Biomimetic Gradient Scaffolds Containing Hyaluronic Acid and Sr/Zn Folates for Osteochondral Tissue Engineering.
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ABSTRACT:
SUBMITTER: Asensio G
PROVIDER: S-EPMC8747647 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Articular cartilage is a structure lack of vascular distribution. Once the cartilage is injured or diseased, it is unable to regenerate by itself. Surgical treatments do not effectively heal defects in articular cartilage. Tissue engineering is the most potential solution to this problem. In this study, methoxy poly(ethylene glycol)-block-poly(?-caprolactone) (mPEG-PCL) and hydroxyapatite at a weight ratio of 2:1 were mixed via fused deposition modeling (FDM) layer by layer to form a solid scaffold. The scaffolds were further infiltrated with glycidyl methacrylate hyaluronic acid loading with 10 ng/mL of Transforming Growth Factor-?1 and photo cross-linked on top of the scaffolds. An in vivo test was performed on the knees of Lanyu miniature pigs for a period of 12 months. The healing process of the osteochondral defects was followed by computer tomography (CT). The defect was fully covered with regenerated tissues in the control pig, while different tissues were grown in the defect of knee of the experimental pig. In the gross anatomy of the cross section, the scaffold remained in the subchondral location, while surface cartilage was regenerated. The cross section of the knees of both the control and experimental pigs were subjected to hematoxylin and eosin staining. The cartilage of the knee in the experimental pig was partially matured, e.g., few chondrocyte cells were enclosed in the lacunae. In the knee of the control pig, the defect was fully grown with fibrocartilage. In another in vivo experiment in a rabbit and a pig, the composite of the TGF-?1-loaded hydrogel and scaffolds was found to regenerate hyaline cartilage. However, scaffolds that remain in the subchondral lesion potentially delay the healing process. Therefore, the structural design of the scaffold should be reconsidered to match the regeneration process of both cartilage and subchondral bone.
| S-EPMC5979374 | biostudies-literature
Project description:Recent developments in 3D printing (3DP) research have led to a variety of scaffold designs and techniques for osteochondral tissue engineering; however, the simultaneous incorporation of multiple types of gradients within the same construct remains a challenge. Herein, we describe the fabrication and mechanical characterization of porous poly(?-caprolactone) (PCL) and PCL-hydroxyapatite (HA) scaffolds with incorporated vertical porosity and ceramic content gradients via a multimaterial extrusion 3DP system. Scaffolds of 0?wt% HA (PCL), 15?wt% HA (HA15), or 30?wt% HA (HA30) were fabricated with uniform composition and porosity (using 0.2?mm, 0.5?mm, or 0.9?mm on-center fiber spacing), uniform composition and gradient porosity, and gradient composition (PCL-HA15-HA30) and porosity. Micro-CT imaging and porosity analysis demonstrated the ability to incorporate both vertical porosity and pore size gradients and a ceramic gradient, which collectively recapitulate gradients found in native osteochondral tissues. Uniaxial compression testing demonstrated an inverse relationship between porosity, ?, and compressive modulus, E, and yield stress, ?y, for uniform porosity scaffolds, however, no differences were observed as a result of ceramic incorporation. All scaffolds demonstrated compressive moduli within the appropriate range for trabecular bone, with average moduli between 86?±?14-220?±?26?MPa. Uniform porosity and pore size scaffolds for all ceramic levels had compressive moduli between 205?±?37-220?±?26?MPa, 112?±?13-118?±?23?MPa, and 86?±?14-97?±?8?MPa respectively for porosities ranging between 14?±?4-20?±?6%, 36?±?3-43?±?4%, and 54?±?2-57?±?2%, with the moduli and yield stresses of low porosity scaffolds being significantly greater (p?<?0.05) than those of all other groups. Single (porosity) gradient and dual (composition/porosity) gradient scaffolds demonstrated compressive properties similar (p?>?0.05) to those of the highest porosity uniform scaffolds (porosity gradient scaffolds 98?±?23-107?±?6?MPa, and 102?±?7?MPa for dual composition/porosity gradient scaffolds), indicating that these properties are more heavily influenced by the weakest section of the gradient. The compression data for uniform scaffolds were also readily modeled, yielding scaling laws of the form E???