Exosomes, also known as extracellular vesicles, play critical roles in a variety of biological processes, including cell proliferation, differentiation, and survival (Mantile et al., 2021). They originate from a variety of sources, including stem cells and immune cells, and are enclosed in a bilayer membrane to safeguard their genetic material and proteins before being delivered to target cells (Hong et al., 2019). Exosome-containing proteins include membrane transport proteins, tetraspanins, biogenesis-related proteins, and heat shock proteins (Vojtech et al., 2019). Scaffolds enriched with exosomes promise to be a potential strategy in regenerative medicine, particularly for lung tissue engineering (Antich-Rosselló et al., 2021). These scaffolds mix exosomes, which are extracellular vesicles necessary for intercellular communication, with biomaterial scaffolds to aid in tissue repair and regeneration (Re et al., 2021; Rahmati et al., 2023). The ability of exosome-loaded scaffolds to overcome the limitations of traditional cell therapies, like immune system rejection and decreased cell survival, is one of its key benefits (Gu et al., 2021).

Exosome-loaded bioactive scaffolds, which can be made into three-dimensional structures like bioactive glasses, offer a special cellular environment that can boost exosomes’ therapeutic potential and encourage tissue repair (Poongodi et al., 2021). The use of bioactive scaffolds can improve tissue repair and regeneration by promoting cell adhesion, proliferation, and differentiation (Pacelli et al., 2017) (Figure 2).

To improve proangiogenic activity in bone healing, for instance, exosomes extracted from human bone marrow MSCs activated by dimethyloxaloylglycine were placed onto a porous hydroxyapatite scaffold (Vig and Fernandes, 2022). Similarly, exosomes extracted from human adipose-derived stem cells were combined with poly (lactic-co-glycolic acid) (PLGA)/polydopamine (pDA) structures to create a cell-free bone tissue engineering system (Torrecillas-Baena et al., 2023). Exosomes were released from the scaffold slowly and continuously, which promoted MSC migration and greatly enhanced bone repair (Swanson et al., 2020).

Recent developments have focused on the use of specific biomaterials and scaffolds to stimulate cells to increase exosome production and on the integration of exosomes into 3D scaffolds with different architectures for implantation into damaged tissue (Brennan et al., 2020). Researchers have also developed several methods to sustainably introduce exosomes into the environment after myocardial infarction (Bellin et al., 2019). For example, exosomes produced from cardiomyocyte-derived induced pluripotent stem cells and encapsulated in hydrogel patches were directly delivered into infarcted rats’ hearts (Cheng et al., 2021). Exosome patches increased ejection fraction, avoided cardiomyocytic hypertrophy, decreased ischemic injury, and improved heart repair (Ping et al., 2023). Bioactive scaffolds can enhance tissue repair and regeneration by stimulating cell adhesion, proliferation, and differentiation. Bioactive scaffolds can enhance tissue repair and regeneration by stimulating cell adhesion, proliferation, and differentiation (Stratton et al., 2016). Wang et al. discovered that stem cell transplants with a biomimetic scaffold promote lung recovery. To alter lung tissue, they used a scaffold loaded with exosomes from mesenchymal stem cells (MSC) (Wang et al., 2023). Exosomes were able to recruit and differentiate MSCs, resulting in the production of functional lung tissue (Wang et al., 2023).

Research by Yang and El Haj (2006) also highlighted the importance and value of designing and manufacturing scaffolds for cell and drug transfer, recognizing the need for biocompatible and biodegradable materials (Yang and El Haj, 2006). Huang et al. (2021) also discussed the practical importance of exosome-filled scaffolds in the tissue regeneration and repair process and emphasized the important role of exosomes in cell communication and tissue regeneration (Huang et al., 2021). Additionally, Goldberg investigated most nanostructured materials for biotechnology and drug delivery and suggested using them to create exosome-loaded structures (Goldberg et al., 2007).

Cell-based scaffolds represent a new approach to tissue engineering that integrates cells into biodegradable and biocompatible scaffolds to mimic the extracellular matrix (Edgar et al., 2016). This mimicry provides structural support and biological, chemical, and mechanical signals that influence the development of new tissue (Barnes et al., 2017). Although cell-based scaffolds have shown promise in several applications, including lung regeneration, they also present challenges, such as the need for a reliable source of human-sized scaffolds and a definitive sterilization method (Tapias and Ott, 2014). Figure 3.

Furthermore, stem cell transplantation based on biomimetic scaffolds has been shown to promote lung regeneration (Willie et al., 2010). A three-dimensional artificial MSC implant based on a biomimetic scaffold was constructed to create a favorable regenerative environment for lung tissue (Wang et al., 2023). This approach could help overcome the problems associated with the shortage of organ donors and avoid the need for lung transplantation (Van Raemdonck et al., 2009). However, further research is needed to overcome the challenges associated with cell-based scaffolds, such as the need for a reliable source of human-sized scaffolds and a method for the final sterilization of the scaffolds (Griffin et al., 2018). Advances in artificial intelligence and stem cell transplantation based on biomimetic scaffolds open promising prospects for the future of lung regeneration (Zhang and Wang, 2019).

