Adult human nasal chondrocytes (NCs) have been shown to exhibit a large degree of plasticity and regenerative properties typical of mesenchymal progenitor/stem cells. In a recent first-in-human clinical trial it was proven that the use of NCs for treating traumatic articular cartilage defects is safe and feasible. With the final goal to assess whether NCs can be used for the repair of degenerative joint diseases (osteoarthritis, OA), often associated with abnormal loading, proper mechanical conditioning must be considered. In this study, we present a novel microbioreactor able to mimic the state of compression that chondrocytes experience in human joints, either under physiological (10%) or hyperphysiological (30%) conditions. Based on a previously reported platform for the generation of 3D cardiac constructs, the PDMS device comprises two integrated compartments separated by a flexible membrane. The upper compartment consists in a central channel hosting a 3D cell-laden hydrogel, divided by two series of overhanging posts from two lateral channels for medium perfusion. The bottom one consists in a pneumatic chamber actuated by a custom-made programmable control unit. The posts were specifically designed to limit the lateral expansion of the cell-laden hydrogel, thus ensuring its confined compression while allowing a physiological fluid motion. A computational model was implemented to evaluate the strain field distribution. An enzymatically cross-linkable and degradable poly(ethylene glycol)-based hydrogel was used to encase cells. The microbioreactor was then exploited for predicting the response of human NCs to normal vs abnormal loading. Pilot tests revealed high cartilage matrix deposition (Aggrecan, Collagen II) after two weeks of static culture. The 10% compression caused a slight increase of the cartilaginous properties of the tissue. The 30% compression led, instead, to a significant decrease in the COL2A1/COL1A1 ratio (index of hyaline cartilage) and to an increase in MMP13 production. The presented platform thus allows the recapitulation in a chip of physiological/pathological compression levels experienced by cells in the joint microenvironment. Further studies are ongoing to couple inflammatory and mechanical signals to more closely model an OA environment. We propose the system as a medium-throughput tool for screening therapeutic agents in combination with NC or cartilage progenitor cells towards treatment of OA conditions.

A microfluidic platform to assess the response of cartilage progenitor cells within 3D hydrogels to mechanical loading

Occhetta P;Mainardi A;Votta E;Rasponi M;
2017

Abstract

Adult human nasal chondrocytes (NCs) have been shown to exhibit a large degree of plasticity and regenerative properties typical of mesenchymal progenitor/stem cells. In a recent first-in-human clinical trial it was proven that the use of NCs for treating traumatic articular cartilage defects is safe and feasible. With the final goal to assess whether NCs can be used for the repair of degenerative joint diseases (osteoarthritis, OA), often associated with abnormal loading, proper mechanical conditioning must be considered. In this study, we present a novel microbioreactor able to mimic the state of compression that chondrocytes experience in human joints, either under physiological (10%) or hyperphysiological (30%) conditions. Based on a previously reported platform for the generation of 3D cardiac constructs, the PDMS device comprises two integrated compartments separated by a flexible membrane. The upper compartment consists in a central channel hosting a 3D cell-laden hydrogel, divided by two series of overhanging posts from two lateral channels for medium perfusion. The bottom one consists in a pneumatic chamber actuated by a custom-made programmable control unit. The posts were specifically designed to limit the lateral expansion of the cell-laden hydrogel, thus ensuring its confined compression while allowing a physiological fluid motion. A computational model was implemented to evaluate the strain field distribution. An enzymatically cross-linkable and degradable poly(ethylene glycol)-based hydrogel was used to encase cells. The microbioreactor was then exploited for predicting the response of human NCs to normal vs abnormal loading. Pilot tests revealed high cartilage matrix deposition (Aggrecan, Collagen II) after two weeks of static culture. The 10% compression caused a slight increase of the cartilaginous properties of the tissue. The 30% compression led, instead, to a significant decrease in the COL2A1/COL1A1 ratio (index of hyaline cartilage) and to an increase in MMP13 production. The presented platform thus allows the recapitulation in a chip of physiological/pathological compression levels experienced by cells in the joint microenvironment. Further studies are ongoing to couple inflammatory and mechanical signals to more closely model an OA environment. We propose the system as a medium-throughput tool for screening therapeutic agents in combination with NC or cartilage progenitor cells towards treatment of OA conditions.
Cartilage, Organ-on-Chip, Microfluidics, Osteoarthrosis, Nasal Chondrocytes
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11311/1144419
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