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Acta biomaterialia
Elsevier
Acta biomaterialia

Elsevier

1742-7061

Acta biomaterialia/Journal Acta biomaterialiaEIISTPSCI
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    Combining sclerostin neutralization with tissue engineering: An improved strategy for craniofacial bone repair

    Maillard S.Sicard L.Andrique C.Torrens C....
    12页
    查看更多>>摘要：? 2021Scaffolds associated with different types of mesenchymal stromal stem cells (MSC) are extensively studied for the development of novel therapies for large bone defects. Moreover, monoclonal antibodies have been recently introduced for the treatment of cancer-associated bone loss and other skeletal pathologies. In particular, antibodies against sclerostin, a key player in bone remodeling regulation, have demonstrated a real benefit for treating osteoporosis but their contribution to bone tissue-engineering remains uncharted. Here, we show that combining implantation of dense collagen hydrogels hosting wild-type (WT) murine dental pulp stem cells (mDPSC) with weekly systemic injections of a sclerostin antibody (Scl-Ab) leads to increased bone regeneration within critical size calvarial defects performed in WT mice. Furthermore, we show that bone formation is equivalent in calvarial defects in WT mice implanted with Sost knock-out (KO) mDPSC and in Sost KO mice, suggesting that the implantation of sclerostin-deficient MSC similarly promotes new bone formation than complete sclerostin deficiency. Altogether, our data demonstrate that an antibody-based therapy can potentialize tissue-engineering strategies for large craniofacial bone defects and urges the need to conduct research for antibody-enabled local inhibition of sclerostin. Statement of significance: The use of monoclonal antibodies is nowadays broadly spread for the treatment of several conditions including skeletal bone diseases. However, their use to potentialize tissue engineering constructs for bone repair remains unmet. Here, we demonstrate that the neutralization of sclerostin, through either a systemic inhibition by a monoclonal antibody or the implantation of sclerostin-deficient mesenchymal stromal stem cells (MSC) directly within the defect, improves the outcome of a tissue engineering approach, combining dense collagen hydrogels and MSC derived from the dental pulp, for the treatment of large craniofacial bone defects.
      原文链接:
    • NSTL
    • Elsevier

    A long-lasting guided bone regeneration membrane from sequentially functionalised photoactive atelocollagen

    Liang H.Yin J.Man K.Yang X.B....
    16页
    查看更多>>摘要：? 2021 Acta Materialia Inc.The fast degradation of collagen-based membranes in the biological environment remains a critical challenge, resulting in underperforming Guided Bone Regeneration (GBR) therapy leading to compromised clinical results. Photoactive atelocollagen (AC) systems functionalised with ethylenically unsaturated monomers, such as 4-vinylbenzyl chloride (4VBC), have been shown to generate mechanically competent materials for wound healing, inflammation control and drug delivery, whereby control of the molecular architecture of the AC network is key. Building on this platform, the sequential functionalisation with 4VBC and methacrylic anhydride (MA) was hypothesised to generate UV-cured AC hydrogels with reduced swelling ratio, increased proteolytic stability and barrier functionality for GBR therapy. The sequentially functionalised atelocollagen precursor (SAP) was characterised via TNBS and ninhydrin colourimetric assays, circular dichroism and UV-curing rheometry, which confirmed nearly complete consumption of collagen's primary amino groups, preserved triple helices and fast (< 180 s) gelation kinetics, respectively. Hydrogel's swelling ratio and compression modulus were adjusted depending on the aqueous environment used for UV-curing, whilst the sequential functionalisation of AC successfully generated hydrogels with superior proteolytic stability in vitro compared to both 4VBC-functionalised control and the commercial dental membrane Bio-Gide?. These in vitro results were confirmed in vivo via both subcutaneous implantation and a proof-of-concept study in a GBR calvarial model, indicating integrity of the hydrogel and barrier defect, as well as tissue formation following 1-month implantation in rats. Statement of significance: Collagen-based membranes remain a key component in Guided Bone Regeneration (GBR) therapy, but their properties, e.g. proteolytic stability and soft tissue barrier functionality, are still far from optimal. This is largely attributed to the complex molecular configuration of collagen, which makes chemical accessibility and structure-function relations challenging. Here, we fabricated a UV-cured hydrogel network of atelocollagen, whereby triple helices were sequentially functionalised with two distinct ethylenically unsaturated monomers. The effects of the sequential functionalisation and UV-curing on the macroscopic properties, degradation behaviour and GBR capability were investigated in vitro and in vivo. The results highlight the key role of the sequential functionalisation and provide important insights for the design of future, longer-lasting resorbable membranes for GBR therapy.
      原文链接:
    • NSTL

