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Temporally Degradable Collagen-Mimetic Hydrogels Tuned Biomaterials 99 (2016) 56e71 Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials Temporally degradable collagenemimetic hydrogels tuned to chondrogenesis of human mesenchymal stem cells Paresh A. Parmar a, b, c, d, Stacey C. Skaalure a, b, c, Lesley W. Chow a, b, c, 1, Jean-Philippe St-Pierre a, b, c, Violet Stoichevska d, Yong Y. Peng d, * Jerome A. Werkmeister d, John A.M. Ramshaw d, Molly M. Stevens a, b, c, a Department of Materials, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom b Department of Bioengineering, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom c Institute of Biomedical Engineering, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom d CSIRO Manufacturing, Bayview Avenue, Clayton, Victoria 3169, Australia article info abstract Article history: Tissue engineering strategies for repairing and regenerating articular cartilage face critical challenges to Received 5 February 2016 recapitulate the dynamic and complex biochemical microenvironment of native tissues. One approach to Received in revised form mimic the biochemical complexity of articular cartilage is through the use of recombinant bacterial 3 May 2016 collagens as they provide a welledefined biological ‘blank template’ that can be modified to incorporate Accepted 4 May 2016 bioactive and biodegradable peptide sequences within a precisely defined threeedimensional system. Available online 10 May 2016 We customized the backbone of a Streptococcal collagenelike 2 (Scl2) protein with heparinebinding, integrinebinding, and hyaluronic acidebinding peptide sequences previously shown to modulate Keywords: e Hydrogel chondrogenesis and then cross linked the recombinant Scl2 protein with a combination of matrix e e Mesenchymal stem cell metalloproteinase 7 (MMP7) and aggrecanase (ADAMTS4) cleavable peptides at varying ratios to form Biodegradation biodegradable hydrogels with degradation characteristics matching the temporal expression pattern of Biomimetic material these enzymes in human mesenchymal stem cells (hMSCs) during chondrogenesis. hMSCs encapsulated Bacterial collagen within the hydrogels crosselinked with both degradable peptides exhibited enhanced chondrogenic Cartilage tissue engineering characteristics as demonstrated by gene expression and extracellular matrix deposition compared to the hydrogels crosselinked with a single peptide. Additionally, these combined peptide hydrogels displayed increased MMP7 and ADAMTS4 activities and yet increased compression moduli after 6 weeks, sug- gesting a positive correlation between the degradation of the hydrogels and the accumulation of matrix by hMSCs undergoing chondrogenesis. Our results suggest that including dual degradation motifs designed to respond to enzymatic activity of hMSCs going through chondrogenic differentiation led to improvements in chondrogenesis. Our hydrogel system demonstrates a bimodal enzymatically degrad- able biological platform that can mimic native cellular processes in a temporal manner. As such, this novel collagenemimetic protein, crosselinked via multiple enzymatically degradable peptides, provides a highly adaptable and well defined platform to recapitulate a high degree of biological complexity, which could be applicable to numerous tissue engineering and regenerative medicine applications. © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction cells, while restoring both biomechanical and biochemical function in damaged tissues, remains a significant engineering challenge. Developing bioengineered constructs for cartilage tissue engi- Human mesenchymal stem cells (hMSCs) provide an autologous neering that promote neocartilage regeneration by encapsulated cell source that can be used to heal large osteoarthritic cartilage lesions [1] and can be induced to undergo chondrogenesis when subjected to specific biochemical and physical cues [2]. * Corresponding author. Threeedimensional (3D) environments have been shown to pro- E-mail address: [email protected] (M.M. Stevens). mote chondrogenesis of hMSCs [3e7]. Due to the importance of 1 & Current address: Department of Materials Science and Engineering Bioen- culturing hMSCs in a 3D environment, a large number of studies gineering Program, Lehigh University, Bethlehem, PA 18015, USA. http://dx.doi.org/10.1016/j.biomaterials.2016.05.011 0142-9612/© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). P.A. Parmar et al. / Biomaterials 99 (2016) 56e71 57 have been conducted with MSCs encapsulated in various types of modified with HAebinding, heparin (H)ebinding, and integrin (I)e hydrogel scaffolds based on both synthetic