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PMC11278433_p7
PMC11278433
sec[1]/p[0]
2. Materials and Methods
3.34375
biomedical
Review
[ 0.96044921875, 0.0096588134765625, 0.030059814453125 ]
[ 0.0083160400390625, 0.007114410400390625, 0.98388671875, 0.0006070137023925781 ]
This systematic review was conducted following the PRISMA 2020 guidelines and registered to PROSPERO .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p8
PMC11278433
sec[1]/sec[0]/p[0]
2.1. Eligibility Criteria
4.019531
biomedical
Review
[ 0.99755859375, 0.0015268325805664062, 0.0008349418640136719 ]
[ 0.1259765625, 0.0018701553344726562, 0.87158203125, 0.0006165504455566406 ]
The systematic review included randomized trials on patients diagnosed with temporomandibular disorders. A necessary condition was the treatment of TMJ or TMJs with intra-articular NSAID administration. Co-interventions of lower invasiveness, e.g., physiotherapy, and the same invasiveness, e.g., arthrocentesis, were allowed. Protocols involving more invasive interventions, i.e., arthroscopic or open surgery, were excluded. The exclusion resulted from the assumption that the impact of the surgical procedure was more significant than the intra-articular deposition of NSAIDs. It was decided to evaluate the results in 3 categories: quality of life, pain intensity, and mandibular mobility. Due to the desire to conduct a review with the highest evidence, only randomized controlled trials were allowed. Reports not available as a full text in English were excluded ( Table 1 ).
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p9
PMC11278433
sec[1]/sec[1]/p[0]
2.2. Information Sources and Search Strategy
1.81543
biomedical
Study
[ 0.97509765625, 0.0024166107177734375, 0.0224456787109375 ]
[ 0.66162109375, 0.32666015625, 0.0098876953125, 0.0019550323486328125 ]
The Bielefeld Academic Search Engine (BASE), PubMed, and Scopus were used to search medical article databases. Final searches were conducted on 16 June 2024. A follow-up search of the Cochrane Central Register of Controlled Trials was conducted on 4 July 2024.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p10
PMC11278433
sec[1]/sec[1]/p[1]
2.2. Information Sources and Search Strategy
3.169922
biomedical
Study
[ 0.9970703125, 0.0005021095275878906, 0.002277374267578125 ]
[ 0.94287109375, 0.055633544921875, 0.0009722709655761719, 0.0003936290740966797 ]
The search strategy was based on a keyword constituting an essential element of diagnosis (“temporomandibular”) and two sets of keywords defining the intervention. These were a set of keywords for substances from the NSAID group and a set of keywords for the route of administration. Logical alternatives are used within the sets. The single keyword for diagnosis and two keyword sets for intervention were combined conjunctively. The following query was applied to all search engines:
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p11
PMC11278433
sec[1]/sec[1]/p[2]
2.2. Information Sources and Search Strategy
1.986328
biomedical
Other
[ 0.98974609375, 0.004955291748046875, 0.005451202392578125 ]
[ 0.004421234130859375, 0.99365234375, 0.0006351470947265625, 0.0010576248168945312 ]
temporomandibular AND (nsaid OR “non-steroidal anti-inflammatory drug*” OR salicylate OR *profen OR *fenac OR *oxicam OR piroxicam OR ampiroxicam OR meloxicam OR tenoxicam OR droxicam OR lornoxicam OR isoxicam OR phenylbutazone OR *fenamic OR fenamate OR *coxib OR nimesulide) AND (intra-articular OR intraarticular OR intra-cavitary OR intracavitary OR injection OR deposition)
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.714282
PMC11278433_p12
PMC11278433
sec[1]/sec[1]/p[3]
2.2. Information Sources and Search Strategy
1.234375
other
Other
[ 0.433349609375, 0.0034275054931640625, 0.56298828125 ]
[ 0.03411865234375, 0.96044921875, 0.004070281982421875, 0.001255035400390625 ]
No filters available in search engines were used. Search results were exported to source files for citation editors.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278433_p13
PMC11278433
sec[1]/sec[2]/p[0]
2.3. Selection Process
3.814453
biomedical
Study
[ 0.99755859375, 0.0006575584411621094, 0.0018262863159179688 ]
[ 0.99755859375, 0.0017728805541992188, 0.0004036426544189453, 0.0000807642936706543 ]
The identified records were entered into the Rayyan automation tool . Manual deduplication (M.C.) was then performed. In the next stage, two researchers conducted a blind selection of records based on titles and abstracts (K.L. and F.B.). In the case of inconsistency between the judges’ decisions, we promoted the record to the next stage. Cohen’s kappa value expressed the inter-rater agreement (version 22.030, MedCalc Software Ltd., Ostend, Belgium). A full-text assessment was then performed (K.L. and F.B.), where discrepancies were resolved by consensus, with a casting vote of a third researcher (M.C.) if necessary.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278433_p14
PMC11278433
sec[1]/sec[3]/p[0]
2.4. Data Collection Process
2.097656
biomedical
Study
[ 0.97900390625, 0.0024509429931640625, 0.01873779296875 ]
[ 0.94189453125, 0.053802490234375, 0.0032482147216796875, 0.0008759498596191406 ]
Data extraction was performed by a pair of authors (K.L. and F.B.). In the case of discrepancies in the interpretation of the report content or inconsistency of the collected numerical data, the decision was made by consensus, if necessary with a third vote from another author (M.C.). No automation tools were used. Numerical data were tabulated using the Google Workspace package .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p15
PMC11278433
sec[1]/sec[4]/p[0]
2.5. Data Items
3.742188
biomedical
Study
[ 0.99560546875, 0.00394439697265625, 0.000576019287109375 ]
[ 0.9912109375, 0.0080108642578125, 0.00046062469482421875, 0.0003478527069091797 ]
Any quality of life questionnaire was accepted. Pain intensity was assessed only concerning joint pain. When different measurements were available, spontaneous pain intensity scores were preferred. The available data were transformed to a scale of 0–10, regardless of whether they were collected visually or numerically. In the assessment of mandibular mobility, maximum voluntary opening was preferred. In the absence of data, any other type of measurement of vertical mandibular mobility was used. This variable was referred to as maximum mouth opening (MMO).
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p16
PMC11278433
sec[1]/sec[5]/p[0]
2.6. Study Risk of Bias Assessment
3.724609
biomedical
Study
[ 0.9990234375, 0.0004973411560058594, 0.00025200843811035156 ]
[ 0.9873046875, 0.010162353515625, 0.0023059844970703125, 0.00021982192993164062 ]
The risk of bias in the source studies was assessed using RoB 2: A revised Cochrane risk-of-bias tool for randomized trials.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p17
PMC11278433
sec[1]/sec[6]/p[0]
2.7. Effect Measures
3.5
biomedical
Study
[ 0.99755859375, 0.0021266937255859375, 0.0004878044128417969 ]
[ 0.99560546875, 0.004016876220703125, 0.00038051605224609375, 0.00021767616271972656 ]
To measure the effectiveness of injection treatment with intra-articular administration of NSAIDs, the difference in mean changes in the overall health-related quality of life, TMJ pain intensity, and range of mandibular abduction was calculated. The MedCalc software was used (version 22.023, MedCalc Software, Ostend, Belgium).
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p18
PMC11278433
sec[1]/sec[7]/p[0]
2.8. Synthesis Methods
4.058594
biomedical
Study
[ 0.9990234375, 0.0005030632019042969, 0.0002524852752685547 ]
[ 0.99755859375, 0.0004115104675292969, 0.00202178955078125, 0.00008970499038696289 ]
Randomized clinical trials that successfully passed the selection and risk of bias assessment were included in the syntheses. First, numerical data were collected and tabulated. The results were then divided according to the domains assessed: (1) health-related quality of life, (2) articular pain, and (3) range of mandibular motion. Both outcomes from source reports (initial averages and averages after available observation periods) and outcomes obtained from own calculations (differences in averages for individual observation periods) were synthesized. The numerical data described above were visualized in charts. The Google Workspace software and MedCalc (version 22.023, MedCalc Software Ltd., Ostend, Belgium) were used.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p19
PMC11278433
sec[1]/sec[8]/p[0]
2.9. Certainty Assessment
4.039063
biomedical
Study
[ 0.9990234375, 0.0005431175231933594, 0.00022995471954345703 ]
[ 0.99755859375, 0.0004591941833496094, 0.0017557144165039062, 0.0000883340835571289 ]
The quality of evidence was independently determined for each of the outcomes assessed. We included (1) the number of source reports, (2) the results of the risk of bias assessment for these studies, (3) the total size of the patient groups included in these studies, (4) the mean difference between study and control group, and (5) the scale effect expressed as Cohen’s d.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p20
PMC11278433
sec[2]/sec[0]/p[0]
3.1. Study Selection
4.003906
biomedical
Study
[ 0.99853515625, 0.0006809234619140625, 0.00054168701171875 ]
[ 0.99609375, 0.0004291534423828125, 0.00319671630859375, 0.00010639429092407227 ]
The search identified 204 records, of which 113 remained after manual deduplication . The initial selection with an inter-rater agreement of 92% (κ = 0.64) led to the exclusion of another 94 records. The report by Vallon et al. was not retrieved due to the lack of digitization of the paper article . The remaining 18 reports were retrieved as a full text and assessed in detail for compliance with the established eligibility criteria. We tabulated the reports rejected at this stage, specifying the reasons for exclusion ( Table A1 ). Ultimately, six randomized controlled trials were included.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p21
PMC11278433
sec[2]/sec[1]/p[0]
3.2. Study Characteristics
3.986328
biomedical
Review
[ 0.99462890625, 0.0029735565185546875, 0.0022754669189453125 ]
[ 0.021881103515625, 0.001224517822265625, 0.9765625, 0.00040531158447265625 ]
The eligible studies were characterized by various detailed diagnoses for the included patients ( Table 2 ). The number of patients in the research groups in the studies included in the review ranged from 7 to 25, and the number of patients in the control groups ranged from 11 to 75. The NSAIDs used by the researchers included diclofenac, piroxicam, and tenoxicam. Drug volumes administered during one intervention ranged from 1 to 2 mL; the only study that did not specify the drug dose was Yapici-Yavuz et al. . The total number of interventions performed ranged from one to two. Follow-ups usually included a maximum period of 6 months, but an exception to this rule was the study by Raiesian et al. (1-week follow-up) and Gupta et al. (3-month follow-up) .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
PMC11278433_p22
PMC11278433
sec[2]/sec[2]/p[0]
3.3. Risk of Bias in Studies
3.857422
biomedical
Study
[ 0.99951171875, 0.00033593177795410156, 0.00028777122497558594 ]
[ 0.99658203125, 0.0022602081298828125, 0.0009832382202148438, 0.00011199712753295898 ]
