Table 1.
Biomaterials regulate the inflammatory microenvironment to repair degenerated intervertebral discs.
| Regulator | Biomaterial | Production Method | Therapeutic components | Target | Result | Reference | |
|---|---|---|---|---|---|---|---|
| TGF | Fibrin hydrogels | Fibrinogen | CCL5 | AF | Fibrin hydrogels release CCL5 for the chemotaxis homing effect of AF cells, but do not promote AF cell repair in sheep. | (38) | |
| TGF | pullulan microbeads | Fitc-pullulan was dissolved in 20 mL of distilled water under magnetic stirring and lyophilized after the addition of a cross-linking agent. Pullulan microbeads (PMBs) and 500 u of LCCL5 and TGF-β1 were magnetically stirred for 24 h. | CCL-5 TGF-β1 |
ECM | PMBs were loaded with CCL5/TGF-β1/GDF-5 continuously and sustainably released growth factors and maintained their biological activities in vitro. Increased distance that ASCs can migrate to NP. | (39) | |
| TGF | Collagen-Polyurethane scaffold | Polyurethane (PU) was dissolved in N,N-dimethylformamide solution, and the PU film was formed after evaporating the solvent. Type I collagen fibers were used as cell carriers to encapsulate AF cells and TGF-β1 on PU membranes to make collagen-PU scaffolds. | AF cells TGF-β1 |
AF ECM |
The TGF-β1 treatment of collagen hydrogels further promotes cell proliferation and matrix production in AF cells in vitro. | (40) | |
| chitosan (CH)- based scaffold |
Mixing chitosan with porcine gelatin at a ratio of 3:2 can further increase the biological response of encapsulated cells by adding gelatin and Link N (a peptide present in IVDs). | Link | ECM | LN increased GAG production in degenerative media to the same level as that of TGF-β. The addition of 1% gelatin to the CH hydrogel further increased GAG production in vitro. | (41) | ||
| TGF-β3@PDA NPs | PDA NP were prepared through chemical oxidative polymerization using dopamine (DA) and tris-(hydroxymethyl)-aminomethane (Tris). TGF-β3 was loaded onto the surface of PDA nanoparticles in a covalent binding manner. | TGF-β3 | AF NP |
The released GFs could induce the differentiation of BSMCs into myeloid and annulus-like cells and maintain high activity. Finally, in vivo experiments confirmed that the reconstituted IVD scaffolds exhibited region-specific stromal phenotypes with histological and immunological features. | (42) | ||
| Genipin Fibrin Gel | Genipin and fibrinogen in a humidified incubator for 3–4 h for polymerization and cross-linking. | TGF-β3 | ECM | Fibrin increases integrin binding sites and prevents partially encapsulated cells from undergoing apoptosis, allowing encapsulated cells to increase ECM synthesis in vitro. | (43) | ||
| gelatin-hyaluronic acid methacrylate (GelHA) hydrogel | Methacrylic anhydride (MA) was added to the gelatin solution and allowed to react for 1 h. The resulting solution was dialyzed for 3 days and lyophilized. Photoinitiators and integrins were added, and photocrosslinking was performed under UV light irradiation for 2 min. | integrin | ECM | The combination of photocrosslinked GelHA hydrogel and ASC can enable ASC to undergo NP-like differentiation and enhance the efficacy of ASC for IVD repair by activating the integrin αvβ6-TGF-β1 pathway in vitro. | (44) | ||
| IL-α | HA-pNIPAM | Gelatin was combined with EGCG, mixed with water, and stirred at 40°C for 4–6 h. Poly-N-isopropylacrylamide was directly grafted onto HA. Gelatin was directly applied to (HA-pNIPAM). | EGCG | ECM | EGCG microparticles combined with a suitable carrier can modulate the activity/release of EGCG in the IVD in vitro. | (45) | |
| IL | HMw-HA Gel | HMw sodium hyaluronate was dissolved in 1 mL of distilled water and mixed with PGE-amine to induce cross-linking to obtain spherical hydrogels. | – | ECM | The hydrogels inhibited the expression of the inflammatory receptors IL-1R1 and MyD88, downregulated NGF and BDNF gene expression, and upregulated CD44 receptor expression in vitro. | (46) | |
