally better when the surface roughness was measured through scanned areas with size (2 Ɨ 2 Āµm) comparable to bacteria cells. Furthermore, the BSA coating altered the surface roughness without correlation with the initial values of such parameter; therefore, better correlations were found between adhesion forces and BSA-coated surfaces when actual surface roughness was used instead of the initial (nominal) values. It was also found that BSA induced a more hydrophilic and electron donor characteristic to the surfaces; in agreement with increasing adhesion forces of hydrophilic bacteria (as determined through microbial adhesion to solvents test) on BSA-coated substrates.


Subject(s)
Boron Compounds/chemistry , Silicates/chemistry , Streptococcaceae/chemistry , Streptococcus/chemistry , Animals , Bacterial Adhesion , Cattle , Glass/chemistry , Particle Size , Serum Albumin, Bovine/chemistry , Surface Properties
7.
Colloids Surf A Physicochem Eng Asp ; 460: 83-89, 2014 Oct 20.
Article in English | MEDLINE | ID: mdl-25431523

ABSTRACT

Cold atmospheric plasma (CAP) treatment was used on ultra-high molecular weight polyethylene (UHMWPE), a common articulating counter material employed in hip and knee replacements. UHMWPE is a biocompatible polymer with low friction coefficient, yet does not have robust wear characteristics. CAP effectively cross-links the polymer chains of the UHMWPE improving wear performance (Perni et al., Acta Biomater. 8(3) (2012) 1357). In this work, interactions between CAP treated UHMWPE and spherical borosilicate sphere (representing model material for bone) were considered employing AFM technique. Adhesive forces increased, in the presence of PBS, after treatment with helium and helium/oxygen cold gas plasmas. Furthermore, a more hydrophilic surface of UHMWPE was observed after both treatments, determined through a reduction of up to a third in the contact angles of water. On the other hand, the asperity density also decreased by half, yet the asperity height had a three-fold decrease. This work shows that CAP treatment can be a very effective technique at enhancing the adhesion between bone and UHMWPE implant material as aided by the increased adhesion forces. Moreover, the hydrophilicity of the CAP treated UHMWPE can lead to proteins and cells adhesion to the surface of the implant stimulating osseointegration process.

8.
BMJ Open ; 14(5): e082501, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38719289

ABSTRACT

BACKGROUND: Prosthetic joint infections (PJIs) are a serious negative outcome of arthroplasty with incidence of about 1%. Risk of PJI could depend on local treatment policies and guidelines; no UK-specific risk scoring is currently available. OBJECTIVE: To determine a risk quantification model for the development of PJI using electronic health records. DESIGN: Records in Clinical Practice Research Datalink (CPRD) GOLD and AURUM of patients undergoing hip or knee arthroplasty between January 2007 and December 2014, with linkage to Hospital Episode Statistics and Office of National Statistics, were obtained. Cohorts' characteristics and risk equations through parametric models were developed and compared between the two databases. Pooled cohort risk equations were determined for the UK population and simplified through stepwise selection. RESULTS: After applying the inclusion/exclusion criteria, 174 905 joints (1021 developed PJI) were identified in CPRD AURUM and 48 419 joints (228 developed PJI) in CPRD GOLD. Patients undergoing hip or knee arthroplasty in both databases exhibited different sociodemographic characteristics and medical/drug history. However, the quantification of the impact of such covariates (coefficients of parametric models fitted to the survival curves) on the risk of PJI between the two cohorts was not statistically significant. The log-normal model fitted to the pooled cohorts after stepwise selection had a C-statistic >0.7. CONCLUSIONS: The risk prediction tool developed here could help prevent PJI through identifying modifiable risk factors pre-surgery and identifying the patients most likely to benefit from close monitoring/preventive actions. As derived from the UK population, such tool will help the National Health Service reduce the impact of PJI on its resources and patient lives.


