Tissue engineering strategies contain three key elements: cells, scaffolds, and biomechanical or biochemical signals Mhanna and Hasan, These elements have been applied and extended in IVD tissue engineering.
Applications of stem cells in IVD and derivative methods gene therapy and extracellular vesicle therapy have shown promising therapeutic potential for IVDD.
Illustrating the interactive mechanisms between the components [IVD cells, biological factors, extracellular matrix ECM components, and environmental factors] in the IVD microenvironment makes therapeutic strategies more rational. Scaffolds can carry and release therapeutic biological factors.
These findings contribute to IVD tissue engineering strategies. The primary function of the IVD is to provide mechanical support for the vertebral body and allow movement of the spine flexion, extension, and rotation Devereaux, PGs are widely found in cartilage, the brain, IVDs, tendons, and corneal tissues.
They provide viscoelastic properties, retain water, maintain osmotic pressure, and arrange collagen tissue. Aggrecan in the IVD contains more keratin sulfated a highly hydrated sulphated glycosaminoglycan. Thus, it provides more hydration ability Iozzo and Schaefer, ; Frapin et al. Thus, it plays a role in morphogenesis, cell migration, cell survival, apoptosis, inflammation, and tumorigenesis Dicker et al. HA binds to PGs to form aggrecan, which highly hydrates NP and generates a hydrostatic pressure to effectively absorb stress, reduce vibration, and maintain the osmotic pressure and disk height of healthy IVDs Raj, ; Brown et al.
A small part of small leucine-rich proteoglycans SLRPs in PGs, which mediate tissue order, cell proliferation, matrix adhesion, and the responses between cell and biological factors, is an important signal transduction factor and receptor for the development, morphogenesis, and immunization activities of IVDs.
The distinctive arrangement equalizes the NP stress in different directions and, together with water, makes the NP elastic Colombier et al. As IVD degeneration progresses, type II collagen is gradually replaced by low-elasticity type I collagen, and the fibrotic NP gradually loses its biomechanical function. The AF is comprised of 15—25 layers of angle-ply collagen fiber lamellas containing PGs, arranged in concentric circles outside the NP Chu et al.
The outer AF mainly consists of dense and organized type I collagen. Thus, it has robust tensile strength, while the inner AF contains a lower ratio of type I collagen as the transition zone between the AF and NP. The multi-lamellated AF structure effectively converts the axial stress to interlamellar stress and produces annular stress to resist it Liu et al.
As the core of this structure, the stable and enclosed microenvironment of the NP guarantees the expression of the ECM, which supports and separates the vertebrae, absorbs shock, permits transient compression, and allows for movement. Besides bearing sagittal stress, the CEP is the sole pathway of metabolite exchange for the avascular NP.
These three parts together form a unique anatomical structure, which maintains homeostasis of the IVD microenvironment in unity and maintains healthy IVD function. The IVD is in a unique microenvironment: avascular, hypoxic, hyperosmotic, acidic, and with low diffusion of metabolites and restricted by biomechanics Roberts et al.
During early embryonic development, a rod-like notochord is located in the central area of the embryo and guides the ectoderm folds in on itself over the notochord to form neural tube mesenchymal cells MSCs to form vertebral bodies and the AF. NCs are trapped inside and participate in the formation of the NP. NCs are considered to be involved in the regeneration of the NP through cellular dialogue with other cells. NCs disappear in most human adults before the bone matures, but signs of IVDD occur not long after their disappearance Hunter et al.
These biological factors can also mediate the IVD microenvironment. One of the critical factors mediating cell metabolism is hypoxia-inducible factor HIF Semenza et al. HIF is a transcription factor that initiates a coordinated cellular cascade in response to a low-oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia Li et al. Hypoxia-inducible factor is associated with most cell activities in the IVD. Vascular endothelial growth factor VEGF is important during vasculogenesis and angiogenesis and mainly targets endothelial cells Apte et al.
VEGF-A has a strong angiogenic activity and specific effects of mitosis and chemotaxis on endothelial cells Risau, The reason may depend on the inhibition of endothelial cell adhesion and migration by the high aggrecan content in the IVD Johnson et al.