(1?-??)1.27 and ?y???(1?-??)1.37, which demonstrated that the compressive properties evaluated in this study were well-aligned with expectations from previous literature and were readily modeled with good fidelity independent of polymer scaffold geometry and ceramic content. All uniform scaffolds were similarly deformed and recovered despite different porosities, while the large-pore sections of porosity gradient scaffolds were significantly more deformed than all other groups, indicating that porosity may not be an independent factor in determining strain recovery. Moving forward, the technique described here will serve as the template for more complex multimaterial constructs with bioactive cues that better match native tissue physiology and promote tissue regeneration. STATEMENT OF SIGNIFICANCE: This manuscript describes the fabrication and mechanical characterization of "dual" porosity/ceramic content gradient scaffolds produced via a multimaterial extrusion 3D printing system for osteochondral tissue engineering. Such scaffolds are designed to better address the simultaneous gradients in architecture and mineralization found in native osteochondral tissue. The results of this study demonstrate that this technique may serve as a template for future advances in 3D printing technology that may better address the inherent complexity in such heterogeneous tissues.
| S-EPMC6744258 | biostudies-literature
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.
| S-EPMC4476659 | biostudies-literature
Project description:Osteochondral tissue repair remains a significant challenge in orthopedic surgery. Tissue engineering of osteochondral tissue has transpired as a potential therapeutic solution as it can effectively regenerate bone, cartilage, and the bone-cartilage interface. While advancements in scaffold fabrication and stem cell engineering have made significant progress towards the engineering of composite tissues, such as osteochondral tissue, new approaches are required to improve the outcome of such strategies. Herein, we discuss the use of a single-unit trilayer scaffold with depth-varying pore architecture and mineral environment to engineer osteochondral tissues in vivo. The trilayer scaffold includes a biomineralized bottom layer mimicking the calcium phosphate (CaP)-rich bone microenvironment, a cryogel middle layer with anisotropic pore architecture, and a hydrogel top layer. The mineralized bottom layer was designed to support bone formation, while the macroporous middle layer and hydrogel top layer were designed to support cartilage tissue formation. The bottom layer was kept acellular and the top two layers were loaded with cells prior to implantation. When implanted in vivo, these trilayer scaffolds resulted in the formation of osteochondral tissue with a lubricin-rich cartilage surface. The osteochondral tissue formation was a result of continuous differentiation of the transplanted cells to form cartilage tissue and recruitment of endogenous cells through the mineralized bottom layer to form bone tissue. Our results suggest that integrating exogenous cell-based cartilage tissue engineering along with scaffold-driven in situ bone tissue engineering could be a powerful approach to engineer analogs of osteochondral tissue. In addition to offering new therapeutic opportunities, such approaches and systems could also advance our fundamental understanding of osteochondral tissue regeneration and repair. STATEMENT OF SIGNIFICANCE:In this work, we describe the use of a single-unit trilayer scaffold with depth-varying pore architecture and mineral environment to engineer osteochondral tissues in vivo. The trilayer scaffold was designed to support continued differentiation of the donor cells to form cartilage tissue while supporting bone formation through recruitment of endogenous cells. When implanted in vivo, these trilayer scaffolds partially loaded with cells resulted in the formation of osteochondral tissue with a lubricin-rich cartilage surface. Approaches such as the one presented here that integrates ex vivo tissue engineering along with endogenous cell-mediated tissue engineering can have a significant impact in tissue engineering composite tissues with diverse cell populations and functionality.