The risk of bias was assessed using RoB 2: A revised Cochrane risk-of-bias tool for randomized controlled trials and is presented in Figure 5 and Figure 6 .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p23
PMC11278433
sec[2]/sec[3]/p[0]
3.4. Results of Individual Studies
3.990234
biomedical
Study
[ 0.99853515625, 0.0009412765502929688, 0.0005655288696289062 ]
[ 0.56689453125, 0.0016021728515625, 0.4306640625, 0.0006747245788574219 ]
Each of randomized control trials that were qualified for inclusion in this systematic review successfully passed the risk of bias assessment. Table 3 and Table 4 present numerical results extracted from the content of the report on these studies regarding temporomandibular joint pain and its changes ( Table 3 ) and MMO and its changes ( Table 4 ). For each value from the observation period, the mean difference was calculated relative to the base value of a given variable for a given group of patients.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278433_p24
PMC11278433
sec[2]/sec[4]/p[0]
3.5. Results of Syntheses
2.607422
biomedical
Study
[ 0.99755859375, 0.0008029937744140625, 0.0016126632690429688 ]
[ 0.98486328125, 0.00843048095703125, 0.00618743896484375, 0.00034236907958984375 ]
The available results are synthesized in Table 5 and Table 6 and presented in graphs . The mean differences between the treated and placebo groups were calculated, along with the effect size. Statistically significant results are marked in the tables.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p25
PMC11278433
sec[2]/sec[5]/p[0]
3.6. Certainty of Evidence
4.0625
biomedical
Study
[ 0.9990234375, 0.0007233619689941406, 0.00024139881134033203 ]
[ 0.9765625, 0.00090789794921875, 0.0225372314453125, 0.00020897388458251953 ]
In randomized controlled trials assessing the difference between arthrocentesis alone and arthrocentesis supplemented with NSAID administration, subtle differences in joint pain intensity values were observed ( Table 7 ). For tenoxicam, 4 weeks after the intervention, the differences did not exceed 1 point on a scale of 0–10. The results were contradictory regarding whether a better effect was achieved in the study or control group. In the case of piroxicam, no statistically significant difference was observed between the groups. At this stage, the average pain intensity was negligible in both groups of this study.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p26
PMC11278433
sec[2]/sec[5]/p[1]
3.6. Certainty of Evidence
4.089844
biomedical
Study
[ 0.99755859375, 0.001983642578125, 0.00030541419982910156 ]
[ 0.99755859375, 0.0011453628540039062, 0.0011758804321289062, 0.000186920166015625 ]
Concerning MMO, after 4 weeks of observation, treatment with tenoxicam did not result in statistically significant differences compared to arthrocentesis alone ( Table 8 ). Piroxicam showed a statistically significant increase in MMO by almost 5 mm compared to the control group, with a large effect size. These results are based on only one trial with study and control groups of 11 patients each and some concerns regarding the risk of bias.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
PMC11278433_p27
PMC11278433
sec[3]/p[0]
4. Discussion
4.21875
biomedical
Review
[ 0.998046875, 0.0011415481567382812, 0.0008401870727539062 ]
[ 0.0927734375, 0.0107574462890625, 0.8955078125, 0.0008378028869628906 ]
Tenoxicam and piroxicam are the representatives of oxicams, which belong to NSAIDs. They inhibit both COX-1 and COX-2, thus providing therapeutic and side effects resulting from the properties of these enzymes . These are inflammation and related symptoms’ (e.g., pain) suppression, gastrointestinal and kidney disorders, or development of hematological complications . Piroxicam can be administered orally and intramuscularly and is characterized by a long half-life in the plasma. The drug penetrates the synovial fluid and joint spaces, which is beneficial in the context of articular symptoms treatment . In the case of tenoxicam, the possible routes of administration are: oral, intravenous, intramuscular, and rectal . In the treatment of joint diseases, drugs such as NSAIDs are used, but their prolonged intraoral administration is associated with an increasing risk of side effects’ development . Administered intra-articularly, NSAIDs are expected to act locally and limit or eliminate systemic complications. Piroxicam and tenoxicam are known for eliminating joint pain; therefore, their local administration is examined, i.e., topical or intra-articular .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p28
PMC11278433
sec[3]/p[1]
4. Discussion
3.966797
biomedical
Review
[ 0.998046875, 0.0010662078857421875, 0.0008802413940429688 ]
[ 0.2337646484375, 0.2744140625, 0.49072265625, 0.0011959075927734375 ]
When selecting the method of drug administration, several factors should be taken into account, such as (1) the characteristics of the specific drug, (2) dose adjustment, (3) the administration route, (4) possible addition of other substances to increase the effectiveness of the active one, (5) systemic and local side effects, (6) pharmacokinetic features such as half-life, and (7) the ability to penetrate the selected tissues . The multitude of combinations forces researchers to test those most likely to be effective in the first place . Thanks to high-quality clinical trials and their syntheses, it is possible to focus future research on not only efficient but primarily safe solutions, which causes some of them to be gradually abandoned .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278433_p29
PMC11278433
sec[3]/p[2]
4. Discussion
4.042969
biomedical
Study
[ 0.99951171875, 0.000278472900390625, 0.0003445148468017578 ]
[ 0.95068359375, 0.0005640983581542969, 0.04840087890625, 0.00018107891082763672 ]
Based on an experimental rat study, Kim et al. discussed the intra-articular administration of piroxicam, emphasizing the concentration and retention in the synovial fluid. Cationic nanoparticle usage was proposed, which could extend the duration and effect of the drug in the joint while minimizing the risk of systemic side effects resulting from too rapid entry of piroxicam from the joint into the bloodstream. The concentration of piroxicam after injection with a cationic nanoparticle was higher than when using a drug solution . Ishaq et al. compared the effects of triamcinolone (a glucocorticoid) and piroxicam administered intra-articularly to rats. The histopathological analysis of, among others, chondrocytes, periosteal fibrosis, and perichondrial fibrosis indicates the advantage of piroxicam over triamcinolone in the context of chondroprotection . Another rat study by Park et al. showed better intra-articular than intramuscular piroxicam effectiveness .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p30
PMC11278433
sec[3]/sec[0]/p[0]
4.1. General Interpretation of the Results
3.998047
biomedical
Review
[ 0.994140625, 0.0035915374755859375, 0.0024585723876953125 ]
[ 0.0178375244140625, 0.001232147216796875, 0.98046875, 0.0004029273986816406 ]
In the protocol comparing arthrocentesis followed by tenoxicam administration with joint lavage alone, repeated in three studies, no statistically significant differences in joint pain or the range of jaw abduction were observed, or they were subtle or contradictory . Therefore, in the current state of knowledge, there is no justification for supplementing arthrocentesis with an injection of tenoxicam. The analogous administration of piroxicam showed promising results, albeit in only one study with a small sample size. This systematic review also identified the administration of tenoxicam and diclofenac without prior joint rinsing, showing promise for pain relief over the saline placebo .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278433_p31
PMC11278433
sec[3]/sec[1]/p[0]
4.2. Limitations of the Evidence
3.910156
biomedical
Review
[ 0.99853515625, 0.0009284019470214844, 0.0007009506225585938 ]
[ 0.243408203125, 0.0018262863159179688, 0.75439453125, 0.0005202293395996094 ]
Despite searching numerous medical databases using broad-spectrum engines, a few clinical studies on the administration of NSAIDs into TMJ cavities were identified. Among these studies, only some had a control group and randomization, which limits the evidence. Eligible randomized controlled trials on the treatment of TMJs with intra-articular injections of NSAIDs are highly heterogeneous. The differences among these studies results, among others, from the type of injection protocol used (number of administrations, injectable volume, number of interventions), type of drug administered (tenoxicam, piroxicam, etc.), and co-interventions (non-surgical treatment, arthrocentesis) .
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278433_p32
PMC11278433
sec[3]/sec[2]/p[0]
4.3. Limitations of the Review Processes
2.537109
biomedical
Study
[ 0.99755859375, 0.0007982254028320312, 0.0014705657958984375 ]
[ 0.97119140625, 0.0221099853515625, 0.00620269775390625, 0.0005574226379394531 ]
The query was prepared in English, which excluded papers without keywords, titles, or abstracts in this language. Studies involving more invasive interventions, i.e., intra-articular administration of NSAIDs during arthrocentesis, were excluded due to the desire to evaluate the treatment results quantitatively.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278433_p33
PMC11278433
sec[3]/sec[3]/p[0]
4.4. Implications of the Results
3.964844
biomedical
Review
[ 0.99560546875, 0.002704620361328125, 0.0017633438110351562 ]
[ 0.019622802734375, 0.0018682479858398438, 0.97802734375, 0.00038361549377441406 ]
The combined treatment of temporomandibular disorders consists of many therapeutic interventions, including, but not limited to, psychotherapy, biofeedback, physiotherapy, pharmacotherapy, splint therapy, minimally invasive surgical interventions, including intra-articular injections, and arthroscopic and open surgery . The selection of appropriate therapeutic methods depends on the clinical case and may be challenging . The administration of drugs directly into the TMJ joint cavity seems tempting due to the expected local and rapid effect . However, the intra-TMJ administration of corticosteroids, for example, turned out to be most strongly correlated with the occurrence of complications in injection treatment . Moreover, the current systematic review did not demonstrate the validity of administering local anesthetics to the TMJs . These emphasize the importance of assessing the feasibility of administering NSAIDs via the intra-articular route in clinical practice.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11278433_p34
PMC11278433
sec[4]/p[0]
5. Conclusions
3.123047
biomedical
Other
[ 0.99560546875, 0.0032367706298828125, 0.0013704299926757812 ]
[ 0.040985107421875, 0.53369140625, 0.421875, 0.0031681060791015625 ]
In the current state of knowledge, no conclusive scientific evidence supports the need to inject non-steroidal anti-inflammatory drugs into the temporomandibular joint cavities to relieve joint pain or increase the range of mandibular abduction. Preliminary reports on piroxicam with arthrocentesis and tenoxicam or diclofenac without rinsing warrant further research.
