No abstract

The socioeconomic impact of osteochondral (OC) damage has been increasing steadily over time in the global population, and the promise of tissue engineering in generating biomimetic tissues replicating the physiological OC environment and architecture has been falling short of its projected potential. The most recent advances in OC tissue engineering are summarised in this work, with a focus on electrospun and 3D printed biomaterials combined with stem cells and biochemical stimuli, to identify what is causing this pitfall between the bench and the patients’ bedside. Even though significant progress has been achieved in electrospinning, 3D-(bio)printing, and induced pluripotent stem cell (iPSC) technologies, it is still challenging to artificially emulate the OC interface and achieve complete regeneration of bone and cartilage tissues. Their intricate architecture and the need for tight spatiotemporal control of cellular and biochemical cues hinder the attainment of long-term functional integration of tissue-engineered constructs. Moreover, this complexity and the high variability in experimental conditions used in different studies undermine the scalability and reproducibility of prospective regenerative medicine solutions. It is clear that further development of standardised, integrative, and economically viable methods regarding scaffold production, cell selection, and additional biochemical and biomechanical stimulation is likely to be the key to accelerate the clinical translation and fill the gap in OC treatment.

Respiratory diseases are among the global leading causes of morbidity and mortality. Acute conditions arising from infection, such as pneumonia and tuberculosis, affect millions of people worldwide, the latter being the most common lethal infectious disease with 1.4 million annual deaths. [1] Upon infection, the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which caused a worldwide pandemic, leads to the clinical picture of the coronavirus disease-2019 (COVID-19) with possibly severe and life-threatening progression. Lung cancer is the most frequently diagnosed malignancy and the main cause of cancer-related death, [2] with markedly low survival rates especially when the diagnosis is performed at an advanced state of the disease. [3] Moreover, chronic respiratory diseases (CRDs), including chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease (ILD), have consistently received less attention in comparison to other non-communicable diseases, continuing to exert a considerable socioeconomic impact. [4,5] Risk factors for the development of respiratory diseases include, for example, tobacco use and second-hand smoke, as well as exposure to air-pollutants, which has been accentuated with the widespread use of fossil fuels. [4] It is clear that a great number of these risks can be mitigated by lifestyle changes, promoted by anti-tobacco campaigns already in place at a global scale and by the use of renewable, clean energy sources, and two recent studies indicate that the age-standardized incidence and prevalence of CRDs has decreased from 1990 to 2017. [4,5] However, the risk of developing CRDs, particularly COPD, appears to increase steeply with age; [4,5] most strikingly, these diseases were the third leading cause of death in 2017 [4] and potentially in 2020. [6] In addition to microbial, environmental, and lifestyle-related factors, a large number of lung diseases have a genetic origin. [7] Cystic fibrosis (CF), for example, is an incurable hereditary disorder known to originate from different mutations in the gene coding for the CF transmembrane conductance regulator (CFTR), an ion transporter, resulting in severe alterations in pulmonary physiology that culminate in impaired lung function, respiratory distress and, ultimately, death. [8,9]

The high target specificity and multifunctionality of proteins has led to great interest in their clinical use. To this end, the development of delivery systems capable of preserving their bioactivity and improving bioavailability is pivotal to achieve high effectiveness and satisfactory therapeutic outcomes. Electrohydrodynamic (EHD) techniques, namely electrospinning and electrospraying, have been widely explored for protein encapsulation and delivery. In this work, monoaxial and coaxial electrospinning and electrospraying were used to encapsulate alkaline phosphatase (ALP) into poly(ethylene oxide) fibres and particles, respectively, and the effects of the processing techniques on the integrity and bioactivity of the enzyme were assessed. A full morphological and physicochemical characterisation of the blend and core-shell products was performed. ALP was successfully encapsulated within monolithic and core-shell electrospun fibres and electrosprayed particles, with drug loadings and encapsulation efficiencies of up to 21% and 99%, respectively. Monoaxial and coaxial electrospinning were equally effective in preserving ALP function, leading to no activity loss compared to fresh aqueous solutions of the enzyme. While the same result was observed for monoaxial electrospraying, coaxial electrospraying of ALP caused a 40% reduction in its bioactivity, which was attributed to the high voltage (22.5 kV) used during processing. This demonstrates that choosing between blend and coaxial EHD processing for protein encapsulation is not always straightforward, being highly dependent on the chosen therapeutic agent and the effects of the processing conditions on its bioactivity.

The restoration of cartilage damage is a slow and not always successful process. Kartogenin (KGN) has significant potential in this space—it is able to induce the chondrogenic differentiation of stem cells and protect articular chondrocytes. In this work, a series of poly(lactic-co-glycolic acid) (PLGA)-based particles loaded with KGN were successfully electrosprayed. In this family of materials, PLGA was blended with a hydrophilic polymer (either polyethyleneglycol (PEG) or polyvinylpyrrolidone (PVP)) to control the release rate. Spherical particles with sizes in the range of 2.4–4.1 µm were fabricated. They were found to comprise amorphous solid dispersions, with high entrapment efficiencies of >93%. The various blends of polymers had a range of release profiles. The PLGA-KGN particles displayed the slowest release rate, and blending with PVP or PEG led to faster release profiles, with most systems giving a high burst release in the first 24 h. The range of release profiles observed offers the potential to provide a precisely tailored profile via preparing physical mixtures of the materials. The formulations are highly cytocompatible with primary human osteoblasts.