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International Journal of Bioprinting 3D-printed scaffolds for osteochondral defect

Therefore, improving the inflammatory microenvironment protected chondrocytes from oxidative stress-induced
at an early stage should be prioritized to achieve better damage by scavenging ROS, while simultaneously
repair outcomes. The alleviation or deterioration of stimulating the HIF-1α and glucose transporter (GLUT)
inflammatory markers can reflect the repair status, signaling pathways to promote chondrocyte proliferation
including the following: (1) pro-inflammatory cytokines, and maturation.
such as IL-1β, IL-6, IL-8, and tumor necrosis factor- Combining ROS-scavenging agents with anti-
alpha (TNF-α); (2) macrophage polarization (M2/M1 inflammatory drugs demonstrates synergistic efficacy
ratio) assessed by flow cytometry ; (3) immune cell in alleviating inflammatory progression. Lu et al.
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191
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infiltration (e.g., T lymphocytes, neutrophils) assessed by developed a dual-layer hydrogel system co-loaded
immunostaining ; and (4) oxidative stress levels, such with diclofenac sodium and BMSC-derived exosomes.
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as reactive oxygen species (ROS), lipid peroxidation During the early phase, the ROS-responsive upper layer
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products (e.g., malonaldehyde), and antioxidant enzyme degrades and releases diclofenac, which rapidly improves
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activities (e.g., superoxide dismutase, catalase).
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the inflammatory microenvironment by suppressing
As an implanted foreign material, the inflammatory lipoxygenase activity, nuclear factor kappa β (NF-κβ)
response induced by scaffolds should be considered. signaling, and M1 macrophage polarization. Subsequently,
Most studies reviewed in this article did not focus on the sustained release of exosomes promotes cartilage
inflammation-related responses. Nedrelow et al. observed repair. In vitro and in vivo analyses confirmed reduced
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CD4+ T cell infiltration following scaffold implantation; expression of pro-inflammatory M1 markers, inhibition
however, this does not necessarily indicate the level of of ECM degradation-related genes, and upregulation of
inflammation. Li et al. quantitatively analyzed IL-1β cartilage repair-associated genes.
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levels after implantation, finding a significant increase in
the early stage (1 week), which gradually decreased after 5.5. In vivo animal model verification
4 weeks, suggesting that scaffold implantation induces a Osteochondral repair research utilizes animal models
mild inflammatory response during the early phase. across the following different size categories: small rodents
(murine and rat models), intermediate species (rabbits
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The balance between anti-inflammatory and pro- and canines), and large animal models (ovine, caprine,
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inflammatory pathways within the microenvironment equine, and porcine). Current studies predominantly
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is closely associated with macrophage phenotypes. employ small animal models, particularly rabbits and
M1 phenotype generates ROS and inflammatory murines, for in vivo experimentation. These models
cytokines. 181,182 ROS directly degrades the chondral ECM, offer practical advantages, including short experimental
inducing lipid peroxidation and DNA fragmentation, timelines, low maintenance cost, simplified husbandry,
thereby imposing significant limitations and challenges for and feasibility for large-scale study. 193
scaffold-based tissue regeneration. Hence, the concept of
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ROS-scavenging hydrogels has been proposed to enhance However, there are notable differences between small
the efficacy of scaffold-based tissue regeneration. Current animals, large animals, and humans, in terms of joint size,
strategies for ROS scavenging include: (1) anti-inflammatory load-bearing capacity, anatomical features, and tissue repair
small-molecule drugs, such as NSAIDs; (2) integration potential, which limits the translational relevance of small
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of antioxidant nanoparticles ; (3) incorporation of animal models. For example, human articular cartilage is
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antioxidant enzymes (e.g., catalase) or nano enzymes 184,185 ; typically 2–4 mm thick, whereas rabbit cartilage is only
and (4) fabrication of scaffolds using bioactive materials 0.25–0.75 mm, and murine cartilage is even thinner.
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with inherent antioxidant properties. 186–189 The area of cartilage defects also varies significantly with
body size. Strategies effective in small animals may be
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Liu et al. incorporated cerium oxide nanoparticles inadequate to support larger defects, presenting a major
functionalized with cerium bifunctional albumin (CeNPs) challenge. Furthermore, osteochondral defects in rodent
into GelMA, which counteracted the toxic effects induced models tend to undergo spontaneous repair, which may
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by hydrogen peroxide. 2ʹ,7ʹ-dichlorofluorescein diacetate lead to an overestimation of scaffold efficacy.
(DCFH-DA) and dihydroethidium (DHE) staining
confirmed a reduction in ROS. Furthermore, the scaffold Guinea pigs, which exhibit spontaneous cartilage
promoted the activation of the PI3K/Akt/EBV1 pathway, degeneration similar to humans and lack the ability for
facilitating the polarization of gliogenic cells toward the spontaneous cartilage repair, are widely used as OA models.
anti-inflammatory M2 phenotype. Deng et al. utilized However, the anatomical features of their knee joints differ
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human hair-derived antioxidant nanoparticles (HNPs) significantly from humans and the medial compartment
and microparticles (HMPs). These bioactive nanoparticles of their knees bears increasing load during movement.
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Volume 11 Issue 4 (2025) 21 doi: 10.36922/IJB025120100