首页期刊导航|Acta biomaterialia
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Acta biomaterialia
Elsevier
Acta biomaterialia

Elsevier

1742-7061

Acta biomaterialia/Journal Acta biomaterialiaEIISTPSCI
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    Sustained local ionic homeostatic imbalance caused by calcification modulates inflammation to trigger heterotopic ossification

    Witte F.Bohner M.Maazouz Y.Ginebra M.-P....
    24页
    查看更多>>摘要：? 2022 The Author(s)Heterotopic ossification (HO) is a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues. Despite being a frequent complication of orthopedic and trauma surgery, brain and spinal injury, the etiology of HO is poorly understood. The aim of this study is to evaluate the hypothesis that a sustained local ionic homeostatic imbalance (SLIHI) created by mineral formation during tissue calcification modulates inflammation to trigger HO. This evaluation also considers the role SLIHI could play for the design of cell-free, drug-free osteoinductive bone graft substitutes. The evaluation contains five main sections. The first section defines relevant concepts in the context of HO and provides a summary of proposed causes of HO. The second section starts with a detailed analysis of the occurrence and involvement of calcification in HO. It is followed by an explanation of the causes of calcification and its consequences. This allows to speculate on the potential chemical modulators of inflammation and triggers of HO. The end of this second section is devoted to in vitro mineralization tests used to predict the ectopic potential of materials. The third section reviews the biological cascade of events occurring during pathological and material-induced HO, and attempts to propose a quantitative timeline of HO formation. The fourth section looks at potential ways to control HO formation, either acting on SLIHI or on inflammation. Chemical, physical, and drug-based approaches are considered. Finally, the evaluation finishes with a critical assessment of the definition of osteoinduction. Statement of significance: The ability to regenerate bone in a spatially controlled and reproducible manner is an essential prerequisite for the treatment of large bone defects. As such, understanding the mechanism leading to heterotopic ossification (HO), a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues, would be very useful. Unfortunately, the mechanism(s) behind HO is(are) poorly understood. The present study reviews the literature on HO and based on it, proposes that HO can be caused by a combination of inflammation and calcification. This mechanism helps to better understand current strategies to prevent and treat HO. It also shows new opportunities to improve the treatment of bone defects in orthopedic and dental procedures.
      原文链接:
    • NSTL
    • Elsevier

    Metal-organic framework-based hydrogel with structurally dynamic properties as a stimuli-responsive localized drug delivery system for cancer therapy

    Zeng Y.Zhang C.Du D.Li Y....
    9页
    查看更多>>摘要：? 2022Metal-organic framework (MOF) is an exciting class of porous biomaterials that have been considered as a carrier to store and deliver therapeutic drugs. However, similar to other nanomaterials, the application of MOF in clinical settings is still limited because of premature diffusion of their payloads and tissue off-targeting behavior. To overcome these challenges, we designed an MOF-based hydrogel with structurally dynamic properties, i.e., self-healing and shear-thinning, as an injectable localized drug delivery platform. The drug-encapsulating MOF hydrogel is formed through a dynamic coordination bond cross-linkage between a doxorubicin-loaded MOF (MOF@DOX) particle and a homemade bisphosphonate-modified hyaluronic acid (HA-BP) polymeric binder. The HA-BP·MOF@DOX hydrogel demonstrates pH- and ATP-responsive drug release characteristic and efficiently kills cancer cells in vitro. The animal experiments reveal that the HA-BP·MOF@DOX hydrogel has enhanced capability in terms of tumor growth suppression as compared to the MOF@DOX group, which can be attributed to drug localization in hydrogel superstructure and sustained release at the tumor site. The presented injectable dynamic MOF-based hydrogel is a promising in vivo localized drug delivery system for cancer treatment. Herein, we report the self-healing and shear-thinning of MOF-based drug carrier cross-linked by coordinate bonds for the first time and provide new insights and a facile chemical strategy for designing and fabricating MOF-based biomaterials by using bisphosphonate-zinc interaction. Statement of significance: Bisphosphonate-zinc interaction is a facile chemical strategy to cross-link metal-organic framework (MOF)-based hydrogel. The presented MOF-based hydrogel demonstrates structurally dynamic properties, including smooth injectability, self-healing, and shear-thinning. The developed MOF-based hydrogel possesses pH- and ATP-responsive drug release characteristic and kills cancer cells in vitro efficiently. The dynamic MOF-based hydrogel shows enhanced in vivo anticancer activity as compared to pure MOF particles. Self-healing and shear-thinning of metal-ligand cross-linked MOF-based drug delivery system are reported for the first time, thus providing new insights for the design and fabrication of MOF-based biomaterials.
      原文链接:
    • NSTL
    • Elsevier