[ "Filip Bliźniak", "Maciej Chęciński", "Kamila Chęcińska", "Karolina Lubecka", "Monika Kamińska", "Mariusz Szuta", "Dariusz Chlubek", "Maciej Sikora" ]
https://doi.org/10.3390/jcm13144056
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p0
PMC11278445
sec[0]/p[0]
1. Introduction
4.121094
biomedical
Study
[ 0.99951171875, 0.00023543834686279297, 0.00042629241943359375 ]
[ 0.935546875, 0.01293182373046875, 0.05120849609375, 0.0003838539123535156 ]
Zirconia (ZrO 2 ) is widely used in restorative dentistry as a framework material or monolithically for single crowns and fixed dental prostheses . Zirconia is a biocompatible oxide ceramic revealing a high fracture toughness and flexural strength . The polycrystalline material can appear in three crystal phases as follows: monoclinic, tetragonal, and cubic, depending on various factors such as the temperature, pressure, and dopants added . At ambient temperatures, pure zirconia stabilizes in the monoclinic phase, while the tetragonal and cubic phases become stable with the addition of dopants with lower valences than zirconium (Zr) to create oxygen anion vacancies . The zirconia used in dentistry as a framework material is mainly stabilized in the tetragonal phase by adding 3 mol% of yttria (Y 2 O 3 ) and is known as 3Y-TZP (3 mol% yttria stabilized tetragonal zirconia polycrystal) .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p1
PMC11278445
sec[0]/p[1]
1. Introduction
3.716797
biomedical
Study
[ 0.7177734375, 0.000896453857421875, 0.28125 ]
[ 0.75146484375, 0.245849609375, 0.0024433135986328125, 0.0003058910369873047 ]
Zirconia exhibits high strength owing to a unique crack-prevention mechanism called transformation toughening . This means that, when stress is applied to 3Y-TZP, the tetragonal crystal phase transforms to monoclinic near the crack tip, forming a transition zone. This phase transformation from tetragonal to monoclinic is accompanied by a volume increase of 3–5%, preventing crack propagation .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p2
PMC11278445
sec[0]/p[2]
1. Introduction
4.015625
biomedical
Study
[ 0.9951171875, 0.00029349327087402344, 0.004444122314453125 ]
[ 0.96875, 0.019195556640625, 0.012115478515625, 0.0001214146614074707 ]
To predict the clinical performance of a restorative material and to suggest the proper indication, mechanical properties such as flexural strength or fracture toughness are measured. However, to determine the flexural strength of zirconia, a wide range of varying methods are available, including the three-point bending test, four-point bending test, and biaxial flexural strength test. To conduct these tests, specimens with specific dimensions are to be prepared. For the three-point bending test, rectangular bars are required, while disc-shaped specimens are needed to measure the biaxial flexural strength . Although there is an ISO 6872 available describing the specimen dimensions, the available blank dimensions of the zirconia material may not fit the proposed dimensions . Additionally, varying laboratory equipment used for processing, polishing, and sintering and various specimen holders used for testing may impair the outcome .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p3
PMC11278445
sec[0]/p[3]
1. Introduction
4.109375
biomedical
Study
[ 0.9638671875, 0.00043773651123046875, 0.03570556640625 ]
[ 0.9951171875, 0.003902435302734375, 0.0008845329284667969, 0.00005799531936645508 ]
It is not known if the strength is affected by the cutting method from the blank by either computer-aided design/computer-aided manufacturing (CAD/CAM) or conventional milling. Additionally, the strength is highly sensitive to the applied polishing procedure as polishing removes microcracks within the superficial layer and consequently increases strength . To polish the specimen surface according to ISO 6872, it is suggested to use a diamond grinding wheel (grain size: 30 μm to 40 μm) and a diamond suspension (grain size: 15 μm to 20 μm) . However, the testing of machined specimens is also possible if the shape and dimensions meet specifications. Additionally, chamfering along the long axis of the three-point bending specimens to minimize grinding damage or chipping is recommended . A previous flexural strength test with a 3-TZP material has shown that even though polishing steps are followed according to a pre-defined protocol, variances in flexural strength were severe among the 12 included laboratories .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11278445_p4
PMC11278445
sec[0]/p[4]
1. Introduction
4.15625
biomedical
Study
[ 0.98583984375, 0.0006837844848632812, 0.0133819580078125 ]
[ 0.99951171875, 0.0002658367156982422, 0.00021398067474365234, 0.0000330805778503418 ]
The specimen preparation of 3Y-TZP for flexural strength measurements seems to be highly sensitive to various factors, and guidance is needed on how specimens should be prepared to achieve the highest strength values. The aim of this study was to evaluate how the cutting method, surface treatment, and strength test affect the flexural strength values of 3Y-TZP. The flexural strength of 3Y-TZP was obtained on specimens prepared for three-point bending and biaxial flexural strength tests that were either produced with CAD/CAM or conventionally milled with three different surface treatments (machined, ground, polished). As an additional outcome, it was tested if chamfering the edges of three-point bending test specimens increases the strength. The research hypotheses were that (1) there is no difference between cutting methods in flexural strength, (2) the flexural strength increases with additional polishing steps, and (3) there is no difference in the flexural strength between three-point bending non-chamfered, chamfered, and biaxial flexural strength tests.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p5
PMC11278445
sec[1]/p[0]
2. Materials and Methods
4.023438
biomedical
Study
[ 0.9892578125, 0.0004589557647705078, 0.010345458984375 ]
[ 0.99951171875, 0.0005116462707519531, 0.00011032819747924805, 0.00003731250762939453 ]
The flexural strength of 3Y-TZP (VITA YZ HT; VITA; Bad Säckingen, Germany) was determined by using either a three-point bending strength test set-up or a biaxial flexural strength test with three different surface treatments (machined, ground, polished). For the 3-point bending test, it was tested if chamfering the edges of the bar-shaped specimens influences the flexural strength. Specimens for the CAD/CAM group were prepared using circular discs (ø 98.4 mm × 14 mm), while conventional specimens were prepared using rectangular blocks (40/19). The zirconia discs and blocks were from the same batch. The test set-up of the different groups of specimens as per the specific cutting method, test method, and surface treatment applied is displayed below .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p6
PMC11278445
sec[1]/sec[0]/sec[0]/p[0]
2.1.1. Three-Point Bending Test
4.078125
biomedical
Study
[ 0.99658203125, 0.0004112720489501953, 0.002887725830078125 ]
[ 0.99755859375, 0.0023365020751953125, 0.00014674663543701172, 0.00006383657455444336 ]
For the specimen preparation for the 3-point bending test, the bar-shaped dimensions of the final dimensions after the sintering and surface treatments of 4.0 mm × 20.0 mm × 1.2 mm (±0.1 mm) were prepared by either CAD/CAM or conventional milling with a wire saw. For the CAD/CAM group, bars were virtually designed overdimensionally (Meshmixer V 3.5; Autodesk Inc., San Francisco, CA, USA). The stereolithography (STL) file was nested for CAM and milled with 4 rods at the end of each bar.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11278445_p7
PMC11278445
sec[1]/sec[0]/sec[0]/p[1]
2.1.1. Three-Point Bending Test
4.074219
biomedical
Study
[ 0.998046875, 0.0007047653198242188, 0.0012884140014648438 ]
[ 0.99951171875, 0.0004940032958984375, 0.00013387203216552734, 0.00005346536636352539 ]
For the conventional processing group, specimens were milled with a diamond wire saw machine (wire 0.28 mm; Well Walter Ebner; Le Locle, Switzerland) under constant water irrigation to obtain square cross-sections of 20 mm × 19 mm × 15 mm that were consequently sectioned to the specimen dimension. The blocks were therefore fixed on the holder using sculpting wax (Esprit; al dente; Goslar; Germany). To test the effect of chamfering the edges, all groups were produced in duplicates and, before sintering, the chamfering of the edges of 0.1 mm of the treated surface was conducted with silicon carbide paper grit 1200 (Struers; Ballerup, Denmark) for half of the specimens ( n = 15 per group).
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p8
PMC11278445
sec[1]/sec[0]/sec[1]/p[0]
2.1.2. Biaxial Flexural Strength Test
3.992188
biomedical
Study
[ 0.998046875, 0.0008397102355957031, 0.0013132095336914062 ]
[ 0.99658203125, 0.003116607666015625, 0.0001361370086669922, 0.000118255615234375 ]
For the group CAD/CAM, disc-shaped specimens with a final diameter of 12.5 mm and a height of 1.2 mm after sintering and surface treatment were produced. STL files were nested and milled with 3 supporting rods per specimen as described above. For the group conventional processing, milling round disc-shaped specimens out of rectangular blocks with the diamond saw was not possible; therefore, it was decided to use rectangular dimensions of 12.0 mm × 12.0 mm × 1.2 mm as previously described . Blocks were mounted on the holders of the diamond wire saw (Well Walter Ebner) and cut as above for the 3-point bending test specimens.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p9
PMC11278445
sec[1]/sec[1]/p[0]
2.2. Surface Treatments
3.839844
biomedical
Study
[ 0.99462890625, 0.0006871223449707031, 0.004817962646484375 ]
[ 0.9609375, 0.0384521484375, 0.0003185272216796875, 0.00019025802612304688 ]
All prepared specimens were divided into the following groups for further surface treatments: Machined (M): No surface treatment was applied after cutting the specimens. Ground (G): Manual grinding was carried out with silicon carbide paper grit 1200 without water-cooling before sintering. Polished (P): Manual grinding was performed with silicon carbide paper grit 1200 (without water-cooling), followed by grit 2500 and grit 4000 with water-cooling using a polishing machine (Minitech 363; Presi SA; Eybens, France). After sintering, additional polishing was conducted using diamond paste (6 µm; Presi SA) on a silicon cloth (DP-Nap; Struers) mounted on a polishing machine (Labopol 5; Struers).
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p10
PMC11278445
sec[1]/sec[2]/p[0]
2.3. Sintering
3.851563
biomedical
Study
[ 0.982421875, 0.0008597373962402344, 0.0168914794921875 ]
[ 0.86279296875, 0.136474609375, 0.00057220458984375, 0.0002923011779785156 ]
Before sintering, the specimens were stored in a drying oven (Biostar Ministar; Scheu Dental; Iserlohn, Germany) for 30 min. Sintering was conducted with the following parameters: the sintering oven was heated at a rate of 17 °C for 47 min until 1000 °C. It was then again heated at a rate of 17 °C for 26 min to reach 1450 °C, and then the furnace was left at this temperature for 2 h. Then, it was cooled down to 1200 °C, to 900 °C, and finally to 200 °C with a total time taken of 3 h 13 min.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11278445_p11
PMC11278445
sec[1]/sec[3]/p[0]
2.4. Flexural Strength Testing
4.140625
biomedical
Study
[ 0.99462890625, 0.00040721893310546875, 0.005130767822265625 ]
[ 0.99853515625, 0.0013637542724609375, 0.00022840499877929688, 0.00004178285598754883 ]
The 3-point bending and biaxial flexural strength testing was carried out according to ISO 6872 . Each specimen dimension was recorded using a Digital Caliper, (TESA-Cal IP 67; TESA, Renes, Switzerland, accuracy: ±0.03 mm). The parallelism of the specimens were checked visually, and non-parallel specimens were prepared again. The holding device for 3-point bending tests consisted of support rollers (1.5 mm in diameter), arranged with a span of 12.0 mm. The force was applied midway between the two support rollers via a third roller (1.5 mm in diameter). The test specimens were placed with the pre-treated surface facing the two support rollers in the device and loaded until fracture with a cross-head speed of 1 mm/min with a universal testing machine (Z020; Zwick/Roell, Ulm, Germany). The flexural strength σ was calculated in MPa using the following equation: σ = 3Fl/2wb 2 . where
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p12
PMC11278445
sec[1]/sec[3]/p[1]
2.4. Flexural Strength Testing
1.257813
other
Other
[ 0.46142578125, 0.0030517578125, 0.53564453125 ]
[ 0.039794921875, 0.95703125, 0.0022716522216796875, 0.0010366439819335938 ]
F is the breaking force in N.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p13
PMC11278445
sec[1]/sec[3]/p[2]
2.4. Flexural Strength Testing
1.899414
biomedical
Other
[ 0.69921875, 0.002712249755859375, 0.2978515625 ]
[ 0.07000732421875, 0.9287109375, 0.0006017684936523438, 0.0006456375122070312 ]
l is the test span (center distance between the support rollers) in mm (=12.0 mm),
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p14
PMC11278445
sec[1]/sec[3]/p[3]
2.4. Flexural Strength Testing
1.775391
biomedical
Other
[ 0.7724609375, 0.0021190643310546875, 0.2252197265625 ]
[ 0.14501953125, 0.85302734375, 0.0012407302856445312, 0.0007333755493164062 ]
w is the width of the test specimen in mm,
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p15
PMC11278445
sec[1]/sec[3]/p[4]
2.4. Flexural Strength Testing
1.451172
biomedical
Other
[ 0.5390625, 0.0036029815673828125, 0.45751953125 ]
[ 0.1572265625, 0.83740234375, 0.003559112548828125, 0.001758575439453125 ]
b is the thickness of the test specimen.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p16
PMC11278445
sec[1]/sec[3]/p[5]
2.4. Flexural Strength Testing
4.015625
biomedical
Study
[ 0.9482421875, 0.0005431175231933594, 0.050994873046875 ]
[ 0.99169921875, 0.0081787109375, 0.0002110004425048828, 0.00006628036499023438 ]
The specimen holder for the biaxial flexural strength test comprised three tempered steel balls with a diameter of 3.2 mm. The steel balls formed an equilateral triangle with an edge length of 10 mm, and the ball support circle was 120°. The specimens were placed with the surface-treated side facing towards the steel balls in the holder. After the positioning, the specimens’ center was loaded from above with a plunger of tempered steel with a diameter of 1.4 mm until failure with a cross-head speed of 1 mm/min in a universal testing machine (Z020; Zwick/Roell).
