Abstract
Low back pain is the leading cause of disability in the United States, with an estimated socioeconomic cost
exceeding $100 billion each year. Intervertebral disc degeneration, a cascade of cellular, compositional,
structural and compositional changes, is strongly implicated as a cause of low back pain. Current clinical
approaches for treating low back pain associated with disc degeneration have limited long term efficacy as
they seek only to manage symptoms without restoring native disc structure and mechanical function. There is
an overwhelming clinical need for new treatment options, which target not only the symptoms of low
back pain, but also the underlying causes. Mesenchymal stem cells (MSCs) are an attractive option for cell-
based disc regeneration due to their safety, ease of isolation and ability to adopt phenotypes similar to those of
disc nucleus pulposus cells. A major challenge to successful MSC-based disc regeneration, however, is the
local cellular microenvironment, which presents conditions of limited nutrition, low oxygen, low pH, and
persistent inflammation that predispose therapeutic interventions to failure. The objective of this proposal is
to develop a novel biological therapy that maximizes the survival and anabolic potential of therapeutic
stem cells by simultaneously neutralizing the degenerate disc microenvironment via the sustained
delivery of nutrients, anti-inflammatory drugs and buffering agents. To accomplish this goal, we will
leverage our newly established goat model of disc degeneration that mimics clinically relevant
structural, composition and biomechanical characteristics, including tissue-level inflammation, and
novel drug delivery methods to enable controlled and sustained release of biofactors that neutralize
the degenerative microenvironment. In Aim 1 we will leverage our goat model define the in vivo cellular
microenvironment of the disc as a function of degeneration severity, using cutting edge in situ physiological
monitoring and ex vivo biomolecular assays. In Aim 2 we will optimize our novel microcapsule drug delivery
system to neutralize the degenerate disc microenvironment through sustained delivery of glucose, anti-
inflammatory drugs and buffering agents. In Aim 3 we will carry out short and long term in vivo studies to
establish therapeutic efficacy in our goat model, including clinically-relevant pain assessments. At the
conclusion of these studies we will have developed a rapidly translatable therapy that maximizes the
regenerative potential of MSCs in the disc microenvironment, and established long term preclinical
efficacy, thus placing us in a strong position to move towards human clinical trials.