    Glucose-responsive multifunctional metal–organic drug-loaded hydrogel for diabetic wound healing

    Yang J.Zeng W.Xu P.Fu X....
    13页
    查看更多>>摘要：? 2021 Acta Materialia Inc.As the incidence of diabetes increases, its complication, diabetic foot ulcers, has become the main type of clinically chronic refractory wounds. Due to the hyperglycemic microenvironment of the diabetic wound, which leads to vascular defects and bacterial growth, the therapeutic effect of wound dressings lacking strategic design is relatively limited. In this study, we designed an injectable, “self-healing”, and glucose-responsive multifunctional metal–organic drug-loaded hydrogel (DG@Gel) for diabetic wound healing. The functionalized hydrogel was prepared by phase-transfer-mediated metallo-nanodrugs, which were made by co-assembling zinc ions, organic ligands, and a small-molecule drug, deferoxamine mesylate (DFO), and the programmed loading of glucose oxidase (GOX). When injected into a diabetic wound, the GOX in DG@Gel changed the hyperglycemic wound microenvironment by decomposing excess glucose into hydrogen peroxide and glucuronic acid, which decreased the pH of the wound site. The low pH promoted the release of zinc ions and DFO, which exhibited synergistic antibacterial and angiogenesis activity for diabetic wound repair. In vitro experiments revealed the antibacterial activity and the cell proliferation, migration, and tube formation ability of DG@Gel. Moreover, in vivo experiments showed that DG@Gel can induce re-epithelialization, collagen deposition, and angiogenesis during wound healing in diabetic mice with good biocompatibility and biodegradability. The results suggest that this hydrogel is a promising innovative dressing for the treatment of diabetic wounds. Statement of significance: Diabetic ulcers, as one of the main types of chronic refractory wounds, are not treated effectively in the clinic due to a lack of strategic approach. In this study, we designed a glucose-responsive multifunctional metal–organic drug-loaded hydrogel (DG@Gel), which can change the hyperglycemic wound microenvironment by decomposing excess glucose into hydrogen peroxide and glucuronic acid. This in turn promoted the release of zinc ions and deferoxamine mesylate (DFO) in the hydrogel, which exhibited synergistic antibacterial and angiogenic activity for diabetic wound repair. Furthermore, the DG@Gel exhibited good biocompatibility and biodegradability in vivo. In general, this innovative strategy design may have great application potential in the treatment of various chronic wounds.
      原文链接:
    • NSTL
    • Elsevier

    Biomimetic crosslinking of collagen gels by energetic electrons: The role of L-lysine

    Wilharm N.Bertmer M.Knolle W.Griebel J....
    14页
    查看更多>>摘要：? 2021Energetic electrons have recently evolved as a powerful tool for crosslinking bio-derived hydrogels without the need for adding potentially hazardous reagents. Application of this approach allows for synthesis of biomimetic collagen-derived networks of highly tunable properties and functionalization. Yet, the underlying reaction kinetics are still not sufficiently established at this point. While hydroxyl radicals are generated by energetic electron-induced hydrolysis of water and play a key role in introducing covalent bonds between network fibers, a detailed mechanistic understanding would significantly increase applicability. We present a comprehensive analysis of central aspects of the reactivity between the hydroxyl radical (?OH) and collagen, elastin, glycine (Gly) and L-lysine (Lys). Pulse radiolysis (PR), solid state nuclear magnetic resonance (NMR), ultraviolet-visible absorption spectroscopy (UV/VIS) and electron spray ionization mass spectrometry (ESI-MS) shine light on distinct features of the crosslinking process. These highlight retained protein backbone integrity in collagen and elastin whilst Lys's ability to form several imine bonded Lys-Lys-species suggests striking similarities to crosslinking via lysyl oxidase catalysis in vivo. Thus, energetic electron based crosslinking opens the venue for customized hybrid gels of outstanding biomimicry and –compatibility. Statement of significance: Energetic electron beam treatment constitutes a highly attractive approach to establish chemical bonds between (bio) molecules. Although a convincing number of publications showed the versatility regarding crosslinking of bioderived hydrogels, insights into the underlying chemistry are still unestablished at this point. The present work unravels the mechanistics of energetic electron induced processes in collagen and elastin hydrogels as well as several abundant amino acids in aqueous solution. As key finding we demonstrate, that i) the connection between polymer chains is dominated by amino acid side chain interaction and ii) two single L-lysine molecules form an imine bond between the terminal amino group of one molecule and the delta carbon of the second molecule. We also consider the formation of H-bonds as a second crosslinking pathway. These findings open up for advanced, optionally spatially resolved biomaterials design.
      原文链接:
    • NSTL
    • Elsevier

