9  Biological Treatment Approaches: Basic Ideas and Principles

Victor Y. Leung and Kenneth M.C. Cheung

Abstract

Clinical studies indicate an association of intervertebral disc (IVD) degeneration severity with low back pain, implying that prevention or relief of the degeneration is relevant to the management of this global disease burden. Although the cause of disc degeneration remains to be fully elucidated, various biological approaches of reparation provide potential solutions as well as important insights into the nature of degeneration. These include the delivery of growth factors, stem cells, and other biologics, which aim to replenish or enhance the function of matrix-producing cells, or to control catabolism. Various lines of evidence suggest that the intervention relies on a proper control of inflammation, reconstructing the microenvironment in the disc, and ultimately rebuilding the disc mechanics. Stage of degeneration may also play a role. In this chapter, we discuss the principles as well as the strengths and weaknesses behind these biological approaches in the context of disc degeneration. Moreover, in view of the irreversible progression of disc degeneration, we discuss how a combination of screening to identify predisposed subjects and development of prophylactics may be critical to the effective treatment of degeneration.

Keywords: biologics, intervertebral disc, microenvironment, regeneration, stem cells

9.1  Historical Perspective

The cause of back pain is thought to be multifactorial. Over the last decade, there has been a dispute about the correlation between back pain and the dysfunction of spinal motion segments. However, with the advances in imaging techniques and refinement of study design and scale, recent reports have provided strong evidence to support a link between intervertebral disc (IVD) degeneration, possibly together with end plate anomalies, and a subset of low back pain cases.^1,2,3 Treatments that slow IVD degeneration progression may reduce the incidence and development of low back pain. The IVD is the largest cartilaginous unit in the body, and its degeneration is often progressive and irreversible by nature.⁴ The IVD is constantly subject to mechanical load through the activity of spinal muscles, body weight, and various body postures and movements. Further mechanical insult can be caused by accidents and obesity. Age-related, environmental, and genetic factors also play roles in IVD function and health.^2,5,6 A thorough understanding of its causes is required to derive rational means to revive the spinal segment function. Because the etiology of disc degeneration is still not exactly clear to date, researchers have attempted to utilize the current knowledge in disc biology together with the experience and concepts from related systems and disorders to device plausible remedies. Although these remedies may not present a complete or ideal solution to treat IVD degeneration, such investigations have uncovered new insights into the degeneration mechanism, which may enhance future reparative strategies. A careful revisit of these investigations may shed light on the principles important to the success of disc engineering and regeneration in the future.

9.2  Goal of Intervention

The principles of current strategies or devices to intervene in IVD degeneration largely derive from the abnormalities and symptoms observed at moderate to severe stages of the degeneration. Current surgical interventions aim to treat the symptoms by removing the problematic motion segment, followed by immobilization of the joint, or otherwise replacement of the joint with a prosthetic disc. In the era of tissue engineering and regeneration, efforts have been made to develop minimally invasive biological or chemical means to preserve the native disc function and even to introduce prophylactic measures for high risk or predisposed subjects. Based on current understanding of IVD degeneration and technological advancement, a spectrum of interventions has been investigated in various labs. Some of them, in particular the cell-based therapies, have made their course into clinical trials.⁷ Although it is not clear if the abnormalities observed in the IVD are part of the primary causes of the degeneration, many of them have been shown to correlate with the severity of degeneration. Dealing with these anomalies, in particular the molecular pathology, has been considered a relevant and rational approach to alleviate the degeneration, ultimately reducing the incidence of back pain and disability. These approaches may be divided into four categories based on principles of action: control of inflammation and catabolic events, conferring instant mechanical strength/function, stimulation of cell anabolism for matrix replenishment, and microenvironmental reconstruction.

9.2.1  Control of Inflammation and Catabolic Events

Disc degeneration initiation and progression is linked to inflammation. These include the findings of increased expression of pro-inflammatory mediators mediated by interleukin (IL)-1 signaling, and to a lesser extent, tumor necrosis factor-α (TNF-α) signaling.^8,9 Inflammation leads to elevated catabolism in IVD, especially the activity of matrix degradative enzyme, which degrades and remodels collagen and proteoglycans of the disc matrix.^10,11 Modulating inflammatory and catabolic factors is therefore considered critical to the inhibition of degeneration progression and hence supportive to intrinsic or assisted IVD repair.

