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This study aims to investigate the effect of the preparation of solid dispersions using supercritical CO 2 (scCO 2 ) on the physicochemical properties and the performance of supramolecular gels based on polymer-cyclodextrin (CD) interactions (named poly(pseudo)rotaxanes, PPR) envisaging a transdermal administration. Solid dispersions containing Soluplus ® , the antihypertensive drug carvedilol (CAR), and CD (αCD or HPβCD) were prepared and characterized by HPLC, XRPD, FTIR, and DSC. PPRs prepared from solid dispersions (SCF gels) and the corresponding physical mixtures (PM gels) were analyzed regarding rheology, morphology, in vitro drug diffusion, and ex vivo drug skin permeation. The application of scCO 2 led to the loss of the crystalline lattice of CAR while preserving its chemical identity. On the contrary, αCD crystals were still present in the SCF solid dispersions. SCF gels were more uniform than their corresponding PM, and the supercritical treatment resulted in changes in the rheological behavior, reducing the viscosity. CAR in vitro diffusion was significantly higher (p < 0.05) for the αCD-based SCF gel than its corresponding PM gel. Drug skin permeation showed a significant increase in drug flux from CD-based SCF gels (containing αCD or HPβCD) compared to corresponding PM gels. Additionally, the pretreatment of the skin with αCD exhibited increased CAR permeation, suggesting an interaction between αCD and the skin membrane. Results evidenced that SCF processing decisively modified the properties of the supramolecular gels, particularly those prepared with αCD., (© 2023. The Author(s).)

