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Contact lenses (CLs) offer a wide variety of advantages as ocular drug-releasing platforms, but the feasibility of medicated CL development is constrained by numerous scientific, technological, and regulatory challenges. One main difficulty is the setting of release rate specifications for each drug, since at present there are no standardized in vitro release models that can appropriately predict the performance of drug-eluting CLs once placed onto the eye. CL-adapted release tests may provide knowledge on how the drug release pattern should perform in vivo to trigger and maintain the therapeutic effects for both anterior and posterior ocular tissues. Moreover, in vitro release tests are valuable tools for quality assessment during production and to investigate the effect of a change in composition or process variables. This review aims to shed light on biorelevant ways of evaluating in vitro drug release from CLs and the feasibility of establishing in vitro-in vivo correlations (IVIVC) to predict in vivo performance. First, general guidelines and Pharmacopeia release tests for topical ophthalmic formulations as well as in vitro release tests implemented for drug-CLs in the last two decades are analyzed. Then, development of an appropriate method to investigate IVIVC is attempted from the few papers simultaneously reporting in vitro release profiles and either in vivo release or therapeutic response. Finally, key points to be considered for in vitro testing drug release from a medicated CL are suggested to pave the way to the clinical arena This project is funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Actions grant agreement N° 813440 (ORBITAL–Ocular Research by Integrated Training And Learning). The work was also partially supported by MCIN [PID2020-113881RB-I00/AEI/10.13039/501100011033] Spain, Xunta de Galicia [ED431C 2020/17], and FEDER SI

The increasing complexity in morphology and composition of modern biomedical materials (e.g., soft and hard biological tissues, synthetic and natural‐based scaffolds, technical textiles) and the high sensitivity to the processing environment requires the development of innovative but benign technologies for processing and treatment. This scenario is particularly applicable where current conventional techniques (steam/dry heat, ethylene oxide, and gamma irradiation) may not be able to preserve the functionality and integrity of the treated material. Sterilization using supercritical carbon dioxide emerges as a green and sustainable technology able to reach the sterility levels required by regulation without altering the original properties of even highly sensitive materials. In this review article, an updated survey of experimental protocols based on supercritical sterilization and of the efficacy results sorted by microbial strains and treated materials was carried out. The application of the supercritical sterilization process in materials used for biomedical, pharmaceutical, and food applications is assessed. The opportunity of supercritical sterilization of not only replace the above mentioned conventional techniques, but also of reach unmet needs for sterilization in highly sensitive materials (e.g., single‐use medical devices, the next‐generation biomaterials, and medical devices and graft tissues) is herein unveiled.

Introduction: Diabetes is a pandemic disease that causes relevant ocular pathologies. Diabetic retinopathy, macular edema, cataracts, glaucoma, or keratopathy strongly impact the quality of life of the patients. In addition to glycemic control, intense research is devoted to finding more efficient ocular drugs and improved delivery systems that can overcome eye barriers. Areas covered: The aim of this review is to revisit first the role of diabetes in the development of chronic eye diseases. Then, commercially available drugs and new candidates in clinical trials are tackled together with the pros and cons of their administration routes. Subsequent sections deal with self-assembled drug carriers suitable for eye instillation combining patient-friendly administration with high ocular bioavailability. Performance of topically administered polymeric micelles, liposomes, and niosomes for the management of diabetic eye diseases is analyzed in the light of ex vivo and in vivo results and outcomes of clinical trials. Expert opinion: Self-assembled carriers are being shown useful for efficient delivery of not only a variety of small drugs but also macromolecules (e.g. antibodies) and genes. Successful design of drug carriers may offer alternatives to intraocular injections and improve the treatment of both anterior and posterior segments diabetic eye diseases This project is funded by Horizon 2020 Marie Sklodowska-Curie Actions [grant agreement – No 813440] SI

