To the Editor: In middle-aged and elderly individuals, intervertebral disc (IVD) degeneration (IVDD) can often cause low back pain (LBP). IVDD has a complex mechanism with many influencing factors. Biological changes in degenerative IVDs mainly include structural abnormalities of the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplate, as well as changes in the composition and amount of extracellular matrix (ECM). IVDD disease is treated conservatively, followed by surgery, but these are symptomatic treatments, with high complication rates.[1] Gelatin-methacryloyl (GelMA) hydrogel system therapy reduces complications while treating the cause. Through minimally invasive surgery, GelMA hydrogels are used to deliver regenerative cells and/or biological factors to the target area to eliminate symptoms and promote IVD cell regeneration. Or, using 3D printing technology, a bionic IVD can be constructed to replace a severely degenerated IVD. This is a research hotspot in the field of regenerative medicine and tissue engineering. The GelMA hydrogel system mainly includes GelMA hydrogels, target cells, and biological factors. GelMA hydrogel is an injectable photosensitive biomaterial that is polymerized from gelatin and methacrylic anhydride (MA) through a complex chemical reaction at 50°C. Gelatin contains a large number of amino acid sequences and matrix metalloproteinase (MMP) target sequences conducive to cell adhesion, thus giving GelMA hydrogels carrier characteristics. MA has stable photosensitivity, which is regulated by light reaction time and space conditions. This controllability is conducive to obtaining hydrogels with different mechanical properties, which meets the stress requirements of special parts of the body. GelMA hydrogels are similar to natural ECM and have the advantages of extremely low immunogenicity and an absence of cytotoxicity or biodegradability.[2] Additionally, the signal transmission between transplanted target cells encapsulated in GelMA hydrogel and the recipients was closer, the contact with ECM in the microenvironment was more sufficient, and the biological behavior was more obvious.[3] Regarding IVDD, GelMA hydrogel system therapy has far-reaching clinical application value. Promoting cell regeneration may be an important direction of GelMA hydrogel system therapy in the treatment of IVDD diseases. The loss of NP cells (NPCs) and ECM is the main cause of IVDD. Theoretically, it may be effective to supplement an appropriate amount of lost components or cells, but in practice, the efficacy of the simple injection of NPCs, stem cells, or ECM in the treatment of IVDD is poor. However, when cells or growth factors are combined with GelMA hydrogels for cotransplantation, satisfactory therapeutic effects can be obtained. In a study of an adipose mesenchymal stem cell-growth differentiation factor-5 (GDF-5)-GelMA hydrogel system transplanted into a degenerated rat IVD model through minimally invasive surgery, adipose derived mesenchymal stem cells (ADMSCs) showed good differentiation ability of NPCs under the directional induction of GDF-5, and a great amount of newly generated ECM was detected in NP tissue.[4] This good carrier property may be related to the high water content and porous structure of the GelMA hydrogel, which not only facilitates the infiltration of oxygen and nutrients but also provides a good local microenvironment for the growth of NPCs. GelMA hydrogels with different concentrations can directly affect the biological activity of NPCs after transplantation, and a 5% GelMA hydrogel concentration is the most suitable for NPC transplantation.[5] Also, a 5% GelMA hydrogel concentration can withstand most of the mechanical pressure of the spine, which maintains the morphology and biological activity of NPCs after transplantation [Supplementary Table 1, https://links.lww.com/CM9/B272]. Eliminating inflammatory symptoms may be another important aspect of IVDD treatment. Inflammatory reactions are the most common and important cause of recurrent LBP caused by IVDD and affect recovery after IVD resection. The inflammatory factors involved in IVDD mainly include tumor necrosis factor-α and interleukin-1β. At present, aspirin (ASP) and celecoxib (CXB) are commonly used in the clinic to effectively remove inflammatory factors and alleviate inflammatory pain, but oral or intravenous administration has a slow effect, and the concentration of effective drugs is low, which may also induce digestive system or cardiovascular system diseases. Anti-inflammatory drugs combined with appropriate carriers can achieve the purpose of local medication to remove inflammatory factors and avoid inducing new diseases through minimally invasive surgery, such as the ASP GelMA hydrogel system or CXB microspheres GelMA hydrogel. Recently, Liu et al[6] transplanted ASP-GelMA hydrogel into pathological IVDs and found that proinflammatory factors MMP-3 and A disintegrin-like and metalloproteinase with thrombospondin motifs type 4 and 5 (ADAMTS-4, -5) were significantly inhibited and shortened the inflammatory cycle. CXB-polyesterimide microspheres (PEAM) have been proven to play an anti-inflammatory role in degenerative IVD tissue in dogs, but their controllability is poor.[7] If CXB-PEAM can be combined with GelMA hydrogel, it will help to improve the anti-inflammatory effect and cover the whole inflammatory cycle. Constructing biological IVDs may be another important application for the treatment of IVDD. Although GelMA hydrogels with certain mechanical properties can be obtained by controlling the GelMA hydrogel concentration and light reaction time, they remain unable to meet the stress requirements of IVDs. Therefore, it is necessary to continuously optimize the mechanical properties of GelMA hydrogels to meet the special stress requirements of IVDs [Figure 1]. Through 3D printing technology, bionic IVDs may completely replace IVDs after surgical resection. The current study found that with a preformed hydrogel containing 20 wt% BaSO4 as the contrast agent injected into a bovine NP cavity with a syringe, the intra-nuclear IVD after hydrogel transplantation had good mechanical properties under the stimulation of axial compression and tension cycles at different frequencies.[8] However, for IVD diseases with NP and AP damage, it is of little significance to simulate NP transplantation alone. Simulating the overall cell and matrix structure of IVDs remains a severe challenge. Figure 1: GelMA and modified hydrogel preparation and mechanism. There are many modified hydrogels based on GelMA hydrogels, and the aim is to better meet the biological performance requirements of clinical tissues and organs. Here, we focus on four modified hydrogels for the treatment of IVDD: GelMA-PEGDA-nHA, GelMA-CNTs, GelMA-SF, and PCL-GelMA-USPIO. First, PEGDA-nHA, CNTs, SF or PCL-USPIO was added to the GelMA hydrogel to synthesize corresponding functional hydrogels under different conditions. Second, the key conditions for playing a special biological role were [HO–Ca2+–HO], elastic modulus, crystallinity, degradable scaffolds, and ammonium contrast agents. Finally, these modified hydrogels reversed or delayed IVDD to some extent. GelMA: Gelatin methacryloyl; IVDD: Intervertebral disc; MA: Methacrylic anhydride; PEGDA: Poly (ethylene glycol) diacrylate; PCL: Polycaprolactone; USPIO: Ultrasmall superparamagnetic iron oxide. Research on GelMA hydrogels in various fields of medicine has been widely explored, and preliminary results have been achieved [Supplementary Figure 1, https://links.lww.com/CM9/B272]. Although GelMA hydrogels have some shortcomings, in the long run, the GelMA hydrogel system is expected to repair degenerative IVDs from the etiological level, which provides a new idea for the treatment of IVDD diseases. Conflicts of interest None.