Chronic retinal diseases, such as age-related macular degeneration (AMD), are a major cause of global visual impairment. However, current treatment methods involving repetitive intravitreal injections pose financial and health burdens for patients. The development of controlled drug release systems, particularly for biological drugs, is still an unmet need in prolonging drug release within the vitreous chamber. To address this, green supercritical carbon dioxide (scCO 2 ) foaming technology was employed to manufacture porous poly(lactic-co-glycolic acid) (PLGA)-based intravitreal implants loaded with dexamethasone. The desired implant dimensions were achieved through 3D printing of customised moulds. By varying the depressurisation rates during the foaming process, implants with different porosities and dexamethasone release rates were successfully obtained. These implants demonstrated controlled drug release for up to four months, surpassing the performance of previously developed implants. In view of the positive results obtained, a pilot study was conducted using the monoclonal antibody bevacizumab to explore the feasibility of this technology for preparing intraocular implants loaded with biologic drug molecules. Overall, this study presents a greener and more sustainable alternative to conventional implant manufacturing techniques, particularly suited for drugs that are susceptible to degradation under harsh conditions., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The outbreak of COVID-19 pandemic unveiled an unprecedented scarcity of personal protective equipment (PPE) available in sanitary premises and for the population worldwide. This situation fostered the development of new strategies to reuse PPE that would ensure sterility and, simultaneously, preserve the filtering properties of the materials. In addition, the reuse of PPEs by reprocessing could reduce the environmental impact of the massive single-use and disposal of these materials. Conventional sterilization techniques such as steam or dry heat, ethylene oxide, and gamma irradiation may alter the functional properties of the PPEs and/or leave toxic residues. Supercritical CO 2 (scCO 2 )-based sterilization is herein proposed as a safe, sustainable, and rapid sterilization method for contaminated face masks while preserving their performance. The functional (bacterial filtration efficiency, breathability, splash resistance, straps elasticity) properties of the processed FFP3 face masks were evaluated after 1 and 10 cycles of sterilization. Log-6 sterilization reduction levels were obtained for face masks contaminated with Bacillus pumilus endospores at mild operating conditions (CO 2 at 39 °C and 100 bar for 30 min) and with low contents of H 2 O 2 (150 ppm). Physicochemical properties of the FFP3 face masks remained unchanged after reprocessing and differences in efficacy were not observed neither in the filtration tests, following UNE-EN 14683, nor in the integrity of FFP3 filtration after the sterilization process. The herein presented method based on scCO 2 technology is the first reported protocol achieving the reprocessing of FFP3 masks up to 10 cycles while preserving their functional properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The access of biodegradable scaffolds to the clinical arena is constrained by the absence of a suitable sterilization technique for the processing of advanced polymeric materials. Sterilization with supercritical CO 2 (scCO 2 ) may circumvent some technological limitations (e.g., low temperature, no chemical residues on the material), although scCO 2 can plasticize the polymer depending on the processing conditions used. In this latter case, the integration of the manufacturing and sterilization processes is of particular interest to obtain sterile and customized scaffolds in a single step. In this work, scCO 2 was exploited as a concomitantly foaming and sterilizing agent for the first time, developing a one-step process for the production of vancomycin-loaded poly(ε-caprolactone) (PCL) bone scaffolds. The effect of the CO 2 contact time on the sterility levels of the procedure was investigated, and the sterilization efficiency was evaluated against dry spores (Bacillus stearothermophilus, Bacillus pumilus and Bacillus atrophaeus). Vancomycin-loaded PCL scaffolds had relevant sustained release profiles for the prophylaxis of infections at the grafted area, even those caused by methicillin-resistant Staphylococcus aureus (MRSA). The biological performance of the scaffolds was evaluated in vitro regarding human mesenchymal stem cells (hMSCs) attachment and growth. Finally, the biocompatibility and angiogenic response of the manufactured sterile scaffolds was assessed in ovo through chick chorioallantoic membrane (CAM) assays., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Sterilization is a quite challenging step in the development of novel polymeric scaffolds for regenerative medicine since conventional sterilization techniques may significantly alter their morphological and physicochemical properties. Supercritical (sc) sterilization, i.e. the use of scCO 2 as a sterilizing agent, emerges as a promising sterilization method due to the mild operational conditions and excellent penetration capability. In this work, a scCO 2 protocol was implemented for the one-pot preparation and sterilization of poly(ε-caprolactone) (PCL)/poly(lactic-co-glycolic acid) (PLGA) scaffolds. The sterilization conditions were established after screening against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) vegetative bacteria and spores of Bacillus stearothermophilus, Bacillus pumilus and Bacillus atrophaeus. The transition from the sterilization conditions (140 bar, 39 °C) to the compressed foaming (60 bar, 26 °C) was performed through controlled depressurization (3.2 bar/min) and CO 2 liquid flow. Controlled depressurization/pressurization cycles were subsequently applied. Using this scCO 2 technology toolbox, sterile scaffolds of well-controlled pore architecture were obtained. This sterilization procedure successfully achieved not only SAL-6 against well-known resistant bacteria endospores but also improved the scaffold morphologies compared to standard gamma radiation sterilization procedures., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Demand of scaffolds for hard tissue repair increases due to a higher incidence of fractures related to accidents and bone-diseases that are linked to the ageing of the population. Namely, scaffolds loaded with bioactive agents can facilitate the bone repair by favoring the bone integration and avoiding post-grafting complications. Supercritical (sc-)foaming technology emerges as a unique solvent-free approach for the processing of drug-loadenu7d scaffolds at high incorporation yields. In this work, medicated poly(ε-caprolactone) (PCL) scaffolds were prepared by sc-foaming coupled with a leaching process to overcome problems of pore size tuning of the sc-foaming technique. The removal of the solid porogen (BA, ammonium bicarbonate) was carried out by a thermal leaching taking place at 37 °C and in the absence of solvents for the first time. Macroporous scaffolds with dual porosity (50-100 µm and 200-400 µm ranges) were obtained and with a porous structure directly dependent on the porogen content used. The processing of ketoprofen-loaded scaffolds using BA porogen resulted in drug loading yields close to 100% and influenced its release profile from the PCL matrix to a relevant clinical scenario. A novel solvent-free strategy has been set to integrate the incorporation of solid porogens in the sc-foaming of medicated scaffolds.