Hierarchically porous synthetic bone grafts (scaffolds) are gaining attention in the clinical arena. Scaffolds should combine morphological (macro- and microporosity, pore interconnectivity), mechanical and biological (biocompatibility, degradation rate) properties to fit this specific use. Supercritical (sc-) foaming is a versatile scaffold processing technology. However, the selection of the optimum operating conditions to obtain a defined scaffold structure is hampered by the lack of a single characterization technique able to fully elucidate the porous features of the resulting scaffolds. In this work, the effect of soaking time (1, 3 and 5 h) on the preparation of poly(ε-caprolactone) (PCL, 50 kDa) scaffolds by sc-foaming was evaluated by a combined X-ray microtomography (μ-CT) and mercury intrusion porosimetry (MIP) 3D-morphological analysis. Mechanical tests and in silico modelling for cell penetration and water permeability of the scaffolds were also conducted. Results evidenced the relevance of μ-CT and MIP as a synergistic analytical duo to fully elucidate the morphology of the sc-foamed scaffolds and the soaking time effect.

Objectives: rAAV vectors are attractive tools for the durable treatment of human osteoarthritis (OA). Still, their adapted use in vivo is impaired by neutralizing antibodies against viral capsid elements in patients. Delivery of rAAV via polymeric micelles may allow overcoming these hurdles. Here, we[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Encapsulating technologies that render spherical particles containing cells or relevant moleculeshave been developed to be used in fields such as tissue engineering, pharmaceutics, cosmetics, agriculture, as also in other bio-related applications, namely biosensors and bioreactors. The multiple bioactive agents release, with an important role in tissue regeneration, constitutes an important strategy in tissue engineering. The control of bioactive agents release may be achieved increasing the complexity of the encapsulating particles by adjusting the chemistry and the architecture. In this context, multi-compartmentalized systems able to simultaneously deliver various bioactive agents at different kinetics have emerged and are envisioned to be the next area of development. Multilayered particles exhibiting predefined diameters and layers thickness may offer additional advantages including higher bioactive agents loads, improved molecules stability, and tailored release schedules such as delayed or pulsatile avoiding initial bursts. The most external layers could even act as rate-limiting barriers to further reduce burst release. Since multilayered particles are compartmented, each particle can load multiple bioactive agents isolated from each other. Similarly, more than one type of cells may be immobilized into different compartments. The layers thickness and composition determine the performance of the system. Compared to monocompartment delivery systems, the development of multi-compartmented structures is still immature and intensive efforts are being done to efficiently produce this type of systems. The production of multi-compartmented particles is quite challenging and the existing methodologies involve wet and aggressive conditions that compromise the encapsulation efficiency of bioactive agents and the viability of cells. Herein we report a simple bottom-up approach suitable for preparing multilayered polymeric particles in a very fast way, which involves the use of biomimetic superhydrophobic surfaces. In the present work, concentric multilayered polymeric particles were prepared by adding layers one-by-one, and then their applications as carriers for sequential multiple drug release and as scaffolds for cells immobilization intended in cell therapies or tissue engineering were explored. The results showed that the engineered particles can be loaded with different molecules confined in different compartments for later sequential and time-programmed release. They can also immobilize cells maintaining them viable for long time, being potentially useful for cell-based therapies.