Subject(s)
Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Prosthesis-Related Infections , Humans , Prosthesis-Related Infections/epidemiology , Male , Female , Arthroplasty, Replacement, Knee/adverse effects , United Kingdom/epidemiology , Middle Aged , Retrospective Studies , Aged , Arthroplasty, Replacement, Hip/adverse effects , Risk Factors , Risk Assessment/methods , Databases, Factual , Electronic Health Records , Adult , Aged, 80 and over
9.
J Mater Chem B ; 12(24): 5930-5939, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38804519

ABSTRACT

Osteoarthritis (OA) is a prevalent chronic health condition necessitating effective treatment strategies. Globally, there were 86 million people with incident knee osteoarthritis in 2020. Pain management remains the primary approach to OA as the nature of cartilage poses challenges for drug delivery. An emulsion-based delivery system, using a class of positively charged and hydrolysable polymers (poly-beta-amino-esters) to coat oil droplets containing drugs, has been shown to enhance and prolong drug localization in ex vivo cartilage models. As the properties of the polymers used in this technology strongly depend on the monomers used in the synthesis, this study presents the screening of a wide range of PBAEs as droplet coating agents and using ketorolac as a model of nonsteroidal anti-inflammatory drugs. The emulsions prepared with this PBAE library were characterized, and drug localisation and retention were evaluated in both native and glycosaminoglycan (GAG) depleted cartilage ex vivo models. Optimal candidates were identified and tested in an ex vivo model showing the ability to protect chondrocyte cell viability and increase both GAG and collagen contents in cartilage exposed to cytokine (IL-1α) simulating acute cartilage damage. This work demonstrates the potential of PBAE coated emulsion as a delivery system for effective drug delivery in OA treatment.


Subject(s)
Emulsions , Ketorolac , Polymers , Emulsions/chemistry , Polymers/chemistry , Animals , Ketorolac/chemistry , Ketorolac/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Survival/drug effects , Humans , Chondrocytes/drug effects , Chondrocytes/metabolism , Drug Delivery Systems , Particle Size
10.
RSC Adv ; 14(1): 15-28, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38173598

ABSTRACT

Disease-modifying osteoarthritis drugs (DMOADs) are a new therapeutic class for osteoarthritis (OA) prevention or inhibition of the disease development. Unfortunately, none of the DMOADs have been clinically approved due to their poor therapeutic performances in clinical trials. The joint environment has played a role in this process by limiting the amount of drug effectively delivered as well as the time that the drug stays within the joint space. The current study aimed to improve the delivery of the DMOADs into cartilage tissue by increasing uptake and retention time of the DMOADs within the tissue. Licofelone was used a model DMOAD due to its significant therapeutic effect against OA progression as shown in the recent phase III clinical trial. For this purpose licofelone was covalently conjugated to the two different A16 and A87 poly-beta-amino-ester (PBAEs) polymers taking advantage of their hydrolysable, cytocompatible, and cationic nature. We have shown cartilage uptake of the licofelone-PBAE conjugates increased 18 times and retention in tissues was prolonged by 37 times compared to the equivalent dose of the free licofelone. Additionally, these licofelone conjugates showed no detrimental effect on the chondrocyte viability. In conclusion, the cationic A87 and A16 PBAE polymers increased the amount of licofelone within the cartilage, which could potentially enhance the therapeutic effect and pharmacokinetic performance of this drug and other DMOADs clinically.

11.
Dent Mater ; 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39117500

ABSTRACT

OBJECTIVE: Silica nanoparticles (SNPs) have been extensively studied and used in different dental applications to promote improved physicochemical properties, high substance loading efficiency, in addition to sustained delivery of substances for therapeutic or preventive purposes. Therefore, this study aimed to review the SNPs applications in nanomaterials and nanoformulations in dentistry, discussing their effect on physicochemical properties, biocompatibility and ability to nanocarry bioactive substances. DATA RESOURCES: Literature searches were conducted on PubMed, Web of Science, and Scopus databases to identify studies examining the physicochemical and biological properties of dental materials and formulations containing SNPs. Data extraction was performed by one reviewer and verified by another STUDY SELECTION: A total of 50 were reviewed. In vitro studies reveal that SNPs improved the general properties of dental materials and formulations, such as microhardness, fracture toughness, flexural strength, elastic modulus and surface roughness, in addition to acting as efficient nanocarriers of substances, such as antimicrobial, osteogenic and remineralizing substances, and showed biocompatibility CONCLUSIONS: SNPs are biocompatible, improve properties of dental materials and serve as effective carriers for bioactive substances CLINICAL SIGNIFICANCE: Overall, SNPs are a promising drug delivery system that can improve dental materials biological and physicochemical and aesthetic properties, increasing their longevity and clinical performance. However, more studies are needed to elucidate SNPs short- and long-term effects in the oral cavity, mainly on in vivo and clinical studies, to prove their effectiveness and safety.