    Vascular Endothelial Growth Factor-Capturing Aligned Electrospun Polycaprolactone/Gelatin Nanofibers Promote Patellar Ligament Regeneration

    Yuan Z.Sheng D.Jiang L.Shafiq M....
    14页
    查看更多>>摘要：? 2021Ligament injuries are common in sports and other rigorous activities. It is a great challenge to achieve ligament regeneration after an injury due the avascular structure and low self-renewal capability. Herein, we developed vascular endothelial growth factor (VEGF)-binding aligned electrospun poly(caprolactone)/gelatin (PCL/Gel) scaffolds by incorporating prominin-1-binding peptide (BP) sequence and exploited them for patellar ligament regeneration. The adsorption of BP onto scaffolds was discerned by various techniques, such as Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, and confocal laser scanning microscope. The accumulation of VEGF onto scaffolds correlated with the concentration of the peptide in vitro. BP-anchored PCL/Gel scaffolds (BP@PCL/Gel) promoted the tubular formation of human umbilical vein endothelial cells (HUVECs) and wound healing in vitro. Besides, BP containing scaffolds exhibited higher content of CD31+ cells than that of the control scaffolds at 1 week after implantation in vivo. Moreover, BP containing scaffolds improved biomechanical properties and facilitated the regeneration of matured collagen in patellar ligament 4 weeks after implantation in mice. Overall, this strategy of peptide-mediated orchestration of VEGF provides an enticing platform for the ligament regeneration, which may also have broad implications for tissue repair applications. Statement of significance: Ligament injuries are central to sports and other rigorous activities. Given to the avascular nature and poor self-healing capability of injured ligament tissues, it is a burgeoning challenge to fabricate tissue-engineered scaffolds for ligament reconstruction. Vascular endothelial growth factor (VEGF) is pivotal to the neo-vessel formation. However, the high molecular weight of VEGF as well as its short half-life in vitro and in vivo limits its therapeutic potential. To circumvent these limitations, herein, we functionalized aligned electrospun polycaprolactone/gelatin (PCL/Gel)-based scaffolds with VEGF-binding peptide (BP) and assessed their biocompatibility and performance in vitro and in vivo. BP-modified scaffolds accumulated VEGF, improved tube formation of HUVECs, and induced wound healing in vitro, which may have broad implications for regenerative medicine and tissue engineering.
      原文链接:
    • NSTL
    • Elsevier

    Transcutaneous tumor vaccination combined with anti-programmed death-1 monoclonal antibody treatment produces a synergistic antitumor effect

    Song X.Jiang Y.Zhang W.Elfawal G....
    14页
    查看更多>>摘要：? 2021Transcutaneous immunization (TCI) has the advantages of safety, high efficiency, non-invasiveness and convenient use. The key for a TCI system is transdermal targeted delivery of antigen to dendritic cells (DCs), the most powerful antigen presenting cells. DCs also play an important role in tumor immunotherapy, which provides a huge imagination for the application of TCI to tumor treatment. In this study, a transcutaneous tumor vaccine (TTV) delivery system was developed using the electrospun silk fibroin (SF) and polyvinyl alcohol (PVA) composite nanofibrous patch loaded with mannosylated polyethyleneimine (PEIman)-modified ethosome (Eth) (termed Eth-PEIman). Eth-PEIman showed a good performance in targeting DCs, and the carriers loaded with antigen (encapsulated in Eths) and adjuvant (absorbed in PEIman) were observed effectively induce DCs maturation in vitro. With the tyrosinase-related protein-2 (TRP2) peptide as antigen and oligodeoxynucleotides containing unmethylated CpG motifs as adjuvant, the TTV-loaded patches (TTVP) significantly inhibited the growth of melanoma in a syngeneic mouse model for melanoma by subcutaneous injection of B16F10 cell lines. Moreover, the combined application of the TTVP and anti-programmed death-1 monoclonal antibody (aPD-1) produced a synergistic antitumor effect, which could be related to the infiltration of more CD4+ and CD8+ T cells in the tumor tissues. The application of TTVP also increased the expression of IL-12, which may be part of the mechanism of synergistic antitumor effect between the TTVP and aPD-1. These results suggest that the combination of the TTVP and immune checkpoint blockers could be an effective strategy for tumor treatment. Statement of significance: Transcutaneous immunization has the advantages of safety, high efficiency, non-invasiveness and convenient use. In this study, a novel transcutaneous tumor vaccine patch (TTVP) was developed using tumor antigens-loaded ethosomes that can target dendritic cells percutaneously. Our data demonstrated that the TTVP can significantly inhibit tumor growth. Furthermore, the combination of TTVP and aPD-1 produced a synergistic anti-melanoma effect. Considering its convenience and non-invasiveness, this TTVP system could find good application prospects in immunotherapy. The combination of TTVP and aPD-1 could be a useful strategy for the prevention and treatment of tumors.
      原文链接:
    • NSTL
    • Elsevier

