Neurobiology

Goal of the review?

In this review 1, the authors focus on recent advances in understanding the nociceptive and neuropathic components of pain, as well as treatments for skeletal pain. 

 

Why are they doing this review?

Skeletal pain neurobiology is widely prevalent and has a significant impact on an individual’s quality of life and the broader society, as it is a leading cause of work disability. For this reason, the authors argue that understanding the mechanism that drives skeletal pain is critical to the prevent and treat pain.

 

What did they find?

Primary afferent sensory nerve fibres that innervate the skeleton

Unlike the skin innervated by various sensory nerve fibres, including A-beta, A-delta, C-fibers and others, the adult skeleton (bone and joint) is predominantly innervated TfkA+ sensory nerve fibres and CGRP.

While the same nociceptive nerve fibres innervate bone and joint, the density, pattern, and morphology are very different. For example, the periosteum (tissue enveloping the bones) has the largest sensory nerve fibres with A-delta and C-sensory nerve fibres that detect injury or alteration. In contrast, the articular cartilage of the knee and temporomandibular joint lack any innervation by sensory nerve fibres or vascularization by blood vessels. Therefore, it is believed that pain from a joint injury must come from the ligaments, synovium, and muscle.

Skeletal pain is also driven by the innervation of adrenergic and cholinergic sympathetic nerve fibres. Research has shown that these regulate bone destruction, bone formation and more, and therefore may play a significant role in disease progression in cartilage, bone, and skeletal pain.

Additionally, studies have shown that following injury to the skeleton, there is an interaction between sensory and sympathetic nerve fibres that may play a role in OA and complex regional pain syndrome. 

 

Nociceptive and neuropathic components of skeletal pain

Bone fractures and injury to articular cartilage are characterized by sharp stabbing pain and a lesser dull aching pain. Following injury, A-delta and C-fibers in the synovium and subchondral bone are sensitized. Normally non-noxious loading and movement of the joint are perceived as noxious stimuli. However, as articular cartilage lacks innervation, the location of the nerves driving pain is not known. Moreover, there is no clear correlation between the extent of joint destruction and the frequency and severity of joint pain. 

Research suggests there may be a neuropathic component in different types of skeletal pain. For example, in some types of cancer pain, the tumour cells destroy the distal ends of sensory nerve fibres that innervate the skeleton, which is then accompanied by an increase in movement-based pain. Another mechanism of neurobiology pain may arise from the sprouting of sensory and sympathetic nerve fibres. In mouse models of bone cancer, the number of nerve fibres per unit increased exponentially in a way not normally seen in bone.  

 

Neurochemical and structural changes to the Central Nervous System (CNS)

Little is known about the mechanisms that drive central sensitization in skeletal pain. However, it is thought to result when chemical, electrophysiological, and pharmacological systems that transmit and modulate pain are changed in the spinal cord and higher brain centers. 

 

Potential treatments for skeletal pain

The authors point out that while analgesics are needed to control pain better, an important therapeutic approach could induce bone or cartilage formation following injury. There are currently two classes of drugs to treat age-related bone loss: antiresorptive and osteoanabolic. However, both classes of drugs have limitations. 

Recent findings have outlined several new therapeutic targets for treating bone loss. Two of these inhibitory proteins that show promise are: sclerostin and Dickkopf-1. A Phase 1 study demonstrated that a dose of anti-sclerostin antibody increased bone density in the hip and spine in healthy men and postmenopausal women.

One question the researchers raise is how much neurobiology pain should be relieved. While it is beneficial for cancer patients to have their pain eliminated, the same is not true for patients with skeletal pain due to OA, bone fracture or ageing. The elimination of all pain could lead to overuse and more deterioration. Therefore, finding a treatment that could block pain while at the same time promoting bone formation and healing is critical. 

 

Why do these findings matter?

Understanding the causes of skeletal pain will help lead to more effective and targeted treatments. 

mechanotherapy

Goal of the Study?

In this study 1, the goal is to answer how physical exercise promotes tissue healing in bone, muscle, tendon, and cartilage.

 

Why are they doing this study?

Physical therapists and other clinicians prescribe exercise to address muscle tears, non-inflammatory arthropathies and controlled loading after injuries. This practice is in line with systematic reviews and controlled trials that demonstrate how exercise and movement can benefit patients with a range of musculoskeletal problems. However, in this short article, the authors focus on what happens at the tissue level to promote the repair and remodelling of tendon, muscle, articular cartilage, and bone. They argue that mechanotransduction, which is the physiological process where cells sense and respond to mechanical loads, is the term that best describes this process. 