and naturallyederived binding sequences via siteedirected mutagenesis to enhance bio- materials including hyaluronic acid (HA) [3], poly(ethylene glycol) logical recognition and adhesion of encapsulated hMSCs. The I- (PEG) [4], agarose [5], alginate [6], and collagen [7], with each binding peptide sequence was included in the Scl2 protein con- presenting different advantages and disadvantages. structs to aid initial cell adhesion to the scaffolds and maintain Hydrogels are particularly attractive cell carriers because their viability. The welleknown RGD motif was not used in the present elasticity and highly aqueous environments permit extracellular study since it has been shown to lead to hMSC hypertrophy in matrix (ECM) evolution and nutrient transport, while physically longeterm culture [4]. As such, the I-binding peptide used in the entrapping cells into the crosselinked network [8,9]. Additionally, present study was an alternative that does not include the RGD biodegradation is ideal to allow for cellular migration and pro- sequence. The inclusion of the HAebinding motif was verified in gressive replacement of the template material by neotissue depo- our previous work [11], and the reason for including all three of sition. Cellemediated degradation occurs in hydrogels made of these biological motifs was to provide celleadhesion and local naturally derived materials such as collagen and fibrin, and these presentation of biomolecules in order to create a hydrogel envi- native molecules present moieties that can enhance cellular ronment that mimics some of the characteristics of the highly adhesion and biorecognition [6]. However, it is difficult to fabricate complex cartilage tissue environment. It was hypothesized that reproducible, mechanically robust, or tunable scaffolds using nat- chondrogenesis and cartilaginous matrix production would be ural materials [8]. The ability to tune the degradation of the further improved by implementing a combination of degradable hydrogel with the deposition of ECM by harnessing cellemediated peptides, where one peptide is targeted to an enzyme expressed by processes has been shown to elicit advantages towards chondro- hMSCs undergoing chondrogenesis and the other susceptible to genesis. Hydrogels can be programmed to degrade by cellemedi- enzymes produced by the newly differentiated chondrocytes in ated mechanisms, such as PEG hydrogels formed with matrix order to trigger ongoing scaffold degradation. Thus, an metalloproteinase (MMP)edegradable crosselinks that were pre- MMP7ecleavable crosselinker to target enzymes produced during viously found to improve chondrogenesis of encapsulated hMSCs the early stages of chondrogenesis was combined with a peptide compared to noneenzymatically degradable PEG hydrogels [10]. crosselinker that degraded specifically through the action of Hydrogels can also provide a welledefined system that increases mature chondrocytes. Two aggrecanases (A Disintegrin And Met- their feasibility for clinical translation while recapitulating features alloproteinase with ThromboSpondin motif (ADAMTS); ADAMTS4 of natural systems such as cellemediated degradation and adhe- and 5) were selected due to their increased activity relative to sion to ECM molecules. MMPs in mature cartilage tissue in vivo [17,18] and inactivity during Recombinantly synthesized bacterial collagens, such as Strep- chondrogenesis before cells have committed to the chondrocyte tococcus collagenelike 2 (Scl2), have recently been explored for lineage [19]. These two aggrecanases specifically cleave aggrecan numerous applications in tissue engineering and regenerative (ACAN) at the TEGEeARG site in the interglobular domain [20], and medicine [11e14]. Scl2 proteins have been investigated largely due a previous study identified the ability of ADAMTS4 secreted by to their modularity and ability to be manipulated via chemical chondrocytes to cleave a novel peptide crosselinker containing functionalization of amino acid residues or siteedirected muta- that specific sequence. In that study, chondrocytes were encapsu- genesis of selected peptide sequences to their backbone enabling lated in photopolymerized 8earm PEG hydrogels crosselinked the tuning of specific cellular processes [11,14,15]. Scl2 proteins with the ADAMTS4ecleavable peptide, and the chondrocyte contain the characteristic (GlyeXaaeYaa)n repeating sequence that phenotype (indicated by increased collagen type II deposition and selfeassembles into a triple helical conformation much like decreased collagen type I and X) was improved with the novel mammalian collagens [12,13,16]. In contrast to mammalian colla-
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