3D-printed Synthetic Polymer Templates for Bone Tissue Engineering : Bulk Modifications and Osteoconduction Assessment

Syntetiske polymerbiomaterialer er enkle å bearbeide, biologisk inerte og brukes derfor i en rekke biomedisinske applikasjoner. Forskning har i lang tid fokusert på å øke biologiske aktivitet til slike materialers, og å tilpasse egenskapene til ulike bruksområder. Tredimensjonal (3D)-printing er velegnet til framstille biomaterialmaler med stor presisjon etter bestemte designparametre. Målet med denne avhandlingen var å undersøke 3D-printede syntetiske polymermaler for bruk til dyrkning og regenerasjon av beinvev (BTE). Undersøkelsene bestod av tre faser: Først ble det utført en systematisk litteraturundersøkelse for å analysere relevante faktorer ved bruk av 3D-printede, nedbrytbare maler og virkningen deres på beinregenerering i kraniale beindefekter hos ulike dyrearter (Studie I). En meta-analyse ble utført for å sammenligne nydannelse av bein for hver materialtype (polymerer, keramer eller kompositter). Man fant at effekten på beinregenereasjon var høyest hos kompositter bestående av polymerer og biokeramer, men også materialstrukturen gitt av 3D-printing. Parallelt ble det utført en studie på funksjonalisering av 3D-printede polykaprolakton (PCL) maler med gelatin (GL) som ble testet in vitro (Studie II). Til tross for at økt mengde GL (ved 8 og 16%) forbedret osteogen differensieringen av stamceller (fra rotter) ble malene ikke videreført på grunn av materialets lave strekkfasthet. I neste fase, ble poly(lactide-co-trimethylenecarbonate) (PLATMC) sammenlignet med PCL, og man fant at PLATMC hadde gunstigere både nedbrytnings- og mekaniske egenskaper enn PCL (studie III). I tillegg viste PLATMC seg bedre egnet for å fremme mineralisering av ekstracellulær matriks (ECM) fra humane stamceller in vitro. I en subkutan implantasjonsmodell i kanin (varighet 8 uker) var vertsresponsen på PLATMC mild, med innvekst av løst bindevevs og høy infiltrasjon av celler, der PCL bar preg av tett fibrøs vevsinnkapsling. Videre, når begge malene ble implantert i skallebensdefekter i kaniner, viste PLATMC-malene størst innvekst av bein. Det ble også funnet nydannelse av bein direkte på materialoverflaten, noe som hittil ikke beskrevet for syntetiske polymer. I tredje fasen valgte man å modifisere PLATMC ved å kombinere polymeren med hydroksapatitt (HA), et mineral og en viktig komponent i beinmasse. 3D-printede blandinger med ulike andeler HA (10, 30 og 50 %) ble sammenlignet med umodifisert PLATMC og testet for fysiske og biologiske egenskaper (Studie IV). Man fant at tilsatt HA reduserte strekkfastheten sammenlignet med ren PLATMC. HA10 viste noe redusert nedbrytningshastighet og lave nivåer av frigitt kalsium, mens de høye nedbrytningsprofilene til HA30 og HA50 ble tidlig ledsaget av omfattende frigivelse av kalsium. Ved bruk av stamceller (fra menneske) (in vitro), fant man for HA10 høyere mineralisering av ECM etter 14 og 21 dager enn for PLATMC alene, mens HA30 og HA50 ikke fremmet mineralisering i like stor grad. I tillegg viste HA30 og HA50 markant mindre beininnvekst når de ble implantert i skallebeinsdefekter i kaniner. Oppsummert fant man at umodifisert 3D-printet PLATMC fremmet mineralisering av ECM både in vitro og in vivo, men at man ved å tilsette HA i for store mengder, gjennom frigivelse av kalsium, forstyrrer denne prosessen i tillegg til å redusere materialets strekkfasthet. Resultatene fra disse studiene samlet støtter bruken av 3D-printede PLATMC-maler for beinregenerering.Synthetic polymer biomaterials are used in numerous biomedical applications providing biological inertness and ease of processing and shaping. Current research is directed towards boosting their biological activity, customized per application. 3D-printing is a promising technique for producing biomaterial templates with the required design parameters. The aim of the thesis was therefore to investigate the fabrication of osteoconductive 3D-printed synthetic polymer-based templates for bone tissue engineering (BTE). The investigation comprised three phases: In phase I, a literature survey was conducted, to review factors of relevance in applying potentially-degradable 3D-printed templates and their influence on bone regeneration in the calvarial bone defect (CBD) model, across various animal species (Study I). A meta-analysis was undertaken to compare the yield of new bone for each type of template material (polymer, ceramic or composites/blends). The highest impact on new bone formation was associated with the blended polymers and bioceramics, and the interconnected porosity generated by the 3D-printing. In parallel, an experimental study was undertaken on the functionalization of 3D-printed polycaprolactone (PCL) templates with gelatin (GL) due to its good biodegradation and biocompatibilty. Their physical and osteoconductive properties were tested in vitro (Study II). The biochemical compatibility contributed by GL (at 8 and 16%) improved the osteogenic differentiation of the seeded rat-BMSCs. However, this led to quite low tensile resistance and PCL/GL templates were therefore not studied in further in vivo trials. In phase II, poly(lactide-co-trimethylene carbonate) (PLATMC) was compared to PCL, and revealed that PLATMC had better degradation and mechanical properties than PCL (Study III), with prominent osteoconductivity and mineralized extracellular matrix (ECM) deposition (in vitro). In a subcutaneous implantation model in rabbits (8 weeks), the host response to PLATMC was mild, with loose connective tissue interface and high cellular invasion. In contrast, PCL was characterized by dense fibrous tissue encapsulation. When both templates were implanted in CBD in rabbits, PLATMC templates showed greater amount of new bone formation together with obvious contact osteogenesis presented on its surface, which was unique and unreported for a synthetic polymer before. In phase III, PLATMC was blended with hydroxyapatite (HA), in several ratios: 10 % HA (HA10), 30 % (HA30) and 50 % (HA50). Printability, physical, mechanical, and biological properties were compared (Study IV). The disclosed tensile properties of all 3D-printed HA blends were reduced, compared to PLATMC. HA10 showed reduced degradation and mild Ca release rate, while the high degradation profile of HA30 and HA50 was accompanied by massive early Ca release rates. On the biological aspect in vitro, using human-BMSCs seeded up to 28 days, HA10 disclosed higher mineralized ECM secretion at 14 and 21 days than PLATMC, while the osteoconductivity of HA30 and HA50 were markedly reduced and exhibited no advantages over pristine PLATMC templates. Moreover, HA30 and HA50, exhibited marked less osteoconductivity and reduced bone ingrowth when implanted in CBD. Thus high Ca release were correlated to reduced bone ingrowth and reduced osteoconduction, and the rate of Ca release should be considered in characterizing new HA-based templates. In summary, 3D-printed PLATMC showed promising osteoconductive activity, stimulating abundant mineralized ECM secretion in vitro, and demonstrated contact osteogenesis in vivo. However, the addition of HA reduced its tensile properties and high Ca release rates exhibited less osteoconductive properties than PLATMC. The results of these studies support the application of 3D-printed PLATMC templates for BTE.Doktorgradsavhandlin