Starch aerogels are attractive materials for biomedical applications because of their low density and high open porosity coupled with high surface areas. However, the lack of macropores in conventionally manufactured polysaccharide aerogels is a limitation to their use as scaffolds for regenerative medicine. Moreover, the stability under storage of polysaccharide aerogels is critical for biomedical purposes and scarcely studied so far. In this work, the induction of a new macropore population (1-2 μm) well integrated into the starch aerogel backbone was successfully achieved by the incorporation of zein as a porogen. The obtained dual-porous aerogels were evaluated in terms of composition as well as morphological, textural, and mechanical properties. Stability of aerogels upon storage mimicking the zone II (25 °C, 65% relative humidity) according to the International Council for Harmonization guideline of climatic conditions was checked after 1 and 3 months from morphological, physicochemical, and mechanical perspectives. Zein incorporation induced remarkable changes in the mechanical performance of the end aerogel products and showed a preventive effect on the morphological changes during the storage period.

The regenerative medicine field is seeking novel strategies for the production of synthetic scaffolds that are able to promote the in vivo regeneration of a fully functional tissue. The choices of the scaffold formulation and the manufacturing method are crucial to determine the rate of success of the graft for the intended tissue regeneration process. On one hand, the incorporation of bioactive compounds such as growth factors and drugs in the scaffolds can efficiently guide and promote the spreading, differentiation, growth, and proliferation of cells as well as alleviate post-surgical complications such as foreign body responses and infections. On the other hand, the manufacturing method will determine the feasible morphological properties of the scaffolds and, in certain cases, it can compromise their biocompatibility. In the case of medicated scaffolds, the manufacturing method has also a key effect in the incorporation yield and retained activity of the loaded bioactive agents. In this work, solvent-free methods for scaffolds production, i.e., technological approaches leading to the processing of the porous material with no use of solvents, are presented as advantageous solutions for the processing of medicated scaffolds in terms of efficiency and versatility. The principles of these solvent-free technologies (melt molding, 3D printing by fused deposition modeling, sintering of solid microspheres, gas foaming, and compressed CO 2 and supercritical CO 2 -assisted foaming), a critical discussion of advantages and limitations, as well as selected examples for regenerative medicine purposes are herein presented.

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., (© 2019 Wiley Periodicals, Inc.)

The subdivision behavior of polymeric tablets produced with the well-known polymers Soluplus® (SOL), polyvinyl pyrrolidone co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose (HPMC) was evaluated in this study. The polymeric tablets were submitted to different post-treatments (aging, thermal and exposure to compressed gaseous carbon dioxide) and its mechanical, spectroscopic and microstructure properties were assessed. SOL tablets showed the best results for tablet subdivision, particularly, the mean mass variation (3.9%) was significantly lower than the other two polymeric tablets (7.2% and 9.1% for PVPVA and HPMC, respectively), and showed better results than common tablets produced from powder matrices (7-14%). SOL tablets were also more sensitive to the different post-treatments applied, which reduced the mass loss and friability from 1.5% and 0.8%, respectively, to values close to zero and without altering their porosity. The thermal treatment of PVPVA tablets, in turn, also led to similar subdivision results, with mass loss of 0.3% and friability of 0.02%. In contrast, the granules of HPMC presented compaction difficulties making its tablets unsuitable for the subdivision process, even after additional post-treatment. Polymeric matrices with uniform internal structure and appropriate mechanical strength are the key to a better adaptation for the tablet subdivision., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aerogels from natural polymers are endowed with attractive textural and biological properties for biomedical applications due to their high open mesoporosity, low density, and reduced toxicity. Nevertheless, the lack of macroporosity in the aerogel structure and of a sterilization method suitable for these materials restrict their use for regenerative medicine purposes and prompt the research on getting ready-to-implant dual (macro + meso)porous aerogels. In this work, zein, a family of proteins present in materials for tissue engineering, was evaluated as a sacrificial porogen to obtain macroporous starch aerogels. This approach was particularly advantageous since it could be integrated in the conventional aerogel processing method without extra leaching steps. Physicochemical, morphological, and mechanical characterization were performed to study the effect of porogen zein at various proportions (0:1, 1:2, and 1:1 zein:starch weight ratio) on the properties of the obtained starch-based aerogels. From a forward-looking perspective for its clinical application, a supercritical CO₂ sterilization treatment was implemented for these aerogels. The sterilization efficacy and the influence of the treatment on the aerogel final properties were evaluated mainly in terms of absence of microbial growth, cytocompatibility, as well as physicochemical, structural, and mechanical modifications.