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Biomimetic Proteoglycans Augment the Cellular Microniche in Cartilage

Wednesday, December 15, 2021

1:00 PM-3:00 PM

BIOMED PhD Research Proposal

Biomimetic Proteoglycans Augment the Cellular Microniche in Cartilage and Serve as a Drug Delivery Platform for Potential Disease Modifying Osteoarthritis Drugs
Elizabeth Kahle, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Michele Marcolongo, PhD
Professor Emerita
Department of Materials Science and Engineering
College of Engineering
Drexel University

Lin Han, PhD
Associate Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Osteoarthritis (OA) is the most common cause of disability in older adults, afflicting an estimated 10-15% of adults aged over 60. In early OA, degeneration of cartilage pericellular matrix (PCM), a 2-4 µm thick region surrounding chondrocytes that facilitates cross-talk between the extracellular matrix (ECM) and chondrocytes in the process of mechanotransduction, is one leading event of disease initiation. Controlled, in part, by an inflammatory response of catabolic enzymes, critical biomolecules of the PCM, such as proteoglycans, are early casualties of the disease resulting in reduced PCM micromodulus, abnormal cellular mechanotransduction, and a corresponding increase in a catabolic metabolism. Successful regeneration of degraded OA cartilage has been challenged by our limited capability of regenerating the biomechanical and biophysical cross-talk between the ECM and chondrocytes. This renders the pericellular matrix (PCM), the immediate chondrocyte microniche, an emerging target for modulating chondrocyte mechanotransduction in both healthy and OA cartilage.

To that end, targeted delivery of small-molecule drugs or enzyme inhibitors to the PCM could ameliorate degraded mechanics and bioactivities, holding potential for arresting this cycle of destruction. However, pharmaceutical intervention of enhanced matrix catabolism, through use of potential disease modifying OA drugs (DMOADs) (e.g., glucocorticoids) is significantly challenged by inadequate drug delivery to target joint tissues. Thus, this proposal aims to develop new OA intervention therapeutics by simultaneously engineering the properties of the PCM while directing cellular metabolism via targeted drug delivery.

Our lab has developed a suite of biomimetic proteoglycans (BPGs) that mimic the natural composition and molecular architecture of proteoglycans. For the present study, we have chemically end-attached 7-8 chondroitin sulfate glycosaminoglycans to a poly(acrylic acid) core (MW ~10 kDa), resulting in a biomimetic proteoglycan, BPG10, with a “bottle-brush”-like nanoarchitecture mimicking the native proteoglycan, aggrecan. When infiltrated into bovine cartilage explants ex vivo or intra-articularly injected into rabbit knees in vivo, BPG10 diffuses throughout the matrix and preferentially localizes in the PCM. This thesis aims to determine how biomimetic proteoglycans can molecularly engineer cartilage PCM, and therefore, how they can be leveraged as a targeted, multi-functional drug delivery platform for potential DMOADs aimed at early OA intervention.

Contact Information

Natalia Broz

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