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Modified hyaluronic acid hydrogels with chemical groups that facilitate adhesion to host tissues enhance cartilage regeneration.

ABSTRACT: Stable integration of hydrogel implants with host tissues is of critical importance to cartilage tissue engineering. Designing and fabricating hydrogels with high adhesive strength, stability and regeneration potential are major challenges to be overcome. This study fabricated injectable adhesive hyaluronic acid (HA) hydrogel modified by aldehyde groups and methacrylate (AHAMA) on the polysaccharide backbone with multiple anchoring mechanisms (amide bond through the dynamic Schiff base reaction, hydrogen bond and physical interpenetration). AHAMA hydrogel exhibited significantly improved durability and stability within a humid environment (at least 7 days), together with higher adhesive strength (43 KPa to skin and 52 KPa to glass), as compared to commercial fibrin glue (nearly 10 KPa) and HAMA hydrogel (nearly 20 KPa). The results showed that AHAMA hydrogel was biocompatible and could be easily and rapidly prepared in situ. In vitro cell culture experiments showed that AHAMA hydrogel could enhance proliferation (1.2-folds after 3 days) and migration (1.5-folds after 12 h) of bone marrow stem cells (BMSCs), as compared to cells cultured in a culture dish. Furthermore, in a rat osteochondral defect model, implanted AHAMA hydrogel significantly promoted integration between neo-cartilage and host tissues, and significantly improved cartilage regeneration (modified O'Driscoll histological scores of 16.0 ± 4.1 and 18.3 ± 4.6 after 4 and 12-weeks of post-implantation in AHAMA groups respectively, 12.0 ± 2.7 and 12.2 ± 2.8 respectively in HAMA groups, 9.8 ± 2.4 and 11.5 ± 2.1 respectively in untreated groups). Hence, AHAMA hydrogel is a promising adhesive biomaterial for clinical cartilage regeneration and other biomedical applications.

SUBMITTER: Chen J

PROVIDER: S-EPMC7708943 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hydrogels have been widely used for cell delivery to enhance cell-based therapies for cartilage tissue regeneration. To better support cartilage deposition, it is imperative to determine hydrogel formulation with physical and biochemical cues that are optimized for different cell populations. Previous attempts to identify optimized hydrogels rely mostly on testing hydrogel formulations with discrete properties, which are time-consuming and require large amounts of cells and materials. Gradient hydrogels encompass a range of continuous changes in niche properties, therefore offering a promising solution for screening a wide range of cell-niche interactions using less materials and time. However, harnessing gradient hydrogels to assess how matrix stiffness modulates cartilage formation by different cell types in vivo have never been investigated before. The goal of this study is to fabricate gradient hydrogels for screening the effects of varying hydrogel stiffness on cartilage formation by mesenchymal stem cells (MSCs) and chondrocytes, respectively, the two most commonly used cell populations for cartilage regeneration. We fabricated stiffness gradient hydrogels with tunable dimensions that support homogeneous cell encapsulation. Using gradient hydrogels with tunable stiffness range, we found MSCs and chondrocytes exhibit opposite trend in cartilage deposition in response to stiffness changes in vitro. Specifically, MSCs require soft hydrogels with Young's modulus less than 5 kPa to support faster cartilage deposition, as shown by type II collagen and sulfated glycosaminoglycan staining. In contrast, chondrocytes produce cartilage more effectively in stiffer matrix (>20 kPa). We chose optimal ranges of stiffness for each cell population for further testing in vivo using a mouse subcutaneous model. Our results further validated that soft matrix (Young's modulus <5 kPa) is better in supporting MSC-based cartilage deposition in three-dimensional, whereas stiffer matrix (Young's modulus >20 kPa) is more desirable for supporting chondrocyte-based cartilage deposition. Our results show the importance of optimizing niche cues in a cell-type-specific manner and validate the potential of using gradient hydrogels for optimizing niche cues to support cartilage regeneration in vitro and in vivo. Impact statement The present study validates the utility of gradient hydrogels for determining optimal hydrogel stiffness for supporting cartilage regeneration using both chondrocytes and stem cells. We demonstrate that such gradient hydrogels can be used for fast optimizing matrix stiffness for specific cell type to support optimal cartilage regeneration. To our knowledge, this is the first demonstration of applying gradient hydrogels for assessing optimal niche cues that support tissue regeneration in vivo and may be used for assessing optimal niche cues for different cell types to regeneration of different tissues.

