Summary. Low back pain is one of the commonest
musculoskeletal complaints that affects individuals of all
ages and is a leading contributor towards work loss
worldwide. The range of current treatment modalities
involving surgeries, injectable agents, and medications is
promising but cannot address the reasons behind the
occurrence of pain in patients with degenerative disc
pathologies. One possible factor for the limited success
is the lack of evidence behind the identification of early,
intermediate, and late stages of painful changes
methodologically in a vast group of populations and the
manifestation of the diseases in terms of increased
physical activity, hereditary patterns, and various risk
factors. However, despite these challenges, steady
progress has been achieved in understanding the
parameters in abnormally loaded progressively
degenerating discs and these features have been
elucidated at a physical, biochemical, and cellular level.
These recent findings can likely lead to the development
of therapeutic interventions that will identify and retard
tissue damage, decrease pain, and improve the quality of
life in these patients. Therefore, the main aim of this
review is to integrate recent updates in intervertebral
disc degeneration research for the development of
evidence-based screening protocols and more targeted
interventions in the management of low back pain. 
Key words: Intervertebral disc, Degeneration, Pain,
Blood vessels, Nerves
Introduction, epidemiology and pain perception
Back pain is a significant health problem in the
world, affecting over two-thirds of the population at some
stage in their lives, and with more than 25% of the people
reporting it in the last 3 months and 12% suffering for 30
days or more in the last year. It is the second leading
cause of disability, and the most common ailment of
working adults and is estimated to cost $50 billion
annually across the world (Strine and Hootman, 2007;
Leboeuf-Yde et al., 2009). Back pain is associated with
greater depression, anxiety, and insomnia (Strine and
Hootman, 2007), recent evidence indicates that it persists
into old age (Bendix et al., 2008; Leboeuf-Yde et al.,
2009), and although its impact is masked by retirement
and immobility, it continues to have significant economic
consequences on the delivery of health care. It is clear,
therefore, that this is a musculoskeletal disorder affecting
enormous numbers and is one of the leading causes of
severe pain and disability in the aging population. Recent
studies provide strong evidence that intervertebral disc
(IVD) degeneration is associated with the most severe
chronic back pain (Cheung et al., 2009; de Schepper et
al., 2010; Livshits et al., 2011). IVD degeneration when
defined in terms of specific structural changes (Adams et
al., 2006 (3rd edition in 2012)), then the relationship with
back pain is clear. However, where IVD is defined in
terms of age-related loss of water and proteoglycans or in
terms of general radial bulging, then the relationship to
pain is more complex (Boden et al., 1990; Jensen et al.,
1994; Videman et al., 2003), however closely associated
with pain are radial fissures in the annulus fibrosus
(Videman and Nurminen, 2004, Peng et al., 2006), disc
herniation (Hartvigsen et al., 2004; Ghahreman and
Bogduk, 2011), and endplate damage (Peng et al., 2009;
Wang et al., 2012) that facilitate processes such as
proteoglycan loss readily. The ultimate collapse in
annulus height is also associated with back pain (Boos et
al., 1995; Videman et al., 2003) and increased neo-
innervations and vascularisation. Evidence from pain-
provocation studies suggests that IVDs account for
approximately 50% of severe and chronic low back pain
cases (Weber et al., 2015).
Intervertebral discs structure and functions
Located between the consecutive vertebral bodies
Degenerative physiochemical events 
in the pathological intervertebral disc
Polly Lama1, Jerina Tewari1, Michael A Adams2 and Christine Le Maitre3
1Sikkim Manipal Institute of Medical Sciences, Sikkim Manipal University, India, 2Centre for Clinical Anatomy, 
University of Bristol and 3Biomolecular Science Research Centre, Sheffield Hallam University, United Kingdom
Histol Histopathol (2022) 37: 11-20
http://www.hh.um.es
Corresponding Author: Dr. Polly Lama, M.Sc., Ph.D., Associate
Professor of Anatomy and Molecular Matrix Research, Sikkim Manipal
Institute of Medical Sciences, Sikkim Manipal University, Sikkim, India.
e-mail: pollylama@smims.smu.edu.in
DOI: 10.14670/HH-18-395
istology and
istopathologyH
REVIEW Open Access
©The Author(s) 2022. Open Access. This article is licensed under a Creative Commons CC-BY International License.