    α-Linolenic acid and linoleic acid modulate the lipidome and the skin barrier of a tissue-engineered skin model

    Simard M.Tremblay A.Morin S.Martin C....
    14页
    查看更多>>摘要：? 2021Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived lipid mediators remains unclear. Skin substitutes were engineered according to the self-assembly method with a culture medium supplemented with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA). The supplementation with ALA and LA decreased testosterone absorption through a tissue-engineered reconstructed skin model, thus indicating an improved skin barrier function following supplementation. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes. Indeed, the dual supplementation increased the levels of eicosapentaenoic acid (EPA) (15-fold), docosapentaenoic acid (DPA) (3-fold), and LA (1.5-fold) in the epidermal phospholipids while it increased the levels of ALA (>20-fold), DPA (3-fold) and LA (1.5-fold) in the epidermal triglycerides. The bioactive lipid mediator profile of the skin substitutes, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols, was next analyzed using liquid chromatography-tandem mass spectrometry. The lipid supplementation further modulated bioactive lipid mediator levels of the reconstructed skin substitutes, leading to a lipid mediator profile more representative of the one found in normal human skin. These findings show that an optimized supply of PUFAs via culture media is essential for the establishment of improved barrier function in vitro. Statement of significance: Supplementation of the culture medium with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA) improved the skin barrier function of a tissue-engineered skin model. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes and further modulated bioactive lipid mediator levels, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols. These findings highlight the important role of ALA and LA in skin homeostasis and show that an optimized supply of polyunsaturated fatty acids via culture media is essential for the establishment of improved barrier function in vitro.
      原文链接:
    • NSTL
    • Elsevier

    Constructing vascularized hepatic tissue by cell-assembled viscous tissue sedimentation method and its application for vascular toxicity assessment

    Naito Y.Yoshinouchi Y.Sorayama Y.Kohara H....
    14页
    查看更多>>摘要：? 2021 Acta Materialia Inc.In vitro Construction of the liver sinusoidal structure using artificial tissue is an important but worthwhile challenge, particularly for assessing the risk of diseases such as sinusoidal obstruction syndrome (SOS). Current models are unsuitable for evaluating the toxicity because of lacking sinusoidal capillary. In this study, we developed a vascularized hepatic tissue (VHT) using a unique tissue engineering technique, the cell assembled viscous tissue by sedimentation (CAViTs) method. The “viscous bodies” created using the CAViTs method exhibited significant self-assembly within 6 h after seeding, promoting cell-cell interaction. The level of albumin secreted by the VHT was four times higher than that of 2D-coculture and maintained for 1 month. The gene expression pattern of the VHT was closer to that of total human liver, compared with the 2D system. Quantitative evaluations of the vascular structure of VHT treated with two typical SOS-inducing compounds, monocrotaline and retrorsine, revealed higher sensitivity (IC50 = 40.35 μM), 19.92 times higher than the cell-viability assay. Thus, VHT represents an innovative in vitro model that mimics the vessel network structure and could become a useful tool for the early screening of compounds associated with a risk of vascular toxicity. Statement of significance: Mimicking sinusoidal structures in in vitro liver model is important to consider from the perspective of predicting hepatotoxicity such like sinusoidal obstruction syndrome (SOS). However, it was difficult to reconstruct the vascular structure within the hepatocyte-rich environment. In this study, we constructed a vascularized hepatic tissue in a high-throughput manner by a unique method using collagen and heparin, and evaluated its applicability to toxicity assessment. Vessel morphology analysis of the model treated by monocrotaline, which is a well-known SOS-inducing compound, could predict the toxicity with higher sensitivity. To the best of our knowledge, this is the first report to provide vascularized hepatic tissues using sinusoidal endothelial cells at least for demonstrating applicability to the evaluation of SOS induction risk.
      原文链接:
    • NSTL
    • Elsevier