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p17
PMC11278445
sec[1]/sec[3]/p[6]
2.4. Flexural Strength Testing
3.214844
biomedical
Study
[ 0.955078125, 0.000514984130859375, 0.04461669921875 ]
[ 0.78662109375, 0.212158203125, 0.0007786750793457031, 0.0002911090850830078 ]
The flexural strength was calculated according to the following equation: σ = −0.2387 F(X − Y)/d 2 . where
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
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https://creativecommons.org/licenses/by/4.0/
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0.999998
PMC11278445_p18
PMC11278445
sec[1]/sec[3]/p[7]
2.4. Flexural Strength Testing
1.917969
other
Other
[ 0.458251953125, 0.0023212432861328125, 0.53955078125 ]
[ 0.10943603515625, 0.8876953125, 0.001834869384765625, 0.0008420944213867188 ]
σ is the biaxial flexural strength,
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p19
PMC11278445
sec[1]/sec[3]/p[8]
2.4. Flexural Strength Testing
1.378906
biomedical
Other
[ 0.52197265625, 0.00241851806640625, 0.475341796875 ]
[ 0.075439453125, 0.9208984375, 0.0026836395263671875, 0.001071929931640625 ]
F is the breaking force in N,
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p20
PMC11278445
sec[1]/sec[3]/p[9]
2.4. Flexural Strength Testing
2.306641
biomedical
Other
[ 0.8935546875, 0.0009751319885253906, 0.1053466796875 ]
[ 0.1422119140625, 0.8564453125, 0.0009870529174804688, 0.000537872314453125 ]
coefficients X and Y with X = (1 + υ) ln[(r 2 /r 3 )] 2 + [(1 − υ)/2] (r 2 /r 3 ) 2 . Y = (1 + υ) [1 + ln(r 1 /r 3 ) 2 ] + (1 − υ) (r 1 /r 3 ) 2 . where
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
cy
0.85714
PMC11278445_p21
PMC11278445
sec[1]/sec[3]/p[10]
2.4. Flexural Strength Testing
2.494141
biomedical
Other
[ 0.96630859375, 0.0011768341064453125, 0.032440185546875 ]
[ 0.19775390625, 0.7998046875, 0.0014734268188476562, 0.0010004043579101562 ]
υ is the Poisson’s ratio (=0.25),
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p22
PMC11278445
sec[1]/sec[3]/p[11]
2.4. Flexural Strength Testing
2.097656
biomedical
Other
[ 0.88037109375, 0.00244903564453125, 0.11724853515625 ]
[ 0.2100830078125, 0.7880859375, 0.0008549690246582031, 0.0010251998901367188 ]
r 1 is the support (mean) contact diameter (mm) (=10.0 mm),
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
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0.999996
PMC11278445_p23
PMC11278445
sec[1]/sec[3]/p[12]
2.4. Flexural Strength Testing
2.291016
biomedical
Other
[ 0.89990234375, 0.0016641616821289062, 0.09820556640625 ]
[ 0.360107421875, 0.63818359375, 0.001003265380859375, 0.0009279251098632812 ]
r 2 is the (mean) loaded contact diameter (mm) (=1.4 mm),
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p24
PMC11278445
sec[1]/sec[3]/p[13]
2.4. Flexural Strength Testing
1.96875
biomedical
Other
[ 0.888671875, 0.0016984939575195312, 0.10968017578125 ]
[ 0.271728515625, 0.72607421875, 0.0013580322265625, 0.0009279251098632812 ]
r 3 is the diameter of the specimen (mm) (=12.5 mm),
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p25
PMC11278445
sec[1]/sec[3]/p[14]
2.4. Flexural Strength Testing
1.453125
biomedical
Other
[ 0.67236328125, 0.0035457611083984375, 0.323974609375 ]
[ 0.09674072265625, 0.8974609375, 0.004116058349609375, 0.0018329620361328125 ]
d is the thickness.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p26
PMC11278445
sec[1]/sec[4]/sec[0]/p[0]
2.5.1. Surface Roughness
3.810547
biomedical
Study
[ 0.99755859375, 0.00024771690368652344, 0.002300262451171875 ]
[ 0.99853515625, 0.0011005401611328125, 0.00021255016326904297, 0.000048279762268066406 ]
Surface roughness parameters were obtained for each specimen with a 3D laser scanning microscope . The surface roughness parameters Sa (arithmetical mean height) and Sz (maximum height) were analyzed using ×20 objective and laser light (intensity) over an area of 2500 µm × 1500 µm.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p27
PMC11278445
sec[1]/sec[4]/sec[1]/p[0]
2.5.2. Scanning Electron Microscopy
4.039063
biomedical
Study
[ 0.99853515625, 0.00018644332885742188, 0.001155853271484375 ]
[ 0.998046875, 0.0015411376953125, 0.0002460479736328125, 0.000051140785217285156 ]
Scanning electron microscopy (SEM) (XL-30 ESEM; Philips, Eindhoven, The Netherlands) was used to visualize the microstructure and topography of the specimens from each group. Before SEM, specimens were sputtered with gold (SCD 005 Sputter Coating Unit; BalTec, Pfäffikon, Switzerland). Imaging was performed at an acceleration of 20 kV and magnifications of ×500, ×2000, ×5000, and ×10,000.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p28
PMC11278445
sec[1]/sec[5]/p[0]
2.6. Statistical Analysis
4.085938
biomedical
Study
[ 0.984375, 0.00034928321838378906, 0.01551055908203125 ]
[ 0.9990234375, 0.000579833984375, 0.00017559528350830078, 0.0000286102294921875 ]
The specimen size was chosen according to ISO 6872 . To describe the reliability of the specimens, Weibull two-parameter distribution was applied to all flexural strength data according to ISO 6872 . The Weibull modulus and Weibull characteristic strength were calculated. Mean and standard deviations were calculated for the flexural strength measurements, as well as the surface roughness values (Sa, Sz). Strength data were tested for normal distribution using the Shapiro–Wilk test. Three-way ANOVA followed by a Bonferroni post hoc test was applied to analyze the effects of the specimen processing method, surface treatment, and flexural strength test method on the flexural strength values (α = 0.05) (StatPlus Pro V6 ; AnalystSoft; Walnut, CA, USA).
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p29
PMC11278445
sec[2]/sec[0]/p[0]
3.1. Flexural Strength
4.121094
biomedical
Study
[ 0.99853515625, 0.0004622936248779297, 0.0009899139404296875 ]
[ 0.99951171875, 0.00016117095947265625, 0.00032401084899902344, 0.00004017353057861328 ]
The overall flexural strength values for specimens processed by CAD/CAM (929 ± 172 MPa) were significantly higher than for the conventional specimens (871 ± 209 MPa) ( p < 0.001). However, within the sub-groups, only values within the three-point bending test non-chamfered group were significantly higher ( p < 0.001), and no difference was found within the three-point bending test chamfered ( p = 0.570) and the biaxial flexural strength test ( p = 0.238) groups. The surface treatment also affected the flexural strength significantly ( p < 0.001), with the highest values for polished followed by ground (910 ± 189 MPa) and machined surfaces (778 ± 148 MPa). Overall, significantly higher flexural strength values were obtained when using the biaxial flexural strength test than when using the three-point bending strength test with chamfered specimens (884 ± 151 MPa) and non-chamfered specimens (800 ± 196 MPa) (all p < 0.001) ( Table 1 and Table 2 ).
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11278445_p30
PMC11278445
sec[2]/sec[0]/p[1]
3.1. Flexural Strength
4.117188
biomedical
Study
[ 0.998046875, 0.0003116130828857422, 0.0014858245849609375 ]
[ 0.99951171875, 0.000324249267578125, 0.00025916099548339844, 0.00003451108932495117 ]
High Weibull modulus values are an indicator of high reliability and, therefore, even the distribution of defects within the specimen volume. The highest values were observed for CAD/CAM specimens that were polished for all three-point bending test non-chamfered (Weibull modulus 6.98) and chamfered (Weibull modulus 6.96) groups, as well as biaxial flexural strength (Weibull modulus 7.10) groups. For specimens of the three-point bending test that were not chamfered, additional surface treatment severely improved Weibull modulus values, especially for conventionally processed specimens. Weibull modulus values were highest overall when conducting the biaxial flexural strength test, followed by the three-point bending test with chamfered specimens and the three-point bending test with non-chamfered specimens .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p31
PMC11278445
sec[2]/sec[1]/p[0]
3.2. Surface Characterization
3.326172
biomedical
Study
[ 0.955078125, 0.0006623268127441406, 0.044403076171875 ]
[ 0.99853515625, 0.0011587142944335938, 0.0002275705337524414, 0.000053822994232177734 ]
The linear correlation between the mean values of surface roughness Sa and mean flexural strength values was weak (R 2 = 0.164). Overall, the Sa and Sz decreased with additional polishing steps ( Table 3 ).
