A Physiology-Based Mathematical Model to Understand Drug Delivery from Contact Lenses to the Back of the Eye.

OBJECTIVE: Therapeutic contact lenses, able to store drug and deliver it to the eye surface in a sustained fashion, gained interest as an effective and patient-friendly alternative to eye drops. Recent animal studies also demonstrated the presence of therapeutic drug levels in the back of the eye after wearing drug-loaded contact lenses, thus opening the possibility of treating the posterior segment without need of invasive intraocular injections. The drug pathways from contact lenses to the back of the eye require further investigation. METHODS: A mechanistic mathematical model was developed to evaluate the drug concentration over time in the tears, sclera and choroid, retina, aqueous humor and vitreous humor after the application of a therapeutic contact lens. The main drug transport mechanisms of the eye and the barrier properties of the different tissues were included in the model. Validation was performed by comparison with experimental data in literature. RESULTS: The model predictions of drug concentration over time reflected the experimental data both in the anterior and posterior segment of the eye. The model can differentiate between contributions to transport from different pathways. CONCLUSIONS: The model constitutes a first step towards the possibility of predicting the ocular drug distribution and the treatment efficacy in the early stage of contact lens development, and it may help reduce both the need for in vivo tests (with ethical and economic advantages) and the gap between the lens design and clinical application. It also allows for an improved understanding of drug transport in the eye.

A multiple criteria approach for building a pandemic impact assessment composite indicator: The case of COVID-19 in Portugal.

The COVID-19 pandemic has caused major damage and disruption to social, economic, and health systems (among others). In addition, it has posed unprecedented challenges to public health and policy/decision-makers who have been responsible for designing and implementing measures to mitigate its strong negative impact. The Portuguese health authorities have used decision analysis techniques to assess the impact of the pandemic and implemented measures for counties, regions, or across the entire country. These decision tools have been subject to some criticism and many stakeholders requested novel approaches. In particular, those which considered the dynamic changes in the pandemic's behaviour due to new virus variants and vaccines. A multidisciplinary team formed by researchers from the COVID-19 Committee of Instituto Superior Técnico at the University of Lisbon (CCIST analyst team) and physicians from the Crisis Office of the Portuguese Medical Association (GCOM expert team) collaborated to create a new tool to help politicians and decision-makers to fight the pandemic. This paper presents the main steps that led to the building of a pandemic impact assessment composite indicator applied to the specific case of COVID-19 in Portugal. A multiple criteria approach based on an additive multi-attribute value theory aggregation model was used to build the pandemic assessment composite indicator. The parameters of the additive model were devised based on an interactive socio-technical and co-constructive process between the CCIST and GCOM team members. The deck of cards method was the adopted technical tool to assist in the assessment the value functions as well as in the assessment of the criteria weights. The final tool was presented at a press conference and had a powerful impact on the Portuguese media and on the main health decision-making stakeholders in the country. In this paper, a completed mathematical and graphical description of this tool is presented.

Editorial for the Special Issue Titled "Design of Polymeric Hydrogels Biomaterials".

Hydrogels have attracted great interest in the biomedical applications field in recent years [...].

Hydrogel-Based Novel Biomaterials: Achievements and Prospects.

In recent decades, hydrogels have garnered significant attention, thanks to their extensive biomedical and pharmaceutical applications [...].

Free-Standing, Water-Resistant, and Conductivity-Enhanced PEDOT:PSS Films from In Situ Polymerization of 3-Hydroxymethyl-3-Methyl-Oxetane.

Free-standing films based on conducting polymers, such as poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (PEDOT:PSS), offer many benefits over traditional metal electrodes for applications in flexible electronics. However, to ensure structural integrity when contacting aqueous environments and high levels of electrical conductivity, solution-processed polymers require additives that act as crosslinking agents and conductivity enhancers. In this work, a new approach is presented to fabricate water-resistant free-standing films of PEDOT:PSS and simultaneously increase their conductivity, using an oxetane compound as an additive. It is shown that at moderate temperatures, oxetane polymerizes within the PEDOT:PSS acidic medium, forming hydroxymethyl-substituted polyether compounds that form a network upon crosslinking with PSS. The polymer composite films show self-sustainability, structural stability in aqueous environments, and enhanced conductivity. Finally, the potential of the free-standing films as health-monitoring electrodes, specifically for human electrocardiography, is explored.

Dexamethasone phosphate and penetratin co-eluting contact lenses: a strategy to enhance ocular drug permeability.