 

What was done?

The authors began with a literature search for the earliest reference to mechanotransduction, finding 2441 citations in Medline. However, the term is not found in the current Oxford English dictionary and lacks a formal definition. Therefore, they suggest that a useful definition of the term would be “the processes whereby cells convert physiological mechanical stimuli into biochemical responses.” They then break down the process of mechanotransduction into three parts: mechanocoupling (the physical load), cell to cell communication (the communication throughout the tissue) and cellular response (the “tissue factory”).

To determine if mechanotherapy is taught in physical therapy programs, they formed international and intergenerational focus groups. The informal results suggest that mechanotransduction was not being taught in physical therapy education programs. To address this deficiency, they re-introduce the term ‘‘mechanotherapy’’ to cover situations where therapeutic exercise is prescribed to promote the repair or remodelling of injured tissue. Using this term, they then summarize clinical studies that have shown or implied a potential for mechanotherapy to promote healing of tendon, muscle, cartilage, and bone. 

 

What did they find?

Their review of clinical studies found that exercise has a beneficial response to controlled loading after injury for tendons, muscles, cartilage, and bone. For example, one study on tendons demonstrated that tendons with Achilles tendinosis treated with exercise showed near-normal structures after almost four years. Similar findings are demonstrated with the application of mechanotherapy for muscle injury. Clinical studies illustrated that the benefits of loading include better alignment, faster regeneration, and less atrophy.  

 

Why do these findings matter?

Patients are often prescribed exercise as a form of treatment for a variety of musculoskeletal issues. Therefore, it is important to understand better how mechanotherapy can benefit patients’ healing and its value for physical therapy.

intervertebral disc degeneration, 3d modeling

Mechanobiology Research

Low back pain is a huge burden on our limited resources with limited knowledge of its pathophysiology. It is widely known that intervertebral disc degeneration (IDD) is intimately related, with the degree of degeneration associated with the severity of low back pain. The characteristics of intervertebral disc degeneration include disc height loss, proteoglycan loss, loss of water, annular fissures, and end plate calcification.

The degenerative process of the intervertebral disc has been seen as a phenotype change within the cells. This anabolic to catabolic shift seems to occur to the cells deep within the disc. One branch of research that studies the influence of mechanical forces on the biology is called Mechanobiology. In other words, can physical stressors on discs influence the process of degeneration? Can moving the disc is a certain way change the outcome of degeneration?



The Study

In this open access study, researchers were the first to investigate this kind of cyclical mechanical tension on the nucleus pulposus cell’s changing behaviour.  They extracted disc cells from caudal spines of (3-month-old) male Sprague-Dawley rats and conducted the mechanical testing using a device after the cells were cultured and prepared. They used this device to apply mechanical force on the cells of the nucleus pulposus (the centre of the disc) to see how the cells behaved under specific loading conditions.

Disc cell senescence involves telomere shortening,  free radical stress, DNA breakdown and cytokine proliferation. Mechanical loading conditions in the upright posture have been found to promote disc cell changes towards intervertebral disc degeneration in rats.  Studying the role of mechanical stress and the influence on disc health will benefit our understanding of disc pathogenesis. 

The results of this study showed a direct relationship of prolonged mechanical cyclic stress towards the catabolic shift of the cells in the nucleus pulposus. They concluded that unphysiological mechanical stress could push a disc into the degenerative cascade. They believe that eventually, too much mechanical stress can influence a cell’s behaviour and suggested that research continue searching the optimal mechanical environment for intervertebral disc cells.

At Dynamic Disc Designs, we work to bring dynamic models to the practitioner to help in the discussions related to motion and the spine.

 



Diurnal Disc Shape

The spine undergoes natural shape and fluid changes over the course of 24 hours. Often, back pain symptoms vary as well over the day and night cycle.  But the small changes and the links to pain have not been researched thoroughly. Here, a group of researchers from Duke University looked at the reliability of measuring intervertebral disc shape with recumbent MRI. This large avascular structure is linked to back pain and has significant diurnal variation in the human body. It would seem wise to further understand its diurnal disc shape changes.

Some people feel pain in the mornings and others feel things more so at the end of the day. Yet others feel pain more so when they lie down.

The intervertebral disc hydraulically keeps vertebrae separated. Water is squeezed out throughout the day as the human frame is vertical, and this water gets resorbed when an individual lays down. During the process, the disc changes shape and height. And when pain is involved, these shape and height changes can bear increased ( or decreased ) physical stress on structures that may be inflammatory. These can include annular fissures, disc bulges, disc herniations, disc protrusions, encroaching nerve or rootlets of nerves and the shingling of facet joints, just to name a few.