BMP-2 and osteogenic protein-1 BMP-7 upregulate the expression of aggrecan and type II collagen, promote the synthesis of GAGs, and concomitantly inhibit the expression of profibrotic genes.
The characteristics of high osmotic pressure and high hydration ensure the biomechanical function of the IVD. As a weight-bearing organ, the metabolic and cellular activities of the IVD are closely related to the biomechanical microenvironment Neidlinger-Wilke et al.
External loads on the spine result in intense pressure on the disk. Intradiscal pressure varies from 0. The cytoskeleton of the IVD cells responds to the mechanical microenvironment. High osmotic pressure has positive effects on metabolic activity and matrix gene expression by IVD cells, and changes in hydrostatic pressure affect the synthesis of PGs by regulating the production of nitric oxide Liu et al.
Interactions between different components in the IVD microenvironment maintain the homeostasis of the microenvironment Figure 1. Figure 1. Physiological microenvironment of intervertebral disk IVD. The degenerative mechanisms are very complex and are related tovarious causes, such as age, genetics, the microenvironment, and biomechanics Frapin et al. Early degeneration may be asymptomatic. Signs may be detectable by radiography, while the reduction in water content of NP can be visualized by magnetic resonance imaging due to the reduced synthesis of PGs and reduced disk height of the IVD on a computed tomography scan Modic et al.
Figure 2. Pathological microenvironment of intervertebral disk IVD. Cellular senescence, which is a fundamental mechanism that mediates age-related dysfunctions and chronic diseases, accumulates in human, bovine, and rat degenerative IVDs during aging Roberts et al.
Unlike apoptosis, senescent cells are metabolically viable and arrest at the cell cycle transition, cease proliferation, and exhibit an altered expression of various catabolic cytokines and degrading enzymes Campisi, ; Davalos et al.
Two intrinsic pathways are related to cellular senescence in IVDs: the ppRB pathway in a telomere-dependent manner and stress-induced premature senescence that activates the p16INK4a -RB pathway independently of telomere length Ben-Porath and Weinberg, A stimulus from the microenvironment can cause damage to IVD cells, resulting in early senescence.
Senescent cells in degenerated disks can form senescent cell clusters, which can cause inflammatory stress by secreting pro-inflammatory cytokines and accelerate the senescence of neighboring cells Wang et al. The ECM provides mechanical support for the IVD and is essential for maintaining the relatively avascular and aneural nature of a healthy disk.
Proteoglycans, which are a primary component of the ECM, retain water and contribute to the osmotic pressure responsible for NP biomechanical properties. In the early stage of degeneration, proteoglycan content gradually decreases and is a sign of early degeneration. The proportions of collagen in the disk change with degeneration of the matrix. The absolute quantity of collagen changes little, but the type and distribution of the collagen can be altered.
As a result, the disk becomes more fibrotic and less elastic Raj, ; Wang et al. The balance between anabolism and catabolism is positively related to the IVD microenvironment, and the cellular dialogue, metabolic enzyme activity, and biomechanical changes affect this balance.
Anabolic activity is mediated by biological factor disorders, while catabolic activity continuously progresses Freemont, Moreover, AF fissures caused by abnormal biomechanics allow neovascularization and neoinnervation from a lack of PG production. As a result, NP is invaded by immune cells transported by new blood vessels. Immune cells respond to the deteriorating microenvironment, eventually leading to inflammation.
Inflammation is an adaptive response triggered by noxious stimuli and conditions, such as infection and tissue injury. Regardless of the cause, inflammation presumably evolved as an adaptive response to restore homeostasis.
If the acute inflammatory response fails to eliminate the pathogen, the inflammatory process persists and acquires new characteristics Majno and Joris, ; Medzhitov, The IVD is an avascular tissue until neovascularization occurs due to degeneration.
After neovascularization occurs, immune cells migrate to the NP to respond to the microenvironment. NP embryologically develops in an enclosed structure, which makes NP an avascular and immune-privileged tissue. Hence, immune cells invade when disk degeneration progresses to a certain stage, making IVD inflammation a chronic process.
