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Väitekirja elektrooniline versioon ei sisalda publikatsioone, Personaal- ehk täppismeditsiini abil soovitakse haiguseid ennetada, diagnoosida ja ravida viisil, mis saavutaks parima tulemuse konkreetsel patsiendigrupil. Mitmekülgsete teadmiste kasutamine sobivaima raviaine, annuse ja ravimvormi valimisel aitab kaasa oodatud ravitulemuse saavutamisele. Neid teadmisi aitab rakendada kolmemõõtmeline (3D) printimine. Tegu on meetodiga, kus arvuti abil disainitud mudel ehitatakse kiht kihi haaval soovitud objektiks. Sõltuvalt kihi lisamise viisist jaguneb 3D printimine erinevateks meetoditeks. Meetodi valik aga omakorda võib seada materjalide valikule lisatingimusi. 3D printimine sai alguse 1980ndatel ning on viimastel aastatel jõudnud ka meditsiinivaldkonda. Kirjandusest leiab põhjalikke ülevaateid selle kasutamisest nt kardioloogias, hambaravis, plastilises kirurgias, bioprintimisel. Ravimitööstuses nähakse 3D printimises võimalikku abimeest personaliseeritud ravimite tootmisel. Aastal 2015 sai müügiloa esimene 3D prinditud ravim Spritam®. Doktoritöös kasutati mikroekstrusioonil ning sulatatud sadestusega modelleerimisel põhinevaid printimistehnoloogiaid. Mõlema meetodi jaoks disainiti sobilik ravi- ja abiainete kombinatsioon. Sobivateks kandurpolümeerideks osutusid polüetüleenoksiid ja polükaprolaktoon, raviaineteks indometatsiin ja teofülliin. Sarnaselt klassikalisele ravimiarendusele vajab ka uudsete tehnoloogiate kasutuselevõtt põhjalikku eeltööd, et õppida tundma kasutatavate materjalide omadusi ning võimalikke protsessi ajal toimuvaid muutuseid. Seetõttu uuritigi doktoritöös nii materjalide printimiseelseid omadusi, näiteks viskoossus, füüsikalised omadused, sobivus filamentide tootmiseks jt kui ka saadud ravimkandursüsteemi printimisjärgseid omadusi nagu raviaine vabanemine, reageerimine kuumutamisele ja kiiritamisele. Lisaks töötati välja uudne meetod pooltahkete materjalide 3D-prinditavuse hindamiseks. Töö tulemused kinnitavad, et 3D printimine on farmaatsiateaduse jaoks paljulubav abimees tulevikuravimite arendamisel., Precision medicine is an approach to enhance the prevention, diagnosis, and treatment of diseases to benefit a specific group of patients. Using this knowledge to select the most suitable active pharmaceutical ingredients (APIs) and doses enables us to achieve the optimal therapeutic efficiency. Three-dimensional (3D) printing is an additive manufacturing technique that has been proposed as tool for the application of these principles. In 3D printing, previously designed model is then layer-by-layer formed into desired object. 3D printing methods differ from each other based on layer formation and can dictate additional material considerations. 3D printing has been studied since 1980s and has been widely used in medicine these previous years. In pharmaceutics, 3D printing can be seen as a possible aid for fabricating personalised drug delivery systems. In 2015 the first 3D printed medicine Spritam® was authorised. In this dissertation, micro-extrusion-based and fused deposition modelling 3D printing methods were used. Suitable active substance and excipient(s) formulations were designed for both methods. Polymers used were polyethylene oxide and polycaprolactone, active substances indomethacin and theophylline. As classical does development, so does the implementation of novel technologies need thorough knowledge of material and process characteristics. Therefore, bulk material properties such as viscosity, physical characteristics, suitability for filament extrusion etc, and final drug delivery system characteristics such as drug release, reaction to heat and radiation were studied. In addition, a novel method for evaluating the 3D printability was designed. We can conclude from the results of this work, that 3D printing promises great aid in developing novel drug delivery systems., https://www.ester.ee/record=b5485778