From Cell Biology to Tissue Engineering
intervertebral discs are white fibrocartilages separating
the vertebrae. An adult intervertebral disc is
approximately 7-10 mm thick and 40 mm in diameter
along the mid-sagittal plane (Roberts et al., 1989; Urban
and Roberts, 2003a,b). They are thinnest in the thoracic
and thickest in the lumbar regions and provide flexibility
allowing bending (flexion, extension) and torsion. They
also act as minor shock absorbers and help in the even
distribution of compressive forces on the vertebral
bodies (Adams et al., 1996). Each intervertebral discs
comprise of three integrated parts: the gelatinous nucleus
pulposus, the laminated annulus fibrosus, and the
cartilage endplate. The nucleus pulposus and annulus
fibrosus are sandwiched superiorly and inferiorly by the
cartilage endplates (Humzah and Soames, 1988), as
shown in Fig. 1.
Annulus fibrosus forms the outer-most part of the
discs, with concentrically arranged 15-25 collagen
lamellae (Fig. 1A,B) (Urban and Roberts, 2003a,b).
Each lamella consists of oblique and regularly arranged
type-I collagen fiber bundles orientated at 30 degrees to
the horizontal plane with the direction of fibers
alternating between adjacent lamellae. The outer annulus
contains relatively dense population of cells that tend to
be fibroblast-like, are elongated and aligned parallel to
the collagen fibers (Errington et al., 1998; Lama et al.,
2013). Towards the inner annulus region, the lamella
present mainly resists compressive forces and
demonstrates a higher amount of proteoglycans
molecules thus are more deformable, consequently the
cells of the inner annulus are rounded and not
necessarily aligned parallel to the collagen fibers
(Bruehlmann et al., 2002). Cells may appear in pairs or
clusters in between the lamellae. Collagen types II, III,
and VI are present around the pericellular matrix of
clustered and non-clustered inner annular cells (Roberts
et al., 1991).
Nucleus pulposus represents the inner soft core of
the intervertebral disc (Fig. 1A-C). It originates from the
notochord, and in the fetus and infants, it contains
actively dividing notochordal cells, which disappear at
approximately eight years of age (Urban and Roberts,
2003a,b). In the adult disc, the nucleus contains type II
collagen fibers which are randomly organized.
Proteoglycans account for 50% of the dry weight of the
adult nucleus (Roughley et al., 2002), and contain type
III, V, VI, IX, and type XI collagens, which are
pericellular in location (Roberts et al., 1991). Aggrecan
is the main component of proteoglycans and has a
protein core to which up to 100 sulphated cationic
glycosaminoglycans (GAG) chains are covalently
attached (Urban et al., 2000). The charge borne on the
surface by each GAG possesses a high affinity to attract
extracellular ions and water, thus the water content of
the nucleus is approximately 80% (McMillan et al.,
1996). The nucleus, therefore, behaves as a viscous fluid
and resists compressive forces by generating a
hydrostatic pressure of approximately 0.05MPa in a
cadaveric disc (Adams et al., 2012a,b). Under high
pressure, nucleus pulposus can insinuate between
collagen fibers of the inner annulus causing micro-
disruptions within and between the lamellae (MacLean
et al., 2008). In the nucleus, chondrocytes-like nucleus
pulposus cells (Urban, 1994) may be present singly, in
pairs, or may frequently form small and large clusters.
The cartilage endplate is the third morphological
distinct region of the discs (Fig. 1C). It is usually present
in the form of a horizontal hyaline cartilage layer with
less than 1 mm thickness and is loosely bonded to the
bony vertebral endplate of perforated cortical bone with
abundant blood vessels and capillaries. The most
important function of the endplate is to act as a physical
12
Physiochemical events in degenerative disc diseases
Fig. 1. Normal Intervertebral disc showing the annulus lamellae, nucleus pulposus and cartilaginous endplate regions. A. Young disc with a clear white
nucleus pulpous region. B. Mature disc ‘yellowed in appearances’ due to overall loss of hydration. C. Sagittal section of a spine showing the
cartilaginous endplate located between the vertebrae and the intervertebral discs. (Fig. A,B are from the Biomechanics Lab of Michael A Adams and
Fig. C from Urban and Roberts, Arthritis Research & Therapy, 2006).
and chemical barrier, thereby preventing the nucleus
from pushing into the spongiosa of the vertebral bodies
(Harris and Macnab, 1954; Roberts et al., 1989). The
endplate also functions as a pressure distributor during
loading (Veres et al., 2010). The cartilage endplate
maintains the internal pressurization of the discs by
hindering the expulsion of water and proteoglycan from
the disc into the vertebrae while facilitating the passage
of nutrients into the discs through the process of
diffusion (Rajasekaran et al., 2004). The elemental
chemical composition of the endplate is proteoglycans,
type II collagen, and chondrocytes in pairs or clusters
(Roberts et al., 1989; Lama et al., 2014).
