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Collagen bioinks redefined: Optimizing ionic strength and growth factor delivery for cartilage tissue engineering

ABSTRACT: This study investigates the impact of ionic strength on the gelation kinetics of collagen biomaterial inks and evaluates the efficiency of TGFβ-1 sequestration within these hydrogels, alongside their compatibility with bioprinting live chondrocyte and adipose-derived stem cell lines for cartilage tissue engineering. By adjusting sodium chloride and phosphate-buffered saline (PBS) concentrations, we demonstrate that reduced ionic strengths accelerate gelation, facilitating high-fidelity bioprinting while supporting high cell viability and post-printing proliferation of chondrocytes. Furthermore, at a 1% collagen concentration, the hydrogel effectively immobilized TGFβ-1, with less than 0.5% released over two weeks, indicating potent sequestration capabilities. Using adipose-derived mesenchymal stem cells, histomorphological and transcriptomic analyses reveal that the presence of TGFβ-1 significantly enhances chondrogenesis. These findings underscore the critical role of ionic strength in optimizing collagen ink properties for advanced bioprinting applications and highlight the potential of collagen hydrogels as effective carriers for sustained growth factor delivery, paving the way for successful cartilage tissue engineering strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271638 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:Successfully replacing damaged cartilage with tissue-engineered constructs requires integration with the host tissue and could benefit from leveraging the native tissue's intrinsic healing capacity; however, efforts are limited by a poor understanding of how cartilage repairs minor defects. Here, we investigated the conditions that foster natural cartilage tissue repair to identify strategies that might be exploited to enhance the integration of engineered/ grafted cartilage with host tissue. We damaged porcine articular cartilage explants and using a combination of pulsed SILAC-based proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies reveal that integration of damaged cartilage surfaces is not driven by neo-matrix synthesis, but rather local depletion of proteoglycans. ADAMTS4 expression and activity are upregulated in injured cartilage explants, but integration could be reduced by inhibiting metalloproteinase activity with TIMP3. These observations suggest that catabolic enzyme-mediated proteoglycan depletion likely allows existing collagen fibrils to undergo cross-linking, fibrillogenesis, or entanglement, driving integration. Catabolic enzymes are often considered pathophysiological markers of osteoarthritis. Our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions and in osteoarthritis, but could also be harnessed in tissue engineering strategies to mediate repair. Statement of significance: Cartilage tissue engineering strategies require graft integration with the surrounding tissue; however, how the native tissue repairs minor injuries is poorly understood. We applied pulsed SILACbased proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies to a porcine cartilage explant model and found that integration of damaged cartilage surfaces is driven by catabolic enzyme-mediated local depletion of proteoglycans. Although catabolic enzymes have been implicated in cartilage destruction in osteoarthritis, our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions. They also suggest that this natural cartilage tissue repair process could be harnessed in tissue engineering strategies to enhance the integration of engineered cartilage with host tissue.

Project description:Proctor2013 - Cartilage breakdown, interventions to reduce collagen release The molecular pathways involved in cartilage breakdown is studied using this model to examine possible interventions to reduce cartilage collagen release. The model contains three separate submodels, one which describes the IL-1/JNK signalling pathway, secondly the OSM/STAT3 signalling pathway, and lastly a module which includes proMMP (Matrix matalloproteinase) activation, and aggrecan and collagen release. This model is described in the article: A computer simulation approach for assessing therapeutic intervention points to prevent cytokine-induced cartilage breakdown. Proctor CJ, Macdonald C, Milner JM, Rowan AD, Cawston TE. Arthritis Rheum. 2013 Nov 27. Abstract: Objective. To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions to reduce collagen release. Methods. We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language (SBML), a computer-readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin-1 (IL-1) and oncostatin M (OSM) act synergistically to up-regulate collagenase protein and activity and initiate cartilage collagen breakdown. Simulations were performed in the COPASI software package. Results. The model predicted that simulated inhibition of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase, and over-expression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Over-expression of TIMP-1 was much less effective than TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of Janus kinase 1 (JAK1), the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets which are downstream, such as the JNK pathway, rather than close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. Conclusion. Our study shows the value of computer modelling as a tool for examining possible interventions to reduce cartilage collagen breakdown. The model predicts interventions that either prevent transcription or inhibit activity of collagenases are promising strategies and should be investigated further in an experimental setting. © 2013 American College of Rheumatology. This model is hosted on BioModels Database and identified by: BIOMD0000000504 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Collagen bioinks redefined: Optimizing ionic strength and growth factor delivery for cartilage tissue engineering

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