Contact lenses (CLs) have been suggested as drug delivery platforms capable of increasing the drug residence time on the cornea and therefore its bioavailability. However, when targeting the posterior segment of the eye, the drug released from CLs still encounters the barrier effect of the ocular tissues, which considerably reduces the efficacy of administration. This work aims at the development of CLs able to simultaneously deliver an anti-inflammatory drug (dexamethasone sodium phosphate) and a cell-penetrating peptide (penetratin), the latter acting as a drug carrier across the tissues. Hydroxyethyl methacrylate (HEMA)-based hydrogels were functionalized with acrylic acid (AAc) and/or aminopropyl methacrylamide (APMA) to serve as CL materials with increased affinity for the drug and peptide. APMA-functionalized hydrogels sustained the dual release for 8 h, which is compatible with the wearing time of daily CLs. Hydrogels demonstrated suitable light transmittance, swelling capacity and in vitro biocompatibility. The anti-inflammatory activity of the drug was not compromised by the presence of the peptide nor by sterilization. The ocular distribution of the drug after 6 h of CL wearing was evaluated in vivo in rabbits and revealed that the amount of drug in the cornea and aqueous humor significantly increased when the drug was co-delivered with penetratin.

Tribomechanical Properties of PVA/Nomex® Composite Hydrogels for Articular Cartilage Repair.

Due to the increasing prevalence of articular cartilage diseases and limitations faced by current therapeutic methodologies, there is an unmet need for new materials to replace damaged cartilage. In this work, poly(vinyl alcohol) (PVA) hydrogels were reinforced with different amounts of Nomex® (known for its high mechanical toughness, flexibility, and resilience) and sterilized by gamma irradiation. Samples were studied concerning morphology, chemical structure, thermal behavior, water content, wettability, mechanical properties, and rheological and tribological behavior. Overall, it was found that the incorporation of aramid nanostructures improved the hydrogel's mechanical performance, likely due to the reinforcement's intrinsic strength and hydrogen bonding to PVA chains. Additionally, the sterilization of the materials also led to superior mechanical properties, possibly related to the increased crosslinking density through the hydrogen bonding caused by the irradiation. The water content, wettability, and tribological performance of PVA hydrogels were not compromised by either the reinforcement or the sterilization process. The best-performing composite, containing 1.5% wt. of Nomex®, did not induce cytotoxicity in human chondrocytes. Plugs of this hydrogel were inserted in porcine femoral heads and tested in an anatomical hip simulator. No significant changes were observed in the hydrogel or cartilage, demonstrating the material's potential to be used in cartilage replacement.

Improved triamcinolone acetonide-eluting contact lenses based on cyclodextrins and high hydrostatic pressure assisted complexation.

Contact lenses (CLs) constitute an advantageous platform for the topical release of corticosteroids due to their prolonged contact with the eye. However, the lipophilic nature of corticosteroids hampers CLs' ability to release therapeutic amounts. Two approaches to improve loading and release of triamcinolone acetonide (TA) from poly(2-hydroxyethyl methacrylate)-based hydrogels were investigated: adding 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to the monomers solution before polymerization (HEMA/i-CD) and an hydrogels' post-treatment with HP-ß-CD (HEMA/p-CD). The effect of HP-ß-CD and sterilization by high hydrostatic pressure (HHP) on the hydrogel properties (water content, oxygen and ion permeability, roughness, transmittance, and stiffness) was evaluated. The HEMA/i-CD hydrogels had stronger affinity for TA, sustaining its release for one day. HHP sterilization promoted the formation of cyclodextrin-TA complexes within the hydrogels, improving their drug-loading capacity ¼60 %. Cytotoxicity and irritability tests confirmed the safety of the therapeutic CLs. TA released from the hydrogels permeated through ocular tissues ex vivo and showed anti-inflammatory activity. Finally, a previously validated mathematical model was used to estimate the ability of the TA-loaded CLs to deliver therapeutic drug concentrations to the posterior part of the eye. Overall, HP-ß-CD-containing CLs are promising candidates for the topical ocular application of TA as an alternative delivery system to intraocular injections.

Evaluation of the in vitro biocompatibility of PMMA/high-load HA/carbon nanostructures bone cement formulations.