Blood supply and Nerve Supply of the disc
The human annulus fibrosus is supplied by blood
vessels for only three years after birth, and these vessels
disappear by late childhood apart from some small
capillaries and lymph vessels confined to the outer 1 to 2
mm of the annulus (Urban and Roberts, 2003a,b) (Fig.
2A,B), and this makes the intervertebral disc one of the
largest avascular tissue in the adult human body.
Essential nutrients such as oxygen, glucose, and
substrates for matrix molecules reach IVD’s by the
process of diffusion and fluid flow through the blood
vessels present at the margins of the outer annulus and
endplate (Ferguson et al., 2004) diffusion varies
according to the duration of axial compression (Adams
and Hutton, 1986; Arun et al., 2009), the
loaded/unloaded state of the discs, and pumping action
generated by the loading or unloading cycles (O'Hara et
al., 1990; Ferguson et al., 2004). The cellular viability
depends upon oxygen, pH, and glucose concentration,
and since the oxygen levels in the center of the nucleus
regions are very low approximately 6-8 mm away from
the nearest blood supply, metabolism is by glycolysis
and accumulation of lactic acid may make the pH of the
discs slightly acidic.
Nerve supply to the intervertebral discs is by the
branches arising from the sympathetic trunk, the spinal
nerves, and the sinuvertebral nerves. The anterior and
lateral aspect of the annulus is supplied through a plexus
primarily derived from the sympathetic trunk (Bogduk,
1988). Posteriorly the annulus receive branches formed
by the sinuvertebral nerves, and the sensory spinal
nerves (Bogduk, 1994) (Fig. 2C). The nerves fibers are
abundant in the outer ligamentous portion of the
annulus, are fewer in the middle third and absent from
the inner third and in the nucleus pulposus region
(Coppes et al., 1990; Edgar, 2007; Adams et al., 2010).
Intervertebral disc degeneration and pain
Adverse mechanical loading is strongly implicated
in the initiation of disc degeneration (Videman et al.,
1990; Newell et al., 2017), with many of the structural
features of disc degeneration associated with pain being
reproducible in cadaveric discs by severe or repetitive
loading (Adams and Roughley, 2006; Stefanakis et al.,
2014). However, loading alone may not inevitably lead
to end-stage disc degeneration (Hutton et al., 2000).
Biological factors are equally important in the etiology
of disc degeneration and pain and may integrate as
genetic influences, inheritance, alongside age-related
changes in the composition of the matrix which
predisposes the discs to physical disruption during
normal activity. Hence, the heritability of disc
degeneration and pain is approximately 70% in middle-
aged women (Sambrook et al., 1999; MacGregor et al.,
2004) but only 30-50% in younger men with greater
levels of physical activity (Battie et al., 2008). Another
crucial biological factor in disc degeneration is
considered to be poor metabolite transport to cells in the
13
Physiochemical events in degenerative disc diseases
Fig. 2. Blood vessels and nerve terminals of the adult intervertebral disc. A. Abundant blood vessels are present at the vertebral bodies (arrow) with
relatively avascular and a neural disc. B. CD-31 immunopositive endothelial blood vessels located at the peripheries in the inner annulus region of a
painful disc. C. 3-D Confocal Z stacked section of a tiny, punctuate and arborizing P.G.P 9.5 immunoreactive nerve terminal, seen in red, within 30 µm
thick sections of a painful disc. (Fig. 2A is from Johnson and Roberts, 2007 and Fig. 2 B,C are from the Molecular matrix Lab of Polly Lama). Scale
bars: B, 50 µm; C, 100 µm.
nucleus from where the degenerative events could
commence (Urban et al., 2004). Disc structural failure
leading to progressive pathogenic etiology and
accelerated degenerative changes stems from both
structural and molecular dissonance, the center-stage
factors in disc degeneration research (Urban et al.,
2004). Neo-innervation and vascularisation of discs have
been associated with disc degeneration in general
(Freemont et al., 1997), and with annulus radial fissures
in particular (Peng et al., 2005), with direct associations
between nerve in-growth and back pain (Freemont et al.,
1997). Recent evidence thus suggests that discogenic
back pain has much to do with nerve in-growth and
nerve sensitization phenomena and appear to be
associated with mechanical disruption of the annulus
fibrosus and alteration of cellular phenotypes.
