Mimicking Transmural Helical Cardiomyofibre Orientation Using Bouligand-like Pore Structures in Ice-Templated Collagen Scaffolds
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ABSTRACT:
SUBMITTER: Zhang H
PROVIDER: S-EPMC10675392 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Porous biomaterials which provide a structural and biological support for cells have immense potential in tissue engineering and cell-based therapies for tissue repair. Collagen biomaterials that can host endothelial cells represent promising tools for the vascularization of engineered tissues. Three-dimensional collagen scaffolds possessing controlled architecture and mechanical stiffness are obtained through freeze-drying of collagen suspensions, followed by chemical cross-linking which maintains their stability. However, cross-linking scaffolds renders their biological activity suboptimal for many cell types, including human umbilical vein endothelial cells (HUVECs), by inhibiting cell-collagen interactions. Here, we have improved crucial HUVEC interactions with such cross-linked collagen biomaterials by covalently coupling combinations of triple-helical peptides (THPs). These are ligands for collagen-binding cell-surface receptors (integrins or discoidin domain receptors) or secreted proteins (SPARC and von Willebrand factor). THPs enhanced HUVEC adhesion, spreading and proliferation on 2D collagen films. THPs grafted to 3D-cross-linked collagen scaffolds promoted cell survival over seven days. This study demonstrates that THP-functionalized collagen scaffolds are promising candidates for hosting endothelial cells with potential for the production of vascularized engineered tissues in regenerative medicine applications.
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Project description:Porous precision-templated scaffolds (PTS) with uniformly distributed 40 μm spherical pores have shown a remarkable ability in immunomodulating resident cells for tissue regeneration. While the pore size mediated pro-healing response observed only in 40 μm pore PTS has been attributed to selective macrophage polarization, monocyte recruitment and phenotype have largely been uncharacterized in regulating implant outcome. Here, we employ a double transgenic mouse model for myeloid characterization and a multifaceted phenotyping approach to quantify monocyte dynamics within subcutaneously implanted PTS. Within 40 μm PTS, myeloid cells were found to preferentially infiltrate into the scaffold. Additionally, macrophage receptor with collagenous structure (MARCO), an innate activation marker, was significantly upregulated within 40 μm PTS. When 40 μm PTS were implanted in monocyte-depleted mice, the transcription of MARCO was significantly decreased and an increase in pro-inflammatory inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNFα) were observed. Typical of a foreign body response (FBR), 100 μm PTS significantly upregulated pro-inflammatory iNOS, secreted higher amounts of TNFα, and displayed a pore size dependent morphology compared to 40 μm PTS. Overall, these results identify a pore size dependent modulation of circulating monocytes and implicates MARCO expression as a defining subset of monocytes that appears to be responsible for regulating a pro-healing host response.
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Project description:Implanted porous precision templated scaffolds (PTS) with 40-µm spherical pores reduce inflammation and foreign body reaction (FBR) while increasing vascular density upon implantation. Larger or smaller pores, however, promote chronic inflammation and FBR. While macrophage (MØ) recruitment and polarization participates in perpetuating this pore-size-mediated phenomenon, the driving mechanism of this unique pro-healing response is poorly characterized. We hypothesized that the primarily myeloid PTS resident cells release small extracellular vesicles (sEVs) that induce pore-size-dependent pro-healing effects in surrounding T cells. Upon profiling resident immune cells and their sEVs from explanted 40-µm- (pro-healing) and 100-µm-pore diameter (inflammatory) PTS, we found that PTS pore size did not affect PTS resident immune cell population ratios or the proportion of myeloid sEVs generated from explanted PTS. However, quantitative transcriptomic assessment indicated cell and sEV phenotype were pore size dependent. In vitro experiments demonstrated the ability of PTS cell-derived sEVs to stimulate T cells transcriptionally and proliferatively. Specifically, sEVs isolated from cells inhabiting explanted 100 μm PTS significantly upregulated Th1 inflammatory gene expression in immortalized T cells. sEVs isolated from cell inhabiting both 40- and 100-μm PTS upregulated essential Treg transcriptional markers in both primary and immortalized T cells. Finally, we investigated the effects of Treg depletion on explanted PTS resident cells. FoxP3+ cell depletion suggests Tregs play a unique role in balancing T cell subset ratios, thus driving host response in 40-μm PTS. These results indicate that predominantly 40-µm PTS myeloid cell-derived sEVs affect T cells through a distinct, pore-size-mediated modality.
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Project description:Little is known about the role of biocompatible protein nanoridges in directing stem cell fate and tissue regeneration due to the difficulty in forming protein nanoridges. Here an ice-templating approach is proposed to produce semi-parallel pure silk protein nanoridges. The key to this approach is that water droplets formed in the protein films are frozen into ice crystals (removed later by sublimation), pushing the surrounding protein molecules to be assembled into nanoridges. Unlike the flat protein films, the unique protein nanoridges can induce the differentiation of human mesenchymal stem cells (MSCs) into osteoblasts without any additional inducers, as well as the formation of bone tissue in a subcutaneous rat model even when not seeded with MSCs. Moreover, the nanoridged films induce less inflammatory infiltration than the flat films in vivo. This work indicates that decorating biomaterials surfaces with protein nanoridges can enhance bone tissue formation in bone repair.
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Project description:BackgroundTechnological constraints limit 3D printing of collagen structures with complex trabecular shapes. However, the Freeform Reversible Embedding of Suspended Hydrogels (FRESH) method may allow for precise 3D printing of porous collagen scaffolds that carry the potential for repairing critical size bone defects.MethodsCollagen type I scaffolds mimicking trabecular bone were fabricated through FRESH 3D printing and compared either with 2D collagen coatings or with 3D-printed polyethylene glycol diacrylate (PEGDA) scaffolds. The porosity of the printed scaffolds was visualized by confocal microscopy, the surface geometry of the scaffolds was investigated by scanning electron microscopy (SEM), and their mechanical properties were assessed with a rheometer. The osteoconductive properties of the different scaffolds were evaluated for up to four weeks by seeding and propagation of primary human osteoblasts (hOBs) or SaOS-2 cells. Intracellular alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) activities were measured, and cells colonizing scaffolds were stained for osteocalcin (OCN).ResultsThe FRESH technique enables printing of constructs at the millimetre scale using highly concentrated collagen, and the creation of stable trabecular structures that can support the growth osteogenic cells. FRESH-printed collagen scaffolds displayed an intricate and fibrous 3D network, as visualized by SEM, whereas the PEGDA scaffolds had a smooth surface. Amplitude sweep analyses revealed that the collagen scaffolds exhibited predominantly elastic behaviour, as indicated by higher storage modulus values relative to loss modulus values, while the degradation rate of collagen scaffolds was greater than PEGDA. The osteoconductive properties of collagen scaffolds were similar to those of PEGDA scaffolds but superior to 2D collagen, as verified by cell culture followed by analysis of ALP/LDH activity and OCN immunostaining.ConclusionsOur findings suggest that FRESH-printed collagen scaffolds exhibit favourable mechanical, degradation and osteoconductive properties, potentially outperforming synthetic polymers such as PEGDA in bone tissue engineering applications.
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