TABLE 3.
Recent applications of continuous gradients for orthopedic interfacial tissue engineering.
| Reference(s) | Gradient type(s) | Targeted interfacial tissues | Geometry and gradient direction | Material(s) used | Fabrication method(s) |
|---|---|---|---|---|---|
| Bretcanu et al.5 | Porosity | Cortical–cancellous bone | Any shape (axial direction) | PU sponges and 45S5 Bioglass slurry | Dipping in bioglass and burnout of PU |
| Liu et al.36 | Porosity, Material | Cartilage–bone or any mineralized tissues | Cylindrical (axial gradient) | Collagen l and nonstoichiometric nano HA | Modified diffusion model of calcium and phosphate across scaffold at pH = 8.5, cross-linking treatment |
| Erisken et al.13 | Material | Soft tissue–bone | Cylindrical (axial gradient) | ε-polycaprolactone and β-TCP | Twin-screw extrusion/electrospinning process, time-dependent feed of TCP |
| Singh et al.56–58 and Dormer et al.12 | Drug loading, Material | Cartilage–bone | Cylindrical (axial gradient) | PLGA 50:50, CaCO3, TiO2 BMP-2, TGF-β1 | Precision particle fabrication for PLGA microspheres, programmable pumps for gradient |
| Wang et al.69 | Drug loading | Cartilage–bone | Cylindrical (axial gradient) | PLGA 50:50, silk fibroin, alginate, BMP-2 and IGF-1 for release, HRP for microsphere gradient magnitude | PLGA microspheres from water-in-oil-in-water dispersion, silk microspheres from lipid film/freeze-thaw/centrifugation process, gradient from controlled pump rate |
| Phillips et al.50 (Fig. 4) | Transcription factor | Soft tissue–bone | 3D slice (longitudinal gradient) | Collagen, poly (L-lysine), Runx2/Cbfa1 | Time-dependent dipping process of collagen scaffold in PLL with bound Runx2/Cbfa1 |
| Reference(s) | Primary gradient value(s) | Mechanical properties | Biological model(s) | Bulk tissue regeneration | Interface regeneration or cell interaction |
|---|---|---|---|---|---|
| Bretcanu et al.5 | Not directly measured after complete process, gradient magnitude proportional to degree of compression | Not directly evaluated | None | None | None |
| Liu et al.36 | Calcium: 3–19%, overall porosity: 45%, gradient in porosity inferred from regional HA crystal morphology | Not directly evaluated | In vitro: resistance to biodegradation, in vivo: 50% of construct remaining at 4 weeks | None | None |
| Erisken et al.13 | Tricalcium phosphate: 0–15 wt.% | Failure properties corresponding with 0–12 wt.% TCP, stress: 880–1100 kPa, elongation: 250–175% | In vitro: mouse preosteoblasts (MC3T3E1) for 4 weeks | Calcium deposition and collagen synthesis, culture significantly increased compressive modulus and toughness by 4 weeks | Graded appearance in calcium deposition and cell nuclei |
| Singh et al.56–58 and Dormer et al.12 | BMP-2 & TGF-β1: 0–100%(opposing gradients), stiffness factors: 0–100% | Up to 400 kPa at onset of culture, ~3 kPa after 6 weeks in vitro | In vitro: hUCMSCs and hBMSCs for 6 weeks | Increased biochemical output from graded scaffolds, upregulation of some bone and cartilage markers on single graded construct | Regionalized bone-like and cartilage-like matrix |
| Wang et al.69 | Factor increase in (1) PLGA microsphere number across scaffold: 2–2.5×, (2) BMP-2 across length 15×, (3) IGF-1 across length: 4.5× as examples | Not directly evaluated | In vitro: MSCs | Homogenous cell distribution, graded increase in biochemical production and gene transcription | Heterogeneous proteoglycan and calcium deposition |
| Phillips et al.50 (Fig. 4) | Post fabrication PLL gradient via FITC intensity: decrease of 2.72 R.F.I/μm scaffold length, after in vivo implantation mineral volume (mm3): decrease from 0.8 to 0.0 in first 8 mm of 14 mm scaffold | Max force at failure, stiffness, Young’s modulus, and maximum stress all at least 2× higher on mineralized (Runx2/Cbfa 1-osteogenic) side than fibroblast side | In vitro: Wistar rat fibroblasts, in vivo: ectopic implanation in syngeneic rats after 24 h preculture, harvest at 2 weeks | In vitro: homogenous cell distribution, Runx2-expressing cells graded in number across construct | In vitro: graded mineral deposition, in vivo: deep gradient in mineral deposition localized to one side of the construct |
PU, polyurethane; HA, hydroxyapatite; TCP, tricalcium phosphate; PLGA, poly(D,L-lactic-co-glycolic acid); CaCO3, calcium carbonate; TiO2, titanium oxide; BMP, bone morphogenetic protein; IGF, insulin-like growth factor; HRP, horseradish peroxidase; Runx2, runt-related transcription factor-2; Cbfa1, core binding factor-α-1; PLL, poly(L-lysine); FITC, fluorescein isothiocyanate; RFI, relative FITC intensity; hUCMSC, human umbilical cord matrix stromal cells; hBMSC, human bone marrow stromal cells.