Cellular changes in relation to nerve in-growth and
annular fissures
Recent research exploring cell-mediated events
leading to discogenic pain has indicated that
proteoglycans (PG) such as aggrecan, inhibit nerve and
blood vessel growth (Johnson et al., 2002, 2005), and
proteoglycan loss is particularly associated with fissures
or disrupted regions of the tissue, (Antoniou et al., 1996;
Stefanakis et al., 2012) and may promote in-growth of
vessels and nerve in degenerated discs (Fig. 3A)
(Melrose et al., 2002). In-growths is induced by
neurotrophic factors, such as nerve growth factor (NGF)
and brain-derived neurotrophic factor (BDNF), secreted
by blood capillaries (Freemont et al., 2002), nucleus
pulposus (NP), and inner annulus fibrosus cells of
degenerate discs triggering release of catabolic cytokines
(Fig. 3B). Nociceptive nerves become ‘sensitized’ by
various inflammatory-like reactions that may involve an
increase in the production of factors such as TNFα
secreted by NP cells (Olmarker et al., 2003; Olmarker,
2008) which contributes towards the central mechanisms
of neurogenic pain. Cell clustering is also associated
with painful discs (Johnson et al., 2001), as is cell
senescence (Roberts et al., 2006a,b; Le Maitre et al.,
2007) which increases expression of matrix-degrading
enzymes (Roberts et al., 2006a,b) all of which are
regulated, at least in part, by the increased production of
catabolic cytokines particularly IL-1[21, 40]. There have
been attempts to block TNFα signaling to cure clinical
sciatica following disc herniations (Karppinen et al.,
2003; Korhonen et al., 2006), and to cure discogenic
back pain by injecting neurotoxic agents such as
methylene blue into painful discs (Peng et al., 2010).
Each had mixed success, suggesting that the approach is
promising but needs to be properly targeted.
Annulus fissures drive focal changes associated with
painful discs
Degeneration in painful discs is often focal, with
loss of PGs, in-growing nerves, and blood vessels, as
well as matrix-degrading enzymes located
predominantly around annulus fissures (Weiler et al.,
2002; Peng et al., 2005; Lama et al., 2018). Preliminary
14
Physiochemical events in degenerative disc diseases
Fig. 3. Inflammatory events in the disc tissue. A. Toluidine blue stained herniated disc annulus region with invading inflammatory cells (arrow) in
fissured and proteoglycan depleted region. B. Expression of cytokine IL-1in degenerated nucleus pulpous cells. (Fig. 3A is from Molecular matrix Lab of
Polly Lama and Fig. 3B is from Biomolecular Research Lab of Christine Le Maitre, Le Maitre et al., 2005). Scale bar: 100 µm.
observations from recent studies show that the
expression of catabolic factors is highest within micro-
fissures in the nucleus pulposus region, and the data
emphasize that painful degenerative changes emanate
from small regions of disrupted tissue (Lama et al.,
2018). Past studies have shown annulus fissures present
a micro-environment in which physical stresses are
remarkably low and proteoglycans have been lost
(Stefanakis et al., 2012), both changes being conducive
to nerve and blood vessel ingrowth (Adams et al.,
2012b). This is in agreement with evidence showing
decreased aggrecan synthesis in disc regions exposed to
reduced pressure (Hutton et al., 1999; Neidlinger-Wilke
et al., 2009). Thus, there are close associations between
annulus fissures, localized swelling, depleted PG, and
nerve in-growth (Adams et al., 2012b). Increases in
collagenolytic MMP expression localized to fissures can
further disrupt the collagen fiber network, reducing its
ability to restrain the swelling tendency of proteoglycan
molecules. In our past work on surgically retrieved
samples of painful disc tissue, a close spatial association
between tissue disruption, proteoglycan loss, cell
clustering, integrin expression (Lama et al., 2019), and
blood vessels and nerve ingrowths (Fig. 4A-G) was
observed, and cells from degenerated disc tissue exhibit
abnormal mechanotransduction pathways, with integrins
unable to convey mechanical stimuli even though they
are still expressed by these cells (Le Maitre et al., 2005
and 2009). Thus, uncoupling of the link between the cell
and extracellular matrix interactions via the integrins
receptors could explain these abnormalities in cellular
phenotypes as degenerative events progress. Weakened
cell-matrix interaction may encourage disc cells to re-
enter the cell cycle, creating cell clusters that typify
subsequent senescence in degenerated tissue. These cell
clusters accelerate the synthesis of catabolic factors and
degrading enzymes produced during severe
degeneration. Therefore, focal swelling around fissures
may be the trigger for cellular changes identified in
painful regions of intervertebral discs.