High-throughput studies in biotechnology areas such as drug screening and tissue engineering have been carried out mainly in 2D environment. However, the low clinical and biological relevance of 2D models is well known. Both in tissues and tumor masses, cells lie in a 3D configuration organized in the self-secreted microenvironment: the extracellular matrix (ECM). In this milieu, cells interact in a totally natural manner, without the interaction of foreign factors, such as materials. The demand for studies using organotypic models is increasing, in order to improve the relevance of the findings achieved in these areas of study. A solution to create such organotypic models is the in vitro construction of cell spheroids. These are micro-masses of cells formed from a cell suspension, where the attachment of cells to any surface is not promoted. As such, cells tend to attach between themselves and form an organized mass, constituted by cells in combination with ECM. Some types of spheroids are grown in order to mimic tumor models: the living spheroid structure contains a necrotic core, similarly to the native tumors. Cell spheroids are also useful as models for the development of complex microtissues [1], and can also be used as building blocks of larger tissues. Several methods to produce cell spheroids are reported in the literature. The hanging drop method is one of those methods: the cells are pulled to the concave bottom of a hanging droplet by gravity effect, and tend to start the natural organization by cell-cell attachment and production of ECM. We propose the use of superhydrophobic surfaces patterned with wettable regions as platforms for the affordable and scale-up production of cell spheroids by the hanging drop method. Moreover, we used the platform - whose wettable regions are transparent and whose drop has its surface totally exposed to the external media allowing its facilitated manipulation – as high-throughput screening platform for drug testing and on-chip cell response analysis by microscopy. For the proof-of-concept we dispensed cell suspensions of distinct cell types (L929 and SaOs-2) with different cell concentrations in the array of wettable regions of the chips. We tested the effect of a cytostatic drug used in clinical practice (doxorubicin), also dispensed in a combinatorial logic in each spot of the chip. By on-chip microscopy analysis we proved the suitability of such platforms for drug screening using tumor-like models.

CAPES A glibenclamida (GLIB) é um hipoglicemiante oral amplamente utilizado no tratamento do diabetes mellitus II, no entanto, apresenta baixa solubilidade e alterações na biodisponibilidade. A prospecção de artigos e patentes averiguou o panorama das pesquisas envolvendo seu problema de solubilidade e corroborou com a importância do desenvolvimento de novos sistemas de liberação. Neste contexto, o desenvolvimento de nanopartículas (NP) contendo Hidróxidos Duplos Lamelares (HDL) organomodificados por dodecilsulfato de sódio carreando GLIB apresentou-se como uma possível alternativa para aumentar a taxa de dissolução e promover sua liberação controlada. A síntese foi realizada através de coprecipitação, as NP foram caracterizadas difratometricamente, espectroscopicamente, termicamente, avaliadas quanto ao perfil de co-liberação de GLIB e zinco e quanto a compatibilidade celular. Além disso, a eficácia e nanotoxicidade foram avaliadas através do tratamento de ratos Wistar induzidos ao diabetes com streptozotocina. Os parâmetros clínicos foram monitorados ao longo de todo o tratamento e os parâmetros bioquímicos, hematológicos e histológicos foram avaliados ao fim do tratamento. Além disso, a síntese das NP foi monitorada através da espectroscopia no infravermelho próximo e avaliada quimiometricamente para explicar o mecanismo e a cinética de formação dos HDL. Os dados mostraram adsolubilização de GLIB e revestimento de NP com Eudragit L100®. A organofilização do HDL e a intercalação da GLIB reduziram a área superfícial (SBET 23,58 m²/g) e observou-se mudança no potencial zeta (-35,5 ζ) em relação ao HDL primitivo (Sʙᴇᴛ 41,34 m²/g, 688,8 nm e +14 ζ) indicando que a funcionalização parece uma abordagem apropriada para produzir NP com maior estabilidade coloidal e funcionalidade aprimorada. Os dados de liberação de zinco (2,96% ± 0,002 ppm) mostraram a eficácia do revestimento em meio ácido e os dados de liberação da GLIB mostraram cinética de liberação de ordem zero com liberação no meio intestinal. Todas as NP foram considerados biocompatíveis e os ensaios de nanotoxicidade e eficácia mostraram a boa resposta clínica para o monitoramento da massa corporal, consumo de ração, consumo de água e capacidade de controle glicêmico das nanopartículas em comparação aos controles ao logo do tratamento. Os ensaios bioquímicos, hematológicos e histológicos realizados ao fim do tratamento também comprovaram ausência de toxicidade das NP e redução significativa da glicemia (111±25mg/dL) em relação ao grupo diabético não tratado (498±26mg/dL) e diabético tratado com a GLIB (421,5±35mg/dL). Para o monitoramento da síntese dos HDL inicialmente partículas instáveis (ζ

Tese de doutoramento em Ciências e Tecnologias da Saúde na especialidade de Biotecnologia, apresentada à Faculdade de Farmácia da Universidade de Coimbra.

