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4.5. Organoids for tissue engineering tailored for biomaterial translation is imperative, as this
With the rapid advancement of tissue engineering will accelerate the exponential advancement of tissue
technologies, the synthesis and fabrication of biomaterials engineering and propel the rapid clinical deployment of
have experienced exponential growth. The ultimate goal of biomaterials.
tissue engineering is to facilitate the in vivo regeneration 5. The challenges of replacing animal
and clinical translation of biomaterials while ensuring
their biocompatibility and repair capabilities. At present, experiments with organoids
the biocompatibility, regenerative ability, and clinical 5.1. Insufficient system complexity
translation potential of biomaterials are predominantly Due to the high complexity of tissues and organs, their
evaluated through animal models, with groundbreaking intricate structural relationships and crosstalk effects have
advances achieved particularly in the field of MSK systems. not yet been effectively recapitulated in vitro. Despite
As for evaluation of biocompatibility and repair ability, significant structural and functional advances in MSK
researchers conducted an evaluation of cranial bone repair organoids in recent years, most existing organoids are
using hydrogels mineralized with distinct metal ions in a rat limited to simple simulations of a single tissue type,
model. In vivo experiments demonstrated significantly lacking significant system complexity. 212,213 For example,
207
enhanced osteogenic efficacy. In addition, Sharma
et al. developed a poly(ethylene glycol) diacrylate-based skeletal muscle organoids usually form only myotubular
208
bioadhesive to repair focal cartilage defects in a caprine structures, but lack key elements, such as vascularization,
model. This soft hydrogel adhesive enhanced the efficacy of innervation, and tendon connections, which significantly
microfracture treatment, promoting cartilage regeneration. limit the in-depth study of muscle contraction function and
123,214
In the context of clinical translation, biomaterials require mechanical properties. The physiological functions
further evaluation in large animal models (porcine, of bone, cartilage, and skeletal muscle tissues are far
ovine, and non-human primates) before human trials. beyond the independent action of a single cell and rely
For example, researchers evaluated the osteogenic ability on the sophisticated synergy of vascularization, nerves,
215-217
of porous ceramic scaffolds in a 48 mm ovine tibia defect mechanical feedback, and hormonal signals. Current
model. Results demonstrated that the scaffold was gradually single-tissue organoid models of the MSK system lack
replaced by new bone over a year and was fully absorbed cross-system functional integration, making it challenging
within 2 years. 209 to realistically reproduce the complex physiological
and pathological processes of the MSK system in vivo.
Due to individual variations in animal model Therefore, the construction of organoids in vitro that can
establishment, biases in construction methods, as well comprehensively recapitulate the MSK system still faces
as the prolonged experimental periods and high costs of significant challenges.
large animals, animal models are increasingly becoming
constraints on the development of tissue engineering and 5.1.1. Absence of vascular network
clinical translation of biomaterials. MSK organoids offer The integration of a perfusable vascular network into
advantages such as low cost, high reproducibility, broad MSK organoids is a key breakthrough in achieving their
applicability, and scalability, and have already become functional maturation and reaching adequate tissue size.
complementary experimental models to animals in tissue The lack of vasculature in traditional organoid cultures
engineering. MSK organoids can be utilized not only to results in insufficient nutrients and oxygen for the internal
evaluate the biocompatibility of biomaterials but also to cells, as well as accumulation of metabolic byproducts,
analyze their ability to facilitate osteogenic differentiation thereby limiting the growth size and functional maturation
and bone tissue formation. For instance, Mikael et al. of the organoids. 218,219 Especially in MSK organoids, the
210
employed bone organoids to investigate the significance high energy demand and metabolic activity make the
of patient-specific biomaterials in promoting bone vascularization of organoids even more important. 220,221
regeneration. Similarly, in cartilage repair, organoids provide
a dynamic system to assess the mechanical and biological The introduction of blood vessels addresses the physical
properties of biomaterials. The study by Vainieri et al. limits of nutrient diffusion. According to the “diffusion
211
demonstrated that biomaterials should not only support limit” theory, the thickness of non-vascularized tissues
the growth of chondrocytes but also respond appropriately usually does not exceed 200 μm; otherwise, the core area
222
to mechanical stimuli, which is crucial for the successful will be necrotic due to hypoxia and nutrient deficiency.
integration and function of repaired cartilage tissue. The By engineering a perfusable vascular network, it is
application of MSK organoids in biomaterial clinical possible to mimic blood circulation in vivo and support
translation remains at an early-stage phase. Establishing the survival of millimeter-sized or even centimeter-sized
standardized evaluation criteria and methodologies organoids. Second, vascular networks can promote the

Volume 1 Issue 3 (2025) 16 doi: 10.36922/OR025280024