Neo vascularisation and innervation in pathological
painful patient’s disc
It has been suggested that the neuropathological
basis of low back pain is the sensitization of nerve
endings and nociceptors (Kuslich et al., 1991) that are
present within the outer three or four lamellae of the
relatively avascular and aneural intervertebral discs
(Ashton et al., 1994). These nociceptive nerve fibers act
as sensors that detect damage or potentially damaging
stimuli that signal pain (Roberts et al., 1995;
Dimitroulias et al., 2010), respond to changes in
intradiscal pressure (Adams et al., 1993), and become
hypersensitive during annular injury/tear, as high tensile
stresses are especially concentrated near radial fissures
(Pezowicz et al., 2006). Stimulation of these nociceptors
releases sensory neuropeptides such as Substance P (sub-
P) and calcitonin gene-related peptides (CGRP) capable
of amplifying the pain response (Fig. 4B) (Brain and
Moore, 1999). These nociceptors and tiny nerve fibers
fail to fire during normal movements within normal
15
Physiochemical events in degenerative disc diseases
Fig. 4. Immunohistochemical expression of various markers and receptors in painful disc pathologies. A. CD-31 positive vessel seen along a
fissure/defect (arrow) with a phase contrast background. Nuclei stained blue with DAPI and the vessels red. B. Substance-P positive nerve terminal
(red), cell nuclei (blue) with phase contrast. C. 3-D confocal Z stack of 30 µm thick section with NGF stained vessels in red, cell nuclei (blue). D. Matrix
degrading enzymes, MMP-1 (E) MMP-3 (F) Integrin alpha 5 beta 1 (G) TLR-2 receptors in cell stimulated with Interleukin-1. All Figs. are from Molecular
matrix lab of Polly Lama. Scale bars: A, 50 µm; B, C, 100 µm D-F 50 µm.
ranges of motion but, in response to tissue damage, they
become involved in the process of neurogenic
inflammation and secrete chemical irritants that
complicate the reparative events initiated by the disc
cells. In degenerated intervertebral discs, such nerve
ingrowths have even been reported to occur within the
nucleus pulposus (Peng et al., 2005), following a fissure
(Stefanakis et al., 2012). Nerves are accompanied by
capillaries that express high-affinity nerve growth factor
(trk-A) receptors. Ingrowth of such vessels and nerves
into the nucleus pulposus has also been suggested to
occur through the discal endplates (Freemont et al., 1997
and 2002) in degenerated discs. Growth factor synthesis
and its receptor activation have also been suggested to
be a response following disc herniation (Tolonen et al.,
1995). Angiogenic receptors are expressed frequently
along with Substance P in both herniated and
degenerated discs, indicating that it may contribute to
pain pathogenesis. Radial annular fissures are strongly
associated with disc degeneration, herniation, and
discogenic low back pain (Videman and Nurminen,
2004; Peng et al., 2006). The severity of the fissure may
determine the degree of herniation, as a well-developed
tear extending from the nucleus to the annulus, rupturing
the outermost annular layer and the surrounding
ligaments, readily allow the disc to herniate and sensitize
the peripherally located blood vessels and nerves leading
to the compression of the dorsal root ganglion (Rothman
et al., 2011). Such fissures may also provide a route for
blood vessels and nerves to grow deeper into the matrix
(Stefanakis et al., 2012), which could make discs as a
painful tissue, and further, the fissure extends into the
annulus, the greater the risk of pain (Videman and
Nurminen, 2004). Fissures may also act as an easy route
for disc tissue to lose its proteoglycan concentration
(Melrose et al., 2002) and it is well known that
proteoglycan inhibits blood vessels and nerve growths
(Johnson et al., 2006). A fully herniated disc may
influence other degenerative changes, as it is known that
disc tissue on losing its pressurized confines becomes
free to swell, and proteoglycans imbibe fluids from the
surrounding environment. Continuous swelling leads to
break down and eventually leaching of proteoglycan
aggregates from the disc tissue (Urban and Maroudas,
1981; Dolan et al., 1987), leaving behind a scaffold of
collagen fibers, and such changes may perhaps trigger
complex altered events at cellular and biochemical level
that may initiate processes leading to the synthesis of
catabolic factors that are capable of further degrading the
matrix.