Recent advances in lung tissue engineering, including the development of smart biomaterials for scaffolds, and the use of on-chip organizational models to mimic the state of lung tissue, represent their important applications (Bennet et al., 2021; Kim et al., 2019). The development of smart biomaterials for scaffolds has also had a significant impact on the field of lung regenerative medicine (Aiman et al., 2022). These biomaterials actually activate certain tissue properties and can respond appropriately to changes in physiological conditions or external stimuli, in the same way that they have been used in various applications, including lung tissue repair and regeneration (Brovold et al., 2018). For example, Balestrini et al. (2015) looked at removing cells from pig pleural membranes to create a tissue engineering alternative to lung tissue repair (Balestrini et al., 2015). In another study by Kim et al. (2019), 3D artificial mesenchymal stem cell transplantation based on a biomimetic scaffold was used to create a positive regenerative niche for in situ lung regeneration from endogenous stem cells (Kim et al., 2019).

Lab-on-a-chip models are useful tools for simulating lung tissue conditions, especially in lung reconstructive medicine (Nichols et al., 2014). These models combine microfluidic systems and the cellular microenvironment to create constructs that mimic the structure and function of human organs and tissues while preserving dynamics (Li K. et al., 2019). Lung-on-a-chip models are especially used to summarize lung function at the level of organs in laboratory conditions, where this feature allows lung-on-a-chip models to simulate the special microenvironment of the lungs (Wang et al., 2021). Lung diseases such as cancer, lung infections, asthma, and pulmonary edema can be studied using lung-on-a-chip models (Jadhav et al., 2021). In addition, bionic lungs, which are self-assembled three-dimensional functional units, provide another application for mimicking lung tissue conditions, helping to study diseases and evaluate drug efficacy (Barreiro Carpio et al., 2021). Cell removal techniques were also used to manufacture bioprostheses (Do et al., 2022). The goal of this approach is to create patient-specific lungs for transplantation using cells derived from induced pluripotent stem cells (Wilkinson et al., 2017).

Gelatin-based scaffolds have shown great promise in lung tissue engineering, as they mimic the natural ECM of lung tissue very well (Doryab and Schmid, 2022). These scaffolds, consisting of a gelatinous matrix, promote the growth and development of lung cells and therefore reflect the cellular microenvironment (Mahfouzi et al., 2021). This property makes gelatin-based scaffolds an ideal platform for research and the potential treatment of lung diseases (Bridge et al., 2018).

One way to improve the therapeutic potential of these scaffolds is to incorporate exosomes into the gelatinous matrix (Kang et al., 2023). Once implanted, these exosomes can be gradually released and provide cells with a continuous supply of nutrients and growth factors (Han et al., 2023). This method is successfully used to regenerate bone tissue, demonstrating the potential utility of gelatin-based scaffolds in tissue engineering beyond lung tissue (Guillén-Carvajal et al., 2023).

This gelatin scaffold exhibited desirable mechanical and degradation properties, flexibility, and cell adhesion (Stratton et al., 2016). Although gelatin-based scaffolds are very promising, other challenges remain, such as ensuring the long-term stability of the scaffolds, maintaining the integrity of the gelatin matrix, and optimizing the release rate of exosomes (Poongodi et al., 2021). Further research and development are needed to overcome these obstacles and maximize the potential of gelatin-based scaffolds for the treatment of lung diseases. In general, gelatin-based scaffolds, alone or in combination with other materials, are very promising for lung tissue development (Yuan et al., 2022). They have unique properties essential for optimal tissue function and have been shown to promote cell adhesion, proliferation and differentiation (Liu et al., 2022). Current research focuses on refining scaffold design and manufacturing and overcoming the challenges associated with integrating and controlling multiple nozzles in each cell (Giannitelli et al., 2014). Further studies are needed to fully understand the behavior of cells seeded on the scaffold and how they might integrate into the recipient nervous system. More supplementary information is also provided in Table 1 (Figure 4).