| S-EPMC6309375 | biostudies-literature
Project description:A major clinical challenge in the reconstruction of large oral and craniofacial defects is the neogenesis of osseous and ligamentous interfacial structures. Currently, oral regenerative medicine strategies are unpredictable for repair of tooth-supporting tissues destroyed as a consequence of trauma, chronic infection or surgical resection. Here, we demonstrate multi-scale computational design and fabrication of composite hybrid polymeric scaffolds for targeted cell transplantation of genetically modified human cells for the formation of human tooth dentin-ligament-bone complexes in vivo. The newly-formed tissues demonstrate the interfacial generation of parallel- and obliquely-oriented fibers that grow and traverse within the polycaprolactone (PCL)-poly(glycolic acid) (PGA) designed constructs forming tooth cementum-like tissue, ligament, and bone structures. This approach offers potential for the clinical implementation of customized periodontal scaffolds that may enable regeneration of multi-tissue interfaces required for oral, dental and craniofacial engineering applications.
| S-EPMC2893240 | biostudies-literature
Project description:Articular cartilage (AC) is a seemingly simple tissue that has only one type of constituting cell and no blood vessels and nerves. In the early days of tissue engineering, cartilage appeared to be an easy and promising target for reconstruction and this was especially motivating because of widespread AC pathologies such as osteoarthritis and frequent sports-induced injuries. However, AC has proven to be anything but simple. Recreating the varying properties of its zonal structure is a challenge that has not yet been fully answered. This caused the shift in tissue engineering strategies toward bioinspired or biomimetic approaches that attempt to mimic and simulate as much as possible the structure and function of the native tissues. Hydrogels, particularly gradient hydrogels, have shown great potential as components of the biomimetic engineering of the cartilaginous tissue.
| S-EPMC5749123 | biostudies-literature
Project description:Temporally and spatially controlled delivery of growth factors in polymeric scaffolds is crucial for engineering composite tissue structures, such as osteochondral constructs. In the present study, microsphere-mediated growth factor delivery in polymer scaffolds and its impact on osteochondral differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) was evaluated. Two growth factors, bone morphogenetic protein 2 (rhBMP-2) and insulin-like growth factor I (rhIGF-I), were incorporated as a single concentration gradient or reverse gradient combining two factors in the scaffolds. To assess the gradient making system and the delivery efficiency of polylactic-co-glycolic acid (PLGA) and silk fibroin microspheres, initially an alginate gel was fabricated into a cylinder shape with microspheres incorporated as gradients. Compared to PLGA microspheres, silk microspheres were more efficient in delivering rhBMP-2, probably due to sustained release of the growth factor, while less efficient in delivering rhIGF-I, likely due to loading efficiency. The growth factor gradients formed were shallow, inducing non-gradient trends in hMSC osteochondral differentiation. Aqueous-derived silk porous scaffolds were used to incorporate silk microspheres using the same gradient process. Both growth factors formed deep and linear concentration gradients in the scaffold, as shown by enzyme-linked immunosorbent assay (ELISA). After seeding with hMSCs and culturing for 5 weeks in a medium containing osteogenic and chondrogenic components, hMSCs exhibited osteogenic and chondrogenic differentiation along the concentration gradients of rhBMP-2 in the single gradient of rhBMP-2 and reverse gradient of rhBMP-2/rhIGF-I, but not the rhIGF-I gradient system, confirming that silk microspheres were more efficient in delivering rhBMP-2 than rhIGF-I for hMSCs osteochondrogenesis. This novel silk microsphere/scaffold system offers a new option for the delivery of multiple growth factors with spatial control in a 3D culture environment for both understanding natural tissue growth process and in vitro engineering complex tissue constructs.
| S-EPMC2698962 | biostudies-literature
Project description:A goal of this project is to evaluate the integrin mRNA expression in human neural stem/progenitor cells (hNSPC) using high-throughput sequencing technologies. We found high levels of mRNA expression for the β1, α7, α3, α6, β5, αV, α5, and α9 integrins. This suggests that hNSPCs may express integrin receptors that can bind fibrinogen and laminin proteins.