Inflammatory factors play essential roles in mediating IVD homeostasis and degeneration. Pro-inflammatory factors are also related to pain. IL-6, IL-8, and prostaglandin E2 synthesis by NPCs stimulate nerve growth factor production, which induces abnormal nerve ingrowth and causes pain Frapin et al.
IL-6 and IL-8 are both higher in severe sciatica patients, and IL-6 is correlates to low back pain frequency Khan et al. Anti-inflammatory activity is also part of the IVD microenvironment.
IL-4 and IL are anti-inflammatory factors produced by activated macrophages and monocytes. Intervertebral disk degeneration can also be affected by the biomechanical environment. A positive dose-response relationship is observed between cumulative lumbar load and early onset of symptomatic lumbar disk space narrowing: the disk disease onset time of workers with the highest exposure to heavy physical constraints is significantly advanced compared to others Petit and Roquelaure, Xing et al.
Due to the forelimb amputation, the IVDs underwent abnormal mechanical loading. Constant pressure on the disk can cause degeneration, which may be related to the upregulation of matrix degradation-related enzymes Yurube et al.
The mechanical load can also induce IVD cell apoptosis through the mitochondrial pathway Rannou et al. Briefly, IVDs are continually adapting to changes in the microenvironment from embryogenesis to degeneration under the regulation of numerous factors Colombier et al.
The avascular and immune-privileged NPs regulate cell activity via cellular dialogue Fontana et al. The CEP ensures transport of nutrients and metabolites Zhang et al. When degeneration begins, interactions between components in the microenvironment break down, resulting in cascades of degeneration Freemont, Therefore, therapeutic strategies should first consider how to relieve pain and regain IVD function in patients and, furthermore, correct the factors causing degeneration to eventually achieve ideal IVD regeneration and functional restoration.
Non-surgical treatments include non-pharmacological treatments, pharmacological treatments, and interventional treatments. Non-pharmacological treatments, such as exercise, traction, acupuncture, massage, physical therapy, and spinal manipulation, are applied in daily life, but only for second-line or adjunctive treatment options with insufficient evidence for cure Kreiner et al.
Non-steroidal anti-inflammatory drugs are most applied drugs for pain relief and improved function. Oral glucocorticoids alleviate the inflammation of nerve roots.
At the same time, muscle relaxants can be useful to relieve muscle spasms, but these drugs are discouraged for lack of sufficient evidence Kreiner et al. However, interventional treatments are discouraged in the guidelines Foster et al. The goal of non-surgical treatments is to relieve symptoms and improve function, but they cannot halt the degeneration. Surgical treatments are required when non-surgical treatments are unable to relieve symptoms. Mixter and Barr reported that a tumor in the spinal canal, which causes sciatica, was a herniated NP.
Laminectomy, combined with excision of the NP, was performed, and satisfactory results were obtained Mixter and Barr, Since then, surgical treatments to treat disk herniation have been developed. The purpose of decompression surgery is to relieve pain and numbness caused by nerve compression, and the most common procedure is discectomy. A discectomy removes disk tissue that oppresses nerve roots in the intervertebral space.
An emergency discectomy is required for patients who already have cauda equina syndrome and a new motor disorder. Selective discectomy is required for patients with persistent neurological symptoms that cannot be relieved by non-surgical treatments Butler and Donnally, Discectomy can be open or minimally invasive.
Open discectomy is performed in a wide range of operations but with more tissue damage. Minimally invasive discectomy causes less tissue damage, but indications are limited. A meta-analysis showed that the incidence of postoperative complications and reoperations is similar, while less blood loss, shorter operating time, and shorter hospital stay are common after minimally invasive discectomy Alvi et al. Discectomy relieves nerve root compression, relieves pain while retaining some of the structure, and restores some of the biomechanical functions of the disk.
However, discectomy cannot change the deteriorating microenvironment. Therefore, further progression of degeneration cannot be prevented, and postoperative complications may occur The AF must be broken to perform this surgery, and no new AF tissue is formed, so the opening remains open or is closed with the formation of scar tissue, which might cause reherniation Sharifi et al.