Assessment of knowledge and healthcare providers’ role in promoting lactation in United Arab Emirates

Background: This study was performed to assess mothers’ knowledge and awareness level regarding maternal medication intake during lactation and health care providers’ role in promoting lactation.Methods: This study is a cross-sectional, questionnaire based survey study and a convenient sample of (820) breastfeeding mothers in Ajman and Sharjah, United Arab Emirates (U.A.E.) participated in the study. The results were analyzed using the Statistical Package for the Social Sciences (SPSS) version 20. Descriptive statistics were used to summarize the data concerning the demographic characteristics and breastfeeding knowledge. Categorical variables (such as nationality and educational level) were described by using frequency, percentages, bar chart and pie chart.Results: The current study revealed a (72%) of maternal knowledge compared to (60.4%) four years ago and the most identified encouraging factor for the initiation of lactation stated by the respondents was their own decision followed by family support (58.4%, 39.8% respectively). The health care providers’ role was positively improved (58.4%) as observed in the current study compared to (52.1%) four years ago in UAE.Conclusions: An improvement was observed in terms of knowledge among breastfeeding mothers in the UAE compared to previous years as well as healthcare providers’ role which was also positively improved. Pharmacists were observed to have a low impact on the initiation of lactation, but on the other hand it was found that they had a significant role in terms of assessing maternal medication safety during lactation