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p32
PMC11278445
sec[2]/sec[1]/p[1]
3.2. Surface Characterization
4.113281
biomedical
Study
[ 0.9853515625, 0.00040268898010253906, 0.0140533447265625 ]
[ 0.9990234375, 0.0005702972412109375, 0.00022995471954345703, 0.000039696693420410156 ]
The surface topography of specimens for three-point bending and biaxial flexural strength tests displayed a similar surface topography; therefore, only SEM images for three-point bending are displayed at ×500 and ×10,000 . Machined surfaces revealed anisotropic topographies with aligned grooves. On ground surfaces, grooves appeared less deep and were not oriented. Polished surfaces seemed smooth with hardly visible grooves in SEM images captured at ×500 . Crystal growth is visible on all surfaces, occurring when a threshold temperature is exceeded during sintering . The boundaries of the individual grains were fused on polished surfaces, especially on CAD/CAM-processed specimens’ topographies.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p33
PMC11278445
sec[3]/p[0]
4. Discussion
4.125
biomedical
Study
[ 0.9990234375, 0.0005984306335449219, 0.0005712509155273438 ]
[ 0.99951171875, 0.0002028942108154297, 0.00040602684020996094, 0.00006222724914550781 ]
Measuring the flexural strength of restorative dental materials such as zirconia is crucial for providing the proper indication for clinical use and predicting their respective performance. As a great variety exists among laboratories regarding the specimen preparation protocols, the present in vitro study evaluated how the cutting method, surface treatment, and applied strength testing affect flexural strength values of 3Y-TZP. A higher flexural strength overall was achieved with specimens prepared using CAD/CAM; however, differences within the test methods were only significant for non-chamfered specimens of the three-point bending test. Therefore, the first hypothesis of this study was partially rejected. The second hypothesis, stating that the flexural strength increases with additional polishing steps, was confirmed for all groups. The flexural strength obtained with the test method biaxial flexural strength showed significantly higher values, followed by the three-point bending test using chamfered specimens, resulting in a rejection of the third hypothesis.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
PMC11278445_p34
PMC11278445
sec[3]/p[1]
4. Discussion
4.210938
biomedical
Study
[ 0.9990234375, 0.00041794776916503906, 0.0005769729614257812 ]
[ 0.9990234375, 0.0003631114959716797, 0.0005917549133300781, 0.00006574392318725586 ]
According to the ISO 6872 for ceramic materials in dentistry, zirconia is a type II ceramic and is further divided into a class between 1 and 5, based on the flexural strength and chemical solubility that determine the clinical indication . For fixed dental prosthesis (FDPs) up to three units in the anterior and premolar region, a flexural strength of 300 MPa is required (class 3), while for FDPs in the molar region, 500 MPa is needed (class 4). FDPs with more than three units necessitate a strength higher than 800 MPa (class 5). The chemical solubility is to be <100 µg/cm 2 . However, ISO 6872 allows the manufacturer to select any standard specimen geometry for the flexural strength testing of ceramics. If the tested material achieves a satisfactory mean strength value with any of the described flexural strength test methods, then the product passes the requirements. This study revealed that the mean flexural strength values can vary from 612 to 1143 MPa for the same 3Y-TZP depending on specimen processing, surface treatment, and the applied testing methods. Zirconia is a brittle material that is highly sensitive to flaws in processing and needs to be handled with great care for restorations in order to not impair its mechanical strength . The manufacturer approved the 3Y-TZP tested in the present study as a class 5 material with a strength of 1200 MPa (three-point bending test chamfered), as depicted in the respective scientific information sheet, and reported a Weibull modulus of 14. The obtained mean flexural strength value for polished and chamfered three-point bending test specimens in this study was 990 MPa with a Weibull modulus of 7. Previous studies reported flexural strength values of 1155 ± 88 (CAD/CAM, machined, three-point bending test, non-chamfered) , 1106 ± 97 MPa (conventional, polished, three-point bending test, chamfered plus heat-treatment) , and 1170 ± 63 MPa (CAD/CAM, machined, biaxial flexural strength) for the same 3Y-TZP. Values within this range in the present study were measured for the CAD/CAM group, where the surface of the specimens were polished, and biaxial flexural strength testing performed. This was also the group achieving the highest strength overall.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p35
PMC11278445
sec[3]/p[2]
4. Discussion
4.015625
biomedical
Study
[ 0.97412109375, 0.0005211830139160156, 0.0253143310546875 ]
[ 0.99951171875, 0.00029587745666503906, 0.00018477439880371094, 0.00003629922866821289 ]
In the present study, it was highlighted that the specimen processing, surface treatment, as well as the applied strength test method clearly affect the measurements. The interaction between specimen processing and surface treatment as well as the strength test method was significant ( Table 1 ), meaning that specimen processing seems to be the most important factor affecting the flexural strength values. Hence, as each laboratory is conducting the strength measurements with slightly different approaches, and due to the high sensitivity of zirconia to defects in the pre-sintered state, varying strength values are to be expected .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
PMC11278445_p36
PMC11278445
sec[3]/p[3]
4. Discussion
4.199219
biomedical
Study
[ 0.99853515625, 0.00035309791564941406, 0.0010423660278320312 ]
[ 0.994140625, 0.00047206878662109375, 0.00554656982421875, 0.00007128715515136719 ]
Overall, preparation with CAD/CAM has shown to provide more reliable results than conventional milling as specimen grinding is automated. Flaws may occur during the fixation of the specimens on the milling holders, and the effect of water-cooling is still unclear. However, the available zirconia blank dimensions and milling machines may disable CAD/CAM specimen processing according to the recommended dimensions . To obtain the flexural strength of zirconia available in discs, the most reliable and convenient method for providing the highest flexural strength values is the processing of disc-shaped specimens using CAD/CAM, polishing the surfaces, and testing these with biaxial flexural strength tests. For zirconia materials that are only available as blocks, conventional milling into square discs that are used for biaxial flexural strength testing as previously suggested is an alternative option, providing higher flexural strength values than when three-point bending tests are applied for these specimens. When the three-point bending test is chosen, producing specimens with CAD/CAM is encouraged, followed by polishing and chamfering to minimize edge defects and consequently increase flexural strength values. The result that higher flexural strength values were achieved with biaxial flexural strength testing compared to the three-point bending testing of specimens was confirmed in previous studies with 3Y-TZP . Bar-shaped specimens that are used for the three-point bending strength test often have edge flaws, acting as stress concentration sites that lead to failure. For the biaxial flexural strength testing of specimens, edge flaws are not relevant as fractures originate from the material’s intrinsic flaws or polishing scratches . Additionally, biaxial flexural strength specimens have a smaller effective volume, meaning that the volume under stress during loading is smaller than for the three-point bending test specimens.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
PMC11278445_p37
PMC11278445
sec[3]/p[4]
4. Discussion
4.203125
biomedical
Study
[ 0.998046875, 0.00041413307189941406, 0.0017099380493164062 ]
[ 0.99951171875, 0.0001608133316040039, 0.0003514289855957031, 0.000043451786041259766 ]
Previously, a round-robin test with the biaxial flexural strength testing of zirconia at 12 different laboratories was conducted . The specimens were CAD/CAM-ground at the same location out of a zirconia disc, and only the sintering and polishing steps were conducted at different laboratories. Large variations in flexural strength may have occurred due to the varying sintering parameters of the available furnaces at the other laboratories for machined specimens. The flexural strength was increased overall when specimens were polished, as observed in the present study. The monoclinic phase content that is induced by grinding during CAD/CAM is partially reverted by polishing . Hence, the presence of the tetragonal phase is consequently increased, and the effect of phase transformation toughening may increase the strength of 3Y-TZP. In SEM images , it is also visible that the polishing procedure partially fused the crystal grain boundaries, eliminating potential crack initiation points. In the round-robin test with polished specimens, variations in flexural strength among laboratories were even larger than for machined specimens. This was probably due to the additional processing step that was performed slightly differently at the laboratories, with an apparent effect on flexural strength . Specimen handling, especially in the sensitive pre-sintered state of zirconia, force application during polishing, and varying polishing protocols among laboratories are difficult to standardize due to the available equipment. After conducting this study, an automated polishing machine was acquired (Tegramin; Struers), and CAD/CAM-processed specimens of the same material were polished in fixable holders for a standardized pressure application using diamond suspensions of 9 µm, 3 µm, and 1 µm after sintering. Using this automated polishing protocol, the surface roughness was lowered to Sa of 0.09 µm, and the flexural strength values and reliability increased for biaxial flexural strength specimens , but remained similar for three-point bending test specimens that were chamfered .
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278445_p38
PMC11278445
sec[3]/p[5]
4. Discussion
4.097656
biomedical
Study
[ 0.9833984375, 0.0004334449768066406, 0.016326904296875 ]
[ 0.99951171875, 0.0003192424774169922, 0.0002294778823852539, 0.00003427267074584961 ]
Although the surface roughness decreased with additional polishing steps, no linear correlation was found between flexural strength values and surface roughness parameters Sa and Sz. This finding was confirmed in a previous study for biaxial flexural strength values of conventionally milled specimens that were ground, polished, or glazed, as well as within the round-robin test . It needs to be emphasized that surface roughness parameters Sa and Sz provide only limited information on the actual surface topography of the specimens that potentially influences flexural strength. Additionally, 3Y-TZP is an unpredictable material with its phase transformation capability that is affected by numerous additional factors, such as the particle size of the pre-sintered material, heat treatment, or surface treatments that all have an impact on the materials’ surface and mechanical behavior.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
PMC11278445_p39
PMC11278445
sec[4]/p[0]
5. Conclusions
4.097656
biomedical
Study
[ 0.99853515625, 0.0005588531494140625, 0.0009431838989257812 ]
[ 0.9990234375, 0.00043201446533203125, 0.00036597251892089844, 0.00006222724914550781 ]
Based on the results of this in vitro study, the following conclusions were drawn: Specimens processed by CAD/CAM rather than conventional milling result in higher flexural strength values, especially with non-chamfered bar-shaped specimens measured using the three-point bending test. Polishing procedures are to be applied to increase the flexural strength of specimens. Biaxial flexural strength testing results in significantly higher flexural strength values than a three-point bending testing method. For three-point bending tests, the chamfering of specimens is recommended to reduce edge defects and consequently increase flexural strength values.
[ "Nashib Pandey", "Sabrina Karlin", "Michael Marc Bornstein", "Nadja Rohr" ]
https://doi.org/10.3390/ma17143479
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p0
39057309
sec[0]/p[0]
1. Introduction
4.191406
biomedical
Study
[ 0.99853515625, 0.0007729530334472656, 0.0004930496215820312 ]
[ 0.62353515625, 0.0021495819091796875, 0.373779296875, 0.0006670951843261719 ]
Over the past few years, nanotechnology has been developing rapidly, and nanomaterials have shown a wide range of applications in the field of biomedical science, including drug delivery, biological imaging, and tumor treatment. Nanomaterials can be categorized into organic and inorganic types. Organic nanomaterials encompass lipid nanoparticles (NPs) (such as liposomes) and polymer NPs (such as chitosan). Inorganic nanomaterials include metal NPs (gold, silver, zinc oxide, etc.) and non-metallic nanomaterials (such as silica, carbon nanotubes, etc.). The physical and chemical properties of NPs, such as morphology, particle size, hardness, surface charge, and functional groups, vary widely. However, what they have in common is that most NPs enter the body along the venous route and work within the circulatory system, resulting in interactions between NPs and blood components. Furthermore, due to their small particle size, NPs can easily cross various physiological barriers and are distributed throughout the body before entering cells through various mechanisms such as macropinocytosis, caveolin-mediated endocytosis, and clathrin-mediated endocytosis . The adverse effects of NPs on red blood cells in structure, function, and in vivo circulation time after entering the circulatory system have been investigated . However, the physicochemical properties of platelets are complex, and NPs can influence their physiological function through various pathways, so that the effects vary depending on the size, type, and charges of NPs. Here we focus on the relationships between the physical and chemical properties of NPs and their biocompatibility with platelets in order to draw our own conclusions and facilitate the design of nanomedicines that are likely to reduce the toxic and side effects on organisms.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
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1. Introduction
4.300781
biomedical
Study