    Zein-induced immune response and modulation by size, pore structure and drug-loading: Application for sciatic nerve regeneration

    Yu J.Lin Y.Wang G.Song J....
    13页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Zein is a biodegradable material with great potential in biomedical applications. However, as a plant-derived protein material, body's immune response is the key factor to determine its clinical performance. Herein, for the first time, the zein-induced immune response is evaluated systemically and locally, comparing with typical materials including alginate (ALG), poly(lactic-co-glycolic) acid (PLGA) and polystyrene (PS). Zein triggers an early inflammatory response consistent with the non-degradable PS, but this response decreases to the same level of the biosafe ALG and PLGA with zein degradation. Changing sphere sizes, pore structure and encapsulating dexamethasone can effectively modulate the zein-induced immune response, especially the pore structure which also inhibits neutrophil recruitment and promotes macrophages polarizing towards M2 phenotype. Thus, porous zein conduits with high and low porosity are further fabricated for the 15 mm sciatic nerve defect repair in rats. The conduits with high porosity induce more M2 macrophages to accelerate nerve regeneration with shorter degradation period and better nerve repair efficacy. These findings suggest that the pore structure in zein materials can alleviate the zein-induced early inflammation and promote M2 macrophage polarization to accelerate nerve regeneration. Statement of significance: Zein is a biodegradable material with great potential in biomedical applications. However, as a plant protein, its possible immune response in vivo is always the key issue. Until now, the systemic study on the immune responses of zein in vivo is still very limited, especially as an implant. Herein, for the first time, the zein-induced immune response was evaluated systemically and locally, comparing with typical biomaterials including alginate, poly(lactic-co-glycolic) acid and polystyrene. Changing sphere sizes, pore structure and encapsulating dexamethasone could effectively modulate the zein-induced immune response, especially the pore structure which also inhibited neutrophil recruitment and promoted macrophages polarizing towards M2 phenotype. Furthermore, the pore structure in zein nerve conduits was proved to alleviate the early inflammation and promote M2 macrophage polarization to accelerate nerve regeneration.
      原文链接:
    • NSTL
    • Elsevier

    Engineering a photosynthetic bacteria-incorporated hydrogel for infected wound healing

    Zhao E.Liu H.Jia Y.Xiao T....
    12页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Treating wounds with multidrug-resistant bacterial infections remains a huge and arduous challenge. In this work, we prepared a “live-drug”-encapsulated hydrogel dressing for the treatment of multidrug-resistant bacterial infections and full-thickness skin incision repair. Our live dressing was comprised of photosynthetic bacteria (PSB) and extracellular matrix (ECM) gel with photothermal, antibacterial and antioxidant properties, as well as good cytocompatibility and blood compatibility. More interestingly, live PSB could be regarded as not only photothermal agents but also as anti-inflammatory agents to promote wound healing owing to their antioxidant metabolites. In vitro and in vivo studies showed that the PSB hydrogel not only had a high killing rate against methicillin-resistant Staphylococcus aureus (MRSA) but it also accelerated collagen deposition and granulation tissue formation by promoting cell proliferation and migration, which significantly promoted skin tissue regeneration and wound healing. We believe that the large-scale production of PSB Gel-based therapeutic dressings has the advantages of easy use and promising clinical applications. Statement of significance: Rapid wound healing and the treatment of bacterial infections have always been the two biggest challenges in the field of wound care. We prepared a “live drug” dressing by encapsulating photosynthetic bacteria into an extracellular matrix hydrogel to sterilize the wound and promote wound healing. First, photosynthetic bacteria are not only a photothermal agent for photothermal wound sterilization, but also possess the anti-inflammatory capacity to enhance wound healing due to their antioxidant metabolites. Second, the extracellular matrix hydrogel is rich in a variety of growth factors and nutrients to promote cell migration and accelerate wound healing. Third, photosynthetic bacteria are not only green and non-toxic, but also can be obtained on a large scale, which facilitates manufacturing and clinical transformation.
      原文链接:
    • NSTL
    • Elsevier