    Disulfide-Mediated Elongation of Amyloid Fibrils of α-Synuclein For Use in Producing Self-Healing Hydrogel and Dye-Absorbing Aerogel

    Ha Y.Kwon Y.Nam E.-J.Park H....
    10页
    查看更多>>摘要：? 2022Due to their mechanical robustness, biocompatibility, and nanoscale size, amyloid fibrils (AFs) have been considered as a potential nanomaterial for biological applications. Unfortunately, however, AFs are usually not fully extended because of their pre-mature breakage, which hampers their use to generate biocompatible suprastructures, although the amounts of AFs could be amplified via their self-propagation property. Here, we have demonstrated the full extension of AFs of α-synuclein (αS) by introducing a cysteine residue to its C-terminus which prevents the shear-induced fragmentation of AFs via site-directed disulfide bond formation on the exposed surface of AFs. These heat- and cold-resistant elongated AFs were entangled into self-healable hydrogels through a mild disulfide-exchange process in the presence of tris(2-carboxyethyl) phosphine, which subsequently developed into dye-absorbing aerogels upon freeze-drying without collapsing the three-dimensional internal fibrillar network. The resulting αS aerogel with high porosity and increased surface area was shown to be capable of absorbing both hydrophilic and hydrophobic substances. In addition, the aerogel was further engineered with 8-arm polyethylene glycol containing a sulfhydryl group to increase its drug loading capacity and protease susceptibility for drug unloading. The elongated AFs, therefore, have been suggested to play a pivotal component for the development of bio-nano-matrix for diverse biological applications including drug delivery, tissue engineering, and environmental remediation. Statement of significance: Due to accurate protein self-assembly process, α-synuclein forms an amyloid fibril which are the major component of Lewy bodies. In general, α-synuclein amyloid fibrils break under thermal fluctuations as these nanofibrils elongate to reach certain length. In this study, we have demonstrated the full extension of α-synuclein amyloid fibrils by introducing a cysteine residue to its C-terminus by forming site-directed disulfide bonds on the exposed surface of amyloid fibrils for the first time. The resulting elongated amyloid fibrils were mechanically robust and stable. By using elongated amyloid fibrils, we have made self-healable amyloid fibril hydrogel and dye-absorbing aerogel.
      原文链接:
    • NSTL
    • Elsevier

    In situ regeneration of bone-to-tendon structures: Comparisons between costal-cartilage derived stem cells and BMSCs in the rat model

    Wu J.Ji Y.Mao S.Li C....
    15页
    查看更多>>摘要：? 2022Bone-tendon interface (BTI), also called enthesis, is composed of the bone, fibrocartilage, and tendon/ligament with gradual structural characteristics. The unique gradient structure is particularly important for mechanical stress transfer between bone and soft tissues. However, BTI injuries result in fibrous scar repairs and high incidences of re-rupture, which is attributed to the lack of local stem cells with tenogenic and osteogenic potentials. In the rat model, we identified unique stem cells from costal cartilage (CDSCs) with a high in situ regeneration potential of BTI structures. Compared to bone-marrow mesenchymal stem cells (BMSCs), CDSCs exhibit higher self-renewal capacities, better adaptability to low-oxygen and low-nutrient post-transplantation environments, as well as strong bi-potent differentiation abilities of osteogenesis and tenogenesis. After transplantation, CDSCs can survive, proliferate, and in situ gradually regenerate BTI structures. Therefore, CDSCs have a great potential for tissue engineering regeneration in BTI injuries, and have future clinical application prospects. Statement of significance: Tissue engineering is a promising technique for bone-to-tendon interface (BTI) regeneration after injury, but it is still a long way from clinical application. One of the major reasons is the lack of suitable seed cells. This study found an ideal source of seed cells derived from costal cartilages (CDSCs). Compared to the traditional seed cell BMSCs, CDSCs have higher proliferation ability, strong chondrogenic and tenogenic differentiation potential, and better adaptability to low-oxygen and low nutrient conditions. CDSCs were able to survive, proliferate, and regenerate BTI structures in situ, in contrast to BMSCs. CDSCs transplantation showed strong BTI structures regeneration potential both histologically and biomechanically, making it a suitable seed cell for the tissue engineering regeneration of BTI.
      原文链接:
    • NSTL
    • Elsevier

    Granular PEG hydrogels mediate osteoporotic MSC clustering via N-cadherin influencing the pro-resorptive bias of their secretory profile

