Dynamic changes in mechanical properties of the adult rat spinal cord after injury

Spinal cord injury (SCI), which typically causes permanent motor and sensory dysfunction, is a serious public health issue worldwide. Significant research is being conducted on the causes, treatments, and prevention of SCIs due to the approximately 180,000 new cases of SCI reported annually worldwide [1], [2], [3].

Several regenerative approaches, coupled with biomaterial-based methods, have recently given rise to regenerative therapies believed to offer innovative approaches for SCI treatment [4]. However, any biomaterial transplanted into the central nervous system must consider its mechanical characteristics. Any excessive force exerted at the biomaterial-tissue interface disrupts its structural continuity and impedes the traversing cells or axons at the macrolevel (tissue level), where mechanical mismatch between the host and engineered tissues can be sufficient to cause additional implant-induced injury [5]. Additionally, mechanical mismatch may result in primary cellular damage at the microlevel (molecular and cellular) and affect the response and phenotype of the therapeutic cells. For example, glial cell stimulation and subsequent inflammation (gliosis) are significantly higher in stiff implants than in softer implants [5, 6]. Further, alterations in neural behaviours, such as proliferation, differentiation, and gene expression, can be induced by the mechanical characteristics of the substrate or tissue [7], [8], [9].

Several recent advancements in tissue engineering and regenerative medicine have been made owing to a better knowledge of cellular and molecular targets [10], [11], [12]. However, relatively little is known about the biomechanical properties of spinal cord tissues, either in healthy individuals or those who suffer from SCI. Describing the precise mechanical characteristics of the spinal cord tissues is very difficult because the complexity of the events leading to SCI occurs at multiple scales, including the macroscopic organ, microscopic cell, mesoscopic tissue, and nanoscopic molecular levels. The variety of scales required reflects the measurement complexity and array of associated physical processes. Furthermore, due to the delicate nature of spinal cord tissues, describing its complex viscoelastic properties using traditional mechanical testing methods (e.g. tension [13], [14], [15], [16], compression [17], [18], [19], [20], or shear [21, 22]) is likely to induce tissue damage and supply only restricted information about their stiffness. Additionally, these findings are often unpredictable. Previous methods also required relatively large specimens, preventing the characterisation of homogeneous samples of small anatomic regions on a spatial scale relevant to the heterogeneous distribution of tissue damage observed in histological examinations. In contrast, indentation testing is well suited for measuring the mechanical properties of spinal cord tissue on the same spatial scale as the anatomical regions because the probe can be easily positioned in the region of interest.

Recent research indicates that the central nervous tissue can soften after injury, in contrast to the other parts of the body where scar tissue is typically stiffer than the surrounding healthy tissue [23, 24]. Moeendarbary et al. [25] used atomic force microscopy (AFM) to verify the spinal cord crush injury in rats caused tissue softening at acute and subacute time points (∼7 and 21 d postinjury [dpi]). However, uncertainty regarding the long-term sustainability of these softening alterations is prevalent. Furthermore, Cooper et al. [26] proposed that chronic SCI may be associated with tissue stiffening. Nevertheless, a recent study examined an injured rat spinal cord at chronic time points (∼18 weeks postinjury [wpi]) and reported that the tissue displayed lower elastic modulus following spinal hemisection injury [27]. Notably, the testing procedures, observation intervals, animal models, and environmental factors used vary significantly from lab to lab, leading to a high degree of variability in the measurement results. Therefore, direct comparisons between published studies can be unreliable. Further, the definition of stiffness frequently varied when researchers discussed the mechanical behaviour of the spinal cord tissues. Although the elastic modulus is a straightforward mechanical parameter, it presents a very constrained understanding of the complexity of the spinal cord. Nevertheless, researchers agree that spinal cord tissues demonstrate typical viscoelastic behaviour. Accordingly, a single value for the tissue elastic modulus may not be completely representative of the local tissue response owing to stress-stiffening behaviours. However, very few studies have attempted investigating the viscous properties of spinal cord tissues. Therefore, enhanced learning regarding the viscosity of the spinal cord based on relevant quantitative metrics to comprehensively understand the dynamic changes in viscoelastic properties over time (i.e. evolution of mechanical characterisation) after SCI is needed.

This study aimed to perform comprehensive mechanical characterisation of adult rat spinal cord tissues after crush injury via microindentation tests. The specific objectives were to (1) measure the elastic stiffness and viscosity of the spinal cord tissue at different time points postinjury and (2) explore the possible spatiotemporal changes in the tissue viscoelastic properties. We hypothesised that the elastic stiffness and viscosity of the injured site were not homeostatic but rather evolved over time.

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