Although commercially-available poly(methyl methacrylate) bone cement is widely used in total joint replacements, it has many shortcomings, a major one being that it does not osseointegrate with the contiguous structures. We report on the in vitro evaluation of the biocompatibility of modified formulations of the cement in which a high loading of hydroxyapatite (67 wt/wt%), an extra amount of benzoyl peroxide, and either 0.1 wt/wt% functionalized carbon nanotubes or 0.5 wt/wt% graphene oxide was added to the cement powder and an extra amount of dimethyl-p-toluidiene was added to the cement's liquid monomer. This evaluation was done using mouse L929 fibroblasts and human Saos-2 osteoblasts. For each combination of cement formulation and cell type, there was high cell viability, low apoptosis, and extensive spread on disc surfaces. Thus, these two cement formulations may have potential for use in the clinical setting.

3D Printing for Dental Applications.

Due to increased life expectancy and greater concern among populations regarding oral health problems and aesthetics, in the last few years, there has been a growing demand for dental structures and devices to replace/restore missing/damaged teeth [...].

Recent Advances on 3D-Printed Zirconia-Based Dental Materials: A Review.

Zirconia-based materials are widely used in dentistry due to their biocompatibility and suitable mechanical and tribological behavior. Although commonly processed by subtractive manufacturing (SM), alternative techniques are being explored to reduce material waste, energy consumption and production time. 3D printing has received increasing interest for this purpose. This systematic review intends to gather information on the state of the art of additive manufacturing (AM) of zirconia-based materials for dental applications. As far as the authors know, this is the first time that a comparative analysis of these materials' properties has been performed. It was performed following the PRISMA guidelines and using PubMed, Scopus and Web of Science databases to select studies that met the defined criteria without restrictions on publication year. Stereolithography (SLA) and digital light processing (DLP) were the techniques most focused on in the literature and the ones that led to most promising outcomes. However, other techniques, such as robocasting (RC) and material jetting (MJ), have also led to good results. In all cases, the main concerns are centered on dimensional accuracy, resolution, and insufficient mechanical strength of the pieces. Despite the struggles inherent to the different 3D printing techniques, the commitment to adapt materials, procedures and workflows to these digital technologies is remarkable. Overall, the research on this topic can be seen as a disruptive technological progress with a wide range of application possibilities.

Antiseptic-Loaded Casein Hydrogels for Wound Dressings.

Chronic wound treatment accounts for a substantial percentage of the medical expenses worldwide. Improving and developing novel wound care systems can potentially help to handle this problem. Wound dressings loaded with antiseptics may be an important tool for wound care, as they inhibit bacterial growth at the wound site. The goal of the present work was to investigate the potential of using casein hydrogel dressings loaded with two antiseptic drugs, Octiset® or polyhexanide, to treat chronic wounds. Casein-based hydrogels are inexpensive and have several properties that make them suitable for biomedical applications. Two types of casein were used: casein sodium salt and acid casein, with the formulations being labelled CS and C, respectively. The hydrogels were characterised with respect to their physical properties (swelling capacity, water content, morphology, mechanical resistance, and stability), before and after sterilisation, and they showed adequate values for the intended application. The hydrogels of both formulations were able to sustain controlled drug-release for, at least, 48 h. They were demonstrated to be non-irritant, highly haemocompatible, and non-cytotoxic, and revealed good antimicrobial properties against Staphylococcus aureus and Pseudomonas aeruginosa. Steam-heat sterilisation did not compromise the material's properties. The in vivo performance of C hydrogel loaded with Octiset® was evaluated in a case study with a dog. The efficient recovery of the wounds confirms its potential as an alternative for wound treatment. To our knowledge, this is the first time that wound dressings loaded with Octiset®, one of the most efficient drugs for wound treatment, were prepared and tested.

Effect of varying functional monomers in experimental self-adhesive composites: polymerization kinetics, cell metabolism influence and sealing ability.