    Rao V.V.Wechsler M.E.Cravens E.Wojda S.J....
    11页
    查看更多>>摘要：? 2022Postmenopausal osteoporosis results from a pro-resorptive bone environment, which decreases bone mineral density causing increased fracture risk. Bone marrow derived mesenchymal stem/stromal cells (MSCs) secrete factors involved in bone homeostasis, but osteoporosis mediated changes to their secretions remain understudied. Herein, we examined the secretome of MSCs isolated from ovariectomized rats (OVX rMSCs), a model of post-menopausal osteoporosis, as a function of cell-cell interactions. Specifically, we controlled clustering of OVX and SHAM rMSCs by assembling them in granular hydrogels synthesized from poly(ethylene glycol) microgels with average diameters of ～10, 100, and 200 μm. We directed both the sizes of rMSC clusters (single cells to ～30 cells/cluster) and the percentages of cells within clusters (～20–90%) by controlling the scaffold pore dimensions. Large clusters of OVX rMSCs had a pro-resorptive secretory profile, with increased concentrations of Activin A, CXCL1, CX3CL1, MCP-1, TIMP-1, and TNF-ɑ, compared to SHAM rMSCs. As this pro-resorptive bias was only observed in large cell clusters, we characterized the expression of several cadherins, mediators of cell-cell contacts. N-cadherin expression was elevated (～4-fold) in OVX relative to SHAM rMSCs, in both cell clusters and single cells. Finally, TIMP-1 and MCP-1 secretion was only decreased in large cell clusters of OVX rMSCs when N-cadherin interactions were blocked, highlighting the dependence of OVX rMSC secretion of pro-resorptive cytokines on N-cadherin mediated cell-cell contacts. Further elucidation of the N-cadherin mediated osteoporotic MSC secretome may have implications for developing therapies for postmenopausal osteoporosis. Statement of significance: Postmenopausal osteoporosis is a prevalent bone disorder that affects tens of millions of women worldwide. This disease is characterized by severe bone loss resulting from a pro-resorptive bone marrow environment, where the rates of bone resorption outpace the rates of bone deposition. The paracrine factors secreted by bone marrow MSCs can influence cell types responsible for bone homeostasis, but the osteoporosis-mediated changes to MSC secretory properties remains understudied. In this study, we used PEG-based porous granular scaffolds to study the influence of cell clustering on the secretory properties of osteoporotic MSCs. We observed increased secretion of several pro-resorptive factors by osteoporotic MSCs in large clusters. Further, we explored the dependence of this altered secretion profile on N-cadherin mediated cell-cell contacts.
      原文链接:
    • NSTL
    • Elsevier

    NIR-activated multi-hit therapeutic Ag2S quantum dot-based hydrogel for healing of bacteria-infected wounds

    Du T.Xiao Z.Cao J.Wei L....
    18页
    查看更多>>摘要：? 2022 Acta Materialia Inc.Hydrogel dressings are highly biocompatible and can maintain a moist wound environment, suggesting constructing an efficient multi-modal antibacterial hydrogel platform is a promising strategy for treating bacterial wound infections. In this work, a composite Ag2S quantum dot/mSiO2 NPs hydrogel (NP hydrogel) with antibacterial ability was constructed by incorporating Ag2S quantum dots (QDs) modified by mesoporous silica (mSiO2) into the network structure of 3-(trimethoxylmethosilyl) propyl methacrylate based on free radical polymerization. The NP hydrogel showed outstanding controllable photothermal and photodynamic characteristics under 808 nm near infrared (NIR) light irradiation, with a photothermal conversion efficiency of 57.3%. Additionally, the release of Ag+ could be controlled by the inherent volume change of the NP hydrogel made of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) during NIR laser exposure, with the embedded Ag2S QDs working as a reservoir to release Ag+ continuously from the hydrogel matrix to achieve bactericidal activity. The synergetic effects between hyperthermia, radical oxygen species, and Ag+ released under NIR radiation endowed the NP hydrogel with prominent antibacterial properties against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), with an inhibition rate of 99.7% and 99.8%, respectively. In vivo wound healing experiments indicated that the NP hydrogel could enhance bacterial clearance, increase collagen coverage area and up-regulate VEGF expression, exhibiting high biocompatibility. Overall, this study proposed an efficient and highly biocompatible multi-modal therapeutic nanohydrogel, opening up a new way for developing broad-spectrum antibacterial wound dressings to treat bacterial wound infections. Statement of significance: Bacterial wound infection is still one of the most difficult medical problems. In this work, a stimulating NIR-responsive hydrogel encapsulating functional Ag2S QDs was prepared, which showed high photothermal conversion efficiency (57.3%) and outstanding antibacterial ability under 808 nm NIR laser, killing 99.7% and 99.8% of E. coli and MRSA in 4 min, respectively. During NIR light irradiation, the release rate of Ag+ could be regulated by the intrinsic volume transition of the hydrogel, leading to remarkable antibacterial properties in vitro and in vivo under the combined action of hyperthermia, radical oxygen species and Ag+ released. This study proposed a novel multi-modal therapeutic nanohydrogel, opening up a new way for developing broad-spectrum antibacterial wound dressings to treat bacterial wound infections.
      原文链接:
    • NSTL
    • Elsevier

