During the workshop, five subgroups met to identify research opportunities.
The following outlines summarize their work and conclusions on knowledge gaps
and research agendas. Because these topics are closely related, duplication is
unavoidable yet underscores key areas.
Aging and Degeneration
Role of genderRole of ethnicityLink between gene mutation and mechanisms of degeneration
Role of gender
Role of ethnicity
Link between gene mutation and mechanisms of degeneration
Study of Disc
Should not study in isolation; functions as whole spinal segmentDifficult to study disc in isolation; organ or cell culture results must be
related to disc in vivoNeed for immortalized disc cell linesNeed for use of transgenic and knockout mouse models to study molecular
functionNeed to study interactions of different cell typesNeed for intact human organ culture model (heparinized donor discs) under
load
Should not study in isolation; functions as whole spinal segment
Difficult to study disc in isolation; organ or cell culture results must be
related to disc in vivo
Need for immortalized disc cell lines
Need for use of transgenic and knockout mouse models to study molecular
function
Need to study interactions of different cell types
Need for intact human organ culture model (heparinized donor discs) under
load
Disc-Cell Phenotypes
Need for cell markers to distinguish which cells are from the anulus
pulposus, which are from the nucleus pulposus, and which are from the end
plateNeed for markers to distinguish disc cells from other cell typesPhenotype will change with ageMay be possible to identify disc-cell phenotype by posttranslational
modification of matrix components (unique)
Need for cell markers to distinguish which cells are from the anulus
pulposus, which are from the nucleus pulposus, and which are from the end
plate
Need for markers to distinguish disc cells from other cell types
Phenotype will change with age
May be possible to identify disc-cell phenotype by posttranslational
modification of matrix components (unique)
Assessment of Disc Function
Need for noninvasive toolsImagingBiomarkersNeed to detect early degenerationTimeSiteDevelop imaging and biomarker technologyConcordance of degeneration with osteoarthritis (genetic link)Existing cohortsConcordance of cardiovascular disease and disc degeneration (impaired blood
supply)
Need for noninvasive tools
Imaging
Biomarkers
Need to detect early degeneration
Time
Site
Develop imaging and biomarker technology
Concordance of degeneration with osteoarthritis (genetic link)
Existing cohorts
Concordance of cardiovascular disease and disc degeneration (impaired blood
supply)
Distinction of Disc-Cell Phenotypes in Degeneration
Gene-array analysisProteomic analysis
Gene-array analysis
Proteomic analysis
Onset of Disc Degeneration
Notochordal cell loss (at approximately twelve years of age)Fibrous nucleus pulposus (at approximately twenty years of age)How does one define "normal" disc?
Notochordal cell loss (at approximately twelve years of age)
Fibrous nucleus pulposus (at approximately twenty years of age)
How does one define "normal" disc?
Potential for Disc Regeneration
Role of cells from the inner portion of the anulus fibrosusIs consistency of nucleus pulposus important? Will any swelling tissue
suffice?Maintain disc heightMaintain swelling on end plate and anulus fibrosus
Role of cells from the inner portion of the anulus fibrosus
Is consistency of nucleus pulposus important? Will any swelling tissue
suffice?
Maintain disc height
Maintain swelling on end plate and anulus fibrosus
Cell-Matrix Interactions
Matrix catabolitesFibronectin fragmentsHyaluronan fragmentSmall leucine-rich proteoglycan fragments
Matrix catabolites
Fibronectin fragments
Hyaluronan fragment
Small leucine-rich proteoglycan fragments
Biomechanics has been widely applied to clarify the role of the
intervertebral disc in governing load support and flexibility in the spine. As
a consequence, physical activity levels and mechanical loading history are
considered risk factors for the onset and progression of intervertebral disc
degeneration and related symptomatic disorders. Recent data have illuminated a
complex relationship between intervertebral disc biomechanics, disc cell
biology, systemic factors, and genetic background that broadly regulates the
symptomatic and anatomic presentation of degeneration and pathology. Given the
central role of the disc as a structural, load-bearing tissue, biomechanics
will continue to be a critical tool to advance our understanding of the
pathogenesis of intervertebral disc degeneration and to design and develop new
methods for the treatment of intervertebral disc degeneration. Biomechanical
metrics will be central—to quantify the efficacy of biologic and
device-based treatments; to predict the effects of inherited, genetic factors;
and to define the utility of noninvasive indices of pathology, such as imaging
and biomarkers. Ultimately, success in these pursuits will require a better
understanding of the pathology and anatomic presentation of intervertebral
disc degeneration as well as the fundamental mechanical and biologic
mechanisms that regulate its onset, progression, and resolution. The
development of these new perspectives will likely be facilitated by advanced
imaging techniques, biochemical assays, and other emerging technologies as
well as in vitro, animal, human, and computational model systems. Eight
subject areas for future research were identified:
Noninvasive assessments and biomarkers of the biomechanical function of
the disc. Functional intervertebral changes are a well-accepted but poorly
characterized feature of intervertebral disc degeneration that may be distinct
from purely anatomic changes observable on radiologic examination. Noninvasive
measures of the ability of the disc to perform its mechanical roles may lead
to substantial improvements in diagnosis, treatment assessment, and
epidemiologic investigation. In particular, emphasis should be placed on
developing noninvasive metrics that are sensitive to disc features that differ
between symptomatic and asymptomatic presentation of intervertebral disc
degeneration.Advance noninvasive assessment tools to serve as biomarkers that quantify
the ability of the intervertebral disc to perform its mechanical function.