Tese de doutoramento em Farmácia (Tecnologia Farmacêutica), apresentada à Faculdade de Farmácia da Universidade de Coimbra O glaucoma é um grupo de doenças que tem em comum uma neuropatia ótica característica, com perda das células ganglionares e cujo principal fator de risco é o aumento da pressão intraocular. A administração de fármacos para o tratamento destas enfermidades oculares é extremamente necessária e, preferencialmente, por meio de vias que atinjam o tecido local, visando reduzir a ocorrência de efeitos indesejáveis e a absorção sistémica. As formas farmacêuticas oftálmicas convencionais (ex: soluções, suspensões, pomadas) apresentam baixa biodisponibilidade na córnea, devido aos mecanismos de defesa do olho e à drenagem nasolacrimal. Recentes esforços de pesquisa têm-se centrado no desenvolvimento de novos sistemas de cedência de fármacos oftálmicos. Neste trabalho procurou-se desenvolver sistemas que fossem capazes de aumentar a solubilidade de fármacos e cedê-los continuamente em níveis elevados e controlados. Entre as novas abordagens terapêuticas em oftalmologia, optou-se pelo uso das micelas poliméricas e ciclodextrinas. Estas representaram excelentes ferramentas no aumento da solubilidade dos inibidores da anidrase carbónica, nomeadamente a acetazolamida e a etoxzolamida, e também podem vir a facilitar o seu acesso através da córnea. Ao mesmo tempo prepararam-se hidrogeles (lentes de contacto) capazes de atuar como sistemas de entrega controlada de fármacos no fluido lacrimal pós-lente. Para o seu desenho utilizaram-se duas abordagens: (i) incorporação das ciclodextrinas (de forma direta ou na preparação de monómeros) à rede polimérica para fazer uso da sua capacidade de formar complexos de inclusão com os fármacos e, (ii) copolimerização e síntese de monómeros que apresentam grupos funcionais similares à dos aminoácidos, que constituem o local ativo da enzima anidrase carbónica. Esta abordagem biomimética combinada com a técnica de impressão molecular originou redes poliméricas que possuem cavidades com alta afinidade pelos fármacos e proporcionou um carregamento mais elevado dos mesmos e uma melhor controlo do processo de libertação. Glaucoma is a group of diseases that have in common a characteristic optic neuropathy with loss of ganglion cells, whose main risk factor is increased intraocular pressure. The administration of drugs for the treatment of eye disorders becomes extremely necessary and, preferably, through routes that reach the local tissue to reduce the occurrence of side effects and systemic absorption. Conventional ophthalmic dosage forms (e.g. solutions, suspensions, ointments) lead to low bioavailability in the cornea, due to the protective mechanism of the eye and her nasolacrimal drainage. Recent research efforts have focused on developing new systems ophthalmic delivery. In this work we seek to develop systems that are able to increase the solubility of drugs and to continually deliver high and sustained levels of the same. Among the new therapeutic approaches in ophthalmology, we chose polymeric micelles and cyclodextrins as tools for increasing the solubility of carbonic anhydrase inhibitors, including acetazolamide and ethoxzolamide, and also for facilitating the cornea penetration. At the same time we prepared hydrogels useful as components of soft contact lenses able to sustain drug release in the post-lens lacrymal fluid. Two approaches were tested for their design: (i) incorporation of cyclodextrins (as such or prior preparation of monomers), the polymer network to make use of their ability to form complexes with drugs and (ii) copolymerization of monomers which have similar functional groups to the amino acids that constitute the active site of the enzyme carbonic anhydrase. This biomimetic approach combined with molecular imprinting technique originated polymer networks that have cavities with high affinity for drugs and provided a higher loading of drugs and an improved control of the release process. Fundação para a Ciência e a Tecnologia (SFRH/BD/40947/2007)