| IL | PLGA Microspheres | After mixing IL-1ra with 1 mL of 75:25 PLGA and sonicating the mixture, 1% polyvinyl alcohol (PVA) magnetic stir bar was added and mixed for 3 h. | IL-1ra | NP | IL-1ra delivered from PLGA microspheres effectively attenuated IL-1β-mediated inflammatory changes in engineered NP constructs in vitro. | (47) | |
| IL | Chitosan/Poly-γ-glutamic acid nanoparticles | Chitosan/Poly-γ-glutamic acid was mixed at a molar ratio of 1:1.5 to prepare nanoparticles by the co-coagulation method. Diclofenac (Df) was added to the nanoparticles and stirred at a constant speed. | Df | ECM | The intradiscal injection of Ch/Df/γ-PGA NPs reduced pro-inflammatory mediators, downregulated MMP 1 and 3 expression, and upregulated Col II and Agg production in a pro-inflammatory/degenerative IVD organ culture model in vitro. | (48) | |
| TNF | ELP-curcumin conjugates | Elastin-like polypeptide (ELP) is a thermoresponsive biopolymer composed of Val-Pro-Gly Xaa-Gly pentapeptide repeating units. Curcumin is chemically modified and coupled with ELP. | Curcumin | ECM | The ELP-curcumin conjugate rapidly forms a depot after physiological administration and slowly releases bioactive curcumin in the perineural space to treat neuroinflammation in vitro. | (49) | |
| pNIPAAM MgFe-LDH Gel | N-isopropylacrylamide forms a pNIPAAM polymer via free radical polymerization. Polymers with MgFe layered double hydroxide (LDH) nanoparticles and CXB were dissolved in water. | CXB | ECM | The controlled release of CXB from this hydrogel resulted in the inhibition of PGE 2 in a mice model of spontaneous IVD degeneration. | (50) | ||
| HIF | Small leucine-rich proteoglycans | – | – | ECM | Biglycan can bind and (TGF-β) to activate the MAPK pathway to enhance HIF-1α translation in vitro. | (51) | |
| Chitosan-alginate gel scaffold | Chitosan was dissolved in acetic acid, and after filtering the solution, the pH was adjusted to 8.5 with 0.1 mol/L NaOH. The sterile alginate solution was then mixed with the chitosan solution at a ratio of 1:1. | ADSC | NP ECM |
ADSCs grew well in the C/A gel scaffolds, differentiated into NP-like cells under certain induction conditions, produced the sameECM as NP cells, and were promoted under hypoxia in vitro. | (52) | ||
| Nanofibrous spongy microspheres | Development of poly (L-lactic acid) grafted poly(hydroxyethyl methacrylate) (PLLA-g-PHEMA) nanoparticles using the phase separation method. miR-199a was encapsulated in nanoparticles using the double emulsion technique. | miR-199a | NP | Sustained release of in situ anti-miR-199a inhibits miR-199a, which in turn enhances HIF-1α and Sox-9 activity, thereby inhibiting calcification and promoting NP regeneration in mice. | (53) | ||
| Polymer capsule | Calcium carbonate was used as a sacrificial template to fabricate catalase-loaded polymer capsules functionalized with an outer layer of tannic acid (TA) by a layer-by-layer approach. | Catalase | ECM | ROS-responsive polymer capsules reduce the potential for oxidative stress and downregulate MMP expression in the ECM. | (54) | ||
| ROS | Rapamycin hydrogel | The ROS-labile linker was synthesized via the quaternization reaction of tetramethylpropane-1,3-diamine with an excess of 4-(bromomethyl) phenylboronic acid. Cross-linking of the ROS-labile linker with poly(vinyl alcohol) (PVA) to form ROS-scavenging hydrogels for loading rapamycin. | Rapamycin | ECM | ROS-responsive hydrogel scaffolds and rapamycin can reduce ROS levels and promote macrophage polarization to M2 type in vitro. | (55) | |
| Alginate scaffold | The sodium alginate solution was diluted with sterile saline, then the Perfluorotributylamine emulsion was added and sonicated. | – | NP ECM |
Perfluorotributylamine -enriched alginate scaffolds promote NP cell survival and proliferation in vitro. Furthermore, Perfluorotributylamine can modulate ECM expression to generate disc-like tissue grafts in mice. | (56) | ||
GAG, glycosaminoglycan; MMP, matrix metalloproteinase; HIF-1α, hypoxia inducible factor-1α; IL-1ra, Interleukin -1 receptor antagonist; TNF, tumor necrosis factor; ROS, reactive oxygen species; ECM, extracellular matrix; CCL-5, chemokine (C–C motif) ligand; ELP, elastin-like polypeptide; CXB, celecoxib; NGF, nerve growth factors.