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Although platelets are the smallest of the blood cells, they are among the active components that nanomedicines encounter early in the human circulatory system. Platelets are produced by megakaryocytes and have a length of 1.5~4 μm and a width of 0.5~2 μm. Some are oval or disc-shaped, while others have a rhombus or irregular shape. Platelets do not have a cell nucleus but contain cellular organelles, and their internal structure contains scattered granular components such as α granules and dense granules. The lifespan of platelets in the human body averages 7 to 14 days. Platelets are normally in a resting state, but they can be activated by physiological and pathological factors before aggregation, release, and adherence upon stimulation. Platelets can be stored in a platelet thermostatic oscillator at 22 °C for five to seven days . However, the function and progressive activation of platelets can diminish during storage. It has been found that zinc oxide NPs can reduce the potential of thrombin production , while silver NPs possess an inherent anti-platelet property that can delay platelet activation and aggregation, which may slow the release and apoptosis of platelets and prolong their ex vivo storage time. In this regard, they are potential novel coating materials for platelet bags. Microfluidic systems have also been used to simulate blood vessels and explore the effects of NPs on platelets inside the body in hopes of finding out more about the interactions between NPs and platelets . In fact, when the interaction between the negative-charged platelets and NPs happens, not only would the surface charge of NPs likely change, but differences in the morphology and size of NPs would likely also be observed, especially in cases of adhesion between them.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
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1. Introduction
4.011719
biomedical
Review
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On this base, we have reviewed the effects of various NPs on platelets. Our findings suggest that, on one hand, the blood compatibility of nanomaterials as drug carriers after entering the body is a real concern, and on the other hand, nanodrugs are increasingly used in the fields of anticoagulation and thrombolysis so that strategies should be adopted to screen for more active candidate drugs. This review will focus on some common NPs and explore the ways in which they interact with platelets and affect their physiological functions ( Table 1 ). We hope that this review can provide some reference for the selection and design of nanocarriers and nanodrugs so that NP–blood compatibility and biological safety can be improved, adverse reactions caused by NPs minimized, and the preservation of platelet function maximized.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
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2. Influence of NPs on Platelets
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Platelet membrane surface proteins include sialic acid, P-selectin, integrin GPIIb/IIIa, and GPVI. One of the most prevalent glycoproteins on platelet membranes is GPIIb/IIIa, a member of the integrin receptor family. It is made up of two glycoproteins, GPIIb and GPIIIIa, which are arranged in a 1:1 ratio on membranes. GPIIIb/IIIa can bind to various platelet ligands, including fibrinogen, fibronectin (Fn), and von Willebrand Factor (vWF). Sialic acid is widely distributed in platelets and various biological tissues. In the presence of a large number of carboxyl groups, sialic acid molecules present a negative charge. Under physiological conditions, platelets carry a negative charge, and electrostatic repulsive forces can prevent platelet aggregation. When activated, platelets have their surface sialic acid desialylated, thereby accelerating platelet aggregation and shortening their lifespan . During participation of platelets in hemostasis, the important adhesion receptor GPVI on the platelet surface is activated by various endogenous or exogenous ligands. Through immunoreceptor tyrosine-activated motifs (ITAMs), phosphorylation signaling is transmitted to drive platelet activation and regulate various functions, including platelet adhesion and aggregation . P-selectin (CD62P) is more highly expressed in activated platelets and activated endothelial cells. In a resting state, P-selectin is stored within platelet granules. When stimulated by external factors, P-selectin rapidly fuses with the cell membrane and is expressed on the cell membrane surface. Therefore, the expression of P-selectin is one of the molecular markers of platelet activation.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
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sec[1]/sec[0]/p[0]
2.1. Impact of NPs on Platelet Membrane Proteins
4.71875
biomedical
Study
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NPs can interact with numerous components of the circulatory blood, including platelets that are thus activated . The interactions and reactions of NPs with platelets can be initiated by stimulating platelet surface receptors or by disrupting the platelet membrane . For instance, NPs interact with integrin GPIIb/IIIa on the surface of platelet membranes that are consequently activated from a resting state. This process is regulated by the size, charge, concentration, and surface area of NPs. Amorphous SiO 2 NPs (10 nm, 50 nm, 150 nm, and 500 nm) were found by Corbalan et al. to induce the release of nitric oxide (NO) from platelets. This is followed by a massive stimulation of peroxynitrite (ONOO − ), which results in an unfavorably low [NO]/[ONOO − ] ratio, the exposure of GPIIb/IIIa on platelet membranes, and an upregulation of P-selectin expressions. These events ultimately cause platelet aggregation through pathways that are dependent on ADP and matrix metalloproteinase-2 (MMP-2). Among them, small-sized (10 nm) amorphous SiO 2 NPs aggregate most quickly by interacting with platelet membrane proteins. To summarize, the impact of amorphous SiO 2 NPs on platelet aggregation is inversely correlated with their size. This is also supported by the research conducted by Zia and colleagues , who found that different-sized polystyrene (25, 50, 119, 151, 201 nm) and platinum (7, 73 nm) NPs induce GPIIIb/IIIa exposure through passive aggregation, which is then regulated by Src and Syk tyrosine kinases, ultimately leading to platelet activation. The intensity of aggregation is also negatively correlated with particle size. In addition, the surface charge and concentration of NPs also affect platelet activation and aggregation. Smyth and others used polystyrene latex NPs (50, 100 nm; PLNPs) modified by different functional groups. Although most of the tested PLNPs induced GPIIIb-/IIIa-mediated platelet aggregation, the intensity is related to physical interactions between PLNPs and platelet membranes or endocytosis of PLNPs. At a concentration of 50 nM, amine-modified PLNP (aPLNP) is more likely to cause platelet aggregation than carboxyl-modified PLNP (cPLNP) by means of physical bridging with adjacent non-activated platelets. Polyvinyl alcohol (PVA)-coated superparamagnetic iron oxide NPs (PVA-SPIONs), measuring 78 ± 22 nm in size, demonstrated dose-dependent anti-platelet action, according to research by Kottana and colleagues . Platelet aggregation is prevented in the presence of PVA-SPIONs because the structure of fibrinogen is changed and bridge connections between platelets fail . This inhibitory effect is more pronounced at higher concentrations (250, 500 μg mL −1 ). The platelet membrane surface receptor P-selectin can be used for the design of targeted drug delivery. For instance, Cao et al. created an NP complex called TM33-GON/TNA, which is modified by the TM33 peptide and loaded with tanshinone IIA (TNA). This NP complex can bind to the activated platelet surface specifically through P-selectin and release TNA into the extracellular space when matrix metalloproteinase-2 (MMP-2) is stimulated, resulting in high local TNA exposure. By inhibiting the conversion of resting platelets to activated ones, the tumor vascular endothelial barrier is disrupted. Consequently, platelet activation, adhesion, and aggregation around activated platelets are effectively inhibited, resulting in tumor endothelial leakage and enhanced tumor treatment efficacy.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p5
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2.1. Impact of NPs on Platelet Membrane Proteins
4.816406
biomedical
Study
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Platelet microparticles (PMPs) are ultra-micro membranous vesicles released by platelets during activation. Their diameter is less than 0.5 μm, they have strong procoagulant activity, and they play an important role in the process of human thrombosis and hemostasis. The coagulation function of PMPs is attributed to the interactions between coagulation factors (primarily factors VII, IX, X, and prothrombin) and the negatively charged phosphatidylserine on the surface of PMPs . Although platelets cannot cross tissue barriers, their extracellular vesicles (EVs) can enter lymph, bone marrow, and synovial fluid, which allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. Looking beyond hemostasis, PMP cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes . This versatility expands the application of PMPs in other physiological and pathological aspects besides hemostasis. In addition, platelets also possess the ability to phagocytose viruses, bacteria, and other particles, and can even engulf NPs. For instance, activated platelets can internalize inert latex microspheres (MS, 200 nm) without affecting blood platelet aggregation , providing an ideal carrier for a platelet-based drug delivery system. Electron microscopy results demonstrate that small-sized silver NPs (13, 20, 29 nm) interact with the platelet membrane and accumulate in platelet granules, effectively inhibiting integrin-mediated blood platelet aggregation in a concentration-dependent manner both in vitro and in vivo . Differently designed platelet-based platforms can be constructed for drug administration by taking advantage of the binding and engulfment between NPs and platelets, as well as the targeting property of platelets directly.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p6
39057309
sec[1]/sec[0]/p[2]
2.1. Impact of NPs on Platelet Membrane Proteins
4.359375
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Study
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When nanomedicines enter the circulatory system, proteins can be spontaneously adsorbed onto the NP surface to form a protein corona . For example, albumin can form a protein corona around NPs . The uptake of NPs into cells and their aggregation in cell culture can both be decreased by albumin adsorption. This has an impact on how NPs interact with biological systems, changing their toxicity and distribution and improving their biocompatibility . In order to study the function of platelet transfusion in vivo, researchers reported a method of modifying the NP surface with human serum albumin (HSA) to improve the uptake of platelets containing Resovist ® (an FDA-approved MRI contrast agent) and reduce the pre-activation of platelets in response to NPs. This approach improved the bio-absorption and toxicity of NPs in platelet labeling and allowed for the recovery of labeled platelets from whole blood using magnetic separation . Additionally, there are reports that perfluorotributylamine NPs (150, 200 nm, PFTBA) have platelet-inhibitory effects. Perfluorotributylamine NPs (PFTBA@Alb) are created when albumin is utilized as the shell. This results in NPs with an improved platelet-inhibitory activity that successfully increases the permeability of tumor blood arteries without having a substantial negative impact on normal capillaries. This approach can effectively increase the permeability of tumor blood vessels by inhibiting platelet function, promoting the infiltration of immune cells into tumors, and thereby significantly enhancing the therapeutic effects of tumors .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
39057309_p7
39057309
sec[1]/sec[0]/p[3]
2.1. Impact of NPs on Platelet Membrane Proteins
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NPs can also interact with endothelial cells. Studies conducted by Saikia and colleagues have demonstrated that the presence of silica NPs in the venous system activates endothelial platelet adhesion receptors, resulting in an increased number of platelets adhering to the endothelial cell surface. One possible explanation is that NPs promote the development of adhesion molecules linked to inflammatory indicators, such as VCAM-1, ICAM-1, and PECAM-1, and produce oxidative stress. These actions also alter the NO/ NO synthase (NOS) cycle. Ultimately, these factors impact the adhesion between platelets and endothelial cells. NPs can also lead to the overexpression of von Willebrand factor (vWF) polyproteins, which is a key step in the damage caused by platelet activation and NP adhesion .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
39057309_p8
39057309
sec[1]/sec[0]/p[4]
2.1. Impact of NPs on Platelet Membrane Proteins
3.914063
biomedical
Review
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NPs can impact platelets either directly or indirectly by inducing changes in membrane proteins, which in turn affects their functional status. Consequently, it is crucial to comprehensively grasp the inherent characteristics of NPs, as well as their interactions with platelets, and to understand the variations that arise from differences in size, charge, and concentration, which play a key role in enhancing the biocompatibility of NPs. Furthermore, by considering the unique properties of NPs, we can strategically select and design NP for specific applications under various scenarios.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
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2.2. Influence of NPs on Morphology of Platelets
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biomedical
Study
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The microscopic morphology of platelets can be examined by various technological means, such as transmission electron microscopy (TEM) and scanning electron microscopy (SEM). When NPs interact with platelets, they cause the contraction of the microtubule annular band and actin skeleton, resulting in the compression of cellular particles towards the central part of the cell. This leads to the fusion of particle surface or membrane with open tubular membranes and the extrusion of particle contents to the cell exterior through the open tubular structure . Consequently, platelets are activated and morphological changes take place. Lipid NPs (LNPs) are crucial to lipid-based carrier drug delivery systems in which they can bind with small molecule drugs to achieve enhanced therapeutic effects . The remodeling of platelet membranes is associated with the maturation of glycosylation in secreted platelet extracellular vesicles (PL-EVs) and B-type I scavenger receptor (SR-B1), initiating the transition from non-glycosylated to glycosylated forms. Mildly oxidized high-density lipoprotein (MoxHDL) remodels itself into corresponding phospholipids by enhancing platelet uptake of hemolytic phospholipids, thereby improving the lipid homeostasis of platelet membranes . Similarly, sphingomyelin (SM) and sphingosine-1-phosphate (S1P) can also produce comparable effects , thus enhancing the quality and storage potential of platelets. Consequently, liposome NPs prepared by loading of small functional molecule substances into liposomes were expected to be used in platelet storage and prolong the storage time of blood products. In the presence of silver NPs, platelet adhesion can be prevented, and integrin-mediated platelet reactions can be effectively inhibited in a concentration-dependent manner. Fluorescence microscopy observation revealed that at a concentration of 5 μM nanoscale silver, the inhibitory effect was most pronounced, with minimal re-organization of F-actin and changes in the cell skeleton . It is speculated that silver NPs may represent a novel strategy for maintaining a low activation state in platelets and preventing vascular thrombosis.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