Spinal fusion is a classic procedure. Hibbs and Albee treated Pott disease using fusion. Fusion abolishes pain by abolishing the motion of adjacent segments Hibbs, Spinal fusion is widely used to treat many spinal diseases and is the gold standard for treating significant, chronic axial low back pain due to IVDD.
Spinal fusion completely removes the IVD and entirely relieves the oppression on the nerve roots, where the degenerated segments become integrated and lose motor function. Although the pain symptoms are relieved, the native IVD microenvironment is destroyed. The motor function is abolished, which may cause long-term complications. The mechanical environment of adjacent segments is affected and may develop into adjacent segmental disease Lee and Langrana, ; Hilibrand and Robbins, ; Virk et al.
Artificial disk prosthesis replacement surgery is performed to restore disk height, biomechanical structure, and motor function of the IVD and overcomes some deficiencies of spinal fusion. This procedure was first applied in the s. As more and more prostheses have been developed, disk replacement surgery has developed quickly Guyer and Ohnmeiss, ; Zhao et al.
Disk replacement surgery effectively relieves pain and improves the quality of life, but it is not a superior substitute surgery for fusion. The average reoperation rate is Postoperative complications, such as prosthesis failure, infection, adjacent segmental disease, and pain, can occur, yet no evidence demonstrates that the surgical effect of disk replacement is better than fusion Thavaneswaran and Vandepeer, ; Cui et al.
The effect of disk replacement surgery greatly depends on the type of prosthesis and surgical technique of the surgeon. An artificial disk prosthesis replicates the anatomical structure of the IVD and attempts to mimic its biomechanical properties. The risk of adjacent segmental disease is reduced compared with fusion Findlay et al. However, it is similar to fusion surgery in that the native IVD microenvironment is destroyed. Further follow-up studies are needed to investigate the long-term efficacy and safety of disk replacement surgery.
Several experimental surgeries have been developed. Annuloplasty is a minimally invasive method in which heat produced by electricity or radiofrequency radiation strengthens the collagen fibers and seals fissures in a process similar to tissue soldering Helm Ii et al.
Nucleoplasty releases the pressure on the outer AF, allowing the disk to return to normal size, thereby decompressing the nerve, with better therapeutic effects than non-surgical treatments. This procedure can be performed in the clinic, and the patient recovers quickly after the procedure, but the indications of this procedure are limited Eichen et al. Patients who undergo surgery may have better pain relief, functional improvement, and satisfaction than those who receive non-surgical treatments.
Nevertheless, long-term follow-up shows that disability outcomes are similar regardless of which treatment a patient receives Atlas et al. Surgical treatments for IVDD have developed rapidly, but the limitations of surgical treatments are becoming apparent.
Thus, researchers have turned their attention to tissue engineering strategies. Mizuno et al. The scaffold was seeded with AF cells. NP cells were injected into the center after 1 day. Then, the scaffolds were implanted in the subcutaneous space of the dorsum of athymic mice. The results showed that the engineered disks strongly resembled native IVDs and synthesized similar collagen components as native NP and AF Mizuno et al. This attempt was initially intended to identify an alternative strategy for IVD replacement due to its long-term deficiencies.
The flaws in that study included the cell source, immunological rejection, and fixation of the scaffold, but that study inspired researchers to try tissue engineering strategies for IVDD. Various strategies have been formulated based on different treatment principles. It is important to note that there are no separate strategies, only those that are focused on in the study.
Scaffolds were initially designed as cell substrates to mimic the microenvironment where cells live. An ECM scaffold is similar to the native microenvironment of cells and has excellent biocompatibility and immunogenicity, which are beneficial for cell proliferation and metabolic activities.
Yang et al. McGuire et al. Collagen patches were obtained from treated pericardial tissue. These patches were assembled into a multi-laminate angle-ply scaffold. This scaffold mimicked the structure of AF, provided similar mechanical support, and supported cell viability, infiltration, and proliferation for bovine AF in vitro McGuire et al.
Complete AF regeneration requires the recovery of biomechanical and structural properties of healthy AF and the restoration of the biological behavior of resident cells in AF Driscoll et al. The alignment and organization of AF cells determine their biomechanical functions. As manufacturing technology develops, fabricating methods, such as electrospinning and 3-D printing, provide the possibility for microstructural scaffolds.