Focal swelling and tissue disruptions in degenerated and
herniated intervertebral discs
At equilibrium, when there is no fluid loss or gain in
the discs, the internal swelling pressure is equal to the
magnitude of the external stress (Urban and McMullin,
1988). The lamellar collagen network of the annulus
fibrosus and the endplate located around the nucleus
pulposus regions thus maintains the internal pressure and
prevents glycosaminoglycans loss. The total ion and
glycosaminoglycans (GAG) concentration is higher in
the nucleus pulposus than the surrounding annulus
fibrosus (Jay Lipson and Muir, 1981). Abnormal stress
imbalances perturb the GAG’s and ion concentrations
within the discs tissue and are expressed as fluid lost
from the discs (Urban and Maroudas, 1981). The fixed
charged density (FCD) of the GAG molecules, the
proteoglycans and the resulting osmotic pressure rises
with loss of fluids until an equilibrium can be reached.
The osmotic pressure tries to balance the applied stress
(McMillan et al., 1996), and during this process any
damage to the collagen fibers increases the swelling
potential of the disc tissue, facilitating more
proteoglycans leaching (Urban and McMullin, 1988).
Thus, fissured, degenerated tissue that escapes from such
pressurized confines swell and undergoes extensive
biochemical changes that start as rapid proteoglycans
loss, changes in hydration, structural orientation,
nutrition, cellular functions, morphology, and micro-
mechanics. These changes could typically occur through
a progressive and stepwise cascade of events resulting in
gradual alterations of the cellular and extracellular
matrix (Pfirrmann et al., 2001), with affects collagen
synthesis, increases fragmentation of small leucine-rich
proteoglycans (SLRP's) and fibronectin (Oegema et al.,
2000; Greg Anderson et al., 2003), increases the
synthesis of matrix-degrading enzymes, cytokines,
increases cell clustering and initiates cell senescence or
death (Tschoeke et al., 2008). As a result, swelling alters
the physiochemical environment of the tissue to
stimulate the increased production of catabolic factors
that are commonly seen in fissured and painful discs.
Conclusion for the physiochemical etiology of painful disc
degeneration
Ageing, loading history, and an unfavorable genetic
inheritance leave some intervertebral discs vulnerable to
physical damage, particularly to the vertebral endplate
and peripheral annulus. Metabolite transport problems
ensure that the disc has a low cell density so that
effective repair is possible only in certain peripheral
regions. Elsewhere, the disrupted collagen network
allows tissue swelling, fissuring, and loss of
proteoglycans that makes IVD’s conducive to
inflammatory cell invasion, and to the ingrowth of blood
vessels and nerves. Focal swelling disturbs disc cell
binding to their matrix, either directly or following
MMP up-regulation, so that the mechanotransduction
events are also disturbed. Affected disc cells then form
clusters, in an attempted repair process that is frustrated
by inadequate metabolite transport and results only in
cell death and unregulated production of matrix-
degrading enzymes. Inflammatory changes are amplified
by repeated minor injuries to a structure that cannot
easily be protected from mechanical loading, and in-
growing disc nerves become sensitized to minor stimuli.
16
Physiochemical events in degenerative disc diseases
In this way, physio-chemical disruption to the disc
matrix could play a significant role in altering the
behavior of disc cells and ensuring that focal disruption
is followed by chronic degeneration and pain rather than
by effective healing.
Acknowledgements. Indian Council for Medical Research
(ICMR/5/7/1290-2015 RCH) and Dr. TMA Pai Major Research Grants
(SMU/131/REG/TMAPURK/164/2020) for the research work carried out
by Dr. Polly Lama with relevance to cellular changes during blood
vessels and nerve ingrowths in intervertebral disc degeneration. Action
Medical Research, United Kingdom (Registered charity) for supporting
the research work carried out by Michael A Adams.
Author Contributions. Polly Lama prepared the manuscript by following
up critical questions, answer and discussions session with Michael A
Adams and Christine Le Maitre for three years during the process of
blood vessels and ingrowths experiments. Jerina Tewari contributed
towards the final submission of the manuscript and preparation of
figures.
Conflict of Interests. Authors declare no conflict of interests.
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Accepted November 10, 2021
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Physiochemical events in degenerative disc diseases