Magistritöö Loodusturismi õppekaval Veekogud pakuvad hulgaliselt erinevaid võimalusi aeru- ja purjelauaga sõitmiseks. Surfamise võib liigitada nii spordi, rekreatiivse tegevuse kui ka turismi alla, olles samal ajal tugevalt seotud elustiiliga. Eestis on võimalik surfamisega tegeleda aastaringselt, kevadest sügiseni vee peal ja talisurfates jääl ning lumel. Töö eesmärgiks on kaardistada Eesti aeru- ja purjelauateenuse pakkujate ja harrastajate profiil, peamised sihtkohad ning teadlikkus veeohutusest ja mõjudest looduskeskkonnale. Autor viis läbi 10 intervjuud aeru- ja purjelauateenuse pakkujatega ning küsitluses osales 55 harrastajat. Aeru- ja purjelauasõitjad on iseõppijad ning instruktoreid koolitatakse üldjuhul surfiklubides kohapeal. Surfamine sobib igas vanuses inimestele ning suurimaks sõitma õppimise eelduseks on soov ennast sel alal arendada. Purjelauasõitjad on Eestis kogunenud rannikualadele, aerulauasõitjaid võib näha väga erinevatel veekogudel. Aeru- ja purjelauasõitjad ning teenusepakkujad on keskkonnateadlikud inimesed ning kuna nad veedavad palju aega looduses on vajalik keskkonnakaitselistes küsimustes ka nende arvamusi kuulda võtta. Veeohutuses on tähtsal kohal ilmastikuolude jälgimine ja ohutusvesti kandmine. Different water bodies offer a wide range of opportunities for stand up paddleboarding (SUP) and windsurfing. Surfing can be classified as sport, recreational activity or tourism, while being strongly connected to lifestyle. In Estonia, it is possible to surf all year round. From spring to autumn on the water and on ice and snow in winter. The purpose of this study was to map the profile of Estonian SUP and windsurfing service providers and participants, the main destinations and awareness of water safety and impacts on the natural environment. The author interviewed 10 SUP and windsurfing service providers and in form got 55 participants replies. SUP and windsurfing are self-taught and instructors are usually trained in on-site surf clubs. Surfing is suitable for people of all ages, and the will to learn is the most important quality. Windsurfers gather mostly in coastal areas of Estonia, but stand up paddleboarders can be seen on very different bodies of water. SUP and windsurfing service providers are environmentally conscious people, and as they spend a lot of time in the natural environment, it is necessary to hear their views on environmental issues. On water safety it is important to pay attention to weather contitions and to wear PFD.

Hot-melt extruded (HME) filaments are an essential intermediate product for the three- dimensional (3D) printing of drug delivery systems (DDSs) by the fused deposition modelling (FDM) process. The aim of this study was to design novel polymeric 3D-printable HME filaments loaded with active pharmaceutical ingredients (APIs). The physical solid-state properties, mechanical properties, drug release and short-term storage stability of the filaments and 3D-printed DDSs were studied. Physical powder mixtures of polycaprolactone (PCL), plasticizer and API were manually blended, extruded by a single-screw extruder, and printed by a table-top FDM 3D-printing system. The composition of PCL and arabic gum (ARA) enabled the incorporation of 20%, 30% and 40% (w/w) of indomethacin (IND) and theophylline (THEO) into the HME filaments. The uneven distribution of API throughout the filaments impaired 3D printing. The HME filaments loaded with 20% IND or THEO were selected for the further analysis and printing tests (the ratio of PCL, ARA and IND or THEO was 7:1:2, respectively). The IND filaments were yellowish, mechanically strong and flexible, and they had a uniform filament diameter and smooth outer surface. The filaments containing THEO were smooth and off-white. The 3D-printed tablets fabricated from IND or THEO-loaded filaments showed sustained drug release in vitro. The drug release rate, however, significantly increased by changing the geometry of 3D-printed tablets from a conventional tablet structure to an unorthodox lattice ("honeycomb") structure. Overall, the combination of PCL and ARA provides an interesting novel polymeric carrier system for 3D-printable HME filaments and tablets.