39057309_p10
39057309
sec[1]/sec[1]/p[1]
2.2. Influence of NPs on Morphology of Platelets
3.134766
biomedical
Other
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These insights open up avenues for research aimed at prolonging the morphological integrity, functional capacity, and lifespan of platelets, as well as advancing the design of innovative blood-storage bags.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
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39057309
sec[1]/sec[2]/p[0]
2.3. NPs Influence Platelet Activation and Aggregation
4.082031
biomedical
Study
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Flow cytometry is an ideal technique for quantitatively detecting changes in the expressions of GPIIb/IIIa and P-selectin (CD62P) on platelets, which were the important markers that could be detected in platelet activation. This is achieved by discriminating platelets based on their size and granularity (forward and side scatter) and determining the expression abundance of the target by the fluorescence value of the antibody bound to it. Typically, light transmission aggregometry is used to identify platelet aggregation. Alternatively, dissipative quartz crystal microbalance (QCM-D) can be employed to characterize small aggregates .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
39057309_p12
39057309
sec[1]/sec[2]/p[1]
2.3. NPs Influence Platelet Activation and Aggregation
4.570313
biomedical
Study
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When platelets are activated, the expression of P-selectin and GPIIb/IIIa (CD41/CD61) increases . Flow cytometry can be used to detect the positive rate on the surface of platelets . Numerous studies have demonstrated that NPs can cause platelet activation, and that glycoprotein receptors may be essential to this process. Specifically, different G protein-coupled receptors mediate platelet-to-platelet contact and aggregation . GPIIb/IIIa (CD41/CD61) is a pair of constitutive integrin receptors found in an inactive state on the surface of resting platelets, having a low affinity for adsorbed fibrinogen. In other words, GPIIb/IIIa induces or triggers platelet aggregation by using fibrinogen as a bridging molecule, thereby playing a pivotal role in primary hemostasis . Furthermore, 20,000–40,000 receptors are present in the membranes lining the open tubular system within platelets, which are exposed on platelet membranes only upon stimulation by activating signals . When NPs engage with platelets, they facilitate the exposure of additional integrins, bridge fibrinogen and surrounding resting platelets, and concurrently secrete cytokines, thereby accelerating platelet activation and aggregation . During this process, one of the molecular markers of platelet activation, P-selectin, becomes exposed.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p13
39057309
sec[1]/sec[2]/p[2]
2.3. NPs Influence Platelet Activation and Aggregation
4.546875
biomedical
Review
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Research has demonstrated that NPs of different concentrations exert distinct effects on platelets. For instance, silver NPs inhibit platelet reactions in a concentration-dependent manner, with optimal inhibitory effects occurring at 5 μM for13–15 nm, 30–35 nm, and 40–45 nm sized ones . Moreover, smaller NPs tend to have a more significant impact on coagulation than larger ones . There have also been reports that contact between platelets and silver NP-coated catheters (characterized by a high surface area to volume ratio) can accelerate the production of thrombin, leading to enhanced platelet activation . Titration experiments indicate that platelet activation may result from collisions with silver particles exposed on the surface, without adhesion to the surface . These findings have boosted the development and improvement of indwelling catheters, prompting the exploration of new coatings with antimicrobial properties and the capacity to prevent thrombus formation. As a result, the procoagulant properties of NPs may increase risks for common diseases such as diabetes, cancer, and cardiovascular diseases. To mitigate the additional risks associated with NPs, Ragaseema et al. prepared polyethylene glycol (PEG)-coated silver NPs (20 nm) (PEGeSNPs) on cardiovascular implant stents, which exhibit a direct inhibitory effect on platelet activation and aggregation. However, the application of this procoagulant effect is particularly urgent in severe local bleeding cases. Chung et al. coated chitosan (CS) NPs with adenosine diphosphate (ADP) to accelerate platelet activation and then measured its hemostatic effect. Studies have found that these ADP-coated CSNPs can shorten the clotting time and produce stronger blood clots. Lord et al. observed that platelet adhesion and activation induced by CS is significantly amplified in the presence of plasma proteins or extracellular matrix proteins. Furthermore, nanomaterials interact with platelets, increasing platelet activation and adhesion, accelerating platelet aggregation, and enhancing their hemostatic effects. Because of the significant antibacterial properties of chitosan and platelets against Escherichia coli and Staphylococcus aureus , their complex has been widely applied to wound dressings . Numerous literature reports indicate that chitosan exhibits a broad-spectrum antimicrobial effect, capable of inhibiting various bacteria, fungi, and even some viruses. On the other hand, researchers have modified the surface of chitosan NPs with polyethylene glycol, polyvinyl alcohol, or ethylenediamine tetraacetic acid to reduce platelet aggregation or coagulation, which results in good blood compatibility .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p14
39057309
sec[1]/sec[2]/p[3]
2.3. NPs Influence Platelet Activation and Aggregation
4.4375
biomedical
Study
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As activation of integrin GPIIb/IIIa is one of the steps in the activation of platelets by numerous NPs , the inhibition of integrin-mediated platelet activation has become one of the crucial approaches to impeding platelet function. Among cancer patients, the efficacy of anticancer treatment is compromised due to the inability of drugs to penetrate the tumor vascular barrier. Albumin-coated perfluorocarbon NPs (PFTBA@Alb) were created by Zhou and colleagues with the potential to non-specifically impair platelet function in tumors. This could cause the tumor vascular wall integrity to be disrupted, immune cell penetration into the tumor to be encouraged, and the anticancer effect to be enhanced. Furthermore, in the field of cancer treatment, it is a commonly used approach to inhibit platelet function to enhance drug penetration . Arachidonic acid, under the action of platelet cyclooxygenase, produces prostaglandins, which play a significant role in promoting platelet aggregation. Another study found that silver NPs coated with polyethylene glycol (PEG) can inhibit the synthesis of arachidonic acid to thromboxane by affecting its metabolism, thereby blocking the exposure of GPIIb/IIIa and inhibiting platelet activation and aggregation. Besides antithrombotic properties, this polymer also possesses antimicrobial properties and good histocompatibility . In addition, PEGylation during platelet storage is also a concern. PEG can react with lysine residues on the platelet surface to form a stable amide bond, thereby preventing the deformation and activation of platelet surface glycophorins during storage. PEGylation has also been employed in platelet storage to prevent bacterial contamination in blood bags and improve the safety of transfusion .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p15
39057309
sec[1]/sec[2]/p[4]
2.3. NPs Influence Platelet Activation and Aggregation
4.847656
biomedical
Study
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Polyamidoamine dendrimers (PAMAM) have come to be one of the most extensively studied dendrimer architectures in recent years. Their surface is densely covered with functional groups that can be easily modified, and they possess a considerable number of cavities inside, making them an ideal choice for drug and gene delivery applications due to their excellent biocompatibility, permeability, and stability. However, research has also revealed that they can exhibit cytotoxicity, activate platelets, and significantly alter their morphology, leading to an increase in aggregation and adhesion . A study conducted by Dobrovolskaia et al. demonstrated that PAMAM dendrimers accelerated platelet aggregation by disrupting the integrity of platelet membranes. The property of PAMAM dendrimers is derived from the surface-active amine groups. Under physiological conditions, the amine groups at the ends are protonated to form positively charged ammonium ions, which may contribute to platelet activation and aggregation. This interaction is mediated through electrostatic interactions between the densely charged cationic dendrimer and anionic fibrinogen domain structures . The degree of platelet aggregation is measured to be directly proportional to the number of amine groups. Further research has also shown that cationic PAMAM dendrimers can cause platelet dysfunction, such as reducing the production of platelet-dependent thrombin . However, this does not essentially lessen hemostatic activity because they can act directly on fibrinogen without the help of thrombin, resulting in fibrinogen aggregates that are dense and have a high molecular weight, which increases the development of thrombi . Unlike cationic PAMAM dendrimers, anionic PAMAM dendrimers with concentrations lower than 0.5 mg/mL usually do limited harm to platelets . More research is needed to focus on the underlying mechanism in platelet activation and aggregation caused by PAMAM and to minimize its toxic effects in the blood. In recent years, PEG conjugation has become the most commonly used method to reduce the toxicity of surface active groups of dendrimers. Researchers have found that partially PEGylated PAMAM can reduce PAMAM polymer-mediated platelet activation and platelet reduction in vitro , thus increasing its biocompatibility and drug loading . Research indicates that the charge, concentration , and size of NPs can prolong the prothrombin time to varied extents . Overall, small-sized, negative-charged, and PEGylated dendrimer NPs with low molecular weight and low concentration have advantages in improving the stability and survival rate of platelets during storage .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
39057309_p16
39057309
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2.3. NPs Influence Platelet Activation and Aggregation
3.521484
biomedical
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This empirical rule can provide some reference for exploring the relationship between the physical and chemical properties and biological effects of nanomaterials in terms of design, as well as improving drug distribution, accelerating circulation, and enhancing blood compatibility and biological safety.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
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39057309
sec[1]/sec[3]/p[0]
2.4. Mechanisms of Activation and Aggregation Promoted by NPs
4.132813
biomedical
Study
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When NP-based adjuvants are introduced into organism, such exposure can trigger the activation of the NLRP3 inflammasome, which in turn promotes the secretion of inflammatory factors . Similarly, silica NPs can induce inflammation by initiating the ROS/PARP-1/TRPM2 signaling pathway . The elevated levels of these inflammatory factors within the body could result in platelet activation and aggregation, consequently raising the risk of thrombotic diseases .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
39057309_p18
39057309
sec[1]/sec[3]/p[1]
2.4. Mechanisms of Activation and Aggregation Promoted by NPs
4.746094
biomedical
Study
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[ 0.9541015625, 0.0023746490478515625, 0.0428466796875, 0.00067901611328125 ]
Platelets are central to the development of thrombosis, performing a pivotal role in the formation of blood clots throughout the body. When nanomedicines enter the circulatory system, they interact with platelets either directly or indirectly, stimulating the activation of the coagulation cascade and the production of thrombin, which in turn activates platelets. Meanwhile, the shape of platelets changes, pseudopodia are extended, and 5-hydroxytryptamine and thromboxane A2 are released, causing vasoconstriction and platelet aggregation . The exposure of integrin GPIIb/IIIa is one of the steps in the activation of platelets by various NPs . After that, integrin GPIIb/IIIa emits a signal through the tyrosine-based sequence in the relevant membrane protein . Platelet activation is caused by increased Ca 2+ flow through pathways regulated by Src and Syk tyrosine kinase in vitro. Upon activation, the platelets undergo a conformational change, exposing the high-affinity binding site for soluble fibrinogen on GPIIb/IIIa , enhancing the interaction between fibrinogen and GPIIb/IIIa, and facilitating the formation of blood clots by binding to blood cells to accelerate the coagulation process. Besides platelets, NPs also engage with other blood components, such as plasma proteins (fibrinogen, coagulation factors, etc.) , and lead to complex changes in a multitude of blood physiological processes, including plasma protein adsorption, coagulation factor activation, platelet activation, and adhesion.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p19
39057309
sec[1]/sec[3]/p[2]
2.4. Mechanisms of Activation and Aggregation Promoted by NPs
4.320313
biomedical
Study
[ 0.99951171875, 0.00022995471954345703, 0.0002582073211669922 ]