    An injectable hemostatic PEG-based hydrogel with on-demand dissolution features for emergency care

    Chen Y.Gao J.Yu L.Ding J....
    16页
    查看更多>>摘要：? 2022Uncontrolled bleeding from internal noncompressible wounds is a major cause of prehospital death in military personnel and civilian populations. An ideal hemostatic sealant for emergency care should quickly control blood loss and be removed without debridement for the follow-up treatment in the operating room, yet the lack of suitable materials to meet both requirements is the bottleneck. Herein, we suggest an injectable and dissolvable hydrogel sealant for hemorrhage management of noncompressible wounds. To this end, a 4-arm poly(ethylene glycol) (PEG) crosslinker modified with thioester linkages and terminated with aldehyde groups is designed and synthesized, and to modulate the gel properties and make it suitable as a hemostatic sealant, a mixed amino component composed of poly(ethylene imine) and adipic dihydrazide is employed to react with the PEG crosslinker to form the adhesive and elastic sealant for the first time. The aldehyde groups provide the adhesion to the tissues, and the amino component affords the procoagulant ability. More importantly, the thioester moieties allow the on-demand dissolution of sealant via a thiol-thioester exchange reaction upon exposure to an exogenous thiolate solution. In the rat femoral artery puncture and liver injury models, the administration of the hydrogel sealant dramatically reduces blood loss, and its subsequent removal does not induce rebleeding. Consequently, this hydrogel sealant with the unique feature of on-demand dissolution can not only efficiently control bleeding in emergent scenarios, but also allow non-traumatic re-exposure of wounds during subsequent surgical care. Statement of significance: Sealants, adhesives or hemostatic dressings currently used in emergency situations not only require manual pressure to control bleeding, but also face removal by cutting and mechanical debridement to enable eventual surgical treatment. In this study, we design and develop an injectable and adhesive hydrogel sealant with good procoagulant capacity and on-demand dissolution feature. The application of the hydrogel sealant substantially reduces bleeding from internal noncompressible wounds without the need for direct pressure, and demonstrates for the first time that its controlled removal without debridement does not cause rebleeding. Considering that there are currently no commercial wound sealant systems with the feature of on-demand dissolution, the hydrogel sealant developed by us is expected to address an unmet clinical need.
      原文链接:
    • NSTL
    • Elsevier

    NIR-responsive polydopamine-based calcium carbonate hybrid nanoparticles delivering artesunate for cancer chemo-photothermal therapy

    Zhong W.Wong K.H.Xu F.Zhao N....
    11页
    查看更多>>摘要：? 2022Artesunate (AS), the first-line treatment of malaria with a satisfactory safety profile, has been repurposed as a potential anticancer candidate as it mainly generates reactive oxygen species (ROS) through its intrinsic endoperoxide bridge reacting with ferrous-based catalysts to suppress cancer cell growth. However, further clinical translation of AS is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for cancer chemo-photothermal therapy, which exerted anticancer effects in the following ways: (1) the heat was generated when PDA was irradiated by near-infrared (NIR) light for photothermal therapy. Meanwhile, the increased temperature accelerated the production of ROS from hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy; (2) hAS-mediated chemotherapy boosted the cancer inhibition effect of photothermal therapy by arousing the intracellular ROS levels in the presence of endogenous ferrous ions and sensitizing cancer cells to thermal ablation; (3) the integration of calcium carbonate into the nanoparticle facilitated the pH-responsive drug release for precise treatment. Such hybrid nanoparticles exhibited a combinational antitumor effect of photothermal therapy and chemotherapy in vivo with no systemic toxicity. Taken together, our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage, which may offer opportunities to pave the way for clinical translation of AS-based nanomedicines. Statement of significance: The clinical translation of artesunate (AS) is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for improved cancer chemo-photothermal therapy. The heat generated from PDA in response to near-infrared light irradiation could locally ablate tumor as well as accelerate the production of ROS by hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy. On the other hand, hAS-based chemotherapy amplified the intracellular oxidative stress, sensitizing cancer cells to thermal ablation. Our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage.
      原文链接:
    • NSTL
    • Elsevier