Crosslinking is an established treatment to alter the physicochemical and functional properties of polymers through the creation of bonds between the polymer chains. Polymers can be crosslinked via radiation in the presence of photo-initiator. The aim of the present study was to formulate 3D-printed theophylline (THEO) tablets using polyethylene oxide (PEO) as a carrier polymer, and to study the influence of crosslinking on the drug release behavior. The tablets were 3D-printed using the aqueous solution of PEO and THEO (80:20 w/w) with a micro-extrusion-based printing setup. A photo-initiator (4-hydroxybenzophenone) was added into the printing solutions, and the injectability of the solutions was investigated prior to printing. The 3D-printed tablets were crosslinked after printing using ultraviolet (UV) or gamma-radiation, and crosslinking was verified by means of Fourier-transform infrared (FTIR) spectroscopy. The maximum injection force of aqueous printing solutions of PEO and THEO was close to that observed with the pure PEO solution. Increasing the number of printing layers in the 3D-printed tablets resulted in a slower drug release in vitro. Gamma-radiation in a nitrogen environment and UV-crosslinking made the carrier polymer (PEO) less water-soluble, but such crosslinking did not affect the release rate of the tablets. Surprisingly, even faster drug release behavior was found with the crosslinked 3D-printed tablets compared to that of non-crosslinked tablets. More research work is needed on the impact of 3D-printed tablet layering thickness and crosslinking for tailoring drug release behavior.

Polymeric wound dressings with advanced properties are highly preferred formulations to promote the tissue healing process in wound care. In this study, a combinational technique was investigated for the fabrication of bi-layered carriers from a blend of polyvinyl alcohol (PVA) and sodium alginate (SA). The bi-layered carriers were prepared by solvent casting in combination with two surface modification approaches: electrospinning or three-dimensional (3D) printing. The bi-layered carriers were characterized and evaluated in terms of physical, physicochemical, adhesive properties and for the safety and biological cell behavior. In addition, an initial inkjet printing trial for the incorporation of bioactive substances for drug delivery purposes was performed. The solvent cast (SC) film served as a robust base layer. The bi-layered carriers with electrospun nanofibers (NFs) as the surface layer showed improved physical durability and decreased adhesiveness compared to the SC film and bi-layered carriers with patterned 3D printed layer. Thus, these bi-layered carriers presented favorable properties for dermal use with minimal tissue damage. In addition, electrospun NFs on SC films (bi-layered SC/NF carrier) provided the best physical structure for the cell adhesion and proliferation as the highest cell viability was measured compared to the SC film and the carrier with patterned 3D printed layer (bi-layered SC/3D carrier). The surface properties of the bi-layered carriers with electrospun NFs showed great potential to be utilized in advanced technical approach with inkjet printing for the fabrication of bioactive wound dressings.

https://www.ester.ee/record=b5168339*est

Printing technologies combined with a computer-aided design (CAD) have found an increasing number of uses in pharmaceutical applications. In extrusion-based printing, the material is forced through a nozzle to form a three-dimensional (3D) structure pre-designed by CAD. The aim of this study was to evaluate the 3D-printability of biocompatible aqueous poly(ethylene oxide) (PEO) gels and to investigate the effects of three formulation parameters on the 3D printing process. The impact of PEO concentration (gel viscosity), printing head speed and printing plate temperature was investigated at three different levels using a full factorial experimental design. The aqueous PEO gels were printed with a bench-top extrusion-based 3D printing system at an ambient room temperature. The viscosity measurements confirmed that the aqueous PEO gels follow a shear-thinning behaviour suitable for extrusion-based printing. Heating the printing plate allowed the gel to dry faster resulting in more precise printing outcome. With the non-heated plate, the gel formed a dumbbell-shaped grid instead of straight lines. Higher concentration and more viscous PEO gels formed the best structured 3D-printed lattices. In conclusion, the accuracy and precision of extrusion-based 3D printing of aqueous PEO gels is highly dependent on the formulation (PEO concentration) and printing parameters (printing head speed, plate temperature). By optimizing these critical process parameters, PEO may be suitable for printing novel drug delivery systems.