These tools should be based on functional indices, including segmental
hypermobility, matrix quality, end-plate deformations, and end-plate
transport. Imaging during functional movements (e.g., dynamic magnetic
resonance imaging, motion analysis systems) and functional behavioral analyses
will likely be central to achieving this goal.Biomechanical scaling from motion segment to the microscopic and/or
nanoscale tissue and cellular levels. The motion segment and
intervertebral disc have a complex and heterogeneous structure such that the
internal tissue and cellular stress-strain environments in response to
physiologic loads and deformations remain unknown. These mechanical
relationships may change as a consequence of normal aging or in response to
acute injury, altering cell and tissue function.Link motion-segment mechanics to tissue-level stresses and strain and to
cell-level mechanics Achieving this linkage may make use of optical and
nonoptical imaging, computational modeling, and mechanical testing at all
scale levelsFunctional outcomes of therapeutic interventions. Biologic therapies
based on gene and/or protein delivery or cell supplementation have the
potential both to modify the physical function of the intervertebral disc and
to be impacted by altered intervertebral disc function in intervertebral disc
degeneration. Studies of treatment-induced changes in intervertebral disc
function will be important for judging outcome quality and optimizing
developing therapies.Develop tools that are based on mechanical measures of motion restoration,
tissue and structure mechanics, and related cellular responses to facilitate
the assessment of intervertebral disc function subsequent to repair or
restorationDetermine how exogenous factors (e.g., cells, proteins, genes, and
bioactive materials) delivered to the intervertebral disc may interact with
the mechanical loading environment to affect relevant features of cell biology
or matrix formationDetermine how tissue-engineered discs or disc replacements may alter the
structure and biologic function of adjacent components of the motion segment,
including the vertebral end plates and facet jointsEnd-plate biomechanics. The vertebral and cartilage end plates of
the intervertebral disc are recognized to have important roles in governing
transport of nutrients and metabolites and in regulating mechanics of the
entire intervertebral disc. Little information is available on end-plate
function and changes with age and degeneration.Determine end-plate deformations and transport parameters and their role in
intervertebral disc degeneration and intervertebral disc pathologyAssess the role of the end plate as a potential pain generatorDetermine whether other diseases that affect bone and joints (e.g.,
systemic arthritis diseases or osteoporosis) or their treatments may adversely
influence the function or the pathology of the intervertebral disc or the
treatment of intervertebral disc degenerationBiomechanics of intervertebral matrix damage and healing in relation to
intervertebral disc degeneration and pain. Biomechanical factors have been
loosely linked to intervertebral disc degeneration and pain. Lifetime physical
exposure associated with activities of daily living, recreation, and
occupation persist as a suspected initiator and accelerator of intervertebral
disc degeneration. Ample in vitro evidence demonstrates that mechanical
loading can initiate damage to intervertebral disc material; however, the
mechanisms by which damage occurs, is healed in vivo, contributes to
intervertebral disc degeneration, and triggers pain are poorly understood.Precisely define and quantify the biomechanical factors associated with
damage to intervertebral disc material and the relationships with
intervertebral disc degenerationDefine and quantify the association between physiologic loading and the
onset of acute painBiomechanics of function and failure at the microscopic and molecular
level. Structural microfailure of the intervertebral disc, characterized
by interruptions in extracellular matrix, is observed as anatomic changes such
as fissures and tears both in vitro and on radiologic examination. Microscopic
and molecular-level events that contribute to microfailure of the
intervertebral disc may be important in determining the pathogenesis and
progression of intervertebral disc degeneration, may drive the intervertebral
disc toward progressive damage by interfering with the capacity for repair,
and may revealnovel interventions for intervertebral disc treatment based on
restoration of damaged structure.Quantify microscopic and molecular-level structure-function relationships
associated with intervertebral disc function and with mechanical failure
(e.g., matrix disorganization or altered molecular interactions)Quantify the mechanics associated with the initiation and progression of