12.
PLoS One ; 18(3): e0282709, 2023.
Article in English | MEDLINE | ID: mdl-36943830

ABSTRACT

BACKGROUND: Prosthetic joint infection (PJI) is a serious complication after joint replacement surgery and it is associated with risk of mortality and morbidity along with high direct costs. METHODS: The Clinical Practice Research Datalink (CPRD) data were utilized to quantify PJI incidence after hip or knee replacement up to 5 years after implant and a variety of risk factors related to patient characteristics, medical and treatment history along with characteristics of the original surgery were analyzed through Cox proportional hazard. RESULTS: 221,826 patients (individual joints 283,789) met all the inclusion and exclusion criteria of the study; during the study follow-up period (5 years), 707 and 695 PJIs were diagnosed in hip and knee, respectively. Patients undergoing joint replacement surgery during an unscheduled hospitalization had greater risk of PJI than patients whose surgery was elective; similarly, the risk of developing PJI after a secondary hip or knee replacement was about 4 times greater than after primary arthroplasty when adjusted for all other variables considered. A previous diagnosis of PJI, even in a different joint, increased the risk of a further PJI. Distribution of average LoS per each hospitalization caused by PJI exhibited a right skewed profile with median duration [IQR] duration of 16 days [8-32] and 13 days [7.25-32] for hip and knee, respectively. PJIs causative micro-organisms were dependent on the time between initial surgery and infection offset; early PJI were more likely to be multispecies than later (years after surgery); the identification of Gram- pathogens decreased with increasing post-surgery follow-up. CONCLUSIONS: This study offers a contemporary assessment of the budgetary and capacity (number and duration of hospitalizations along with the number of Accident and Emergency (A&E) visits) posed by PJIs in UK for the national healthcare system (NHS). The results to provide risk management and planning tools to health providers and policy makers in order to fully assess technologies aimed at controlling and preventing PJI. The findings add to the existing evidence-based knowledge surrounding the epidemiology and burden of PJI by quantifying patterns of PJI in patients with a relatively broad set of prevalent comorbidities.


Subject(s)
Arthritis, Infectious , Arthroplasty, Replacement, Hip , Hip Prosthesis , Prosthesis-Related Infections , Humans , Retrospective Studies , Arthroplasty, Replacement, Hip/adverse effects , Arthritis, Infectious/etiology , Hip Prosthesis/adverse effects , Risk Factors , United Kingdom/epidemiology , Prosthesis-Related Infections/epidemiology , Prosthesis-Related Infections/etiology , Prosthesis-Related Infections/prevention & control
13.
Biomater Adv ; 153: 213538, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37390562

ABSTRACT

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 >50Ā 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.


Subject(s)
Bone Cements , Nanocomposites , Nanoparticles , Nanocomposites/chemistry , Bone Cements/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Humans , Animals , Rats , Rats, Wistar , Cell Line, Tumor , Nanoparticles/chemistry , Gentamicins/pharmacology , Orthopedics
14.
Dent Mater ; 39(5): 469-477, 2023 05.
Article in English | MEDLINE | ID: mdl-36934036

ABSTRACT

OBJECTIVE: In this study a dentistry nanocomposite with prolonged antibacterial activity using silica nanoparticles (SNPs) loaded with chlorhexidine (CHX) was developed. METHODS: SNPs were coated with the Layer-by-Layer technique. Dental composites were prepared with organic matrix of BisGMA/TEGDMA and SNPs with or without CHX (0, 10, 20 or 30% w/w). The physicochemical properties of the developed material were evaluated and agar diffusion method was used to test the antibacterial. In addition, the biofilm inhibitory activity of the composites was evaluated against S. mutans. RESULTS: SNPs were rounded with diameters about 50Ā nm, the organic load increased with increasing deposited layers. Material samples with SNPs loaded with CHX (CHX-SNPs) showed the highest values of post-gel volumetric shrinkage, that ranged from 0.3% to 0.81%. Samples containing CHX-SNPs 30% w/w showed the highest values of flexural strength and modulus of elasticity. Only samples containing SNPs-CHX showed growth inhibition against S. mutans, S. mitis and S. gordonii in a concentration-dependent manner. The composites with CHX-SNPs reduced the biofilm formation of S. mutans biofilm at 24Ā h and 72Ā h. SIGNIFICANCE: The nanoparticle studied acted as fillers and did not interfere with the evaluated physicochemical properties while providing antimicrobial activity against streptococci. Therefore, this initial study is a step forward to the synthesis of experimental composites with improved performance using CHX-SNPs.


