Saving the joint: new methods for early diagnosis and treatment

Research output: ThesisPhD Thesis - Research UT, graduation UT

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Abstract

Osteoarthritis (OA) is a debilitating joint disease affecting millions of patients
worldwide, with the prevalence set to increase further due to an aging population.
Despite high morbidity and associated health costs, no curative treatment yet exists. This
is caused in part by the highly complex nature of the disease, with multiple phenotypes,
and by late diagnosis reducing efficacy of therapies. This results in the reality that most
patients experience severe joint pain for multiple years before they inevitably undergo
total joint replacement. The goal of this thesis is to make steps to upend this status quo
through saving the joint by applying new methods for early diagnosis and treatment of
osteoarthritis.
As mentioned, the disease is highly complex and is only diagnosed at a late stage. In
the current situation, osteoarthritis is diagnosed via X-Ray many years after disease onset
and limited information can be obtained on the specific subtype experienced by the
patient. This demands for new diagnostic tools that can identify the multiple phenotypes
of the disease at an early stage, to allow for effective personalized treatments. A
promising approach is to measure biomarkers that present information on disease
progression, locally in the effected joints. This requires a tool that can measure multiple
biomarkers simultaneously, to detect the different phenotypes, with large sensitivity, for
early diagnosis, in small volumes of joint fluids. Currently, no diagnostic tool exists that
can meet these requirements.
In this work, we have developed a diagnostic method based on surface plasmon
resonance array imaging (SPRi) which allows us to measure the desired biomarkers in
multiplex. To achieve the required sensitivity for early diagnosis we applied a signal
enhancement cascade using gold nanoparticles. In a proof of concept study, we showed
we could measure relevant OA biomarkers below physiological limits with broad
dynamic range in multiplex in small volumes of joint fluids. To improve the applicability
of this method in a clinical setting, we developed a toolbox for extensive quality control,
calibration free measurements and simple assay optimization. This was achieved by
kinetically defining the SPRi enhancement cascade, allowing for prediction of the signal
at any biomarker concentration. This diagnostic tool has large potential in the early
specific diagnosis of OA and can therefore help improve the efficacy of existing
treatment options.
However, in order to save the joint new improved early treatment options are required.
Early treatment of articular cartilage defects has shown potential in this respect.
Promising results have been shown by injecting a combination of cells and biomaterials
at a defect site in the affected joint. While injection is suitable for small defects, larger
irregular defects could benefit from spraying the cell-biomaterial combination. In this
work, we looked at the effect of spraying on the viability of the cells after impact. We
developed a validated analytical model that can predict cell survival based on spraying
parameters. We showed that the viability is dependent on the air pressure applied to the
nozzle, impact distance, viscosity and surface stiffness and that our model accurately
vi
recapitulates these processes. Subsequently, we expanded this model by determining the
effect of cell type and cellular properties on the survival. We showed that the cell type
has a large influence on survival, captured by the cellular properties in our model.
Furthermore, we demonstrated that changing these cellular properties could improve
the survival in the spraying. Finally, we applied a custom controllable droplet impact setup to validate our model in a large parameter space. This resulted in further
improvements in our model and expanded its use to other biofrabrication methods. To
further improve this treatment, we developed a toolbox for optimal biomaterials for joint
repair. We demonstrated an injectable hydrogel with tuneable mechanical and biological
properties that can be tailored to obtain an optimal cell response. Together, this work
can result in the effective application of optimal cell/biomaterial combinations to the
joint with an increased cell survival leading to a promising early treatment.
With the combination of new methods for early diagnosis and early treatment we have
made steps to address the main challenges facing our joints. While no single step is ever
large enough, we believe this work is a significant leap in saving the joint.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Twente
Supervisors/Advisors
  • Karperien, H.B.J., Supervisor
  • Saris, Daniël B.F., Supervisor
Award date16 Oct 2019
Place of PublicationEnschede
Publisher
Print ISBNs978-90-365-4872-4
DOIs
Publication statusPublished - 16 Oct 2019

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