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Osteochondral defect repair using bilayered hydrogels encapsulating both chondrogenically and osteogenically pre-differentiated mesenchymal stem cells in a rabbit model.

ABSTRACT: To investigate the ability of cell-laden bilayered hydrogels encapsulating chondrogenically and osteogenically (OS) pre-differentiated mesenchymal stem cells (MSCs) to effect osteochondral defect repair in a rabbit model. By varying the period of chondrogenic pre-differentiation from 7 (CG7) to 14 days (CG14), the effect of chondrogenic differentiation stage on osteochondral tissue repair was also investigated.Rabbit MSCs were subjected to either chondrogenic or osteogenic pre-differentiation, encapsulated within respective chondral/subchondral layers of a bilayered hydrogel construct, and then implanted into femoral condyle osteochondral defects. Rabbits were randomized into one of four groups (MSC/MSC, MSC/OS, CG7/OS, and CG14/OS; chondral/subchondral) and received two similar constructs bilaterally. Defects were evaluated after 12 weeks.All groups exhibited similar overall neo-tissue filling. The delivery of OS cells when compared to undifferentiated MSCs in the subchondral construct layer resulted in improvements in neo-cartilage thickness and regularity. However, the addition of CG cells in the chondral layer, with OS cells in the subchondral layer, did not augment tissue repair as influenced by the latter when compared to the control. Instead, CG7/OS implants resulted in more irregular neo-tissue surfaces when compared to MSC/OS implants. Notably, the delivery of CG7 cells, when compared to CG14 cells, with OS cells stimulated morphologically superior cartilage repair. However, neither osteogenic nor chondrogenic pre-differentiation affected detectable changes in subchondral tissue repair.Cartilage regeneration in osteochondral defects can be enhanced by MSCs that are chondrogenically and osteogenically pre-differentiated prior to implantation. Longer chondrogenic pre-differentiation periods, however, lead to diminished cartilage repair.

SUBMITTER: Lam J

PROVIDER: S-EPMC4150851 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Osteochondral defect repair using bilayered hydrogels encapsulating both chondrogenically and osteogenically pre-differentiated mesenchymal stem cells in a rabbit model.

Lam J J Lu S S Lee E J EJ Trachtenberg J E JE Meretoja V V VV Dahlin R L RL van den Beucken J J J P JJ Tabata Y Y Wong M E ME Jansen J A JA Mikos A G AG Kasper F K FK

Osteoarthritis and cartilage 20140704 9

<h4>Objective</h4>To investigate the ability of cell-laden bilayered hydrogels encapsulating chondrogenically and osteogenically (OS) pre-differentiated mesenchymal stem cells (MSCs) to effect osteochondral defect repair in a rabbit model. By varying the period of chondrogenic pre-differentiation from 7 (CG7) to 14 days (CG14), the effect of chondrogenic differentiation stage on osteochondral tissue repair was also investigated.<h4>Methods</h4>Rabbit MSCs were subjected to either chondrogenic or ...[more]

PMID: 25008204

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Project description:Osteochondral defects present a unique clinical challenge due to their combination of phenotypically distinct cartilage and bone, which require specific, stratified biochemical cues for tissue regeneration. Furthermore, the articular cartilage exhibits significantly worse regeneration than bone due to its largely acellular and avascular nature, prompting significant demand for regenerative therapies. To address these clinical challenges, we have developed a bilayered, modular hydrogel system that enables the click functionalization of cartilage- and bone-specific biochemical cues to each layer. In this system, the crosslinker poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT) was click conjugated with either a cartilage- or bone-specific peptide sequence of interest, and then mixed with a suspension of thermoresponsive polymer and mesenchymal stem cells (MSCs) to generate tissue-specific, cell-encapsulated hydrogel layers targeting the cartilage or bone. We implanted bilayered hydrogels in rabbit femoral condyle defects and investigated the effects of tissue-specific peptide presentation and cell encapsulation on osteochondral tissue repair. After 12 weeks implantation, hydrogels with a chondrogenic peptide sequence produced higher histological measures of overall defect filling, cartilage surface regularity, glycosaminoglycan (GAG)/cell content of neocartilage and adjacent cartilage, and bone filling and bonding compared to non-chondrogenic hydrogels. Furthermore, MSC encapsulation promoted greater histological measures of overall defect filling, cartilage thickness, GAG/cell content of neocartilage, and bone filling. Our results establish the utility of this click functionalized hydrogel system for in vivo repair of the osteochondral unit. STATEMENT OF SIGNIFICANCE: Osteochondral repair requires mimicry of both cartilage- and bone-specific biochemical cues, which are highly distinct. While traditional constructs for osteochondral repair have mimicked gross compositional differences between the cartilage and bone in mineral content, mechanical properties, proteins, or cell types, few constructs have recapitulated the specific biochemical cues responsible for the differential development of cartilage and bone. In this study, click biofunctionalized, bilayered hydrogels produced stratified presentation of developmentally inspired peptide sequences for chondrogenesis and osteogenesis. This work represents, to the authors' knowledge, the first application of bioconjugation chemistry for the simultaneous repair of bone and cartilage tissue. The conjugation of tissue-specific peptide sequences successfully promoted development of both cartilage and bone tissues in vivo.