Contact osteogenesis by biodegradable 3D-printed poly(lactide-co-trimethylene carbonate)

Background To support bone regeneration, 3D-printed templates function as temporary guides. The preferred materials are synthetic polymers, due to their ease of processing and biological inertness. Poly(lactide-co-trimethylene carbonate) (PLATMC) has good biological compatibility and currently used in soft tissue regeneration. The aim of this study was to evaluate the osteoconductivity of 3D-printed PLATMC templates for bone tissue engineering, in comparison with the widely used 3D-printed polycaprolactone (PCL) templates. Methods The printability and physical properties of 3D-printed templates were assessed, including wettability, tensile properties and the degradation profile. Human bone marrow-derived mesenchymal stem cells (hBMSCs) were used to evaluate osteoconductivity and extracellular matrix secretion in vitro. In addition, 3D-printed templates were implanted in subcutaneous and calvarial bone defect models in rabbits. Results Compared to PCL, PLATMC exhibited greater wettability, strength, degradation, and promoted osteogenic differentiation of hBMSCs, with superior osteoconductivity. However, the higher ALP activity disclosed by PCL group at 7 and 21 days did not dictate better osteoconductivity. This was confirmed in vivo in the calvarial defect model, where PCL disclosed distant osteogenesis, while PLATMC disclosed greater areas of new bone and obvious contact osteogenesis on surface. Conclusions This study shows for the first time the contact osteogenesis formed on a degradable synthetic co-polymer. 3D-printed PLATMC templates disclosed unique contact osteogenesis and significant higher amount of new bone regeneration, thus could be used to advantage in bone tissue engineering.publishedVersio

Bone regeneration in rat calvarial defects using dissociated or spheroid mesenchymal stromal cells in scaffold-hydrogel constructs

Background Three-dimensional (3D) spheroid culture can promote the osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSC). 3D printing offers the possibility to produce customized scaffolds for complex bone defects. The aim of this study was to compare the potential of human BMSC cultured as 2D monolayers or 3D spheroids encapsulated in constructs of 3D-printed poly-L-lactide-co-trimethylene carbonate scaffolds and modified human platelet lysate hydrogels (PLATMC-HPLG) for bone regeneration. Methods PLATMC-HPLG constructs with 2D or 3D BMSC were assessed for osteogenic differentiation based on gene expression and in vitro mineralization. Subsequently, PLATMC-HPLG constructs with 2D or 3D BMSC were implanted in rat calvarial defects for 12 weeks; cell-free constructs served as controls. Bone regeneration was assessed via in vivo computed tomography (CT), ex vivo micro-CT and histology. Results Osteogenic gene expression was significantly enhanced in 3D versus 2D BMSC prior to, but not after, encapsulation in PLATMC-HPLG constructs. A trend for greater in vitro mineralization was observed in constructs with 3D versus 2D BMSC (p > 0.05). In vivo CT revealed comparable bone formation after 4, 8 and 12 weeks in all groups. After 12 weeks, micro-CT revealed substantial regeneration in 2D BMSC (62.47 ± 19.46%), 3D BMSC (51.01 ± 24.43%) and cell-free PLATMC-HPLG constructs (43.20 ± 30.09%) (p > 0.05). A similar trend was observed in the histological analysis. Conclusion Despite a trend for superior in vitro mineralization, constructs with 3D and 2D BMSC performed similarly in vivo. Regardless of monolayer or spheroid cell culture, PLATMC-HPLG constructs represent promising scaffolds for bone tissue engineering applications.publishedVersio

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

PREVALENCE AND RISK FACTORS OF VITAMIN B12 DEFICIENCY AMONG PATIENTS WITH TYPE II DIABETES ON METFORMIN: A STUDY FROM NORTHERN REGION OF UNITED ARAB EMIRATES

