Development and Translation of Granulated Human-Derived Biomaterials for Integrative Cartilage Repair - PROJECT SUMMARY / ABSTRACT
The objective of this proposal is to study how a new human-derived biomaterial with granulated structure,
NatruLage, stimulates adult stem cell differentiation for integrative cartilage repair. Recent advances in the
treatment of articular cartilage and bone injuries have shown exciting potential to address matrix degeneration
associated with osteoarthritis (OA), a joint disease afflicting millions of people in the United States. New
candidate therapies utilize animal- or human-sourced materials to formulate unique microenvironments
favorable to stem cell responses that promote healing and integration. In healthy osteochondral tissue, the
extracellular matrix is organized into interstitial and pericellular domains with specialized cells and signaling
molecules. Together, these components define tissue-specific and structure-function relationships which are
lost during disease progression. Unfortunately, integrative cartilage repair still remains as a major medical
need, and new products are required for enhanced and improved therapies. Successful adoption of
osteochondral tissue therapies requires extensive technical and manufacturing de-risking to meet stringent
regulatory approval requirements. New innovations must meet current good manufacturing practice (cGMP)
specifications and demonstrate pre-clinical evidence of positive cellular and biological responses as well as
lack of toxicity prior to submission of an investigational device exemption (IDE) package and, later, execution
of a clinical trial. To improve integrative cartilage repair, we developed a novel granulated extracellular matrix
with a proprietary crosslinking technology, termed NatruLage, that is injected into the defect in bone and
cartilage layers to form osteochondral tissue that closely mimics the natural zonal tissue structure. Our device
is ‘flowable’ to deliver densely-packed tissue particles, and enable forming and shaping after delivery through
unique crosslinking via thiol-functionalized macromolecules. We have evaluated the same NatruLage
technology, using porcine instead of human tissue, and found promising regeneration and integration in a 12-
month large animal (goat) study of osteochondral repair. We are now focused on the development of
NatruLage using human-derived allograft tissue for delivery of distinct layers of osteochondral tissue. We will
define the appropriate chemistry, manufacturing, and quality controls to support the cGMP production of
NatruLage for future clinical trials, and we will contribute to understanding the stem cell responses to
NatruLage. We will pursue three related specific aims. In Aim 1, we will adapt established cGMP facilities for
production of human NatruLage. In Aim 2, we will define specifications for NatruLage reproducibility and donor
variability. In Aim 3, we will quantify NatruLage stimulation of adult stem cell proliferation and differentiation. If
successful, we will create an ideal secondary osteochondral repair market for otherwise discarded or nonviable
allograft tissue, and the grant will support the submission of an IDE package for NatruLage.