The purpose of this study was to determine intra and inter-rater reliability using MRI to measure diurnal changes of the intervertebral discs.

They did find excellent reliability, and interestingly they saw the most significant change in the posterior annulus region of L5-1. The diurnal variations were in line with what others had seen in previous work. Boos at al. in 1996 saw a 1-2mm change over the course of an 8h workday while Hutton et al. in 2003 saw a volume change of 1-2 cm3.

This research is essential if we are to fully understand back pain origins. Often pain syndromes related to the lower back present with symptoms that are diurnal. At Dynamic Disc Designs, we have models to help explain these subtle but significant changes to the discs, assisting patients to understand the onset of their pains and the diurnal disc shape and the natural variations.

 

Dynamic, Disc , Modeling, Research

Dynamic Loading of the Intervertebral Disc – Ex vivo culturing and what can we learn?

For decades, the study of the intervertebral disc and the process that leads to degeneration has kept researchers very busy. This quest to fully understand the mechanisms that lead to water loss and proteoglycan content of the nucleus pulposus seems to be in the forebrain of spine investigators in hopes that it will provide clues on how to reverse the degenerative process…or at least prevent it.

Degenerative discs are arguably the most common cause of low back pain 1 with the cost affecting millions of people worldwide 2. The intervertebral disc plays a crucial role in the maintenence of bony vertebral spacing in the spine to allow movement. And when it starts to fail, it compromises the biomechanics. So, the search for regenerative strategies continues and hence the reason for this write-up.

One of the foregoing approaches to studying ways to rebuild human discs is to culture them outside of the body which is called ex vivo (outside life) research. In a recent publication in European Cells and Materials 3 these researchers were able to maintain cell life by loading the disc in a dynamic way. The branch of science that looks at how forces can influence real living tissues is called mechanobiology.

By stimulating the discs with motion, the cells remained alive for 14 days without any blood supply. Interestingly, the cells died when too much force was used whereas using medium cyclic forces maintained their viability. You can read the full text here.

This kind of research is VERY important in the greater understanding of how to keep the most important structure in the spine happy and viable. It also leads the way in revealing how much force is optimal (and the timing of it) for a healthy spine.

 

  1. Adams MA, Lama P, Zehra U, Dolan P (2015) Why do some intervertebral discs degenerate, when others (in the same spine) do not? Clin Anat 28: 195-204.
  2.  Katz JN (2006) Lumbar disc disorders and low-back pain: Socioeconomic factors and consequences. J Bone Joint Surg Am 88 Suppl 2: 21-24.
  3.  European Cells and Materials Vol. 31 2016 (pages 26-39).
regeneration - degenerated disc

Will there be regeneration of degenerated discs?

For decades a degenerated disc was thought to be a slow descent towards spinal dysfunction. However, when searching out terms like “degeneration” in PubMed, for example, the word “regeneration” is starting to show up in the searches along side degeneration.

Recently, at the Engineering in Medicine and Biology Society, 2004. IEMBS ’04. 26th Annual International Conference of the IEEE , Lotz et al. presented a paper (Mechanobiology in Intervertebral Disc Degeneration and Regeneration) explaining that while viewing the disc cells in-vivo they observed a temporal and spatial relationship to disc loading and the potential to influence their behaviour. They stated that by studying these load influences, it could lead to understand disc health and tolerance injury states.

“Our data demonstrates that these cells respond differently to pressure and distortion and survive in the discs mechanical/loading environment…intriguingly setting the stage for disc repair”

Mechanobiology is the study of how mechanics influences biology. Why does exercise help and why does sitting in a chair, without movement, often makes thing worse? Understanding the mechanics will give us insights on how we can influence cells to kick start anabolic behaviour and repair.

In 2004, Setton described  “Information on the mechanisms that govern cell responses to mechanical stimuli in the intervertebral disc are just emerging” in Cell Mechanics and Mechanobiology in the Intervertebral Disc . Back pain is the leading cause of disability wordwide and the second most common cause of physician visits. Therefore it only makes sense to look carefully at the influence of mechanics on the intervertebral disc cells. 

So, the future does look promising…especially when we are learning that the inflow fluid dynamics are greater than the outflow across the endplate.

At Dynamic Disc Designs Corp. we like to stay abreast of the literature, and highlight it, especially when it comes to mechanobiological strategies that can potentially regenerate degenerated discs.