Project description:Cartilage injury represents a frequent dilemma in clinical practice owing to its inherently limited self-renewal capacity. Biomimetic strategy-based engineered biomaterial, capable of coordinated regulation for cellular and microenvironmental crosstalk, provides an adequate avenue to boost cartilage regeneration. The level of oxidative stress in microenvironments is verified to be vital for tissue regeneration, yet it is often overlooked in engineered biomaterials for cartilage regeneration. Herein, inspired by natural cartilage architecture, a fibril-network glycopeptide hydrogel (Nap-FFGRGD@FU), composed of marine-derived polysaccharide fucoidan (FU) and naphthalenephenylalanine-phenylalanine-glycine-arginine-glycine-aspartic peptide (Nap-FFGRGD), was presented through a simple supramolecular self-assembly approach. The Nap-FFGRGD@FU hydrogels exhibit a native cartilage-like architecture, characterized by interwoven collagen fibers and attached proteoglycans. Beyond structural simulation, fucoidan-exerted robust biological effects and Arg-Gly-Asp (RGD) sequence-provided cell attachment sites realized functional reinforcement, synergistically promoted extracellular matrix (ECM) production and reactive oxygen species (ROS) elimination, thus contributing to chondrocytes-ECM harmony. In vitro co-culture with glycopeptide hydrogels not only facilitated cartilage ECM anabolic metabolism but also scavenged ROS accumulation in chondrocytes. Mechanistically, the chondro-protective effects induced by glycopeptide hydrogels rely on the activation of endogenous antioxidant pathways associated with nuclear factor erythroid 2-related factor 2 (NRF2). In vivo implantation of glycopeptide hydrogels successfully improved the de novo cartilage generation by 1.65-fold, concomitant with coordinately restructured subchondral bone structure. Collectively, our ingeniously crafted bionic glycopeptide hydrogels simultaneously rewired chondrocytes' function by augmenting anabolic metabolism and rebuilt ECM microenvironment via preserving redox equilibrium, holding great potential for cartilage tissue engineering.

Project description:Articular cartilage has limited capacity for regeneration and when damaged cannot be repaired with currently available metallic or synthetic implants. We aim to bioengineer a microfibre-reinforced hydrogel that can capture the zonal depth-dependent mechanical properties of native cartilage, and simultaneously support neo-cartilage formation. With this goal, a sophisticated bi-layered microfibre architecture, combining a densely distributed crossed fibre mat (superficial tangential zone, STZ) and a uniform box structure (middle and deep zone, MDZ), was successfully manufactured via melt electrospinning and combined with a gelatin-methacrylamide hydrogel. The inclusion of a thin STZ layer greatly increased the composite construct's peak modulus under both incongruent (3.2-fold) and congruent (2.1-fold) loading, as compared to hydrogels reinforced with only a uniform MDZ structure. Notably, the stress relaxation response of the bi-layered composite construct was comparable to the tested native cartilage tissue. Furthermore, similar production of sulphated glycosaminoglycans and collagen II was observed for the novel composite constructs cultured under mechanical conditioning w/o TGF-ß1 supplementation and in static conditions w/TGF-ß1 supplementation, which confirmed the capability of the novel composite construct to support neo-cartilage formation upon mechanical stimulation. To conclude, these results are an important step towards the design and manufacture of biomechanically competent implants for cartilage regeneration. STATEMENT OF SIGNIFICANCE: Damage to articular cartilage results in severe pain and joint disfunction that cannot be treated with currently available implants. This study presents a sophisticated bioengineered bi-layered fibre reinforced cell-laden hydrogel that can approximate the functional mechanical properties of native cartilage. For the first time, the importance of incorporating a viable superficial tangential zone (STZ) - like structure to improve the load-bearing properties of bioengineered constructs, particularly when in-congruent surfaces are compressed, is demonstrated. The present work also provides new insights for the development of implants that are able to promote and guide new cartilaginous tissue formation upon physiologically relevant mechanical stimulation.

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Modified hyaluronic acid hydrogels with chemical groups that facilitate adhesion to host tissues enhance cartilage regeneration.

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