microfailure in the intervertebral discCell response to mechanical stimuli. Cellular responses are involved
in the progression of intervertebral disc degeneration in ways that remain
poorly understood. A component of these responses will involve interaction
with mediators of pain and inflammation (e.g., proteases, hormones, cytokines,
and chemokines) and physicochemical stimuli within the organ or at the
cellular level that may be difficult to elucidate. Cellular responses may vary
among cell types, with age, and with intervertebral disc degeneration.Determine physiologically relevant biomechanical signals for intervertebral
disc cellsDetermine interactions among physicochemical stimuli, cytokines, growth
factors, and other mediators held to be relevant in intervertebral disc
degenerationDetermine the mechanisms that govern the cellular responses of
intervertebral discs to physicochemical stimuli and the mechanisms that
regulate homeostasis and deviations from this stateDetermine the involvement of appropriate aging-dependent and
pathology-dependent responses of intervertebral disc cells to their
physicochemical and biochemical milieuInteractions between mechanics and predisposing genetic factors.
Studies demonstrate the existence of familial predisposition to intervertebral
disc disorders, which may explain the notable percentage of patients who
present with intervertebral disc degeneration. Little is known with regard to
how functional intervertebral disc loading interacts with relevant genetic
backgrounds in the progression of intervertebral disc degeneration.Determine interactions between functional loading and genetic factors that
are relevant to the premature onset of intervertebral disc disorders or
intervertebral disc degeneration, using tools of functional assessment,
imaging, mechanics, and/or epidemiology
Noninvasive assessments and biomarkers of the biomechanical function of
the disc. Functional intervertebral changes are a well-accepted but poorly
characterized feature of intervertebral disc degeneration that may be distinct
from purely anatomic changes observable on radiologic examination. Noninvasive
measures of the ability of the disc to perform its mechanical roles may lead
to substantial improvements in diagnosis, treatment assessment, and
epidemiologic investigation. In particular, emphasis should be placed on
developing noninvasive metrics that are sensitive to disc features that differ
between symptomatic and asymptomatic presentation of intervertebral disc
degeneration.
Advance noninvasive assessment tools to serve as biomarkers that quantify
the ability of the intervertebral disc to perform its mechanical function.
These tools should be based on functional indices, including segmental
hypermobility, matrix quality, end-plate deformations, and end-plate
transport. Imaging during functional movements (e.g., dynamic magnetic
resonance imaging, motion analysis systems) and functional behavioral analyses
will likely be central to achieving this goal.
Advance noninvasive assessment tools to serve as biomarkers that quantify
the ability of the intervertebral disc to perform its mechanical function.
These tools should be based on functional indices, including segmental
hypermobility, matrix quality, end-plate deformations, and end-plate
transport. Imaging during functional movements (e.g., dynamic magnetic
resonance imaging, motion analysis systems) and functional behavioral analyses
will likely be central to achieving this goal.
Biomechanical scaling from motion segment to the microscopic and/or
nanoscale tissue and cellular levels. The motion segment and
intervertebral disc have a complex and heterogeneous structure such that the
internal tissue and cellular stress-strain environments in response to
physiologic loads and deformations remain unknown. These mechanical
relationships may change as a consequence of normal aging or in response to
acute injury, altering cell and tissue function.
Link motion-segment mechanics to tissue-level stresses and strain and to
cell-level mechanics Achieving this linkage may make use of optical and
nonoptical imaging, computational modeling, and mechanical testing at all
scale levels
Link motion-segment mechanics to tissue-level stresses and strain and to
cell-level mechanics Achieving this linkage may make use of optical and
nonoptical imaging, computational modeling, and mechanical testing at all
scale levels
Functional outcomes of therapeutic interventions. Biologic therapies
based on gene and/or protein delivery or cell supplementation have the
potential both to modify the physical function of the intervertebral disc and
to be impacted by altered intervertebral disc function in intervertebral disc
degeneration. Studies of treatment-induced changes in intervertebral disc
function will be important for judging outcome quality and optimizing
developing therapies.