Subject(s)
Chlorhexidine , Nanoparticles , Chlorhexidine/pharmacology , Chlorhexidine/chemistry , Silicon Dioxide/pharmacology , Silicon Dioxide/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Nanoparticles/chemistry , Streptococcus mutans
15.
Sci Rep ; 12(1): 14215, 2022 08 20.
Article in English | MEDLINE | ID: mdl-35987777

ABSTRACT

Despite the large prevalence of diseases affecting cartilage (e.g. knee osteoarthritis affecting 16% of population globally), no curative treatments are available because of the limited capacity of drugs to localise in such tissue caused by low vascularisation and electrostatic repulsion. While an effective delivery system is sought, the only option is using high drug doses that can lead to systemic side effects. We introduced poly-beta-amino-esters (PBAEs) to effectively deliver drugs into cartilage tissues. PBAEs are copolymer of amines and di-acrylates further end-capped with other amine; therefore encompassing a very large research space for the identification of optimal candidates. In order to accelerate the screening of all possible PBAEs, the results of a small pool of polymers (n = 90) were used to train a variety of machine learning (ML) methods using only polymers properties available in public libraries or estimated from the chemical structure. Bagged multivariate adaptive regression splines (MARS) returned the best predictive performance and was used on the remaining (n = 3915) possible PBAEs resulting in the recognition of pivotal features; a further round of screening was carried out on PBAEs (n = 150) with small variations of structure of the main candidates from the first round. The refinements of such characteristics enabled the identification of a leading candidate predicted to improve drug uptake > 20 folds over conventional clinical treatment; this uptake improvement was also experimentally confirmed. This work highlights the potential of ML to accelerate biomaterials development by efficiently extracting information from a limited experimental dataset thus allowing patients to benefit earlier from a new technology and at a lower price. Such roadmap could also be applied for other drug/materials development where optimisation would normally be approached through combinatorial chemistry.


Subject(s)
Acrylates , Polymers , Acrylates/chemistry , Amines/chemistry , Cartilage , Feasibility Studies , Humans , Machine Learning , Polymers/chemistry
16.
J Mater Chem B ; 9(29): 5837-5847, 2021 07 28.
Article in English | MEDLINE | ID: mdl-34254088

ABSTRACT

Delivering drugs directly into cartilage is still the major challenge in the management and treatment of osteoarthritis (OA) resulting from the aneural, avascular and alymphatic nature of an articular cartilage structure. Progress has been made in the design of drug delivery systems that enhance corticosteroid uptake and retention in cartilage; however also non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for patients affected by OA and a drug delivery system specifically designed for this drug category is currently unavailable. We developed an approach based on the preparation of NSAID oil-in-water emulsions coated with poly-beta-amino-esters (PBAEs) to exploit the cartilage penetrating ability of such polymers and the high solubility of drugs in oil. These emulsions containing different NSAIDs (indomethacin, ketorolac, diclofenac and naproxen) exhibited enhanced and prolonged drug localisation not only in healthy cartilage tissues but also in early-stage OA samples. The critical role of the PBAE layer on oil droplets was established along with the retained biological activity of the drug as glycosaminoglycan (GAG) and collagen degradation induced by interleukin-1 (IL-1) was prevented by the novel technology. Oil-in-water coated emulsions are very flexible and cost-effective drug delivery systems and such an approach presented here could provide a substantial improvement in the therapeutic treatments of OA and thus patients' outcomes.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cartilage, Articular/drug effects , Coated Materials, Biocompatible/chemistry , Osteoarthritis/drug therapy , Polymers/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cattle , Drug Carriers/chemistry , Emulsions/chemistry , Molecular Structure , Particle Size
17.
Sci Rep ; 11(1): 7275, 2021 03 31.
Article in English | MEDLINE | ID: mdl-33790379

ABSTRACT

Light-activated antimicrobial agents (photosensitisers) are promising alternatives to antibiotics for the treatment of skin infections and wounds through antimicrobial photo dynamic therapy (aPDT); utilisation of this technique is still restricted by general low efficacy requiring long exposure time (in the order of tens of minutes) that make the treatment very resource intensive. We report for the first time the possibility of harvesting the cell penetrating properties of poly-beta-amino esters (PBAEs) in combination with toluidine blue O (TBO) to shorten aPDT exposure time. Candidates capable of inactivation rates 30 times quicker than pure TBO were discovered and further improvements through PBAE backbone optimisation could be foreseen. Efficacy of the complexes was PBAE-dependent on a combination of TBO uptake and a newly discovered and unexpected role of PBAEs on reactive species production. Chemometric approach of partial least square regression was employed to assess the critical PBAE properties involved in this newly observed phenomenon in order to elicit a possible mechanism. The superior antimicrobial performance of this new approach benefits from the use of well established, low-cost and safe dye (TBO) coupled with inexpensive, widely tested and biodegradable polymers also known to be safe. Moreover, no adverse cytotoxic effects of the PBAEs adjuvated TBO delivery have been observed on a skin cells in vitro model demonstrating the safety profile of this new technology.


