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. 2021 Jan 5;13(1):60. doi: 10.3390/pharmaceutics13010060

Table 2.

Overview of advantages and disadvantages of in vitro OA models and their application in IA DDSs development.

In Vitro OA Model Advantages Disadvantages Models Applied in IA DDS Development (as per Table 1) Outcome Evaluation (as per Table 1)
2D cellular culture Monolayer High throughput, low cost. Homogenous cell exposition to nutrients. Allows for differences in cellular phenotype studies [12] Furthest from natural in vivo tissue conditions. High variability (different passages). Better suited for synoviocytes than chondrocytes. 2D substrate induces de-differentiation and changes in morphology [12]
  • -

    Synoviocytes (human, mouse and rat)

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    Chondrocytes (human, murine, rat and bovine)

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    Macrophages (human and murine)BMSCs (human)

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    BMSCs (human)

 RAW 264.7 macrophages [33,57,60,68,70]:
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    Cytotoxicity assays

  • -

    Quantification of NO. cAMP, IL-6, IL-1β and TNF-α

Synoviocytes [10,40,43,48,52,64]:
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    Cytotoxicity and proliferation

  • -

    Quantification of IL-6, PGE2, IL-1β, TNF-α, MMP-3, MMP-13, COX-2 and ADAMTS-5

Chondrocytes [47,53,59,62,63,66,72,73,81,84]:
  • -

    Cytotoxicity, apoptosis and proliferation assays

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    Quantification of IL-6, IL-1β, TNF-α, GAG/DNA, Aggrecan, Collagen II, MMP-1, MMP-3, TAC-1, MMP-13, COX-2, PGE2, iNOS and ADAMTS-5

  • -

    Senescence assays after genotoxic and oxidative stress [53]

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    Expression of inflammatory transcription factors: p-IKKα/β [80]
Co-culture Important in studies of cell-to-cell interactions and studies of influence of different cellular phenotypes together [12] Expensive and difficult to maintain. Lacks in three-dimensional characteristics of cartilage growth [87] (examples not included in Table 1)
  • -

    Synoviocytes-chondrocytes

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    Chondrocytes-osteoblasts [89,90]
3D cellular culture Without Scaffold High similarity with in vivo tissue conditions as it maintains structure from ECM growth. Cellular phenotype is preserved. Important in studies of intercellular and cell to ECM relationship and loading capacity assays [88,91] Expensive and difficult to maintain. Restricted throughput (hard to propagate without compromising cell quality). Nature of scaffold plays role in cellular growth [92]
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    Chondrocyte pellets

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    Hanging drop BMSCs
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    Quantification of: GAG/DNA, Collagen II, Aggrecan [35]
With Scaffold
  • -

    Hydrogels: biomaterial and synthetic

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    Polymeric scaffolds (osteochondral plugs)

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    Micro- and nanocarriers

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    Fiber/Mesh scaffolds [88]
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    GAG/DNA, MMP-13 and hydroxyproline quantification; proliferation in agarose assay by DNA quantification [44]

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    GAG/DNA, Collagen II and Young’s/dynamic modulus (Eγ and G) [77]

  • -

    Proliferation in alginate beads

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    Quantification of IL-6, MMP-13, Collagen II and Aggrecan [85]
Explants Easy to obtain and inexpensive. Allows for studies of intercellular and cell to ECM relationship because it maintains tissue as a whole [93] High variability and limited amounts of replicates from source. Cell death at edge of extracted tissues [12]
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    Articular cartilage and synovial membrane (human and bovine)

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    Osteochondral plugs (human)

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    Femoral chondyles (human, murine and equine)
  • -

    Cytotoxicity and cartilage penetration assays

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    Quantification of IL-6 [9,57]