Develop tools that are based on mechanical measures of motion restoration,
tissue and structure mechanics, and related cellular responses to facilitate
the assessment of intervertebral disc function subsequent to repair or
restorationDetermine how exogenous factors (e.g., cells, proteins, genes, and
bioactive materials) delivered to the intervertebral disc may interact with
the mechanical loading environment to affect relevant features of cell biology
or matrix formationDetermine how tissue-engineered discs or disc replacements may alter the
structure and biologic function of adjacent components of the motion segment,
including the vertebral end plates and facet joints
Develop tools that are based on mechanical measures of motion restoration,
tissue and structure mechanics, and related cellular responses to facilitate
the assessment of intervertebral disc function subsequent to repair or
restoration
Determine how exogenous factors (e.g., cells, proteins, genes, and
bioactive materials) delivered to the intervertebral disc may interact with
the mechanical loading environment to affect relevant features of cell biology
or matrix formation
Determine how tissue-engineered discs or disc replacements may alter the
structure and biologic function of adjacent components of the motion segment,
including the vertebral end plates and facet joints
End-plate biomechanics. The vertebral and cartilage end plates of
the intervertebral disc are recognized to have important roles in governing
transport of nutrients and metabolites and in regulating mechanics of the
entire intervertebral disc. Little information is available on end-plate
function and changes with age and degeneration.
Determine end-plate deformations and transport parameters and their role in
intervertebral disc degeneration and intervertebral disc pathologyAssess the role of the end plate as a potential pain generatorDetermine whether other diseases that affect bone and joints (e.g.,
systemic arthritis diseases or osteoporosis) or their treatments may adversely
influence the function or the pathology of the intervertebral disc or the
treatment of intervertebral disc degeneration
Determine end-plate deformations and transport parameters and their role in
intervertebral disc degeneration and intervertebral disc pathology
Assess the role of the end plate as a potential pain generator
Determine whether other diseases that affect bone and joints (e.g.,
systemic arthritis diseases or osteoporosis) or their treatments may adversely
influence the function or the pathology of the intervertebral disc or the
treatment of intervertebral disc degeneration
Biomechanics of intervertebral matrix damage and healing in relation to
intervertebral disc degeneration and pain. Biomechanical factors have been
loosely linked to intervertebral disc degeneration and pain. Lifetime physical
exposure associated with activities of daily living, recreation, and
occupation persist as a suspected initiator and accelerator of intervertebral
disc degeneration. Ample in vitro evidence demonstrates that mechanical
loading can initiate damage to intervertebral disc material; however, the
mechanisms by which damage occurs, is healed in vivo, contributes to
intervertebral disc degeneration, and triggers pain are poorly understood.
Precisely define and quantify the biomechanical factors associated with
damage to intervertebral disc material and the relationships with
intervertebral disc degenerationDefine and quantify the association between physiologic loading and the
onset of acute pain
Precisely define and quantify the biomechanical factors associated with
damage to intervertebral disc material and the relationships with
intervertebral disc degeneration
Define and quantify the association between physiologic loading and the
onset of acute pain
Biomechanics of function and failure at the microscopic and molecular
level. Structural microfailure of the intervertebral disc, characterized
by interruptions in extracellular matrix, is observed as anatomic changes such
as fissures and tears both in vitro and on radiologic examination. Microscopic
and molecular-level events that contribute to microfailure of the
intervertebral disc may be important in determining the pathogenesis and
progression of intervertebral disc degeneration, may drive the intervertebral
disc toward progressive damage by interfering with the capacity for repair,
and may revealnovel interventions for intervertebral disc treatment based on
restoration of damaged structure.
Quantify microscopic and molecular-level structure-function relationships
associated with intervertebral disc function and with mechanical failure
(e.g., matrix disorganization or altered molecular interactions)Quantify the mechanics associated with the initiation and progression of
microfailure in the intervertebral disc
Quantify microscopic and molecular-level structure-function relationships
associated with intervertebral disc function and with mechanical failure
(e.g., matrix disorganization or altered molecular interactions)
Quantify the mechanics associated with the initiation and progression of
microfailure in the intervertebral disc
Cell response to mechanical stimuli. Cellular responses are involved
in the progression of intervertebral disc degeneration in ways that remain
poorly understood. A component of these responses will involve interaction
with mediators of pain and inflammation (e.g., proteases, hormones, cytokines,
and chemokines) and physicochemical stimuli within the organ or at the
cellular level that may be difficult to elucidate. Cellular responses may vary
among cell types, with age, and with intervertebral disc degeneration.