Microstructural scaffolds guide the cells to form a specific order and are widely applied in AF tissue engineering due to their unique structure. Ma et al. This hybrid scaffold consisted of traditional electrospun aligned nanofibrous scaffolds AFS as a baseline scaffold and electrospun aligned nanoyarn scaffolds AYS. Morphological measurements showed that this hybrid scaffold replicates the tensile strength, axial compression, and anisotropic properties of AF tissues to some degree.
Gluais et al. The results showed that, in addition to numerous dense collagen fibers in the aligned scaffolds, the fibers were arranged in the same direction as the scaffold Gluais et al. Kang et al.
These results show that these scaffolds can form and integrate collagen fibers Kang et al. However, electrospun scaffolds often face several limitations, including low porosity that restricts uniform cell infiltration and a discrepancy of mechanical properties compared with native AF.
To recapitulate the form and function of the complex anatomy of AF, Bhunia et al. The fabricated bio-discs supported the primary AF or human mesenchymal stem cell proliferation, differentiation, and deposition of a sufficient amount of specific ECM in vitro. The subcutaneous implantation results showed a negligible immune response Bhunia et al. Three-dimensional printing precisely fabricates the scaffold structure. To generate a scaffold with angle-ply architecture similar to natural AF, Christiani et al.
The mechanical characterization results showed that the mechanical properties of the scaffolds were similar to native AF tissue. The SEM micrographs of the scaffolds showed that cells cultured on etched PCL had a tendency to align along the underlying surface, and the alignment of proteins with the underlying surface texture can be observed Christiani et al.
However, PCL materials have poor hydrophilicity, have a long degradation time, and lack cell recognition sites. PCL materials bind poorly to surrounding host tissues after implantation in vivo Cheng et al.
Three-dimensional bioprinting achieves precise bionics according to the structure and size of native tissues and organs Kang et al. As a novel technology, 3D bioprinting shows great potential and enormous advantages in the repair of IVDs. Sun et al. In vitro experiments confirmed that the growth factors were released from the IVD scaffolds in a spatially controlled manner and induced the corresponding BMSCs to differentiate into NP-like cells and AF-like cells. After being implanted subcutaneously into the dorsum of nude mice, the reconstructed IVDs exhibited a zone-specific matrix: primarily type II collagen and glycosaminoglycan in the core zone and type I collagen in the surrounding zone Sun et al.
In addition to providing mechanical support and topographic stimulus for cells, scaffolds can also be loaded with therapeutic drugs or cells. Cheng et al. FA is an excellent antioxidant drug. The results showed that these scaffolds achieved excellent antioxidant properties after loading with FA Cheng et al. Scaffolds are a crucial element of this strategy, as they provide a similar microenvironment for IVD cells by mimicking the structure of native IVDs.
The scaffold strategy can also be combined with other strategies, such as delivery of therapeutic drugs or cells. Cell therapy is a classic strategy. An increasing number of studies have shown the efficacy of therapeutic cells in several IVDD animal models Hiyama et al.
One study reported that stem cells and stem-like cells are found in almost all adult tissues da Silva Meirelles et al. Due to the potential of stem cells to differentiate, replacing damaged cells in target tissues, stem cells are ideal therapeutic cells for IVD tissue engineering Krause, ; Meirelles Lda et al.
Several studies have demonstrated the ability of BMSCs and adipose-derived stem cells to differentiate into an NP-like phenotype, and in vivo studies have demonstrated the ability of implanted MSCs to enhance matrix production, particularly GAG synthesis, and increase disk height and hydration Richardson et al. Researchers have attempted different methods to transport therapeutic cells to diseased areas, such as direct injection of therapeutic cells or loading of cells onto scaffolds.
Hiyama et al. The results showed that transplantation of human MSCs has a positive repair effect on the xenogeneic animal disk degeneration model. Sheyn et al. However, direct injection by needle puncture causes damage to the AF, and implanted cells could leak out through annular fissures.