In lung tissue engineering, significant progress has been made in scaffold manufacturing, with a focus on hybrid bioactive scaffolds (Edgar et al., 2016). These new scaffolds use a synthetic beta copolymer membrane with the ECM, creating a unique cellular microenvironment that supports tissue engineering in the lung (De Santis et al., 2018). Hybrid scaffolds are critical for tissue engineering as they provide essential properties such as strength, elasticity, nutrient transfer, and cellular remodeling, all of which are vital for optimal tissue functionality (Wasyłeczko et al., 2020). The use of hybrid materials in tissue engineering scaffolds in the lung is a growing area of research aimed at creating an optimal environment for tissue regeneration (Silva et al., 2010). The challenges and requirements for constructing such scaffolds are being resolved through interdisciplinary collaboration, and ongoing research focuses on perfecting scaffold design and manufacturing (Hollister, 2009). An important innovation in this area is the use of hybrid materials to build an optimized lung structure (Vallet-Regí et al., 2011). In this strategy, the favorable properties of two or more materials are combined to create a final scaffold that overcomes the limitations of each component (Pina et al., 2019). For example, the favorable properties of Acellular scaffolds for cell adhesion sites, organization, and differentiation signals combined with synthetic materials and advanced manufacturing techniques can lead to a desirable lung scaffold (Ratheesh et al., 2017).

Despite the promising potential of these hybrid scaffolds, it must be recognized that they represent an ambitious goal that requires further scientific research and development (Roseti et al., 2017). Ultimately, the goal is to create functional and biocompatible constructs for tissue regeneration, a challenge that must be addressed through in-depth research and experimentation (Leikeim, 2022). Furthermore, the integration of synthetic and natural materials into scaffolds not only promises to revolutionize the field of tissue engineering but also opens new avenues for the treatment of various lung diseases (Kim et al., 2015).

Lee et al. (2011) discovered that hybrid scaffolds that combine the mechanical strength of synthetic materials with the biological activity of natural materials have the potential to create an environment conducive to lung tissue growth and regeneration (Lee et al., 2011). Biodegradable polymers including poly (ε-caprolactone), polyethylene glycol, and poly (lactic-co-glycolic acid) are commonly used in hybrid scaffolds due to their mechanical stability and rapid decomposition. offers control (Lebourg et al., 2008). However, their natural fraction is frequently formed from extracellular matrix proteins and polysaccharides such as collagen, hyaluronic acid, and fibrin, all of which play critical roles in controlling cell activity and tissue integrity (Bindi et al., 2023). Electrospinning and 3D printing were among the advanced fabrication techniques used to fabricate these hybrid scaffolds with a specific microarchitecture and precise porosity (Abel et al., 2020). Although progress is being made in this area, more research is needed to address challenges such as long-term biocompatibility.

In general, over the past 2 decades, regenerative medicine has experienced significant technological advancements. Each milestone has introduced new methods that enhance tissue regeneration, scaffold design, and treatment efficiency. Table 2 outlines the chronological development of key technologies in this field, demonstrating how innovations have evolved to meet the growing demand for more effective and personalized therapeutic options.

The term “organoid,” meaning “resembling an organ,” was first used by Smith et al., in 1946 to describe an instance of cystic teratoma (Dutta et al., 2017). Organoids are three-dimensional, self-organizing are created by pluripotent or adult tissue stem cells. They provide an in vitro model for drug screening and replicate interactions between cells and niches in tissue formation, homeostasis, regeneration, and disease (Lu et al., 2021a). A unique organoid culture system has been developed due to the technological advancements in in vitro culture technology over the past decade. Organoid cultures have now been adapted to cells of many different epithelial lineages (Rosenbluth et al., 2020).

Lung organoids have been successfully generated using adult stem cells, human pluripotent stem cells (hPSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). However, recent improvements in lung organoid systems have focused on organoid findings, particularly those from distal airway stem/progenitor cells (Lu et al., 2021a).

Many human lung airways are lined with pseudostratified epithelium, which is composed of various cell types including airway basal cells, secretory cells, ciliated cells, tuft cells, and neuroendocrine cells. Basal cells are present throughout the airways of the human lungs, including the small bronchioles with a diameter of 1 mm. These basal cells constitute approximately 30% of the pseudostratified lung epithelium and are firmly attached to the basal lamina. During homeostasis and repair, they can self-renew and produce secretory and ciliated luminal cells (Lu et al., 2021b).

Lung organoids can originate from several types of cells: basal cells, alveolar type II cells, and airway secretory cells. The genes that are expressed characteristically in basal cells are Integrin α6, p63, cytokeratin 5 (Krt5), and nerve growth factor receptor (NGFR) (Lu et al., 2021b). The term “tracheosphere” refers to 3D organoids formed from trachea basal cells, and “bronchosphere” refers to organoids derived from bronchi or large airways (Barkauskas et al., 2017) According to Rock et al. (2009a) the first tracheosphere was formed in a week in Matrigel using Krt5-GFPpos murine tracheal basal cells, and it had a visible lumen. After 14 days, p63pos Krt5/Krt14pos basal cells formed the outer layer of a pseudostratified epithelium, whereas Krt8pos ductal secretory cells and ciliated cells formed the inner layer (Rock et al., 2009b) (Figure 6).