Determine physiologically relevant biomechanical signals for intervertebral
disc cellsDetermine interactions among physicochemical stimuli, cytokines, growth
factors, and other mediators held to be relevant in intervertebral disc
degenerationDetermine the mechanisms that govern the cellular responses of
intervertebral discs to physicochemical stimuli and the mechanisms that
regulate homeostasis and deviations from this stateDetermine the involvement of appropriate aging-dependent and
pathology-dependent responses of intervertebral disc cells to their
physicochemical and biochemical milieu
Determine physiologically relevant biomechanical signals for intervertebral
disc cells
Determine interactions among physicochemical stimuli, cytokines, growth
factors, and other mediators held to be relevant in intervertebral disc
degeneration
Determine the mechanisms that govern the cellular responses of
intervertebral discs to physicochemical stimuli and the mechanisms that
regulate homeostasis and deviations from this state
Determine the involvement of appropriate aging-dependent and
pathology-dependent responses of intervertebral disc cells to their
physicochemical and biochemical milieu
Interactions between mechanics and predisposing genetic factors.
Studies demonstrate the existence of familial predisposition to intervertebral
disc disorders, which may explain the notable percentage of patients who
present with intervertebral disc degeneration. Little is known with regard to
how functional intervertebral disc loading interacts with relevant genetic
backgrounds in the progression of intervertebral disc degeneration.
Determine interactions between functional loading and genetic factors that
are relevant to the premature onset of intervertebral disc disorders or
intervertebral disc degeneration, using tools of functional assessment,
imaging, mechanics, and/or epidemiology
Determine interactions between functional loading and genetic factors that
are relevant to the premature onset of intervertebral disc disorders or
intervertebral disc degeneration, using tools of functional assessment,
imaging, mechanics, and/or epidemiology
Investigate possibilities of using imaging technology to demonstrate
inflammation in discs and in nerve rootsIn well-defined patient groups and with use of large sample sizesHighlighting the importance of correlation to symptomsUse of quantitative magnetic resonance imaging and functional magnetic
resonance imagingInvestigate improved clinical methods to evaluate pain in the discogenic
population that would correlate with the behavioral methodology used in
experimental animal pain modelsReassessment of acute, subacute, and chronic terminologyFocus on pain patterns and/or number of painful episodesInvestigate why intervertebral disc degeneration and/or herniated nucleus
pulposus causes symptoms in some patients but not othersDetermine the criteria for the disc as a pain generatorWhat are the components of the intervertebral disc that may give rise to
pain?Resolve whether or not facet joints and/or intervertebral discs (normal and
degenerated) activate nociceptorsDevelop clinically relevant animal intervertebral disc degeneration models
that demonstrate functional and/or sensory deficits for the study of central
nervous system pathophysiologic mechanisms and can be applied to the
assessment of treatment optionsDesign clinical trials that combine surgical interventions with nonopioid
drug therapy and other therapies to address both initiation and maintenance of
persistent painDetermine the influence of genetics on painful intervertebral disc
degenerationImpact of genderGenetic polymorphisms in symptomatic versus asymptomatic intervertebral
disc degenerationIdentify cerebrospinal fluid and/or peripheral biomarkers for
intervertebral disc degeneration and painConsider use of novel magnetic resonance imaging spectroscopy
Investigate possibilities of using imaging technology to demonstrate
inflammation in discs and in nerve roots
In well-defined patient groups and with use of large sample sizesHighlighting the importance of correlation to symptomsUse of quantitative magnetic resonance imaging and functional magnetic
resonance imaging
In well-defined patient groups and with use of large sample sizes
Highlighting the importance of correlation to symptoms
Use of quantitative magnetic resonance imaging and functional magnetic
resonance imaging
Investigate improved clinical methods to evaluate pain in the discogenic
population that would correlate with the behavioral methodology used in
experimental animal pain models
Reassessment of acute, subacute, and chronic terminologyFocus on pain patterns and/or number of painful episodes
Reassessment of acute, subacute, and chronic terminology
Focus on pain patterns and/or number of painful episodes
Investigate why intervertebral disc degeneration and/or herniated nucleus
pulposus causes symptoms in some patients but not others
Determine the criteria for the disc as a pain generator
What are the components of the intervertebral disc that may give rise to
pain?Resolve whether or not facet joints and/or intervertebral discs (normal and
degenerated) activate nociceptors
What are the components of the intervertebral disc that may give rise to
pain?