The aim was to evaluate the effects of adding different functional monomers to experimental self-adhesive composites (SACs) on polymerization kinetics, cell metabolic activity, and sealing ability. SACs were formulated using urethane dimethacrylate as the base monomer and triethylene glycol dimethacrylate. Additionally, 10 wt.% of distinct functional monomers were added - 10-methacryloyloxydecyl dihydrogen phosphate, glycerol phosphate dimethacrylate (GPDM), 2-hydroxyethyl methacrylate (HEMA) or hydroxyethyl acrylamide (HEAA). ATR-FTIR was used to determine real-time polymerization kinetics (20 min,n= 3). The final extrapolated conversion and polymerization rates were determined (DC,max;Rp,max). TheDC,maxvalues were employed to calculate volumetric shrinkage. The MTT assay was performed on MDPC-23 cells using disc extracts at different concentrations (n= 8). Class V cavities were prepared in 60 sound human molars, assigned to six groups (n= 10), depending on the composite used and aging type (T0 or TC, if thermocycled for 10 000 cycles). One-way ANOVA, two-way, andKruskal-Wallistests were employed to treat the data (ɑ= 0.05). Varying the functional monomers had a large impact on DC,max, as confirmed by one-way ANOVA (p<0.001). The highest was obtained for HEMA (64 ± 3%). The HEMA and HEAA formulations were found to be significantly more toxic at concentrations below 100%. For microleakage, having a functional monomer or not did not show any improvement, irrespective of margin or aging period (Mann-Whitney U,p> 0.05). Larger functional monomers MDP and GPDM affected polymerization properties. Conversely, their acidity did not seem to be detrimental to cell metabolic activity. Regarding sealing ability, it seems that the functional monomers did not bring an advantage to the composites. Varying the functional monomer in SACs had a clear impact on the polymerization kinetics as well as on their cytotoxic potential. However, it did not confer better microleakage and sealing. Claiming self-adhesiveness based only on functional monomers seems dubious.

Recent Advances in Ophthalmic Drug Delivery.

Due to population aging and to the increasing prevalence of diseases such as diabetes, chronic eye disorders such as glaucoma, age-related macular degeneration, and diabetic retinopathy have increased significantly, becoming responsible for a high percentage of blindness and vision impairment cases at a global level [...].

3D Bioprinting of Novel κ-Carrageenan Bioinks: An Algae-Derived Polysaccharide.

Novel green materials not sourced from animals and with low environmental impact are becoming increasingly appealing for biomedical and cellular agriculture applications. Marine biomaterials are a rich source of structurally diverse compounds with various biological activities. Kappa-carrageenan (κ-c) is a potential candidate for tissue engineering applications due to its gelation properties, mechanical strength, and similar structural composition of glycosaminoglycans (GAGs), possessing several advantages when compared to other algae-based materials typically used in bioprinting such as alginate. For those reasons, this material was selected as the main polysaccharide component of the bioinks developed herein. In this work, pristine κ-carrageenan bioinks were successfully formulated for the first time and used to fabricate 3D scaffolds by bioprinting. Ink formulation and printing parameters were optimized, allowing for the manufacturing of complex 3D structures. Mechanical compression tests and dry weight determination revealed young's modulus between 24.26 and 99.90 kPa and water contents above 97%. Biocompatibility assays, using a mouse fibroblast cell line, showed high cell viability and attachment. The bioprinted cells were spread throughout the scaffolds with cells exhibiting a typical fibroblast-like morphology similar to controls. The 3D bio-/printed structures remained stable under cell culture conditions for up to 11 days, preserving high cell viability values. Overall, we established a strategy to manufacture 3D bio-/printed scaffolds through the formulation of novel bioinks with potential applications in tissue engineering and cellular agriculture.

Effects of Non-Conventional Sterilisation Methods on PBO-Reinforced PVA Hydrogels for Cartilage Replacement.

Articular cartilage (AC) degradation is a recurrent pathology that affects millions of people worldwide. Polyvinyl alcohol (PVA) hydrogels have been widely explored for AC replacement. However, their mechanical performance is generally inadequate, and these materials need to be reinforced. Moreover, to be used in a clinical setting, such materials must undergo effective sterilisation. In this work, a PVA hydrogel reinforced with poly(p-phenylene-2,6-benzobisoxazole) (PBO) nanofibres was submitted to three non-conventional sterilisation methods: microwave (MW), high hydrostatic pressure (HHP), and plasma (PM), in order to evaluate their impact on the properties of the material. Sterilisation was achieved in all cases. Properties such as water content and hydrophilicity were not affected. FTIR analysis indicated some changes in crystallinity and/or crosslinking in all cases. MW was revealed to be the most suitable method, since, unlike to PM and HHP, it led to a general improvement of the materials' properties: increasing the hardness, stiffness (both in tensile and compression), and shear modulus, and also leading to a decrease in the coefficient of friction against porcine cartilage. Furthermore, the samples remained non-irritant and non-cytotoxic. Moreover, this method allows terminal sterilisation in a short time (3 min) and using accessible equipment.

Contact lenses for pravastatin delivery to eye segments: Design and in vitro-in vivo correlations.

Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design contact lenses (CLs) that can sustainedly deliver pravastatin and thus improve the ocular efficacy while avoiding systemic side effects of statins. Bioinspired hydrogels were prepared with monomers that resemble hydrophobic (ethylene glycol phenyl ether methacrylate) and amino (2-aminoethyl methacrylamide hydrochloride) functionalities of the active site of HMG-CoA. Best performing CLs loaded >6 mg/g, in vitro fulfilled the release demands for daily wearing, and showed anti-inflammatory activity (lowering TNF-α). High hydrostatic pressure sterilization preserved the stability of both the drug and the hydrogel network. Ex vivo tests revealed the ability of pravastatin to accumulate in cornea and sclera and to penetrate through transscleral route. In vivo tests (rabbits) confirmed that, compared to eye drops and for the same dose, CLs provided significantly higher pravastatin levels in tear fluid within 1 to 7 h of wearing. Moreover, after 8 h wearing pravastatin was present in cornea, sclera, aqueous humour and vitreous humour. Strong correlations between percentages of drug released in vitro and in vivo were found. Effects of volume and proteins on release rate and Levy plots were identified.

Intraocular lenses as drug delivery devices.

Cataract surgery is one of the most common and safe surgical procedures nowadays. However, it is not free of risks as endophthalmitis, ocular inflammation and posterior capsule opacification (PCO) can appear as post-surgery complications. The usual eye drop therapy used as prophylaxis for the former two complications has limited bioavailability. In turn, the prevention of PCO involves an adequate surgical technique and a careful choice of intraocular lens (IOL) design and material. Also, different drugs have been tested to reduce incidence of PCO, but no prophylaxis demonstrated to be completely effective. In the past few years, IOLs have been proposed as drug delivery devices to replace or/assist the usual eye drop therapy in the post-operatory period. The great advantage of drug loaded IOLs would be to ensure a continuous drug delivery, independent of patient's compliance without requiring any further action besides IOL implantation. The biggest challenge of drug loaded IOLs production is to achieve a controlled and extended release that meet therapeutic needs without inducing toxicity to the surrounding ocular tissues or affecting the physical properties of the lens. This review starts by addressing the possible complications after cataract surgery, as well as the most commonly adopted prophylaxis for each of them. The various types of IOLs are described and their main advantages/disadvantages are discussed. The different strategies pursued to incorporate drugs into the IOLs and control their release, which include soaking the IOL in the drugs solution, supercritical impregnation, surface modifications, and attachment of drug reservoirs to the IOL, among others, are reported. For each strategy, a summary of the publications is presented, which includes the target complication, the types and amounts of released drugs and the IOL materials. A brief description of each individual study is given afterwards. Optimization of drug loaded IOLs through mathematical modelling and possible issues raised by their sterilization are also tackled. At the end, the future commercialization of drug loaded IOLs is commented.

Asymmetry in Drug Permeability through the Cornea.

The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.

Resveratrol-Loaded Hydrogel Contact Lenses with Antioxidant and Antibiofilm Performance.

Contact lenses (CLs) are prone to biofilm formation, which may cause severe ocular infections. Since the use of antibiotics is associated with resistance concerns, here, two alternative strategies were evaluated to endow CLs with antibiofilm features: copolymerization with the antifouling monomer 2-methacryloyloxyethyl phosphorylcholine (MPC) and loading of the antioxidant resveratrol with known antibacterial activity. MPC has, so far, been used to increase water retention on the CL surface (Proclear® 1 day CLs). Both poly(hydroxyethyl methacrylate) (HEMA) and silicone hydrogels were prepared with MPC covering a wide range of concentrations (from 0 to 101 mM). All hydrogels showed physical properties adequate for CLs and successfully passed the hen's egg-chorioallantoic membrane (HET-CAM) test. Silicone hydrogels had stronger affinity for resveratrol, with higher loading and a slower release rate. Ex vivo cornea and sclera permeability tests revealed that resveratrol released from the hydrogels readily accumulated in both tissues but did not cross through. The antibiofilm tests against Pseudomonas aeruginosa and Staphylococcus aureus evidenced that, in general, resveratrol decreased biofilm formation, which correlated with its concentration-dependent antibacterial capability. Preferential adsorption of lysozyme, compared to albumin, might also contribute to the antimicrobial activity. In addition, importantly, the loading of resveratrol in the hydrogels preserved the antioxidant activity, even against photodegradation. Overall, the designed hydrogels can host therapeutically relevant amounts of resveratrol to be sustainedly released on the eye, providing antibiofilm and antioxidant performance.