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The physicochemical properties of nanomaterials can also be adjusted to regulate coagulation processes. It was found that SiO 2 NPs activated the endogenous coagulation pathway, and the degree of activation increased with the specific surface area and silanol groups . Another study reported that compared to high surface curvature (small size), low surface curvature (large size) had a greater degree of denaturing coagulation factor XII, resulting in higher coagulation activity in vitro . Coagulation factor XII is activated by larger SiO 2 particles instead of small-sized ones. It is speculated that larger particles may cause greater changes in the state of coagulation factors with blood clotting, and provides a basis for the treatment of traumatic injury . In addition, when the body is stimulated or injured, platelets may release microparticles (MPs) with the size of about 100 nm and a lifespan of 10–30 min. As liposome NPs are derived from cells, the negatively charged phosphatidylserine on their surface interacts with coagulation factors in plasma (mainly factors VII, IX, X, and prothrombin) . It is worth noting that these microparticles have a procoagulant activity 50–100 times higher than that of activated platelets under the same surface area .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p20
39057309
sec[1]/sec[3]/p[3]
2.4. Mechanisms of Activation and Aggregation Promoted by NPs
3.791016
biomedical
Study
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By elucidating the molecular mechanisms behind NP-induced thrombosis, we gain new insights and potential therapeutic targets for the prevention and treatment of thrombotic disorders associated with nanomaterial exposure.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
39057309_p21
39057309
sec[1]/sec[4]/p[0]
2.5. NPs Influence Platelet Release and Apoptosis
4.542969
biomedical
Study
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Upon activation, platelets release a multitude of molecules. The majority of these bioactive molecules are released from α-granules, which are unique to platelets and contain an incredibly diverse repertoire of cargo, including integral membrane proteins; pro-coagulant molecules; chemokines; mitogenic, growth, and angiogenic factors; adhesion proteins; and microbicidal proteins. The irreversible nature of α-granule secretion makes it ideally suited as a marker of platelet activation . The process of secretion and release of dense alpha particles in platelets is called ‘release reaction’. Typically, NP tracking analysis (NTA) is used to analyze the release of platelet-derived vesicles (PEVs) . Generally speaking, the activation of platelets depends on mitochondrial function , and the lifespan of most platelets is strictly regulated by mitochondrial apoptosis, mainly controlled by the BCL-2 protein family, which is crucial to maintaining platelet physiological function . Triphenylphosphine compounds increase the exposure of phosphatidylserine on the platelet membrane surface, and a series of in vitro experiments have shown that they cause a decrease in mitochondrial potential, suggesting the impact of mitochondrial function on platelets . Therefore, the changes in the mitochondrial membrane potential of platelets and the surface exposure of phosphatidylserine are important indicators for evaluating blood compatibility of NPs.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999995
39057309_p22
39057309
sec[1]/sec[4]/p[1]
2.5. NPs Influence Platelet Release and Apoptosis
4.703125
biomedical
Study
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During the activation of platelets by NPs, membrane proteins such as GPIIb/IIIa and P-selectin, which mostly undergo conformational changes and migrate from the cytoplasm, are exposed on the cell surface and participate in the activation and aggregation of platelets. For instance, after activation, the affinity of surface glycoproteins on platelets for NPs increases, and their interaction is enhanced and characterized by elevated adhesion and aggregation and the release of cytokines. However, it remains unclear whether this process is connected to apoptosis. Research has shown that inhibiting the anti-apoptotic protein BCL-XL can lead to rapid platelet apoptosis, resulting in a decrease in platelet count . Using Bcl-xL–inhibitory BH3 mimetics was shown by Schoenwaelder and others to accelerate platelet apoptosis and downregulate integrin GPIIb/IIIa adhesion function, meaning that GPIb and GPVI surface expression is reduced, PS exposure is increased, aggregation is decreased, and blood-clotting ability is decreased. However, the question of whether the change in the expression level of the anti-apoptotic protein BCL-XL can be used as one of the indicators of platelet apoptosis promoted by NPs requires more research. Andelman and others observed that the biological compatibility of NPs with different microscopic morphologies differs. Compared to spherical and rod-shaped particles, nanosheets have much higher cytotoxicity . Zinc oxide NPs induce various changes in cell parameters in platelets and other cells and cause mitochondrial membrane damages and the production of reactive oxygen species, resulting in cell toxicity and genotoxicity effects and accelerating cell apoptosis . Some NPs may actually delay platelet apoptosis. For instance, mildly oxidized HDL (MoxHDL), a biological small molecule derived from the human liver, can enhance the lipid stability of platelet membranes by reducing the release of vesicles during storage . Lipid NPs can also collaborate with small molecules as a more effective treatment of diseases . Furthermore, small silver NPs can inhibit platelet activation and aggregation, slowing down degranulation . This may also delay platelet apoptosis.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p23
39057309
sec[1]/sec[4]/p[2]
2.5. NPs Influence Platelet Release and Apoptosis
3.916016
biomedical
Review
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In this subsection, we encapsulate the effects and general mechanisms of NPs on platelet secretion and apoptosis, expanding the choices available in the utilization of nanomaterials. The elucidation of the molecular pathways through which NPs trigger the release and apoptosis of platelets offers novel targets for the prevention and therapeutic intervention of nanomaterial-induced platelet-related diseases.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999999
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39057309
sec[2]/p[0]
3. NPs in Anticoagulation and Anti-Thrombosis Applications
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biomedical
Study
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Thromboembolic conditions were estimated to account for one in four deaths worldwide and are the leading cause of mortality . Platelets play a central role in thrombus formation, and therefore, it is of great importance to regulate and maintain platelet homeostasis and keep them in an inactive state. Clinical experts consider this the primary treatment goal for thrombotic diseases . Researchers have found that silver NPs effectively inhibit integrin-mediated platelet functional responses in a dose-dependent manner, such as adhesion to fibrinogen and changes in the platelet cell cytoskeleton, significantly inhibiting platelet coagulation function . Salidroside can inhibit platelet activation through the SIRT1/ROS/mtDNA pathway without increasing the risk of bleeding, thereby preventing thrombus formation , which offers hope for its application as an anti-platelet agent. As lipid NPs can be employed as a drug carrier of small molecules , it is worthwhile to construct engineered liposomes by encapsulating salidroside in them to increase biocompatibility, targeted delivery, and therapeutic effects.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
39057309_p25
39057309
sec[2]/p[1]
3. NPs in Anticoagulation and Anti-Thrombosis Applications
4.164063
biomedical
Study
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Some clinical diseases lead to secondary platelet activation, which, in turn, activates surrounding resting platelets, thus forming multicellular aggregates connected by fibrin bridges and resulting in thrombus formation . Platelet activation is a precursor to platelet aggregation. Generally speaking, the activation state of the platelet cannot be changed. However, Kottana and others have found that PVA-SPIONs affect the structure of fibrinogen and prevent the bridging between platelets and fibrinogen, thereby slowing down thrombus formation and inhibiting platelet aggregation . Poly-L-lactic acid fiber mats, prepared by electrospinning and modified with poly-dopamine (PDA) and silver NPs (AgNPs) on the surface, provide a dual-function antibacterial/anticoagulant coating, offering hope for the development of a novel platelet blood bag . Wang et al. combined 3D printing and coating techniques that encapsulated ZnO NPs in corn alcohol soluble protein NPs and enabled heparin to be adsorbed onto the surface to combat thrombus formation and postoperative infection caused by stent implantation .
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p26
39057309
sec[3]/p[0]
4. Summary and Outlook
3.869141
biomedical
Review
[ 0.99609375, 0.0020618438720703125, 0.001949310302734375 ]
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Nanomedicine has long been used in the field of modern medicine. NPs can serve as carriers or nanocoatings that enhance drug delivery efficiency or improve circulation cycles. Additionally, they can act as nanodrugs to treat various diseases due to their inherent properties. For instance, NPs have been applied in the fields of anticoagulation and antibacterial therapy by promoting platelet activation and aggregation, mediating thrombus formation, and achieving faster hemostasis.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999996
39057309_p27
39057309
sec[3]/p[1]
4. Summary and Outlook
3.964844
biomedical
Study
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The field of nanomedicine has been garnering increasing attention, and the blood compatibility of nanomaterials is a significant concern for researchers. Numerous reports have indicated that NPs can facilitate platelet activation, induce morphological changes, and generate a large number of pseudopodia, alter their shape, and enhance their cytoskeletal rearrangement. However, it remains unclear whether NPs will impact platelet transendothelial migration ability and other immunological functions. Furthermore, research on the interactions between NPs and platelets focuses on the activation degree and coagulation function, with relatively little attention to the structural changes in platelets themselves, which is why it is difficult to gain insights into the damage inflicted on platelets. Therefore, further research in this area is necessary.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997
39057309_p28
39057309
sec[3]/p[2]
4. Summary and Outlook
4.09375
biomedical
Review
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In summary, this article focuses on the impact of NPs on platelet structure and function by delving into the mechanisms underlying their influence. These findings and trends can be summarized as follows. First, some NPs, such as chitosan, amorphous SiO 2 NPs, and polystyrene NPs, can interact with platelet surface glycoprotein receptors, enhancing the interaction between fibrinogen and GPIIb/IIIa, and accelerate platelet activation, adhesion, and granule exocytosis. Related factors include the morphology, charge, concentration, and size of NPs. Second, NPs such as polyvinyl alcohol-coated superparamagnetic iron oxide NPs, amorphous SiO2 NPs, and polystyrene NPs can inhibit platelet activation by altering the conformational changes in fibrinogen. This alteration results in the failure of bridging between platelets, thereby slowing down platelet aggregation. Moreover, small-sized and negatively-charged polyethylene glycolized dendrimer NPs with relative low molecular weight and low concentration are more conducive to the stability and survival rate of platelets during storage. Thus far, we propose that nanomedical research would benefit from the proper use of nano-carriers with more understanding of the interaction between them and blood cells, including platelets, in the in vivo environment, to mitigate potential unforeseen complications during clinical trials.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
39057309_p29
39057309
sec[3]/p[3]
4. Summary and Outlook
3.751953
biomedical
Review
[ 0.9873046875, 0.005962371826171875, 0.00670623779296875 ]
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This review can provide reference for exploring the relationship between the physicochemical properties and biological effects of nanomaterials. It may also help to enhance the in vivo safety of NPs and offer guidance for the development of novel nanomedicines or drug carriers.
[ "Dongxin Peng", "Sujing Sun", "Man Zhao", "Linsheng Zhan", "Xiaohui Wang" ]
https://doi.org/10.3390/jfb15070188
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278469_p0
PMC11278469
sec[0]/p[0]
1. Introduction
3.878906
biomedical
Review
[ 0.99853515625, 0.0007958412170410156, 0.00084686279296875 ]
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ADHD is a neurodevelopmental disorder characterized by persistent patterns of inattention, hyperactivity, and impulsivity. These symptoms often manifest in childhood and can persist into adolescence and adulthood . The global prevalence of ADHD ranges from 5.9% to 7.1% in children and 1.2% to 7.3% in adults, indicating its significant impact across different age groups .
[ "Carlos Ramos-Galarza", "Deyaneira Brito", "Brayan Rodríguez", "Brenda Guerrero", "Jorge Cruz-Cárdenas", "Mónica Bolaños-Pasquel" ]
https://doi.org/10.3390/jcm13144208
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999998
PMC11278469_p1
PMC11278469
sec[0]/p[1]
1. Introduction
3.529297
biomedical
Review
[ 0.99560546875, 0.0004611015319824219, 0.00373077392578125 ]
[ 0.356689453125, 0.01412200927734375, 0.62841796875, 0.00046515464782714844 ]
However, prevalence rates of ADHD can vary based on ethnic differences. Contrary to previous beliefs, recent studies contradict the notion that the prevalence of ADHD is lower in certain ethnic groups. For instance, while it was once thought that Black children and adolescents had lower rates of ADHD compared to their White counterparts, research has shown that the prevalence rates between these groups do not significantly differ . Moreover, Asian and Latino children and adolescents tend to present lower prevalence rates of ADHD than both their Black and White counterparts. These differences may be influenced by factors such as access to healthcare, socioeconomic status, and cultural attitudes toward mental health .
[ "Carlos Ramos-Galarza", "Deyaneira Brito", "Brayan Rodríguez", "Brenda Guerrero", "Jorge Cruz-Cárdenas", "Mónica Bolaños-Pasquel" ]
https://doi.org/10.3390/jcm13144208
N/A
https://creativecommons.org/licenses/by/4.0/
en
0.999997