Reactive oxygen species (ROS) play important roles in cellular senescence and organismic aging. Furthermore, they have been implicated in some of the adverse effects of chronic stress due to elevated peripheral levels of catecholamines. Here, we applied three different techniques to individually compare the systemic and intracellular oxidative stress in aged (23 months) and young (5 months) Sprague-Dawley rats, and in young rats treated for 12 or 24 h with norepinephrine (NE). Thiol groups of blood serum proteins (RSH) were determined by means of Ellman's reaction. Intracellular ROS were assessed in spleen cells and peripheral blood lymphocytes (PBL) by carbonylation of cellular (spleen) proteins as determined by immunoblotting (Oxyblot) and/or by means of 2',7'-dichlorofluorescein (DCF) fluorescence. As compared to the young, untreated controls, both old rats and NE treated young rats showed similarly lowered RSH values paralleled by elevated intracellular ROS levels or enhanced Oxyblot signals. Individual RSH values were highly significantly, negatively correlated with respective Oxyblot data as well as with DCF fluorescence. The results confirm the roles of ROS in aging and adrenergic stress in the rat model, and suggest that the decrease in RSH of blood serum may be taken as a valid indicator for the enhanced oxidative stress in lymphocytes.

Background and aims: Moderate physical exercise and dietary restriction have both been demonstrated to delay some of the adverse effects of aging. In order to elucidate similarities or dissimilarities in their mode of action on the aging immune system in a comparative setting, we examined significant parameters of cell-mediated immunity in Sprague- Dawley rats. Methods: Male Sprague-Dawley rats, housed individually, were divided into four groups, living from 5 months (baseline group BL) up to 15, 19 and 23 months of age as follows: voluntary running in wheels (RW), food restricted by feeding to pair weight with RW animals (PW), forced running on treadmills (TM), and sedentary controls with ad libitum access to food (S1). White blood cell counts, capacity for lymphocyte proliferation in response to Concanavalin A, and interleukin-2 (IL-2) plasma concentrations were determined. Results: White blood cell counts and the cell numbers of lymphocytes, neutrophil and eosinophil granulocytes were significantly lower in the older RW and PW groups. We observed influences of forced exercise on lymphocyte proliferation: blastogenic reactivity was higher in TM animals compared with RW and PW animals at 23 months of age. Exclusively for RW animals, we found lower plasma concentrations of IL-2 at 23 months. Conclusions: Our data support the idea that moderate physical exercise modulates age-associated decline in the cell-mediated immunity of old Sprague-Dawley rats significantly more than corresponding dietary restrictions.

Background and Aims: Moderate physical exercise, dietary restriction as well as enriched environment in separate studies have been reported to delay some of the adverse effects of aging on brain function, parallel to an increase in brain-derived neurotrophic factor (BDNF). In order to elucidate these influences in a comparative setting, we examined the tissue concentrations of BDNF in the cerebral parietotemporal cortex of old Sprague-Dawley rats. Methods: Male Sprague-Dawley rats were divided randomly into six groups, living from 5 months (baseline group BL) up to 23 months of age as follows: voluntary running in wheels (RW), food restricted by feeding to pair weight with RW animals (PW), forced running on treadmills (TM), and sedentary controls with ad libitum access to food, either housed individually (S1) or in groups of 4 animals (S4). BDNF concentrations were determined by a commercially available ELISA. Results: We found higher BNDF concentrations in the 5 months old animals than in the 23 months old animals of group S1. The old sedentary group S4 showed significantly higher BNDF concentrations in comparison with the old individually caged groups RW, TM, PW and S1. Their BNDF concentrations were even higher than those of the young baseline group. Conclusions: Our data suggest that housing and social interactions have more influence on BDNF concentrations in the cerebral parietotemporal cortex of aging Sprague-Dawley rats than physical exercise and food restriction.

Elderly people report less negative affect than the young, and women report more negative affect than men. This study investigated whether age and gender differences in negative affect could be explained by emotion regulation, measured as defensiveness and rumination, while controlling for the influence of life events. One-hundred-and-ninety-five young (20–35 years) and 302 elderly (70–85 years) men and women completed the Emotional Control Questionnaire-Rehearsal, Marlowe–Crowne Social Desirability Scale, Profile of Mood States, Beck’s Depression Inventory and List of Recent Experiences. Hierarchical regressions with negative affects as dependent variables showed that age was reduced to non-significance when controlling for defensiveness, and gender was reduced to non-significance when controlling for the interaction between age and gender, which in turn was reduced when entering rumination. Life events also influenced the association between age and negative affect. The results indicate that age differences in negative affect are mediated by defensiveness and life events and that when these two influences are accounted for elderly people score higher on sadness. Gender differences in negative affect were due to the young women’s higher scores on negative affect and this is partly explained by rumination.