Resolve whether or not facet joints and/or intervertebral discs (normal and
degenerated) activate nociceptors
Develop clinically relevant animal intervertebral disc degeneration models
that demonstrate functional and/or sensory deficits for the study of central
nervous system pathophysiologic mechanisms and can be applied to the
assessment of treatment options
Design clinical trials that combine surgical interventions with nonopioid
drug therapy and other therapies to address both initiation and maintenance of
persistent pain
Determine the influence of genetics on painful intervertebral disc
degeneration
Impact of genderGenetic polymorphisms in symptomatic versus asymptomatic intervertebral
disc degeneration
Impact of gender
Genetic polymorphisms in symptomatic versus asymptomatic intervertebral
disc degeneration
Identify cerebrospinal fluid and/or peripheral biomarkers for
intervertebral disc degeneration and pain
Consider use of novel magnetic resonance imaging spectroscopy
Consider use of novel magnetic resonance imaging spectroscopy
Models of disc degeneration are used to identify causative mechanisms of
disc degeneration and to develop therapeutic interventions.
In Vivo Models
Improved linkage of pain and/or disability with anatomic changes in
existing models of disc degeneration. Although limited correlation exists
between anatomic degenerative changes in the spine and clinical pain, pain is
the primary driver of disability and cost to society. As a result, animal
models of disc degeneration should strive to include mea-sures of pain,
behavioral changes, and/or functional disability as part of the outcomes
criteria.Need to define translatability of the various models to the human
situation. Although numerous animal models have been partially
characterized, none have been validated with regard to translatability to the
human situation. The elements that affect translation must be better defined,
including:Better characterization of the cell types present in the nucleus, the cell
density in tissues, and changes with age and degenerationSize and scale-up from animal to human disc size, and compensation for
differing age, cell density, mechanical stress, and lifespanIdentification of any physiologic response differences to potential
therapeutics based on species or disc size and/or transport differences in
humansIncorporation of new technologies, such as quantitative imaging, that can
be applied to models and in the clinical setting
Improved linkage of pain and/or disability with anatomic changes in
existing models of disc degeneration. Although limited correlation exists
between anatomic degenerative changes in the spine and clinical pain, pain is
the primary driver of disability and cost to society. As a result, animal
models of disc degeneration should strive to include mea-sures of pain,
behavioral changes, and/or functional disability as part of the outcomes
criteria.
Need to define translatability of the various models to the human
situation. Although numerous animal models have been partially
characterized, none have been validated with regard to translatability to the
human situation. The elements that affect translation must be better defined,
including:
Better characterization of the cell types present in the nucleus, the cell
density in tissues, and changes with age and degenerationSize and scale-up from animal to human disc size, and compensation for
differing age, cell density, mechanical stress, and lifespanIdentification of any physiologic response differences to potential
therapeutics based on species or disc size and/or transport differences in
humansIncorporation of new technologies, such as quantitative imaging, that can
be applied to models and in the clinical setting
Better characterization of the cell types present in the nucleus, the cell
density in tissues, and changes with age and degeneration
Size and scale-up from animal to human disc size, and compensation for
differing age, cell density, mechanical stress, and lifespan
Identification of any physiologic response differences to potential
therapeutics based on species or disc size and/or transport differences in
humans
Incorporation of new technologies, such as quantitative imaging, that can
be applied to models and in the clinical setting
Development of genetic models of intervertebral disc degeneration.
Many genetic models for osteoporosis and bone disorders have been defined that
greatly facilitate screening of potential interventions. For disc
degeneration, the majority of models have been injury induced with the
exception of the sand rat model. A variety of genetic mice exist with collagen
and other matrix component mutations that have not been well studied with
respect to their intervertebral disc phenotypic effects.Better definition of the cell population present in a disc model.
