1. IVD Degeneration
Intervertebral discs (IVDs) are cartilaginous structures between the vertebral bodies that mainly provide flexibility and elasticity
[13][1] and have a wide range of movement to the spine as a whole. In addition, IVDs strongly provide pressure and tensile resistance while transmitting mechanical load through the spinal column
[14][2] and therefore support a variety of loads during daily activities. A healthy IVD is comprised of a proteoglycan-rich gelatinous center called the NP, which is peripherally enclosed by the collagen-rich annulus fibrosus (AF) and the cartilaginous endplate (CEP), which limit the peripheral rim of the disc superiorly and inferiorly
[15][3]. The primary components of IVDs are water, cells (mainly chondrocyte-like cells and fibroblasts), proteoglycan, collagen, and other matrix components
[16][4]. Fibrillar collagens, aggrecan, and water are the three main structural components of the IVD, all together contributing to around 90–95% of the volume of a healthy IVD
[17][5], although their percentages vary across the disc
[14][2].
Several etiological factors such as aging, smoking, infection, abnormal biomechanical loading, and nutrition insufficiency are thought to be involved in the pathogenesis of IVD degeneration
[17,18][5][6]. Among these factors, genetic heritability is estimated to account for up to 74%
[19][7]. As the degeneration process is highly correlated with aging, its pathologic changes occur starting from the second decade of life
[6,20][8][9]. Substantial changes in biochemical composition and progressive loss of structural integrity are hallmarks of IVD degeneration
[15][3] (as illustrated in
Figure 1, where curved arrows define the transition from normal disc structure to later degenerative disc), which occurs mostly in adults aged over 30 years in one or more discs or during trauma and injury. Loss of proteoglycans and a decrease in the ratio of proteoglycan to collagen
[17][5] consequently results in the loss of hydrostatic properties, which induces structural wear of the IVD
[21][10] and thus progresses towards a fibrotic nature. Dehydration of NP and gradual disappearance of the NP–AF border contributes to the loss of normal architecture. Stress distribution over the NP tends to reduce at the center and accumulates more pressure around the periphery, effectively disabling the NP’s load transfer function
[22][11]. Due to a lack of intradiscal pressure, the load absorption and transmission in such dehydrated discs is significantly altered and subsequently, it results in disc-height reduction, osteophyte formation, facet joint arthritis, and deformation of vertebral bodies
[23][12]. With continuing degeneration, the structural deficit is accompanied by leakage of the central NP material through cracks in the AF into the periphery. This results in immune cell activation, thereby evoking chronic back pain
[24,25][13][14]. Since biochemical changes within IVDs have not yet been directly associated with chronic back pain, it is difficult to determine if the observed changes are due to aging or pathology
[26][15].
Figure 1.
Schematic illustration of intervertebral disc (IVD) pathophysiology during degeneration.
IVD degeneration often results in lower back pain but is not always the only causative factor. Location of the affected disc, degree of nerve damage, and amount of pressure on the spinal column contribute to define the degree of degeneration. For example, some patients may not feel pain, while others with similar degrees and extents of IVD damage may experience chronic back pain. Therefore, the degree and extent of degeneration does not correlate with the degree of pain. IVD degeneration is the most common cause of lower back pain
[27][16]. The worldwide prevalence of chronic back pain is approximate 60%, with the majority seen in the elderly
[28][17].
2. Nucleus pulposus (NP) Repair
Tissue engineering approaches over the past few years have been addressing the objective to restore functional and structural features of the healthy IVD. Reparative treatment mainly targets intervention at early stages of IVD degeneration to restore extracellular matrix (ECM) homeostasis, control inflammation, and prevent angiogenesis
[2][18]. Current surgical procedures mainly focus on alleviating symptoms associated with IVD degeneration but fail to promote tissue remodeling. Tissue engineering offers an alternative to design biomaterials by encompassing cells and growth factors that will aid IVD tissue regeneration. Thereby, it offers multiple strategies to prevent and possibly cure IVD degeneration by encouraging disc repair. The exact mechanisms of IVD regeneration are still not known, however several studies have focused on the effect of segmental distraction in IVD disease
[11,12,52][19][20][21]. Synthetic and / or natural material based scaffolds for IVD tissue engineering were regarded as the prominent method over the past decades
[53,54][22][23]. In spite of considerable progress, some issues related to scaffold integration and tissue repair still remained unsolved
[55][24]. Alternatively, scaffold free tissue engineering (refer
Table 1) is an emerging field, where cells, growth factors, or peptide delivery are mainly responsible for regaining the tissue integrity upon the application
[56,57][25][26]. Stimulatory factors together with cells either unaided or together with biomaterials have aimed to provide suitable repair site to ensure maximum cell differentiation or deposition of appropriate ECM. Nonetheless, selection of biomaterials, cells and appropriate stimulatory factors is crucial as the ideal combination is yet to be established.
Table 1. Advantages and disadvantages of scaffold-free IVD tissue engineering.
Methods |
Categories |
Advantages |
Disadvantages/Limitations |
References |
Cell therapy |
NP cells |
|
|
[88,89,90,91][27][28][29][30] |
MSCs |
-
Abundant cell resources
-
High proliferation rate and chondrogenic differentiation capacity
-
Immunomodulatory abilities
-
Simplicity and ease of the injection
|
|
[94,95,96,102][31][32][3397,][3498,][3599,][36100,][37101,][38][39] |
Growth factors |
TGF-β |
Enhances cartilage formation and extracellular matrix production |
|
[58,77][40][41] |
BMP2 |
Enhances ECM production and phenotypic characteristics of NP cells |
Induces apoptosis, Col I accumulation, and aggrecan-production hindrance |
[60,61,,65][4262,][4363,][44][45]64[46][47] |
BMP7 |
Promotes proliferation and accelerates chondrogenesis |
Short half-life time and biodegradation in vivo |
[66,67,68,69,70,71,72,73][48][49][50][51][52][53][54][55] |
GDF-5 |
Induces NP-like differentiation of MSCs |
Possible association between GDF-5 gene polymorphisms and IDD |
[74,75,76][56][57][58] |
IGF-1 |
Enhances the ECM production and proliferation of IVD cells |
Enhances glucose consumption and lactate concentration |
[78,79][59][60] |
Injectable hydrogel |
Cell-free hydrogel |
Physiological swelling and greasing |
Limited payload |
[51,110][61][62] |
Cell-seeded hydrogel |
|
No direct cell contact |
[111,112,113,114][63][64][65][66] |