Subject(s)
Anti-Infective Agents/pharmacology , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Polymers/pharmacology , Anti-Infective Agents/chemical synthesis , Biological Transport , Cell Line , Cells, Cultured , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Keratinocytes/drug effects , Keratinocytes/metabolism , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/metabolism , Photosensitizing Agents/chemical synthesis , Polymers/chemical synthesis , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/metabolism , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/metabolism
18.
PLoS One ; 16(9): e0257947, 2021.
Article in English | MEDLINE | ID: mdl-34587194

ABSTRACT

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.


Subject(s)
Bacteria/growth & development , Bone Cements/chemistry , Chlorhexidine/pharmacology , Polymethyl Methacrylate/chemistry , Prosthesis-Related Infections/microbiology , Silicon Dioxide/chemistry , Bacteria/drug effects , Cell Line , Chlorhexidine/chemical synthesis , Chlorhexidine/chemistry , Delayed-Action Preparations , Drug Resistance, Bacterial/drug effects , Humans , Microbial Sensitivity Tests , Microbial Viability , Nanoparticles , Particle Size , Prosthesis-Related Infections/prevention & control
19.
Langmuir ; 26(22): 17028-36, 2010 Nov 16.
Article in English | MEDLINE | ID: mdl-20925373

ABSTRACT

A new approach to the multiasperities contact interaction between two surfaces is presented. Each asperity is individually considered with its own different height and radius of curvature. Different materials, such as polyvinylchlorine (PVC) and stainless steel, are used as model systems. For each of the model materials, a set of asperities was generated using Monte Carlo method. Both asperity heights and radii were based on their statistical distributions experimentally obtained. Contact forces were determined for each asperity at a given distance between the two surfaces, while the deformation of each asperity was calculated according to the Johnson-Kendall-Roberts (JKR) or the Derjaguin-Muller-Toporov (DMT) model (depending on the material). The contribution of each asperity to the overall surface was summed, and the overall contact force was determined. The developed method was validated against contact force measurements obtained with atomic force microscopy (AFM).


Subject(s)
Adhesives/chemistry , Models, Molecular , Microscopy, Atomic Force , Monte Carlo Method , Polyesters/chemistry , Polyvinyls/chemistry , Reproducibility of Results , Stainless Steel/chemistry , Surface Properties
20.
J Mater Sci Mater Med ; 21(2): 815-21, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19784866

ABSTRACT

The adhesion of microbes to catheter surfaces is a serious problem and the resulting infections frequently lead to longer hospitalisation and higher risk for the patient. Several approaches have been developed to produce materials that are less susceptible to microbial colonisation. One such approach is the incorporation of photoactivated compounds, such as Toluidine Blue O (TBO), in the polymeric matrix resulting in 'light-activated antimicrobial materials'. The insertion and removal of catheters can cause tissue damage and patient discomfort through frictional forces; hence the lubricity of a catheter material is also very important. In this work the tribological performance of silicone and polyurethane containing TBO and gold nanoparticles were evaluated using two different surfaces, the inner part of the aorta and the superior vena cava of sheep. Static and kinetic friction coefficients of these materials were measured using a tribometric device developed for in vitro applications using dry materials and those lubricated with blood. It was found that neither the preparation process nor the presence of TBO or gold nanoparticles, had an effect on the friction factors in comparison to those of untreated materials. In all cases, static and kinetic friction coefficients on aorta tissue were higher than those on vena cava due to higher surface roughness of the aorta. The presence of blood as a lubricant resulted in lower friction coefficients.


Subject(s)
Anti-Infective Agents/chemistry , Blood Vessels/physiology , Catheters, Indwelling , Coated Materials, Biocompatible/chemistry , Device Removal/methods , Silicone Elastomers/chemistry , Tolonium Chloride/chemistry , Animals , Anti-Infective Agents/radiation effects , Coated Materials, Biocompatible/radiation effects , Friction , Gold/chemistry , Nanoparticles/chemistry , Photochemistry/methods , Sheep
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