Extensive research has been conducted on the level and the predictors of well-being in old age, but less is known about the cognitive processes used by the aging individual to evaluate life satisfaction. To investigate the relationship between well-being in the present and in previous decades in life and explore the cognitive processes involved in these evaluations, 203 old participants aged 70-85 years were interviewed and their level of present life satisfaction and depressive symptoms was measured. One year later, depressive symptoms were recorded for a follow-up sample of 65 participants. The results showed that evaluating old age as the best part of life was related to increased well-being. Evaluations of positive periods in life were based on general positive qualities, whereas specific negative events were given as reasons for nominations of negative periods in life. Deviations from this general pattern were related to lower levels of well-being. Use of comparison strategies to evaluate present life satisfaction was frequently reported, and the use of temporal comparisons was predictive of changes in depression over a one-year period. The present study indicates that the cognitive processes used in the evaluation of life satisfaction are related to present and future well-being.

Background: Obesity combined with decreasing physical fitness in the ageing Western populations promotes a number of degenerative diseases, including chronic kidney disease. It has further been shown in rodent models that prevention of obesity by food restriction mitigates development of kidney lesions. Whether lifelong physical activity also has a positive effect is not known. Objective: To compare the effects of physical exercise and food restriction on the development of chronic kidney lesions in ageing rats. Methods: Male Sprague-Dawley rats were divided into groups: voluntarily running in wheels (RW), food restriction to the degree necessary to attain pair weight to RW rats (PW), forced running in treadmills (TM) and sedentary controls housed individually (S1) or 4 in each cage (S4). The interventions began at the age of 5 months and kidneys were sampled and analysed histologically at the ages of 15, 19 and 23 months. Results: Total score for kidney lesions (sum of the scores for glomerular changes, interstitial non-purulent inflammation, proteinaceous casts in tubules and increased amount of connective tissue, the possible maximum being 10.0) increased from 0.5 ± 0.2 at 5 months of age to 1.6 ± 0.3 for RW, 2.3 ± 0.4 for PW, 4.5 ± 0.4 for TM, 3.6 ± 0.5 for S1 and 5.4 ± 0.6 for S4 at the age of 23 months. The increase from 5 months of age was gradual for all groups through 15, 19 and 23 months. The patterns for the various lesions followed the same pattern with the exception of connective tissue, which did not increase. Conclusion: Voluntary running in wheels is as effective in mitigating kidney lesions as is food restriction, while forced running in a treadmill is not effective in this respect.

Background and aims: Obesity and lack of physical exercise characterize increasing numbers of people in Western societies, resulting in increasing morbidity and mortality. Regular physical exercise, on the other hand, has been shown to be beneficial. Beneficial effects have also been shown in laboratory rodent studies - lifelong physical exercise increases the mean life span but not the maximum life span, while food restriction increases both life spans. We studied male Sprague-Dawley rats in order to further analyze these beneficial effects. Methods: We compared voluntary running in wheels (RW) with food restriction to pair weight with RW (PW), and mild forced running in treadmill (TM) - all animals housed individually. Control groups were sedentary ad libitumfed animals housed individually (S1) and four to a cage (S4). The collagen biomarker of aging was calculated as a composite parameter from thermal stability data for 5 (baseline), 15, 19 and 23 months of age. Results: In RW and PW, the increase in the composite parameter was retarded to the same extent. The retardation in TM was less efficient. S4 had the highest value for the composite parameter, together with the highest body weight and fat content. In groupwise comparisons, the composite parameter tended to predict survival in the groups up to the age of 23 months. Conclusions: Voluntary running in wheels is more beneficial than mild-forced exercise on the treadmill. The composite parameter is a useful indicator of different interventions on aging rats.