9.2.2  Conferring Instant Mechanical Strength/Function

Although it is not entirely clear how IVD degeneration may cause back pain, perturbed stability and biomechanics of the spinal segment are proposed to play a major role. One school of thought to alleviate the degeneration-induced symptoms is to provide a direct immediate support to the mechanical function of the degenerated motion segment instead of dealing with the cause of degeneration. These treatments range from implementation of a scaffold to replace the nucleus pulposus (NP)¹² or patch the disrupted annulus,¹³ to the bioengineering of whole disc constructs¹⁴ and IVD allograft transplantation.¹⁵

9.2.3  Stimulation of Cell Anabolism for Matrix Replenishment

A major anabolic function of disc cells is to produce extracellular matrix (ECM) that contributes to the disc tissue mechanics. To balance the enhanced matrix degradation and restore the matrix content in a degenerated disc, strategies have been designed to directly augment the anabolism in the disc cells, or otherwise to increase the quantity of functional cells.¹⁶ This can be achieved through directly delivering relevant matrix-producing cells, or stem cells that may differentiate in situ to produce matrices. Apart from cells, delivery of important genes and proteins that positively regulate matrix production and/or cell proliferation has also been investigated.

9.2.4  Microenvironment Reconstruction

The microenvironment that cells reside within is important to cell function and is therefore thought to be the potential rate limiting factor for disc regeneration. This microenvironment includes nutritional supply, oxygenation, osmolarity, the surrounding matrix meshwork, and the availability of the growth factor or cytokine reservoir. Strategies that modify nutrient diffusion, hypoxic stress, collagen fibril architecture, and other factors that have a role in the disc cell niche have been proposed to hold promise in promoting IVD repair.^17,18

9.3  A Consideration of Disease Stage

Therapies often work within a window of disease severity. For IVD degeneration, the degenerative stage can be determined using different methods, such as evaluation of disc height, histological score, and various molecular markers. Clinically, IVD degeneration is graded under specific imaging techniques, which usually reflect the water content (which in turn correlates with proteoglycan level) and/or collagen integrity in disc matrix. On the other hand, studying the degeneration nature and progression at histological and molecular levels in animal models as well as clinical specimens has expanded our understanding of stage-specific characteristics. Such investigations also extend to cadaveric samples to interrogate age-related degeneration. Overall, studies have suggested that the IVD exhibits trends of changes ranging from nano- to macroscale levels (▶ Table 9.1) during the degeneration:

Table 9.1 Nano- to macroscale changes at different IVD degeneration stages

9.3.1  Nanoscale Anomalies

The IVD contains a high matrix-to-cell content. Collagens and proteoglycans form a meshwork of macromolecular structure in the disc matrix. In addition to providing mechanical strength to the disc, this matrix meshwork also interacts with cytokines and growth factors and therefore provides a reservoir of inductive signals. Moreover, the matrix can directly regulate mechano-transduction signals to the adhered cells and regulate their activity. It is therefore believed that a disrupted matrix meshwork may not only impact on the mechanical properties of the disc, but also significantly influence disc cell behaviors. Injurious stimuli or other forms of stresses, such as excessive mechanical load, reduced nutritional supply, and hypoxia, may also compromise the cell anabolism and induce inflammatory cascades that lead to matrix breakdown. The damage in matrices is presumably the lead cause of the mechanical instability in the motion segment at early degeneration.^19,20

9.3.2  Deterioration of Microscale Structures and Cell Activity

Under continual stresses, inflammation signals and damage of matrix elicit a tissue repair response. This is thought to be analogous to wound healing, involving a deposition of provisional matrices and subsequent remodeling. This process may include inflammatory cell and fibroblast-like cell infiltration. Cell death, possibly due to the inability to counter stresses, may amplify the inflammatory process. However, without removal of the stresses, the remodeling process is thought to remain dysfunctional. Consequently, the disc matrices become constituted by a fibrous meshwork with compromised function. Moreover, water content is reduced due to loss of proteoglycans. The sustained stimuli, as well as the abnormal matrices, further impact on cell function and phenotype. It is believed that resident disc stem/progenitor cell activity is also affected, thereby disabling the self-repair mechanism.²¹

