# Advances in Tissue Engineering for Disc Repair
## 3 Tissue Engineering for IVD Regeneration
### Biomaterials
The use of synthetic materials as injectable fillers or cell carriers is a promising strategy to prevent the biomechanical limitations of natural polymer-based hydrogels. Many synthetic biomaterials, such as polyethylene glycol (PEG), PLGA, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and hydroxyethyl methacrylate (HEMA), have been used as drug delivery and cell carriers [71; 72]. The first approach used to restore NP height, function, and motion focused on the use of in situ hydrated synthetic polymers to restore NP hydration, IVD pressure, and disc height. This tactic aimed at mimicking the hydration properties of the NP glycosaminoglycans, which are slowly degraded and modified as they age and degenerate [57]. A copolymeric hydrogel, with the longest history of clinical use, has served as an alternative to NP. However, similar to previously used in situ hydrated polymers, some complications have already been reported, including gel fragmentation during swelling [73]. Other biomaterials, such as NP implant devices, have been developed from an injectable polymer that physically transitions to a gel or solid form. This approach has the advantage of minimizing tissue damage to AF during transplantation. In addition, various strategies, such as chemical cross-linking agents and heat- or pH-induced transition, have been developed. The cross-linked material inhibits proteolysis and induces the stiffness for disc implant [57]. Many scientists have attempted to develop monophasic NP or AF scaffolds such as ECM-based scaffold [74], adipose-derived MSCs (AD-MSCs)-loaded NP tissue-engineered construct [75], ASCs-seeded type II collagen/chondroitin sulfate composite hydrogel [76], and decellularized NP-based scaffold [77] (Table 2). Extensive efforts have also been made to develop biphasic tissue-engineered AF-NP composite scaffolds such as a collagen-GAG co-precipitate (NP-like core)/photochemically crosslinked collagen membranes (AF-like lamellae) composite [78], multiple AF-like lamellae encasing an NP-like core (MSCs-seeded collagen-GAG) [79], engineered nanofibrous disk-like angle-ply structure [80], biomimetic glycosaminoglycan analogues based on sulphonate-containing polymers [81], and multiple HA-PEG composite hydrogel [82] (Table 2). Animal studies using these biphasic scaffolds have shown excellent mechanical and biochemical results, suggesting that mimicking the morphology of the IVD is important for long-term stability and function of the implanted scaffolds [78; 79; 80; 81; 82]. In addition, many studies have demonstrated that differentiation of stem cell into the IVD cell phenotype is promoted by various types of biomaterials; (1) natural biomaterials: collagen type II-chondroitin sulphate hydrogel, gelatin-HA methacrylate hydrogel, silk-protein-based multilayered angle-ply scaffold, chitosan-HA hydrogel, decellularized allogenic IVD, acellular porcine NP hydrogel, NP cell-derived acellular matrix, dextran chitosan and teleostan combined hydrogel, temperature sensitive hydrogel (chitosan-glycerophosphate), chitosan and alginate gel scaffold, alginate and chitosan hydrogels, and self-assembling peptides; (2) Synthetic biomaterials: poly(N-isopropylacrylamide (pNIPAM) hydrogel system, nanofibrous poly(l-lactide) (PLLA) scaffolds, and heparin-poly(ethylene arginineylaspartate diglyceride) (PEAD) conjugated vehicle; (3) Biosynthetic biomaterials: T1307-fibrinogen hydrogel, HA-pNIPAM hydrogel, and pentosan polysulfate (PEG-HA-PPS) hydrogel [83]. In summary, transplanted stem cells should survive, proliferate, and differentiate into NP-/AF-like cells. The combination of biomaterials and stem cells can provide an effective strategy to enhance effective cell delivery and stem cell differentiation capacity.