2016-12-14 | GSE76011 | GEO
Project description:Repairing damaged articular cartilage is particularly challenging because of the limited ability of cartilage to perform self-repair. Intra-articular injections of N-acetylglucosamine (GlcNAc) comprise a method of repairing full-thickness articular cartilage defects in the rabbit knee joint model. To date, the effects of administration of GlcNAc and hyaluronic acid (HA) have been investigated only in the context of osteoarthritis treatment. Therefore, we evaluated the therapeutic effects of using cell-free porous poly lactic-co-glycolic acid (PLGA) graft implants and intra-articular injections of GlcNAc or HA in a rabbit model of osteochondral regeneration to investigate whether they have the potential for inducing osteochondral regeneration when used alone or simultaneously. Twenty-four rabbits were randomized into one of four groups: the scaffold-only group (PLGA), the scaffold with intra-articular injections of GlcNAc (PLGA+G) group, twice per week for four weeks; the scaffold with intra-articular injections of HA group (PLGA+HA) group, once per week for three weeks; and the scaffold with intra-articular injections of GlcNAc and HA (PLGA+G+HA) group, once per week for three weeks. Knees were evaluated at 4 and 12 weeks after surgery. At the end of testing, only the PLGA+G+HA group exhibited significant bone reconstruction, chondrocyte clustering, and good interactions with adjacent surfaces at 4 weeks. Additionally, the PLGA+G+HA group demonstrated essentially original hyaline cartilage structures that appeared to have sound chondrocyte orientation, considerable glycosaminoglycan levels, and reconstruction of the bone structure at 12 weeks. Moreover, the PLGA+G+HA group showed organized osteochondral integration and significantly higher bone volume per tissue volume and trabecular thickness. However, there were no significant differences between the PLGA+G and PLGA+HA groups except for gap formation on subchondral bone in the PLGA+G group. This study demonstrated that PLGA implantation combined with intra-articular injections of GlcNAc and HA allowed for cartilage and bone regeneration and significantly promoted osteochondral regeneration in rabbits without supplementation of exogenous growth factors. And the combination of this two supplements with PLGA scaffold could also prolong injection interval and better performance than either of them alone for the reconstruction of osteochondral tissue in the knee joints of rabbits.
| S-EPMC6312252 | biostudies-literature
Project description:Osteoarthritis is a highly prevalent rheumatic musculoskeletal disorder that commonly affects many joints. Repetitive joint overloading perpetuates the damage to the affected cartilage, which undermines the structural integrity of the osteochondral unit. Various tissue engineering strategies have been employed to design multiphasic osteochondral scaffolds that recapitulate layer-specific biomechanical properties, but the inability to fully satisfy mechanical demands within the joint has limited their success. Through computational modeling and extrusion-based bioprinting, we attempted to fabricate a biphasic osteochondral scaffold with improved shear properties and a mechanically strong interface. A 3D stationary solid mechanics model was developed to simulate the effect of lateral shear force on various thermoplastic polymer/hydrogel scaffolds with a patterned interface. Additionally, interfacial shear tests were performed on bioprinted polycaprolactone (PCL)/hydrogel interface scaffolds. The first simulation showed that the PCL/gelatin methacrylate (GelMA) and PCL/polyethylene glycol diacrylate (PEGDA) scaffolds interlocking hydrogel and PCL at interface in a 1:1 ratio possessed the largest average tensile (PCL/GelMA: 80.52 kPa; PCL/PEGDA: 79.75 kPa) and compressive stress (PCL/GelMA: 74.71 kPa; PCL/PEGDA: 73.83 kPa). Although there were significant differences in shear strength between PCL/GelMA and PCL/PEGDA scaffolds, no significant difference was observed among the treatment groups within both scaffold types. Lastly, the hypothetical simulations of potential biphasic 3D printed scaffolds showed that for every order of magnitude decrease in Young's modulus (E) of the soft bioink, all the scaffolds underwent an exponential increase in average displacement at the cartilage and interface layers. The following work provides valuable insights into the biomechanics of 3D printed osteochondral scaffolds, which will help inform future scaffold designs for enhanced regenerative outcomes.
| S-EPMC8918066 | biostudies-literature