Clear identification of the cell populations (as notochordal, nuclear
chondrocyte, peripheral anular, etc.) and how they change with disc
degeneration is required.Improved understanding of the differences between an acute injury model
and natural (age-related) degeneration. The majority of disc models
involve some type of mechanical or chemical injury to accelerate disc
degeneration. Natural aging models exist but are much slower to develop and
therefore less practical. It is important to determine if the degenerative
cascade following injury is the same as or different from the cascade involved
in age-related spontaneous degeneration.Identify additional biomarkers of disc degeneration. A major
impediment to characterization of animal models, tracking of therapeutic
interventions, and identification of clinical patients who would be candidates
for early treatment is the lack of specific biomarkers of disease. The goal
would be to identify early and quantitative markers of disc degeneration for
the purpose of diagnosis and monitoring progress of natural history and
interventions.Develop models of transport and/or nutritional defects. One leading
theory of the etiology of disc degeneration revolves around altered transport
in and out of the disc. There are currently no validated models to manipulate
transport to validate this theory and develop interventions.Develop models of anular tear with chemical irritation. Clinically,
the presence of anular tears is often associated with low-back pain in the
absence of advanced morphologic deterioration of the disc. The assumed
hypothesis to explain this pain is leakage of inflammatory cytokines from the
disc through the anular tear to sensitize peripheral anular nerves or the
dorsal root ganglion. The current models do not address this phenomenon; if a
model were developed to replicate this situation, a variety of therapeutic
interventions could be tested.Development of a standardized magnetic resonance imaging grading and/or
scoring system. The primary tool for identifying and grading disc
degeneration experimentally and clinically is the T2-weighted intranuclear
signal on the magnetic resonance imaging scan. This is largely a qualitative
assessment and is not currently standardized between investigators and models.
It would be useful to see what measurement parameters (e.g., T2-weighted
signal intensity, T2 raw values, or new contrast agents with better disc
penetration) are most capable of early detection and quantification of disc
degeneration. Priority should be given to techniques that can be performed at
clinically available magnetic field strengths to facilitate translation.
Development of genetic models of intervertebral disc degeneration.
Many genetic models for osteoporosis and bone disorders have been defined that
greatly facilitate screening of potential interventions. For disc
degeneration, the majority of models have been injury induced with the
exception of the sand rat model. A variety of genetic mice exist with collagen
and other matrix component mutations that have not been well studied with
respect to their intervertebral disc phenotypic effects.
Better definition of the cell population present in a disc model.
Clear identification of the cell populations (as notochordal, nuclear
chondrocyte, peripheral anular, etc.) and how they change with disc
degeneration is required.
Improved understanding of the differences between an acute injury model
and natural (age-related) degeneration. The majority of disc models
involve some type of mechanical or chemical injury to accelerate disc
degeneration. Natural aging models exist but are much slower to develop and
therefore less practical. It is important to determine if the degenerative
cascade following injury is the same as or different from the cascade involved
in age-related spontaneous degeneration.
Identify additional biomarkers of disc degeneration. A major
impediment to characterization of animal models, tracking of therapeutic
interventions, and identification of clinical patients who would be candidates
for early treatment is the lack of specific biomarkers of disease. The goal
would be to identify early and quantitative markers of disc degeneration for
the purpose of diagnosis and monitoring progress of natural history and
interventions.
Develop models of transport and/or nutritional defects. One leading
theory of the etiology of disc degeneration revolves around altered transport
in and out of the disc. There are currently no validated models to manipulate
transport to validate this theory and develop interventions.
Develop models of anular tear with chemical irritation. Clinically,
the presence of anular tears is often associated with low-back pain in the
absence of advanced morphologic deterioration of the disc. The assumed
hypothesis to explain this pain is leakage of inflammatory cytokines from the
disc through the anular tear to sensitize peripheral anular nerves or the
dorsal root ganglion. The current models do not address this phenomenon; if a
model were developed to replicate this situation, a variety of therapeutic
interventions could be tested.
Development of a standardized magnetic resonance imaging grading and/or
scoring system. The primary tool for identifying and grading disc
degeneration experimentally and clinically is the T2-weighted intranuclear
signal on the magnetic resonance imaging scan. This is largely a qualitative
assessment and is not currently standardized between investigators and models.
It would be useful to see what measurement parameters (e.g., T2-weighted
signal intensity, T2 raw values, or new contrast agents with better disc
penetration) are most capable of early detection and quantification of disc
degeneration. Priority should be given to techniques that can be performed at
clinically available magnetic field strengths to facilitate translation.
