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Mohanraj B.,University of Pennsylvania | Farran A.J.,University of Pennsylvania | Mauck R.L.,University of Pennsylvania | Mauck R.L.,Collaborative Research Partner Acute Cartilage Injury Program of AO Foundation | And 2 more authors.
Journal of Biomechanics | Year: 2014

One of the most critical parameters in cartilage tissue engineering which influences the clinical success of a repair therapy is the ability to match the load-bearing capacity of the tissue as it functions in vivo. While mechanical forces are known to positively influence the development of cartilage matrix architecture, these same forces can induce long-term implant failure due to poor integration or structural deficiencies. As such, in the design of optimal repair strategies, it is critical to understand the timeline of construct maturation and how the elaboration of matrix correlates with the development of mechanical properties. We have previously characterized a scaffold-free method to engineer cartilage utilizing primary chondrocytes cultured at high density in hydrogel-coated culture vessels to promote the formation of a self-aggregating cell suspension that condenses to form a cartilage-like biomass, or cartilage tissue analog (CTA). Chondrocytes in these CTAs maintain their cellular phenotype and deposit extracellular matrix to form a construct that has characteristics similar to native cartilage; however, the mechanical integrity of CTAs had not yet been evaluated. In this study, we found that chondrocytes within CTAs produced a robust matrix of proteoglycans and collagen that correlated with increasing mechanical properties and decreasing cell-matrix ratios, leading to properties that approached that of native cartilage. These results demonstrate a unique approach to generating a cartilage-like tissue without the complicating factor of scaffold, while showing increased compressive properties and matrix characteristics consistent with other approaches, including scaffold-based constructs. To further improve the mechanics of CTAs, studies are currently underway to explore the effect of hydrodynamic loading and whether these changes would be reflective of in vivo maturation in animal models. The functional maturation of cartilage tissue analogs as described here support this engineered cartilage model for use in clinical and experimental applications for repair and regeneration in joint-related pathologies. © 2013 Elsevier Ltd. Source


D'Este M.,AO Research Institute Davos | D'Este M.,Collaborative Research Partner Acute Cartilage Injury Program of AO Foundation | Eglin D.,AO Research Institute Davos | Eglin D.,Collaborative Research Partner Acute Cartilage Injury Program of AO Foundation | And 2 more authors.
Carbohydrate Polymers | Year: 2014

The activation of carboxyl groups with N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC/NHS) for amide formation is the standard method for amine ligation to hyaluronan (HA), and a very well established wide-ranging bioconjugation method. In this paper we compare 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) to EDC/NHS activation chemistry for HA ligation using an array of substrates including small, large and functional molecules. For all the substrates tested DMTMM yields were superior at parity of feed ratio. DMTMM chemistry resulted effective also in absence of pH control, which is essential for EDC/NHS conjugation. Overall our results demonstrate that DMTMM is more efficient than EDC/NHS for ligation of amines to HA and does not require accurate pH control or pH shift during the reaction to be effective. DMTMM-mediated ligation is a new promising chemical tool to synthesize HA derivatives for biomedical and pharmaceutical applications. © 2014 Elsevier Ltd. Source


Mohanraj B.,University of Pennsylvania | Hou C.,University of Pennsylvania | Meloni G.R.,University of Pennsylvania | Cosgrove B.D.,University of Pennsylvania | And 5 more authors.
Journal of Biomechanics | Year: 2014

Articular cartilage enables efficient and near-frictionless load transmission, but suffers from poor inherent healing capacity. As such, cartilage tissue engineering strategies have focused on mimicking both compositional and mechanical properties of native tissue in order to provide effective repair materials for the treatment of damaged or degenerated joint surfaces. However, given the large number design parameters available (e.g. cell sources, scaffold designs, and growth factors), it is difficult to conduct combinatorial experiments of engineered cartilage. This is particularly exacerbated when mechanical properties are a primary outcome, given the long time required for testing of individual samples. High throughput screening is utilized widely in the pharmaceutical industry to rapidly and cost-effectively assess the effects of thousands of compounds for therapeutic discovery. Here we adapted this approach to develop a high throughput mechanical screening (HTMS) system capable of measuring the mechanical properties of up to 48 materials simultaneously. The HTMS device was validated by testing various biomaterials and engineered cartilage constructs and by comparing the HTMS results to those derived from conventional single sample compression tests. Further evaluation showed that the HTMS system was capable of distinguishing and identifying 'hits', or factors that influence the degree of tissue maturation. Future iterations of this device will focus on reducing data variability, increasing force sensitivity and range, as well as scaling-up to even larger (96-well) formats. This HTMS device provides a novel tool for cartilage tissue engineering, freeing experimental design from the limitations of mechanical testing throughput. © 2013 Elsevier Ltd. Source

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