9.3.3  Deformation of the Motion Segment Unit

At the late stage of degeneration, the abnormal disc matrix fails to provide the mechanical strength necessary to support the load in the spine, causing the IVD to deform.²² This severely damages the compartmental structures that likely lead to major cell death in the IVD, in particular the NP. The collapse of the IVD further causes the facet joints to be subjected to abnormal load and subsequent degeneration.²³ Osteophyte formation is also induced. As a result, the whole intervertebral motion unit becomes mechanically incompetent and grossly deformed in anatomical appearance.

9.4  Advantages and Disadvantages of Treatments

9.4.1  Long-term Effects

One of the targets of intervening in IVD degeneration is to inhibit or delay its progression. Intervention, especially those aiming to promote cell anabolism or inhibit catabolism, which may exert moderate to long-term effects, is therefore desirable. However, due to the relatively short half-lives of proteins, therapies involving use of gene and protein constructs may require multiple treatments or carefully designed delivery devices to obtain sustained results. It remains to be determined if cellular- or biomolecule-based interventions will generate an outcome comparable to total disc replacement.

9.4.2  On-shelf Availability and Consistency

Shelving and consistent efficacy is an important aspect for biologics. Gene and protein-based therapeutics are in general superior in on-shelf availability and activity consistency compared with other types of interventions. Cell- or plasma-derived products by nature tend to have more variation in therapeutic activity and therefore require an implementation of rigorous quality control. Allogenic cell transplantation may overcome the issues of on-shelf availability and may provide consistency in efficacy related to the use of autogeneic sources. In particular, mesenchymal stem cells (MSCs)/stromal cells can avoid allogenic recognition and may serve as a promising cell therapy in this aspect.²⁴

9.4.3  Cost to Patients

Cost of therapy is determined by many factors. It depends not only on the type of intervention, but also the treatment regime. Compared with recombinant protein and gene products, living tissue-derived cell and plasma products may be subject to more stringent regulation and quality control in preparation which in turn leads to higher costs. Moreover, intervention that requires local delivery such as intradiscal injection, as an essential feature of aforementioned therapies, also adds cost to treatment. Nonetheless, this becomes negligible if the delivery can be conducted along with discography. On the other hand, the recent realization of disc allograft transplantation may provide a less expensive alternative to total disc or nucleus replacement.^15,25 Although a long way to clinical practice, the cost of tissue engineered IVD or bioengineering of complete spinal segment is rather difficult to predict.

9.4.4  Repeatability

Apart from motion segment replacement, satisfactory control of IVD degeneration may likely necessitate repeated treatments, especially when the long-term effectiveness of therapies is not clear. In fact, due to the unclear etiology, degeneration progression may recur. Unlike systemic therapies or oral drugs, intradiscal regimes obviously do not favor multiple treatments.

9.5  Insights from Other Degenerative Diseases

9.5.1  A Historical View of the Therapies

Effective therapeutics often require a good understanding of the disease mechanism, in particular the molecular pathogenic events. Owing to the relatively limited understanding in IVD degeneration, the search for therapies leverages the knowledge from related tissues such as articular joints. Because of the similarities in the disease features and shared genetic components,²⁶ osteoarthritis has been a relevant model to facilitate generation of insights and development of therapeutics for IVD degeneration. Among the many options, gene/protein therapies and stem cell-based therapies/engineering have been widely explored (▶ Fig. 9.1).

Related posts:

What Makes Biological Treatment Strategies and Tissue Engineering for DDD Interesting to Industry? What Will the Future Bring? Perspectives From Around the World Learning from Successes of Tissue Engineering Strategies for Cartilaginous Disorders Disc Regeneration: In Vitro Approaches and Experimental Results Total Disc Transplantation: Current Results and Future Development Differences between Human and Animal Discs: Pros and Cons of Current Animal Models for Preclinical Development of Biological Therapies for Low Back Pain

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