In Vitro/Computational Models
Development of better cell and organ culture models. Given the
complexity of the disc as an organ with multiple cell types and a highly
sophisticated extracellular matrix, organ culture models would facilitate the
screening of therapeutic interventions in a more physiologic environment than
monolayer culture. The conditions that optimize long-term organ culture models
need to be established. Better three-dimensional systems that recognize the
structural complexity of the matrix, especially in the anulus, are required,
particularly for defining biomechanical responses of cells.Determine tissue and material properties of degenerative and healthy
discs. Computational models can be used to estimate behaviors of disc that
are difficult or impossible to measure directly. Models can demonstrate the
effects of altered disc composition or structure and can facilitate the design
of spinal implants and indicate how they modify disc mechanics, providing that
the model properties and loading conditions are correct. Models can include
multiple, spatially varying tissue properties, but their values must be
determined accurately. Such models can be directed at simulating specific
perturbations (e.g., composition changes or lesions) and predicting
interactions between changes at different levels of the spine (e.g., the
effects on adjacent segments), but the in vivo loading and boundary conditions
should be specified more realistically. Computational models have thepotential
to achieve substantially improved realism after incorporation of the
alteration of cell activity in response to mechanical stimuli, but the
credibility of computational models for predicting tissue injury and cellular
mechanotransduction must be established.
Development of better cell and organ culture models. Given the
complexity of the disc as an organ with multiple cell types and a highly
sophisticated extracellular matrix, organ culture models would facilitate the
screening of therapeutic interventions in a more physiologic environment than
monolayer culture. The conditions that optimize long-term organ culture models
need to be established. Better three-dimensional systems that recognize the
structural complexity of the matrix, especially in the anulus, are required,
particularly for defining biomechanical responses of cells.
Determine tissue and material properties of degenerative and healthy
discs. Computational models can be used to estimate behaviors of disc that
are difficult or impossible to measure directly. Models can demonstrate the
effects of altered disc composition or structure and can facilitate the design
of spinal implants and indicate how they modify disc mechanics, providing that
the model properties and loading conditions are correct. Models can include
multiple, spatially varying tissue properties, but their values must be
determined accurately. Such models can be directed at simulating specific
perturbations (e.g., composition changes or lesions) and predicting
interactions between changes at different levels of the spine (e.g., the
effects on adjacent segments), but the in vivo loading and boundary conditions
should be specified more realistically. Computational models have thepotential
to achieve substantially improved realism after incorporation of the
alteration of cell activity in response to mechanical stimuli, but the
credibility of computational models for predicting tissue injury and cellular
mechanotransduction must be established.
The following points represent areas that need further clarification to
ensure the success of different treatment alternatives.
Biologics
What to deliver (e.g., proteases, cells, growth factors, etc.) and better
delivery systemsCell characterization and fate of transplanted cellsSafety (i.e., pharmacokinetics, toxicology, immunology, and methods to
regulate gene expression)
What to deliver (e.g., proteases, cells, growth factors, etc.) and better
delivery systems
Cell characterization and fate of transplanted cells
Safety (i.e., pharmacokinetics, toxicology, immunology, and methods to
regulate gene expression)
Disc Replacement
Nucleus versus total disc; anulus repair and tissue-engineered discsTotal disc versus biomaterialsRevision surgery alternativesNeed for assessment criteria
Nucleus versus total disc; anulus repair and tissue-engineered discs
Total disc versus biomaterials
Revision surgery alternatives
Need for assessment criteria
Wear
Effects of debris on nerve cells and central nervous system transportCharacterization of particlesUnderstanding in vivo wear measurementsMethods to assess osteolysis
Effects of debris on nerve cells and central nervous system transport
Characterization of particles
Understanding in vivo wear measurements
Methods to assess osteolysis
Testing
Standardized test methods (i.e., spine stimulation and animal models)Compare disc designsRoentgen stereophotogrammetric analyses (RSA) of movement and migrationMeasurement of loads on instrumented discs
Standardized test methods (i.e., spine stimulation and animal models)
Compare disc designs
Roentgen stereophotogrammetric analyses (RSA) of movement and migration
Measurement of loads on instrumented discs
Other
Indications in patient selection (menu and/or algorithms)Prevention of disc diseaseStandardize grading systemCost-effectiveness of disc replacementRetrieval registry and outcome registryBetter links between biologics, mechanics, and pain
Indications in patient selection (menu and/or algorithms)
Prevention of disc disease
Standardize grading system
Cost-effectiveness of disc replacement
Retrieval registry and outcome registry
Better links between biologics, mechanics, and pain