Objectives: This study focused on the prevalence of Vitamin B12 deficiency in UAE patients with type 2 diabetes mellitus (T2DM) who were treated with or without metformin.Methods: A cross-sectional study was conducted on 213 patients having diabetes type II were randomly selected to be part of the study in Northern Regions of the UAE, from June 2014 to February 2015. The patients aged >45 years and who had taken metformin for at least 3 months were recruited with regular follow-up at the outpatient clinic. The patients were included in a survey after which they had their serum B12 levels measured. Serum B12 levels <150 pg/ml are defined as the B12 deficiency.Results: About 48% of diabetic patients had confirmed the B12 insufficiency through laboratory tests. The patients on metformin had statistically lower values of B12 (p=0.002). The majority of participants n (%) took metformin had neuropathy, hypertension, dyslipidemia, numbness or paresthesia, and depression, or mood changes 140 (70%), 183 (91.5%), 134 (67%), 136 (68%), 161 (80.5%), and 120 (60%), respectively.Conclusion: Our study shows that for the patients with T2DM, long-term treatment with metformin is associated with higher chances of developing Vitamin B12 deficiency. Clinicians should, therefore, recognize this significant element and should screen diabetics who are on metformin treatment for any B12 insufficiency, which may be hidden, especially patients coming with neurologic symptoms

Nationwide survey on attitudes and perceived barriers toward provision of pharmaceutical care among final year undergraduate pharmacy students in the United Arab Emirates.

Pharmaceutical care (PC) practice is still limited in the United Arab Emirates. It is crucial to understand pharmacy students' attitudes and their perceived barriers towards PC provision, to evaluate the effectiveness of theoretical and practical curricula in creating positive attitudes toward PC. This study aims to assess attitudes of final year undergraduate pharmacy students in the United Arab Emirates (UAE), and the barriers perceived by them to practice PC. A cross-sectional survey-based study was conducted in February and March, 2020, involving colleges in UAE offering undergraduate pharmacy programs and having students in their final year. Participants filled a questionnaire covering attitudes' items, based on the Pharmaceutical Care Attitudes Survey (PCAS), and several perceived barriers. A stratified sample of 193 students participated from six universities, 85% were females, 92.2% and 64.8% completed or engaged in community and hospital pharmacy training respectively, at the time of the study. Attitudes' items receiving the highest agreement were PC will improve patient health (95.3%), all pharmacists should perform PC (93.3%) and PC would benefit pharmacists (92.7%). However, 44.6% agreed PC is not worth the additional workload. Females showed higher attitudes' total scores, median (IQR): 55 (51-58) and 52 (49-55.5) for females and males respectively, P = 0.032. Having incomplete courses was also associated with lower scores, median (IQR): 55 (51-58) and 52 (48.5-55.5) for "No" and "Yes" respectively, P = 0.048. Poor image of the pharmacist's role and lack of private counseling area or inappropriate pharmacy layout were the most perceived barriers, with around 78% agreement. In conclusion, final year undergraduate pharmacy students in the UAE have positive attitudes towards pharmaceutical care. The current curricula may be satisfactory in fostering positive attitudes among students. Poor image of the pharmacist's role and lack of counseling area or inappropriate pharmacy layout were the main barriers identified, among other barriers

Knowledge, attitude and practice of antibiotic use among university students: a cross sectional study in UAE

Abstract Background Antibiotic resistance became a marker of irrational and overuse of these medicines in many countries. This study aims to evaluate the knowledge, attitude and practice (KAP) of medical students (MS) and non-medical students (NS) towards antibiotic use in the United Arabs Emirates (UAE). Method A descriptive cross-sectional study was conducted amongst 1200 MS and NS from Ajman University in UAE. A self-administered questionnaire was used to assess the knowledge, attitude and practice of antibiotic use. The later was composed into knowledge, attitude and practice of antibiotic use. Descriptive analysis was used to analyse the qualitative variables while quantitative variables were summarised using mean ± Standard Deviation (±SD). A Chi-square test was used to compare differences in the proportions of qualitative variables. Unpaired student’s t-test was used to test the average differences in quantitative variables across medical and non-medical students. A p < 0.05 was considered statistically significant. Results One thousand two hundred students (MS: 600 and NS: 600) were considered valid for analysis. On average, participants scored higher in attitude score followed by knowledge and practice scores. The average attitude score was 76% (95% CI: [75, 78%]) compared to 59% for knowledge (95% CI: [58, 60%]) and 45% (95% CI: [44, 47%]) for practice. The results suggest that overall, medical students scored remarkably better than non-medical students on KAP of antibiotic use, respectively (p = 0.0001), (p = 0.000) and (p = 0.002). Conclusion The students’ knowledge, attitude and practice regarding antibiotic use, which drive the practice of self-medication, reflect a gap in medical curricula in UAE institutes and medical colleges

Factors affecting pharmacist’s practice.

Factors affecting pharmacist’s practice.</p