AF damage can lead to further degeneration and an increased risk of disk herniation Oehme et al. Scaffolds could be pivotal to provide transplanted cells with a supportive environment. Bhunia et al. However, such a factor could require multiple injections due to its short life in vivo Jin et al. Xia C. Then, they injected these cell-seeded polymeric microspheres into rat coccygeal IVDs, and the results indicated that disk height was recovered, water content was increased, and the NP ECM was partially restored Xia K.
This study utilized growth factors to enhance the therapeutic efficacy of cells and prolong the life of growth factors via a polymeric gelatin microsphere as a sustained release platform. Multiple strategies complementing each other will become more important in IVD tissue engineering.
Ying et al. These cells might be a promising source for cell therapy. Cell-based therapies have the advantages of modulating inflammation and concomitantly affecting the remodeling process, without presenting toxicity or immunosuppression Lopes-Pacheco et al.
These properties make cell therapy an exceptionally advantageous therapeutic approach for IVD tissue engineering. Nevertheless, various complications occur with stem cells, including tumorigenesis and immune reactions.
Certain cases of tumorigenesis and immune reaction of iPSCs and embryonic stem cells which are also a cell source for iPSCs have been reported, and the application risks are always discussed Pera et al. Although the transplantation of stem cells may have risks, their efficacy cannot be denied.
Risks may be hedged by enhancing the immune compatibility of stem cells. Immune rejection is caused by HLA mismatching. Xu et al. Cell strategies have potential in tissue engineering, but improving safety and avoiding risks should be given more attention in future studies. Biological factors are promising therapeutic drugs for IVDD as native mediators in the IVD microenvironment since they are key signaling factors in the cellular dialogue.
Unlike conventional drugs, biological factors are secreted by IVD cells and have fewer side effects. Therapeutic biological factors should be able to restore the healthy microenvironment of IVD. The application of biological factors is limited by their short life in vivo.
Thus, biological factors are often used in conjunction with other strategies. Researchers can customize biological factor scaffolds according to different conditions, with the key concept of restoring the balance of the microenvironment.
Several widely used factors are introduced in Table 1. Two basic strategies have been proposed. An integrating vector is introduced into a precursor or stem cell so the gene is passed to every daughter cell or the gene is delivered in a non-integrating vector to long-lived post-mitotic or slowly dividing cells, ensuring the expression of that gene for the life of the cell High and Roncarolo, Although the application of gene therapy to the IVD has lagged behind other tissues, gene therapy shows excellent potential and safety for IVD tissue engineering.
As an encapsulated and avascular tissue, the sealing property of IVD effectively prevents leakage of the disk contents to other sites in the body Levicoff et al.
Some researchers are using gene-editing techniques, such as CRISPR, to precisely alter DNA sequences or genetically modify immune cells to imbue them with the ability to fight cancer. To regulate this signaling, Farhang et al. Gene therapy provides a potentially ideal tool for many diseases by delivering synthetic miRNAs to regulate gene expression Deverman et al. However, there are obstacles to delivering miRNAs directly to target tissues due to their inactivation, low transfection efficiency, and short half-life.
Chen W. Agomir penetrates the barriers of the cell membrane and tissues in vivo to enrich target cells. Chen et al. After 8 weeks, the rat IVD was gradually restored to normal height, similar to the healthy group. Six gene therapy products have been approved since High and Roncarolo, However, there are still some problems to be solved, such as safety issues and high treatment expense.
Gene therapy is aimed at specific targets, which have been studied thoroughly, to regulate cell activities. Thus, gene therapy cannot be used to regulate a series of therapeutic targets or pathways as in cell therapy. MH Intervertebral Disk Fibrocartilage Fibrocartilage is a mixture of dense regular connective tissue and hyaline cartilage.
Note that the cytoplasm has been extracted from most of the cells during sample preparation. Collagen Fibers - the majority of the fibrocartilage is a mixture of type I and type II collagen. Fibroblasts - scattered cells within fibrous regions with elongated or flattened nuclei. Few are seen in this specimen. Chondrocytes - are dispersed between collagen fibers singularly , in columns , or in isogenous groups and are surrounded by a basophilic matrix.
Matrix - much less material surrounds each chondrocyte than in hyaline cartilage. It is composed of type II collagen and a ground substance of proteoglycans.
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