    Nano-hydroxyapatite-evoked immune response synchronized with controllable immune adjuvant release for strengthening melanoma-specific growth inhibition

    Chen Z.Deng J.Cao J.Wu H....
    13页
    查看更多>>摘要：? 2022 Acta Materialia Inc.Concerns about the potential systematic toxicity limit the extensive application of traditional therapeutic drugs for melanoma therapy, nano-hydroxyapatite (nHA) with good biocompatibility and anti-tumor ability could be an alternative choice. In this study, nHA was employed as an anti-tumor biomaterial due to its tumor-specific toxicity. Meanwhile, granulocyte-macrophage colony-stimulating factor (GM-CSF) served as the immune adjuvant to activate the immune response. The delivery platform was fabricated by co-encapsulation of both nHA and GM-CSF into a biocompatible thermosensitive PLGA-PEG-PLGA hydrogel. The results showed that the bio-activities of nHA and GM-CSF could be well-maintained within the hydrogel. Interestingly, the addition of nHA could attenuate the burst release of GM-CSF due to possible protein absorption capacity of nHA, which is beneficial for GM-CSF sustainable release at the tumor site, achieving boosted and prolonged anti-tumor immunity. The in vitro and in vivo data demonstrated that nHA/GM-CSF hydrogel exhibited greater potency to inhibit tumor growth via enhanced CD8+ T-cell response compared with hydrogel and nHA hydrogel groups, contributed by the synergistic effects of nHA and GM-CSF. Overall, the strategy combining nHA and immune adjuvant shows great promise, which largely broadens the choice of combinational therapies for melanoma. Statement of significance: Nano-hydroxyapatite (nHA) has been confirmed to specifically inhibit melanoma tumor growth and induce immune response. However, its antitumor efficiency and immunity-evoking capacity are limited. In this study, granulocyte-macrophage colony-stimulating factor (GM-CSF) was introduced to serve as the immune adjuvant. Both of them were encapsulated into a biocompatible thermosensitive PLGA-PEG-PLGA hydrogel. The addition of nHA could attenuate the burst release of GM-CSF due to the interaction with nHA, which is beneficial for GM-CSF sustainable release at tumor site, achieving boosted and prolonged anti-tumor immunity. Anti-tumor immune response could be activated due to the release of tumor-associated antigen and tumor debris induced by the specifically tumor inhibition effect of nHA and GM-CSF. The combination of nHA and GM-CSF could play synergistic inhibiting effect on tumor growth via boosting and prolonging anti-tumor immunity.
      原文链接:
    • NSTL
    • Elsevier

    Iron ion and sulfasalazine-loaded polydopamine nanoparticles for Fenton reaction and glutathione peroxidase 4 inactivation for enhanced cancer ferrotherapy

    Zhu X.Chen Q.Xie L.Chen W....
    12页
    查看更多>>摘要：? 2022Ferroptosis shows promising potential in tumor treatment; however, factors that compromise the efficiency of the Fenton catalyst have limited its therapeutic effectiveness. We developed a polydopamine-based nanoplatform constructed with ferric ion and sulfasalazine-loaded nanoparticles (Fe(III)PP@SAS NPs) for dual-functional ferrotherapy strategy of “sword and shield” through enhanced Fenton reaction and inactivation of glutathione peroxidase 4 (GPX4), respectively. Both the Fenton reaction-based hydroxyl radical (·OH) production and sulfasalazine-driven GPX4 inhibition induced ferroptotic cell death, thus achieving synergistic cancer therapy. Near-infrared light irradiation and acidic tumor microenvironment enhanced the release of ferric ions and sulfasalazine from the Fe(III)PP@SAS NPs. In addition, the released iron ions underwent valence state change due to Fenton reaction and thus provided a supplementary T1-weighted signal for in situ visualization of the tumor based on magnetic resonance imaging. The Fe(III)PP@SAS NPs exhibited high pro-ferroptosis performance by utilizing ·OH radicals as a “sword” to attack cancer cells and the GPX4 inhibitor to break down the “shield” of cancer cells, thus showing potential for cancer treatment. Statement of significance: Several strategies of cancer therapy based on ferroptosis have emerged in recent years, which have provided new insights into designing materials for therapeutic applications. The antitumor efficacy of ferroptosis is, however, still unsatisfactory, mainly because of insufficient intracellular pro-ferroptotic stimuli. In the current study, we report a multifunctional theranostic nanoplatform, namely Fe(III)PP@SAS, with three-fold synergistic effect; this nanoplatform has excellent theranostic potential with multifunctional ferrotherapy.
      原文链接:
    • NSTL
    • Elsevier