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myocardial tissue under progressive stretching conditions, promote endothelial cell adhesion and growth. A dual-
promoting its growth and maturation. In the study, a collagen- channel vessel-on-chip device was employed to enhance
fibrin hybrid hydrogel provided mechanical strength and the complexity and functionality of the system, enhancing
passive tension. Given the constraints on the maximal stretch its biomimicry performance. This setup allows hierarchical
and size of myocardial cells and the impaired contraction and interconnected microvascular network formation
performance of engineered heart tissues (EHTs), the study without imposing geometric constraints on vessel growth,
proposed a novel method for stretching and growing EHTs effectively mimicking the physiological behavior of
under defined diastolic loads to achieve more physiological natural blood vessels (Figure 2E). This method is both
growth. This method enhances cellular cohesion through straightforward and reproducible, with the needle-based
high cell density and low ECM quality, inducing maturation template technique offering a simpler and more repeatable
and alignment of myocardial cells through progressive alternative to traditional sacrificial molding methods.
stretching under biomimetic conditions. The results 99
significantly improved contraction force, tissue compliance, Enrico et al. introduced a method for 3D printing blood
cellular alignment, electrophysiological properties, and vessels using collagen hydrogels, where microchannels and
99
excitation-contraction coupling of EHTs. This innovative cavities are formed through femtosecond laser irradiation.
tissue engineering approach generates highly mature human This approach allows for the creation of millimeter-
EHTs and provides insights into cardiac developmental long channels with diameters ranging from 20 to 60 μm,
biomechanics, thus addressing critical needs for disease remaining stable for at least 8 days under physiological
modeling and therapeutic tissue replacement. 93 conditions. This technology enables the generation of 3D
microchannels and cavities of arbitrary shapes and sizes
The complexity of the heart’s structure and function while preserving cellular bioactivity within the hydrogel. Its
necessitates innovative approaches in cardiac tissue advantage lies in its ability to provide biologically relevant
engineering incorporating advanced technologies, such yet controllable vascularization, enabling the development
as 3D bioprinting, microfluidics, and biomimetic culture of 3D tissue models for studying complex tissue targets,
systems. While these studies do not directly address the such as tumors and neural tissues.
synthesis and application of cardiac organoids, they provide
valuable tools for modeling and treating cardiac diseases However, present 3D vascular models often lack
and offer insights into the biomechanical mechanisms physiological complexity, particularly in simulating
of heart development. Future research should focus on dynamic behaviors and responses. Future research
optimizing these technologies to enhance organ mimicry should focus on developing models that can dynamically
and facilitate clinical translation. simulate blood flow dynamics and enhance cell viability for
applications in regenerative medicine and drug screening.
4.1.2. Vessels
4.2. Respiratory system
The vascular system is one of the first to develop during
embryogenesis, essential for nutrient transport and waste 4.2.1. Lungs
removal. 94,95 Capillaries, the most common blood vessels, The lungs, essential for respiration, are located within the
consist of a single layer of endothelial cells supported thoracic cavity, extending from the collarbone or the first
96
by a basement membrane and pericytes. They form a rib to the sixth and seventh ribs. They contain a complex
complex branching network distributed throughout the network of blood vessels, nerves, lymphatic vessels, alveoli,
body, ensuring a stable supply of oxygen and nutrients and connective tissue. Lung development begins with
100
while facilitating timely waste removal. Maintaining the ventral budding from the anterior foregut endoderm,
97
complex structure and 3D network of blood vessels is leading to bronchial airways and alveolar progenitor cell
essential for cell viability in regenerative medicine. formation. During the primordial lung sac stage (around
101
Orge et al. proposed an innovative microvascularization 4 weeks), the lungs are encased by ectodermal epithelial
98
strategy by utilizing fibrin-based hydrogels for the 3D cells. By the 5 week, these sacs differentiate into smaller
th
printing of blood vessels. They employed modular “vascular lung vesicles, with bronchi branching into finer bronchioles
th
units” to construct a perfusable 3D microvascular network and alveoli. By the 8 week, smooth muscle in the airways
embedded within a matrix using a bottom-up approach. begins to receive neural innervation. As blood vessels grow
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102
Specifically, fibrin-based hydrogels formed hollow into the lungs, the alveoli mature as sites of gas exchange.
channels in the hydrogel using a needle-based template. The lungs consist of bronchial epithelial cells, endothelial
Fibrin solution was injected into these channels to form cells, macrophages, and smooth muscle cells. This
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a stable matrix (Figure 2D). Following the removal of the complexity necessitates advancements in lung organoid
needle template, the hollow channels were established development using biocompatible composites that can
and coated with fibronectin and collagen solutions to mimic the lung microenvironment.

Volume 1 Issue 2 (2025) 10 doi: 10.36922/or.8262