Project description:Scaffolds with continuous gradients in material composition and bioactive signals enable a smooth transition of properties at the interface. Components like chondroitin sulfate (CS) and bioactive glass (BG) in 3D scaffolds may serve as "raw materials" for synthesis of new extracellular matrix (ECM), and may have the potential to completely or partially replace expensive growth factors. We hypothesized that scaffolds with gradients of ECM components would enable superior performance of engineered constructs. Raw material encapsulation altered the appearance, structure, porosity, and degradation of the scaffolds. They allowed the scaffolds to better retain their 3D structure during culture and provided a buffering effect to the cells in culture. Following seeding of rat mesenchymal stem cells, there were several instances where glycosaminoglycan (GAG), collagen, or calcium contents were higher with the scaffolds containing raw materials (CS or BG) than with those containing transforming growth factor (TGF)-?3 or bone morphogenetic protein (BMP)-2. It was also noteworthy that a combination of both CS and TGF-?3 increased the secretion of collagen type II. Moreover, cells seeded in scaffolds containing opposing gradients of CS/TGF-?3 and BG/BMP-2 produced clear regional variations in the secretion of tissue-specific ECM. The study demonstrated raw materials have the potential to create a favorable microenvironment for cells; they can significantly enhance the synthesis of certain extracellular matrix (ECM) components when compared to expensive growth factors; either alone or in combination with growth factors they can enhance the secretion of tissue specific matrix proteins. Raw materials are promising candidates that can be used to either replace or be used in combination with growth factors. Success with raw materials in lieu of growth factors could have profound implications in terms of lower cost and faster regulatory approval for more rapid translation of regenerative medicine products to the clinic.

Project description:Adequate bony support is the key to re-establish both function and esthetics in the craniofacial region. Autologous bone grafting has been the gold standard for regeneration of problematic large bone defects. However, poor graft availability and donor-site complications have led to alternative bone tissue-engineering approaches combining osteoinductive biomaterials and three-dimensional cell aggregates in scaffolds or constructs. The goal of the present study was to generate novel cell aggregate-loaded macroporous scaffolds combining the osteoinductive properties of titanium dioxide (TiO2) with hydroxyapatite-gelatin nanocomposites (HAP-GEL) for regeneration of craniofacial defects. Here we investigated the in vivo applicability of macroporous (TiO2)-enriched HAP-GEL scaffolds with undifferentiated and osteogenically differentiated multipotent adult progenitor cell (MAPC and OD-MAPC, respectively) aggregates for calvaria bone regeneration. The silane-coated HAP-GEL with and without TiO2 additives were polymerized and molded to produce macroporous scaffolds. Aggregates of the rat MAPC were precultured, loaded into each scaffold, and implanted to rat calvaria critical-size defects to study bone regeneration. Bone autografts were used as positive controls and a poly(lactic-co-glycolic acid) (PLGA) scaffold for comparison purposes. Preimplanted scaffolds and calvaria bone from pig were tested for ultimate compressive strength with an Instron 4411(®) and for porosity with microcomputerized tomography (?CT). Osteointegration and newly formed bone (NFB) were assessed by ?CT and nondecalcified histology, and quantified by calcium fluorescence labeling. Results showed that the macroporous TiO2-HAP-GEL scaffold had a comparable strength relative to the natural calvaria bone (13.8±4.5?MPa and 24.5±8.3?MPa, respectively). Porosity was 1.52±0.8?mm and 0.64±0.4?mm for TiO2-HAP-GEL and calvaria bone, respectively. At 8 and 12 weeks postimplantation into rat calvaria defects, greater osteointegration and NFB were significantly present in the TiO2-enriched HAP-GEL constructs with OD-MAPCs, compared to the undifferentiated MAPC-loaded constructs, cell-free HAP-GEL with and without titanium, and PLGA scaffolds. The tissue-engineered TiO2-enriched HAP-GEL constructs with OD-MAPC aggregates present a potential useful therapeutic approach for calvaria bone regeneration.

Dataset Information

Osteochondral defect repair using bilayered hydrogels encapsulating both chondrogenically and osteogenically pre-differentiated mesenchymal stem cells in a rabbit model.

Publications

Osteochondral defect repair using bilayered hydrogels encapsulating both chondrogenically and osteogenically pre-differentiated mesenchymal stem cells in a rabbit model.

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